United States 

Environmental Protection February 2006 

Agency EPA EPA 600/R-05/004bF

Air Quality Criteria for 

Ozone and Related 

Photochemical Oxidants 

Volume II of III
EPA 600/R-05/004bF 

February 2006 

Air Quality Criteria for Ozone and Related 

Photochemical Oxidants 

Volume II 

National Center for Environmental Assessment-RTP Office 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 
DISCLAIMER 

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

Agency policy and approved for publication. Mention of trade names or commercial products 

does not constitute endorsement or recommendation for use. 

PREFACE 

National Ambient Air Quality Standards (NAAQS) are promulgated by the United States 

Environmental Protection Agency (EPA) to meet requirements set forth in Sections 108 and 109 

of the U.S. Clean Air Act (CAA). Sections 108 and 109 require the EPA Administrator 

(1) to list widespread air pollutants that reasonably may be expected to endanger public health 

or welfare; (2) to issue air quality criteria for them that assess the latest available scientific 

information on nature and effects of ambient exposure to them; (3) to set “primary” NAAQS to 

protect human health with adequate margin of safety and to set “secondary” NAAQS to protect 

against welfare effects (e.g., effects on vegetation, ecosystems, visibility, climate, manmade 

materials, etc); and (5) to periodically review and revise, as appropriate, the criteria and NAAQS 

for a given listed pollutant or class of pollutants. 

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. The EPA promulgates the NAAQS on the basis of scientific 

information contained in air quality criteria issued under Section 108 of the Clean Air Act. 

Following the review of criteria as contained in the EPA document, Air Quality Criteria for 

Ozone and Other Photochemical Oxidants published in 1978, the chemical designation of the 

standards was changed from photochemical oxidants to ozone (O3) in 1979 and a 1-hour O3 

NAAQS was set. The 1978 document focused mainly on the air quality criteria for O3 and, to a 

lesser extent, on those for other photochemical oxidants (e.g., hydrogen peroxide and the 

peroxyacyl nitrates), as have subsequent revised versions of the document. 

To meet Clean Air Act requirements noted above for periodic review of criteria and 

NAAQS, the O3 criteria document, Air Quality Criteria for Ozone and Other Photochemical 

Oxidants, was next revised and released in August 1986; and a supplement, Summary of Selected 

II-ii 
New Information on Effects of Ozone on Health and Vegetation, was issued in January 1992. 

These documents were the basis for a March 1993 decision by EPA that revision of the existing 

1-h NAAQS for O3 was not appropriate at that time. That decision, however, did not take into 

account newer scientific data that had become available after completion of the 1986 criteria 

document. Such literature was assessed in the next periodic revision of the O3 air quality criteria 

document (O3 AQCD) which has completed in 1996 and provided scientific bases supporting the 

setting by EPA in 1997 of the current 8-h O3 NAAQS. 

The purpose of this revised air quality criteria document for O3 and related photochemical 

oxidants is to critically evaluate and assess the latest scientific information published since that 

assessed in the above 1996 O3 AQCD, with the main focus being on pertinent new information 

useful in evaluating health and environmental effects data associated with ambient air O3 

exposures. However, other scientific data are also discussed 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 mainly 

assesses pertinent literature published through 2004, but also includes assessment of a few 

additional important studies published or accepted for publication in 2005. 

A First External Review Draft of this O3 AQCD (dated January 2005) was released for 

public comment and was reviewed by the Clean Air Scientific Advisory Committee (CASAC) 

in May, 2005 to obtain. Public comments and CASAC recommendations were then taken into 

account in making revisions to the document for incorporation into a Second External Review 

Draft (dated August, 2005), which underwent further public comment and CASAC review at a 

December, 2005 public meeting. Public comments and CASAC advice derived from review of 

that Second External Review Draft were considered in making revisions incorporated into this 

final version of the document (dated February, 2006). Evaluations contained in the present 

document will be drawn on to provide inputs to associated O3 Staff Paper analyses prepared by 

EPA’s Office of Air Quality Planning and Standards (OAQPS) to pose options for consideration 

by the EPA Administrator with regard to proposal and, ultimately, promulgation of decisions on 

potential retention or revision, as appropriate, of the current O3 NAAQS. 

Preparation of this document was coordinated by staff of EPA’s National Center for 

Environmental Assessment in Research Triangle Park (NCEA-RTP). NCEA-RTP scientific 

staff, together with experts from other EPA/ORD laboratories and academia, contributed to 

II-iii 
writing of document chapters. Earlier drafts of document materials were reviewed by non-EPA 

experts in peer consultation workshops held by EPA. The document describes the nature, 

sources, distribution, measurement, and concentrations of O3 in outdoor (ambient) and indoor 

environments. It also evaluates the latest data on human exposures to ambient O3 and 

consequent health effects in exposed human populations, to support decision making regarding 

the primary, health-related O3 NAAQS. Lastly, the document also evaluates ambient O3 

environmental effects on vegetation and ecosystems, surface level solar UV radiation flux and 

global climate change, and man-made materials to support decision making on secondary 

O3 NAAQS. 

NCEA acknowledges the valuable contributions provided by authors, contributors, and 

reviewers and the diligence of its staff and contractors in the preparation of this document. 

II-iv 
Air Quality Criteria for Ozone and Related 

Photochemical Oxidants 

VOLUME I

Executive Summary .................................................... E-1

1. INTRODUCTION ................................................ 1-1

2. PHYSICS AND CHEMISTRY OF OZONE IN THE ATMOSPHERE ....... 2-1

3. ENVIRONMENTAL CONCENTRATIONS, PATTERNS, AND 

EXPOSURE ESTIMATES .......................................... 3-1

4. DOSIMETRY, SPECIES HOMOLOGY, SENSITIVITY, AND 

ANIMAL-TO-HUMAN EXTRAPOLATION ........................... 4-1

5. TOXICOLOGICAL EFFECTS OF OZONE AND RELATED

PHOTOCHEMICAL OXIDANTS IN LABORATORY ANIMALS 

AND IN VITRO TEST SYSTEMS ................................... 5-1

6. CONTROLLED HUMAN EXPOSURE STUDIES OF OZONE AND 

RELATED PHOTOCHEMICAL OXIDANTS .......................... 6-1

7. EPIDEMIOLOGICAL STUDIES OF HUMAN HEALTH EFFECTS

ASSOCIATED WITH AMBIENT OZONE EXPOSURE .................. 7-1

8. INTEGRATIVE SYNTHESIS: EXPOSURE AND HEALTH EFFECTS ..... 8-1

9. ENVIRONMENTAL EFFECTS: OZONE EFFECTS ON 

VEGETATION AND ECOSYSTEMS ................................ 9-1

10. TROPOSPHERIC OZONE EFFECTS ON UV-B FLUX AND 

CLIMATE CHANGE PROCESSES ................................. 10-1

11. OZONE EFFECTS ON MAN-MADE MATERIALS .................... 11-1

II-v 
Air Quality Criteria for Ozone and Related 

Photochemical Oxidants 

(cont’d) 

VOLUME II 

CHAPTER 2 ANNEX (ATMOSPHERIC PHYSICS/CHEMISTRY) . . . . . . . . . . AX2-1

CHAPTER 3 ANNEX (AIR QUALITY AND EXPOSURE) . . . . . . . . . . . . . . . . . AX3-1

CHAPTER 4 ANNEX (DOSIMETRY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX4-1

CHAPTER 5 ANNEX (ANIMAL TOXICOLOGY) . . . . . . . . . . . . . . . . . . . . . . . AX5-1

CHAPTER 6 ANNEX (CONTROLLED HUMAN EXPOSURE) . . . . . . . . . . . . . AX6-1

CHAPTER 7 ANNEX (EPIDEMIOLOGY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX7-1

VOLUME III 

CHAPTER 9 ANNEX (ENVIRONMENTAL EFFECTS) . . . . . . . . . . . . . . . . . . . AX9-1

II-vi 
II-vii

Table of Contents

Page

List of Tables ............................................................... II-xiv

List of Figures .............................................................. II-xix

Authors, Contributors, and Reviewers ........................................... II-xxxi

U.S. Environmental Protection Agency Project Team for Development of 

Air Quality Criteria for Ozone and Related Photochemical Oxidants . . . . . . . . II-xxxviii

U.S. Environmental Protection Agency Science Advisory Board (SAB)

Staff Office Clean Air Scientific Advisory Committee (CASAC)

Ozone Review Panel .................................................. II-xli

ABBREVIATIONS AND ACRONYMS ......................................... II-xliv

AX2. PHYSICS AND CHEMISTRY OF OZONE IN THE ATMOSPHERE . . . . . . . . . . AX2-1

AX2.1 INTRODUCTION ......................................... AX2-1

AX2.2 TROPOSPHERIC OZONE CHEMISTRY . . . . . . . . . . . . . . . . . . . . . . AX2-2

AX2.2.1 Atmospheric Structure ........................... AX2-2

AX2.2.2 Overview of Ozone Chemistry . . . . . . . . . . . . . . . . . . . . AX2-3

AX2.2.3 Initiation of the Oxidation of VOCs . . . . . . . . . . . . . . . . AX2-6

AX2.2.4 Chemistry of Nitrogen Oxides in the Troposphere . . . . AX2-11

AX2.2.5 The Methane Oxidation Cycle . . . . . . . . . . . . . . . . . . . . AX2-14

AX2.2.6 The Atmospheric Chemistry of Alkanes . . . . . . . . . . . . AX2-20

AX2.2.7 The Atmospheric Chemistry of Alkenes . . . . . . . . . . . . AX2-23

AX2.2.8 The Atmospheric Chemistry of Aromatic 

Hydrocarbons ................................. AX2-31

AX2.2.8.1 Chemical Kinetics and Atmospheric 

Lifetimes of Aromatic 

Hydrocarbons ..................... AX2-32

AX2.2.8.2 Reaction Products and Mechanisms 

of Aromatic Hydrocarbon Oxidation . . . AX2-36

AX2.2.8.3 The Formation of Secondary 

Organic Aerosol as a Sink for 

Ozone Precursors .................. AX2-44

AX2.2.9 Importance of Oxygenated VOCs . . . . . . . . . . . . . . . . . AX2-44

AX2.2.10 Influence of Multiphase Chemical Processes . . . . . . . . AX2-45

AX2.2.10 x.1 HO and Aerosols . . . . . . . . . . . . . . . . . AX2-47

AX2 x.2.10.2 NO Chemistry .................... AX2-50

AX2.2.10.3 Halogen Radical Chemistry . . . . . . . . . . AX2-52

AX2.2.10.4 Reactions on the Surfaces of Crustal 

Particles ......................... AX2-56

AX2.2.10.5 Reactions on the Surfaces of 

Aqueous H2 4 SO Solutions . . . . . . . . . . . AX2-57

AX2.2.10.6 Oxidant Formation in Particles . . . . . . . AX2-58

AX2.2.10.7 Ozone Reaction Indoors . . . . . . . . . . . . AX2-60
II-viii

Table of Contents

(cont’d)

Page

AX2.3 PHYSICAL PROCESSES INFLUENCING THE ABUNDANCE 

OF OZONE ............................................. AX2-60

AX2.3.1 Stratospheric-Tropospheric Ozone Exchange . . . . . . . . AX2-62

AX2.3.2 Deep Convection in the Troposphere . . . . . . . . . . . . . . AX2-71

AX2.3.2.1 Observations of the Effects of 

Convective Transport . . . . . . . . . . . . . . AX2-73

AX2.3.2.2 Modeling the Effects of Convection . . . AX2-76

AX2.3.3 Nocturnal Low-Level Jets . . . . . . . . . . . . . . . . . . . . . . . AX2-79

AX2.3.4 Intercontinental Transport of Ozone and Other 

Pollutants .................................... AX2-83

AX2.3.4.1 The Atmosphere/Ocean Chemistry 

Experiment, AEROCE . . . . . . . . . . . . . AX2-83

AX2.3.4.2 The North Atlantic Regional 

Experiment, NARE ................ AX2-86

AX2.3.5 Small-Scale Circulation Systems . . . . . . . . . . . . . . . . . . AX2-89

AX2.3.5.1 Land-Sea Breeze . . . . . . . . . . . . . . . . . . AX2-90

AX2.3.6 The Relation of Ozone to Solar Ultraviolet 

Radiation, Aerosols, and Air Temperature . . . . . . . . . . AX2-90

AX2.3.6.1 Solar Ultraviolet Radiation 

and Ozone ....................... AX2-90

AX2.3.6.2 Impact of Aerosols on Radiation 

and Photolysis Rates and 

Atmospheric Stability . . . . . . . . . . . . . . AX2-91

AX2.3.6.3 Temperature and Ozone . . . . . . . . . . . . . AX2-92

AX2.4 THE RELATION OF OZONE TO ITS PRECURSORS AND 

OTHER OXIDANTS ...................................... AX2-95

AX2.4.1 Summary of Results for the Relations Among 

Ozone, its Precursors and Other Oxidants from 

Recent Field Experiments ....................... AX2-99

AX2.4.1.1 Results from the Southern Oxidant 

Study and Related Experiments . . . . . . . AX2-99

AX2.4.1.2 Results from Studies on Biogenic and

Anthropogenic Hydrocarbons and

Ozone Production ................ AX2-103

AX2.4.1.3 Results of Studies on Ozone 

Production in Mississippi and 

Alabama ........................ AX2-103

AX2.4.1.4 The Nocturnal Urban Plume over 

Portland, Oregon ................. AX2-104

AX2.4.1.5 Effects of VOCs in Houston on 

Ozone Production ................ AX2-104
II-ix

Table of Contents

(cont’d)

Page

AX2.4.1.6 Chemical and Meteorological 

Influences on the Phoenix Urban 

Ozone Plume .................... AX2-105

AX2.4.1.7 Transport of Ozone and Precursors

on the Regional Scale . . . . . . . . . . . . . AX2-105

AX2.4.1.8 Model Calculations and Aircraft

Observations of Ozone over 

Philadelphia ..................... AX2-106

AX2.4.1.9 The Two-Reservoir System . . . . . . . . . AX2-107

AX2.5 METHODS USED TO CALCULATE RELATIONS BETWEEN 

OZONE AND ITS PRECURSORS .......................... AX2-107

AX2.5.1 Chemistry-Transport Models . . . . . . . . . . . . . . . . . . . . AX2-109

AX2.5.2 Emissions of Ozone Precursors . . . . . . . . . . . . . . . . . . AX2-123

AX2.5.3 Observationally-Based Models . . . . . . . . . . . . . . . . . . AX2-130

AX2.5.4 Chemistry-Transport Model Evaluation . . . . . . . . . . . AX2-131

AX2.5.4.1 Evaluation of Emissions

Inventories ...................... AX2-144

AX2.5.4.2 Availability and Accuracy of 

Ambient Measurements . . . . . . . . . . . . AX2-146

AX2.6 TECHNIQUES FOR MEASURING OZONE AND ITS 

PRECURSORS ......................................... AX2-147

AX2.6.1 Sampling and Analysis of Ozone . . . . . . . . . . . . . . . . AX2-147

AX2.6.2 Sampling and Analysis of Nitrogen Oxides . . . . . . . . AX2-149

AX2.6.2.1 Calibration Standards . . . . . . . . . . . . . AX2-150

AX2.6.2.2 Measurement of Nitric Oxide . . . . . . . AX2-151

AX2.6.2.3 Measurements of Nitrogen Dioxide . . AX2-152

AX2.6.2.4 Monitoring for NO2 Compliance

Versus Monitoring for Ozone 

Formation ...................... AX2-153

AX2.6.3 Measurements of Nitric 3 Acid Vapor, HNO . . . . . . . . AX2-154

AX2.6.4 Sampling and Analysis of Volatile Organic 

Compounds ................................. AX2-156

AX2.6.4.1 Polar Volatile Organic Compounds . . . AX2-156

REFERENCES ................................................... AX2-159

AX3. ENVIRONMENTAL CONCENTRATIONS, PATTERNS, AND 

EXPOSURE ESTIMATES ............................................ AX3-1

AX3.1 INTRODUCTION ......................................... AX3-1

AX3.2 SURFACE OZONE CONCENTRATIONS . . . . . . . . . . . . . . . . . . . . . AX3-4

AX3.2.1 Nationwide Distribution of Metrics for Characterizing

Exposures of Vegetation to Ozone . . . . . . . . . . . . . . . . AX3-27
II-x

Table of Contents

(cont’d)

Page

AX3.3 SPATIAL VARIABILITY IN OZONE CONCENTRATIONS . . . . . AX3-30

AX3.3.1 Spatial Variability of Ozone Concentrations in 

Urban Areas ................................. AX3-30

AX3.3.2 Small-scale Horizontal and Spatial Variability in 

Ozone Concentrations .......................... AX3-56

AX3.3.3 Ozone Concentrations at High Elevations . . . . . . . . . . . AX3-58

AX3.4 DIURNAL PATTERNS IN OZONE CONCENTRATION . . . . . . . . AX3-68

AX3.4.1 Introduction .................................. AX3-68

AX3.4.2 Diurnal Patterns in Urban Areas . . . . . . . . . . . . . . . . . . AX3-70

AX3.4.3 Diurnal Patterns in Nonurban Areas . . . . . . . . . . . . . . . AX3-87

AX3.5 SEASONAL VARIATIONS IN OZONE CONCENTRATIONS . . . . AX3-95

AX3.5.1 Seasonal Variations in Urban Areas . . . . . . . . . . . . . . . AX3-95

AX3.5.2 Seasonal Variations in Nonurban Areas . . . . . . . . . . . . AX3-98

AX3.6 TRENDS IN OZONE CONCENTRATIONS . . . . . . . . . . . . . . . . . . AX3-104

AX3.7 RELATIONS BETWEEN OZONE, OTHER OXIDANTS, 

AND OXIDATION PRODUCTS ........................... AX3-114

AX3.8 RELATIONSHIP BETWEEN SURFACE OZONE AND 

OTHER POLLUTANTS .................................. AX3-121

AX3.8.1 Introduction ................................. AX3-121

AX3.8.2 Co-Occurrence of Ozone with Nitrogen Oxides . . . . . AX3-123

AX3.8.3 Co-Occurrence of Ozone with Sulfur Dioxide . . . . . . AX3-125

AX3.8.4 Co-Occur 2.5 rence of Ozone and Daily PM . . . . . . . . . . AX3-127

AX3.8.5 Co-Occurrence of Ozone with Acid Precipitation . . . . AX3-128

AX3.8.6 Co-Occurrence of Ozone with Acid Cloudwater . . . . . AX3-130

AX3.9 THE METHODOLOGY FOR DETERMINING POLICY 

RELEVANT BACKGROUND OZONE CONCENTRATIONS . . . AX3-131

AX3.9.1 Introduction ................................. AX3-131

AX3.9.2 Capability of Global Models to Simulate 

Tropospheric Ozone .......................... AX3-147

AX3.9.3 Mean Background Concentrations: Spatial and 

Seasonal Variation ............................ AX3-150

AX3.9.4 Frequency of High-Ozone Occurrences at 

Remote Sites ................................ AX3-153

AX3.10 OZONE EXPOSURE IN VARIOUS MICROENVIRONMENTS ... AX3-161

AX3.10.1 Introduction ................................. AX3-161

AX3.10.2 Summary of the Information Presented in

the Exposure Discussion in the 1996 Ozone 

Criteria Document ............................ AX3-161

AX3.10.3 Concepts of Human Exposure . . . . . . . . . . . . . . . . . . . AX3-162

AX3.10.4 Quantification of Exposure . . . . . . . . . . . . . . . . . . . . . AX3-162
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(cont’d)

Page

AX3.10.5 Methods to Estimate Personal Exposure . . . . . . . . . . . AX3-163

AX3.10.5.1 Direct Measurement Method . . . . . . . . AX3-163

AX3.10.5.2 Indirect Measurement Method . . . . . . . AX3-165

AX3.10.6 Ozone Exposure Models . . . . . . . . . . . . . . . . . . . . . . . AX3-167

AX3.10.6.1 Population Exposure Models . . . . . . . . AX3-172

AX3.10.6.2 Ambient Concentrations Models . . . . . AX3-180

AX3.10.6.3 Microenvironmental Concentration 

Models ......................... AX3-182

AX3.10.7 Measured Exposures and Monitored 

Concentrations ............................... AX3-186

AX3.10.7.1 Personal Exposure Measurements . . . . AX3-186

AX3.10.7.2 Monitored Ambient 

Concentrations ................... AX3-190

AX3.10.7.3 Ozone Concentrations in 

Microenvironments . . . . . . . . . . . . . . . AX3-191

AX3.10.8 Trends in Concentrations within 

Microenvironments ........................... AX3-216

AX3.10.9 Characterization of Exposure . . . . . . . . . . . . . . . . . . . AX3-217

AX3.10.9.1 Use of Ambient Ozone 

Concentrations ................... AX3-217

AX3.10.9.2 Exposure Selection in Controlled 

Exposure Studies ................. AX3-219

AX3.10.9.3 Exposure to Related Photochemical

Agents ......................... AX3-219

REFERENCES ................................................... AX3-223

AX4. DOSIMETRY OF OZONE IN THE RESPIRATORY TRACT . . . . . . . . . . . . . . . . AX4-1

AX4.1 INTRODUCTION ......................................... AX4-1

AX4.2 EXPERIMENTAL OZONE DOSIMETRY INVESTIGATIONS . . . . . AX4-3

AX4.2.1 Bolus-Response Studies . . . . . . . . . . . . . . . . . . . . . . . . . AX4-3

AX4.2.2 General Uptake Studies . . . . . . . . . . . . . . . . . . . . . . . . . . AX4-9

AX4.2.3 Dosimetry Modeling ........................... AX4-11

AX4.3 SPECIES HOMOLOGY, SENSITIVITY AND

ANIMAL-TO-HUMAN EXTRAPOLATION . . . . . . . . . . . . . . . . . . . AX4-17

REFERENCES .................................................... AX4-20

AX5. ANNEX TO CHAPTER 5 OF OZONE AQCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-1

REFERENCES .................................................... AX5-62
II-xii

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(cont’d)

Page

AX6. CONTROLLED HUMAN EXPOSURE STUDIES OF OZONE AND 

RELATED PHOTOCHEMICAL OXIDANTS ............................. AX6-1

AX6.1 INTRODUCTION ......................................... AX6-1

AX6.2 PULMONARY FUNCTION EFFECTS OF OZONE EXPOSURE 

IN HEALTHY SUBJECTS .................................. AX6-2

AX6.2.1 Introduction ................................... AX6-2

AX6.2.2 Acute Ozone Exposures for Up to 2 Hours . . . . . . . . . . . AX6-3

AX6.2.3 Prolonged Ozone Exposures . . . . . . . . . . . . . . . . . . . . . AX6-10

AX6.2.3.1 Effect of Exercise Ventilation Rate 

on FEV1 Response to 6.6 h Ozone 

Exposure ........................ AX6-13

AX6.2.3.2 Exercise Ventilation Rate as a

Func 1tion of Body/Lung Size on FEV

Response to 6.6 h Ozone Exposure . . . . AX6-14

AX6.2.3.3 Comparison of 6.6 h Ozone Exposure 

Pulmonary Responses to Those 

Observed in 2 h Intermittent Exercise 

Ozone Exposures .................. AX6-16

AX6.2.4 Triangular Ozone Exposures . . . . . . . . . . . . . . . . . . . . . AX6-17

AX6.2.5 Mechanisms of Pulmonary Function Responses . . . . . . AX6-21

AX6.2.5.1 Pathophysiologic Mechanisms . . . . . . . AX6-22

AX6.2.5.2 Mechanisms at a Cellular and 

Molecular Level ................... AX6-28

AX6.3 PULMONARY FUNCTION EFFECTS OF OZONE EXPOSURE 

IN SUBJECTS WITH PREEXISTING DISEASE . . . . . . . . . . . . . . . AX6-29

AX6.3.1 Subjects with Chronic Obstructive Pulmonary 

Disease ...................................... AX6-29

AX6.3.2 Subjects with Asthma .......................... AX6-34

AX6.3.3 Subjects with Allergic Rhinitis . . . . . . . . . . . . . . . . . . . AX6-38

AX6.3.4 Subjects with Cardiovascular Disease . . . . . . . . . . . . . . AX6-40

AX6.4 INTERSUBJECT VARIABILITY AND REPRODUCIBILITY 

OF RESPONSE .......................................... AX6-41

AX6.5 INFLUENCE OF AGE, GENDER, ETHNIC, ENVIRONMENTAL 

AND OTHER FACTORS .................................. AX6-45

AX6.5.1 Influence of Age .............................. AX6-45

AX6.5.2 Gender and Hormonal Influences . . . . . . . . . . . . . . . . . AX6-51

AX6.5.3 Racial, Ethnic, and Socioeconomic Status Factors . . . . AX6-58

AX6.5.4 Influence of Physical Activity . . . . . . . . . . . . . . . . . . . . AX6-59

AX6.5.5 Environmental Factors .......................... AX6-60

AX6.5.6 Oxidant-Antioxidant Balance . . . . . . . . . . . . . . . . . . . . AX6-65

AX6.5.7 Genetic Factors ............................... AX6-68
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AX6.6 REPEATED EXPOSURES TO OZONE . . . . . . . . . . . . . . . . . . . . . . AX6-70

AX6.7 EFFECTS ON EXERCISE PERFORMANCE . . . . . . . . . . . . . . . . . . AX6-81

AX6.7.1 Introduction .................................. AX6-81

AX6.7.2 Effect on Maximal Oxygen Uptake . . . . . . . . . . . . . . . . AX6-82

AX6.7.3 Effect on Endurance Exercise Performance . . . . . . . . . AX6-84

AX6.8 EFFECTS ON AIRWAY RESPONSIVENESS . . . . . . . . . . . . . . . . . AX6-86

AX6.9 EFFECTS ON INFLAMMATION AND HOST DEFENSE . . . . . . . . AX6-97

AX6.9.1 Introduction .................................. AX6-97

AX6.9.2 Inflammatory Responses in the Upper

Respiratory Tract ............................. AX6-113

AX6.9.3 Inflammatory Responses in the Lower

Respiratory Tract ............................. AX6-115

AX6.9.4 Adaptation of Inflammatory Responses . . . . . . . . . . . AX6-120

AX6.9.5 Effect of Anti-Inflammatory and Other

Mitigating Agents ............................ AX6-122

AX6.9.6 Changes in Host Defense Capability Following 

Ozone Exposure.............................. AX6-124

AX6.10 EXTRAPULMONARY EFFECTS OF OZONE . . . . . . . . . . . . . . . . AX6-126

AX6.11 OZONE MIXED WITH OTHER POLLUTANTS . . . . . . . . . . . . . . AX6-129

AX6.11.1 Ozone and Sulfur Oxides . . . . . . . . . . . . . . . . . . . . . . . AX6-129

AX6.11.2 Ozone and Nitrogen-Containing Pollutants . . . . . . . . . AX6-135

AX6.11.3 Ozone and Other Pollutant Mixtures Including 

Particulate Matter ............................ AX6-137

AX6.12 CONTROLLED STUDIES OF AMBIENT AIR EXPOSURES . . . . AX6-138

AX6.12.1 Mobile Laboratory Studies . . . . . . . . . . . . . . . . . . . . . AX6-138

AX6.12.2 Aircraft Cabin Studies . . . . . . . . . . . . . . . . . . . . . . . . . AX6-139

REFERENCES ................................................... AX6-142

AX7. EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH EFFECTS 

ASSOCIATED WITH AMBIENT OZONE EXPOSURE . . . . . . . . . . . . . . . . . . . . AX7-1

AX7.1 TABLES OF EPIDEMIOLOGIC STUDIES OF HUMAN 

HEALTH EFFECTS ASSOCIATED WITH AMBIENT 

OZONE EXPOSURE ...................................... AX7-2

LIST OF STUDIES BY AUTHOR ............................. AX7-3

AX7.2 DESCRIPTION OF SUMMARY DENSITY CURVES . . . . . . . . . . AX7-121

AX7.3 ESTIMATING THE GOMPERTZ CONCENTRATIONRESPONSE MODEL .................................... AX7-130
II-xiv

List of Tables

Number Page

AX2-1 Comparison of the Atmospheric Lifetimes (J) of Low Molecular Weight

Hydroca 3 3 rbons Due to Reaction with OH, NO , Cl, Br, and O . . . . . . . . . . . . AX2-7

AX2-2 Calculated Atmospheric Lifetimes of Biogenic Volatile Organic 

Compounds ................................................... AX2-25

AX2-3 Hydroxyl Rate Constants and Atmospheric Lifetimes of Mono- and 

Di-cyclic Aromatic Hydrocarbons ................................. AX2-34

AX2-4 Chemistry-Transport Models (CTM) Contributing to the Oxcomp 

Evaluation of Predicting T 3ropospheric O and OH . . . . . . . . . . . . . . . . . . . AX2-122

AX2-5 Emissions of Nitrogen Oxides by Various Sources in the United States 

in 1999 ..................................................... AX2-124

AX2-6 Emissions of Volatile Organic Compounds by Various Sources in the 

United States in 1999 .......................................... AX2-125

AX2-7 Emissions of Ammonia by Various Sources in the United States 

in 1999 ..................................................... AX2-126

AX2-8 Emissions of Carbon Monoxide by Various Sources in the United States 

in 1999 ..................................................... AX2-127

AX3-1 Ozone Monitoring Seasons by State ................................. AX3-3

AX3-2 Summary of Percentiles of Pooled Data Across Monitoring Sites for 

May to September 2000-2004 Concentrations are in ppb . . . . . . . . . . . . . . . AX3-11

AX3-3 Seasonal (April to October) Percentile Distribution of Hourly Ozone 

Concentrations (ppm), Number of Hourly Mean Ozone Occurrences 

$0.08 and $0.10, Seasonal 7-h Average Concentrations, SUM06, and 

W126 Values for Sites Experiencing Low Maximum Hourly Average 

Concentrations with Data Capture of $75% .......................... AX3-18

AX3-4 The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for

Sites Experiencing Low Maximum Hourly Average Concentrations

with Data Capture of $75% ...................................... AX3-23

AX3-5 Summary Statistics for Ozone (in ppm) Spatial Variability in Selected 

U.S. Urban Areas .............................................. AX3-42
II-xv

List of Tables

(cont’d)

Number Page

AX3-6 Description of Mountain Cloud Chemistry Program Sites . . . . . . . . . . . . . . . AX3-60

AX3-7 Seasonal (April-October) Percentiles, SUM06, SUM08, and W126 

Values for the MCCP Sites ....................................... AX3-61

AX3-8 Summary Statistics for 11 Integrated Forest Study Sites . . . . . . . . . . . . . . . . AX3-66

AX3-9 Trends in Warm Season (May 3 to September) Daily Maximum 8-h O

Concentrations at National Parks in the United States (1990 to 2004) . . . . AX3-113

AX3-10 Range of Annual (January-December) Hourly Ozone Concentrations

(ppb) at Background Sites Around the World (CMDL, 2004) . . . . . . . . . . . AX3-137

AX3-11 Range of annual (January-December) Hourly Median and Maximum

Ozone Concentrations (ppb) at Background Stations in Protected Areas 

of the United States (CASTNet, 2004) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-137

AX3-12 Range of Annual (January-December) Hourly Median and Maximum

Ozone Concentrations (ppb) at Canadian Background Stations

(CAPMoN, 2003) ............................................. AX3-138

AX3-13 Numbe 3r of Hours $0.05 ppm for Selected Rural O Monitoring in the 

United States by Month for the Period 1988 to 2001 . . . . . . . . . . . . . . . . . . AX3-139

AX3-14 Numbe 3r of Hours $0.06 ppm for Selected Rural O Monitoring Sites 

in the United States by Month for the Period of 1988 to 2001 . . . . . . . . . . . AX3-141

AX3-15 Global Budgets of Tropospheric Ozone (Tg year ) for the Present-day !1

Atmosphere ................................................. AX3-146

AX3-16 Description of Simulations Used for Source Attribution . . . . . . . . . . . . . . . AX3-151

AX3-17 Number of Hours with Ozone Above 50 or 60 ppbv at U.S. 

CASTNet Sites in 2001 ........................................ AX3-155

AX3-18 Activity Pattern Studies Included in the Consolidated Human Activity 

Database (CHAD)............................................. AX3-174

AX3-19 Personal and Population Exposure Models for Ozone . . . . . . . . . . . . . . . . . AX3-179

AX3-20 Personal Exposure Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-187
II-xvi

List of Tables

(cont’d)

Number Page

AX3-21 Indoor/Outdoor Ozone Ratios ................................... AX3-192

AX3-22 3Indoor and Outdoor O Concentrations in Boston, MA . . . . . . . . . . . . . . . . AX3-197

AX3-23 3Indoor and Outdoor O Concentrations in Hong Kong . . . . . . . . . . . . . . . . AX3-199

AX3-24 Indoor and Outdoor Ozone Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . AX3-202

AX3-25 Rate Constants (h ) for the Removal of Ozone by Surfaces in –1

Different Indoor Environments................................... AX3-211

AX4-1 New Experimental Human Studies on Ozone Dosimetry . . . . . . . . . . . . . . . . AX4-4

AX4-2 New Ozone Dosimetry Model Investigations . . . . . . . . . . . . . . . . . . . . . . . . . AX4-13

AX5-1 Cellular Targets of Ozone Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-2

AX5-2 Effects of Ozone on Lung Monooxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-3

AX5-3 Antioxidants, Antioxidant Metabolism, and Mitochondrial Oxygen 

Consumption................................................... AX5-4

AX5-4 Lipid Metabolism and Content of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-5

AX5-5 Effects of Ozone on Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-7

AX5-6 Effects of Ozone on Differential Gene Expression . . . . . . . . . . . . . . . . . . . . . AX5-7

AX5-7 Effects of Ozone on Lung Host Defenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-8

AX5-8 Effects of Ozone on Lung Permeability and Inflammation . . . . . . . . . . . . . . AX5-17

AX5-9 Effects of Ozone on Lung Structure: Acute and Subchronic Exposures . . . . AX5-27

AX5-10 Effects of Ozone on Lung Structure: Subchronic and Chronic Exposures ... AX5-31

AX5-11 Effects of Ozone on Pulmonary Function . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-34

AX5-12 Effects of Ozone on Airway Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . AX5-36

AX5-13 Effects of Ozone on Genotoxicity/Carcinogenicity . . . . . . . . . . . . . . . . . . . . AX5-43
II-xvii

List of Tables

(cont’d)

Number Page

AX5-14 Systemic Effects of Ozone ....................................... AX5-44

AX5-15 Interactions of Ozone With Nitrogen Dioxide . . . . . . . . . . . . . . . . . . . . . . . . AX5-51

AX5-16 Interactions of Ozone with Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-53

AX5-17 Interactions of Ozone with Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-54

AX5-18 Interactions Of Ozone With Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-55

AX5-19 Effects of Other Photochemical Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-61

AX6-1 Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours 

During Exercise ................................................ AX6-5

AX6-2 Pulmonary Function Effects after Prolonged Exposures to Ozone . . . . . . . . AX6-11

AX6-3 Ozone Exposure in Subjects with Preexisting Disease . . . . . . . . . . . . . . . . . AX6-30

AX6-4 Classification of Asthma Severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX6-37

AX6-5 Age Differences in Pulmonary Function Responses to Ozone . . . . . . . . . . . . AX6-46

AX6-6 Gender and Hormonal Differences in Pulmonary Function Responses 

to Ozone ..................................................... AX6-52

AX6-7 Influence of Ethnic, Environmental, and Other Factors . . . . . . . . . . . . . . . . . AX6-62

AX6-8 Changes in Forced Expiratory Volume in One Second After Repeated 

Daily Exposure to Ozone ........................................ AX6-71

AX6-9 Pulmonary Function Effects with Repeated Exposures to Ozone . . . . . . . . . AX6-73

AX6-10 Ozone Effects on Exercise Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX6-83

AX6-11 Airway Responsiveness Following Ozone Exposures . . . . . . . . . . . . . . . . . . AX6-88

AX6-12 Studies of Respiratory Tract Inflammatory Effects from Controlled 

Human Exposure to Ozone ....................................... AX6-99

AX6-13 Studies of Effects on Host Defense, on Drug Effects and Supportive 

In Vitro Studies Relating to Controlled Human Exposure to Ozone . . . . . . AX6-106
II-xviii

List of Tables

(cont’d)

Number Page

AX6-14 Ozone Mixed with Other Pollutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX6-131

AX6-15 Acute Effects of Ozone in Ambient Air in Field Studies with a 

Mobile Laboratory ............................................ AX6-140

AX7 3-1 Effects of Acute O Exposure on Lung Function and Respiratory 

Symptoms in Field Studies ........................................ AX7-9

AX7-2 Effects of Acute O3 Exposure on Cardiovascular Outcomes in 

Field Studies .................................................. AX7-33

AX7-3 Ef 3fects of O on Daily Emergency Department Visits . . . . . . . . . . . . . . . . . . AX7-40

AX7-4 Effects of O3 on Daily Hospital Admissions . . . . . . . . . . . . . . . . . . . . . . . . . AX7-52

AX7-5 Ef 3fects of Acute O Exposure on Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . AX7-71

AX7-6 Ef 3fects of Chronic O Exposure on Respiratory Health . . . . . . . . . . . . . . . . AX7-102

AX7-7 Effects of Chronic O3 Exposure on Mortality and Incidence of Cancer . . . . AX7-118

AX7-8 Ozone-Associated Cardiovascular Mortality Risk Estimates per

Standardized Increment ........................................ AX7-126

AX7-9 Estimated Parameters of the Gompertz Model . . . . . . . . . . . . . . . . . . . . . . . AX7-131
II-xix

List of Figures

Number Page

AX2-1 Schematic ove 3rview of O photochemistry in the stratosphere

and troposphere................................................. AX2-4

AX2-2 General chemical mechanism for the oxidative degradation of VOCs . . . . . AX2-21

AX2-3 Hydroxyl radical initiated oxidation of a) propane and b) propene . . . . . . . . AX2-24

AX2-4 Structures of a selected number of terpene and sesquiterpene compounds ... AX2-27

AX2-5 Products from the reac 3tion of terpenes with O . . . . . . . . . . . . . . . . . . . . . . . AX2-30

AX2-6 Initial steps in the photooxidation mechanism of toluene initiated by 

its reaction with OH radicals ..................................... AX2-39

AX2-7a Cross section through a tropopause folding event on March 13, 1978 

at 0000 GMT ................................................. AX2-64

AX2-7b Ozone mixing ratios pphm (parts per hundred million) corresponding 

to Figure AX2-7a .............................................. AX2-67

AX2-7c Condensation nuclei concentrations (particles cm ) corresponding to !3

Figure AX2-7a ................................................ AX2-68

AX2-8 Schematic diagram of a meteorological mechanism involved in high 

concentrations of O3 found in spring in the lower troposphere off the 

American east coast ............................................ AX2-71

AX2-9a,b (a) Contour plot of CO mixing ratios (ppbv) observed in and near the

June 15, 1985, mesoscale convective complex in eastern Oklahoma . . . . . . AX2-75

AX2-10 The diurnal evolution of the planetary boundary layer while high 

pressure prevails over land ....................................... AX2-80

AX2-11 Locations of low level jet occurrences in decreasing order of prevalence

(most frequent, common, observed) ................................ AX2-81

AX2-12 Schematic diag 3ram showing the diurnal behavior of O and the 

development of 3 secondary O maxima resulting from downward 

transport from the residual layer when a low-level jet is present . . . . . . . . . . AX2-82

AX2-13 The nocturnal low-level jet occupies a thin slice of the atmosphere

near the Earth’s surface ......................................... AX2-82
II-xx

List of Figures

(cont’d)

Number Page

AX2 3-14 A scatter plot of daily maximum 8-h O concentration versus daily 

maximum temperature in the Baltimore, MD Air Quality Forecast Area . . . AX2-93

AX2-15 A sca 3tter plot of daily maximum 1-h average O concentration versus

daily maximum temperature in the Baltimore, MD Air Quality 

Forecast Area ................................................. AX2-93

AX2-16 A sca 3tter plot of daily maximum 8-h average O concentrations versus

daily maximum temperature downwind of Phoenix, AZ . . . . . . . . . . . . . . . . AX2-94

AX2-17 Mea 3 z y xsured values of O and NO (NO – NO ) during the afternoon at 

rural sites in the eastern United States (gray circles) and in urban areas 

and urban plumes associated with Nashville, TN (gray dashes), Paris, FR 

(black diamonds) and Los Angeles, CA (X’s) . . . . . . . . . . . . . . . . . . . . . . . . AX2-98

AX2-18 Conceptual two-reservoir model showing conditions in the PBL and 

3

in the lower free troposphere during a multiday O episode . . . . . . . . . . . . AX2-108

AX2-19 Seasonal va 3riability in O concentrations observed at a number of 

pressure surfaces at six ozonesonde sites and the predictions of 

13 global scale chemistry-transport models . . . . . . . . . . . . . . . . . . . . . . . . . AX2-120

AX2-20 Seasonal va 3riability in O concentrations observed at a number of 

pressure surfaces at six ozonesonde sites and the predictions of 

13 global scale chemistry-transport models . . . . . . . . . . . . . . . . . . . . . . . . . AX2-121

AX2-21a 3,b Impact of model uncertainty on control strategy predictions for O for 

two days (August 10[a] and 11[b], 1992) in Atlanta, GA . . . . . . . . . . . . . . AX2-134

AX2-22 Ozone isopleths (ppb) as a function of the average emission rate

x

for NO and VOC (10 molec. cm s ) in zero dimensional box 12 !2 !1

model calculations ............................................ AX2-135

AX2-23a Time series for measured gas-phase species in comparison with results

from a photochemical model .................................... AX2-136

AX2-23b Time series for measured gas-phase species in comparison with results

from a photochemical model .................................... AX2-137

AX2-24 Cor 3 z y xrelations for O versus NO (NO – NO ) in ppb from chemical 

transport models for the northeast corridor, Lake Michigan, Nashville, 

the San Joaquin Valley, and Los Angeles . . . . . . . . . . . . . . . . . . . . . . . . . . . AX2-139
II-xxi

List of Figures

(cont’d)

Number Page

AX2-25a 3 y ,b Evaluation of model versus measured O versus NO for two model 

scenarios for Atlanta ........................................... AX2-140

AX2-26a 3 z ,b Evaluation of model versus: (a) measured O versus NO and 

3 2 2 z

(b) O versus the sum 2H O + NO for Nashville, TN . . . . . . . . . . . . . . . . AX2-142

AX2-27 Time 2 2 series of concentrations of RO , HO , and OH radicals, local 

O3 x photochemical production rate and concentrations of NO from 

measurements made during BERLIOZ ............................. AX2-143

AX3-1 Countywide mean daily 3 maximum 8-h O concentrations, May to 

September 2002 to 2004 .......................................... AX3-6

AX3-2 Countywide 95th percentile va 3lue of daily maximum 8-h O

concentrations, May to September 2002 to 2004 . . . . . . . . . . . . . . . . . . . . . . . AX3-7

AX3-3 Locations of monitoring sites used for calculating countywide averages 

across the United States .......................................... AX3-8

AX3-4 Di 3stribution of nationwide daily maximum 1-h average O concentrations

from May to September 2000 to 2004 ............................... AX3-9

AX3-5 Di 3stribution of nationwide daily maximum 8-h average O concentrations

from May to September 2000 to 2004 ............................... AX3-9

AX3-6 Di 3stribution of nationwide 24-h average O concentrations from 

May to September 2000 to 2004 ................................... AX3-10

AX3-7 Box plots showing 3 O averaged by month from 1993 to 2002 in the five 

regions in the eastern United States derived by Lehman et al. (2004) . . . . . . AX3-12

AX3-8 Hour 3ly average O concentrations observed at selected rural-agricultural 

sites from April to October 2001 .................................. AX3-13

AX3-9 Hour 3ly average O concentrations observed at selected rural-forest sites 

from April to October 2001 ...................................... AX3-14

AX3-10 Hour 3ly average O concentrations observed at selected rural-commercial 

or -residential sites from April to October 2001 . . . . . . . . . . . . . . . . . . . . . . . AX3-15

AX3-11a 3-d Daily 8-h maximum O concentrations observed at selected national 

park sites ..................................................... AX3-16
II-xxii

List of Figures

(cont’d)

Number Page

AX3-12 Seasonal SUM06 and W126 exposure indices for the Ouachita National 

Forest for the period of 1991 to 2001 ............................... AX3-27

AX3-13 Six-month (April to September) 24-h cumulative W126 exposure index 

with the number of hourly average concentrations $0.10 ppm (N100) 

occurring during 2001 for the eastern United States . . . . . . . . . . . . . . . . . . . AX3-29

AX3-14 Six-month (April to September) 24-h cumulative SUM06 exposure index 

with the number of hourly average concentrations $0.10 ppm (N100) 

occurring during 2001 for the eastern United States . . . . . . . . . . . . . . . . . . . AX3-31

AX3-15 Six-month (April to September) 24-h cumulative W126 exposure index 

with the number of hourly average concentrations $0.10 ppm (N100) 

occurring during 2001 for the central United States . . . . . . . . . . . . . . . . . . . . AX3-32

AX3-16 Six-month (April to September) 24-h cumulative SUM06 exposure index 

with the number of hourly average concentrations $0.10 ppm (N100) 

occurring during 2001 for the central United States . . . . . . . . . . . . . . . . . . . . AX3-33

AX3-17 Six-month (April to September) 24-h cumulative W126 exposure index 

with the number of hourly average concentrations $0.10 ppm (N100) 

occurring during 2001 for the western United States . . . . . . . . . . . . . . . . . . . AX3-34

AX3-18 Six-month (April to September) 24-h cumulative SUM06 exposure index 

with the number of hourly average concentrations $0.10 ppm (N100) 

occurring during 2001 for the western United States . . . . . . . . . . . . . . . . . . . AX3-35

AX3-19 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative W126 exposure index for 2001 for the eastern 

United States .................................................. AX3-36

AX3-20 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative SUM06 exposure index for 2001 for the eastern 

United States .................................................. AX3-36

AX3-21 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative N100 exposure index for 2001 for the eastern 

United States .................................................. AX3-37

AX3-22 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative W126 exposure index for 2001 for the central 

United States .................................................. AX3-37
II-xxiii

List of Figures

(cont’d)

Number Page

AX3-23 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative SUM06 exposure index for 2001 for the central 

United States .................................................. AX3-38

AX3-24 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative N100 exposure index for 2001 for the central 

United States .................................................. AX3-38

AX3-25 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative W126 exposure index for 2001 for the western 

United States .................................................. AX3-39

AX3-26 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative SUM06 exposure index for 2001 for the western 

United States .................................................. AX3-39

AX3-27 The 95% confidence interval for the 6-month (April to September) 

24-h cumulative N100 exposure index for 2001 for the western 

United States .................................................. AX3-40

AX3-28 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Charlotte, NC-Gastonia-Rock Hill, 

SC MSA ..................................................... AX3-44

AX3-29 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Baton Rouge, LA MSA . . . . . . . . . . . . . . . . AX3-45

AX3-30 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Detroit-Ann Arbor-Flint, MI CMSA . . . . . . AX3-46

AX3-31 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the St. Louis, MO-IL MSA . . . . . . . . . . . . . . . . . AX3-47

AX3-32 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Phoenix-Mesa, AZ MSA . . . . . . . . . . . . . . . AX3-49

AX3-33 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Fresno, CA MSA . . . . . . . . . . . . . . . . . . . . . AX3-50

AX3-34 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Bakersfield, CA MSA . . . . . . . . . . . . . . . . . . AX3-51
II-xxiv

List of Figures

(cont’d)

Number Page

AX3-35 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Los Angeles-Orange County, 

CA CMSA ................................................... AX3-52

AX3-36 Locations of O3 sampling sites (a) by AQS ID# (b) and intersite 

correlation statistics (c) for the Riverside-Orange County, CA CMSA . . . . . AX3-54

AX3-37 Ver 3tical profile of O obtained over low vegetation . . . . . . . . . . . . . . . . . . . . AX3-58

AX3-38 Ve 3rtical profile of O obtained in a spruce forest . . . . . . . . . . . . . . . . . . . . . . AX3-59

AX3-39a-d Seven- and 12-h seasonal means at (a) Whiteface Mountain and 

(b) Shenandoah National Park for May to September 1987, and 

integrated exposures at (c) Whiteface Mountain and (d) Shenandoah 

National Park for May to September 1987 . . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-64

AX3-40a-e Cumulative exposures for three non-Mountain Cloud Chemistry 

Program Shenandoah National Park sites, 1983 to 1987 . . . . . . . . . . . . . . . . AX3-65

AX3-41 Composite, nationwide diurnal var 3iability in hourly averaged O in 

urban areas ................................................... AX3-70

AX3-42 Composite, nationwide diurnal var 3iability in 8 hour average O in 

urban areas ................................................... AX3-71

AX3-43a 3-f Diurnal variability in hourly averaged O in selected urban areas . . . . . . . . . AX3-72

AX3-43g 3-l Diurnal variability in hourly averaged O in selected urban areas . . . . . . . . . AX3-73

AX3-44a 3-f Diurnal variability in 8 hour averaged O in selected urban areas . . . . . . . . . AX3-74

AX3-44g 3-l Diurnal variability in 8 hour averaged O in selected urban areas . . . . . . . . . AX3-75

AX3-45a 3-d Time of occurrence of daily maximum 1-h O concentration in four 

cities, averaged from April to October, 2000 to 2004 . . . . . . . . . . . . . . . . . . AX3-77

AX3-46a 3-d Time of occurrence of daily maximum 8-h average O concentration in 

four cities, averaged from April to October, 2000 to 2004 . . . . . . . . . . . . . . AX3-78

AX3-47a 3-d Diurnal variations in hourly averaged O on weekdays and weekends

in four cities .................................................. AX3-80
II-xxv

List of Figures

(cont’d)

Number Page

AX3-47e 3-h Diurnal variations in hourly averaged O on weekdays and weekends 

in four cities .................................................. AX3-81

AX3-48a 3-d Diurnal variations in 8-h averaged O on weekdays and weekends in 

four cities .................................................... AX3-82

AX3-48e 3-h Diurnal variations in 8-h averaged O on weekdays and weekends in 

four cities .................................................... AX3-83

AX3-49a Diurnal va 3riations in hourly averaged O at a site in downtown 

Detroit, MI ................................................... AX3-84

AX3-49b Diurnal va 3riations in hourly averaged O at a site downwind of 

downtown Detroit .............................................. AX3-84

AX3-50a Diurnal va 3riations in hourly averaged O at a site in downtown 

St. Louis, MO ................................................. AX3-85

AX3-50b Diurnal va 3riations in hourly averaged O at a site downwind of 

downtown St. Louis ............................................ AX3-85

AX3-51a Diurnal va 3riations in hourly averaged O at a site in 

San Bernadino, CA ............................................. AX3-86

AX3-51b Diurnal va 3riations in hourly averaged O at a site in Riverside 

County well downwind of sources ................................. AX3-87

AX3-52a Diurna 3l variations in 8-h average O at a site in downtown Detroit, MI . . . . AX3-88

AX3-52b Diurnal va 3riations in 8-h average O at a site downwind of downtown 

Detroit, MI ................................................... AX3-88

AX3-53a Diurnal variations in 8-h average ozone at a site in downtown 

St. Louis, MO ................................................. AX3-89

AX3-53b Diurnal va 3riations in 8-h average O at a site downwind of downtown 

St. Louis, MO ................................................. AX3-89

AX3-54a Diurna 3l variations in 8-h average O at a site in San Bernadino, CA . . . . . . . AX3-90

AX3 3-54b Diurnal variations in 8-h average O at a site in Riverside County 

well downwind of sources ....................................... AX3-90
II-xxvi

List of Figures

(cont’d)

Number Page

AX3-55 Composite diurna 3l variability in hourly O concentrations observed 

at CASTNET sites ............................................. AX3-91

AX3-56 Compo 3site diurnal variability in 8-h average O concentrations

observed at CASTNET sites ...................................... AX3-91

AX3-57 The comparison of the seasonal diurnal patterns for urban-influenced 

(Jefferson County, KY) and a rural-influenced (Oliver County, ND) 

monitoring sites using 2002 hourly data for April-October . . . . . . . . . . . . . . AX3-93

AX3-58a 3-d Diurnal behavior of O at rural sites in the United States in July . . . . . . . . . . AX3-94

AX3-59 Composite diurna 3l O pattern at selected national forest sites in the 

United States using 2002 hourly average concentration data . . . . . . . . . . . . . AX3-95

AX3-60a,b Composite diurnal pattern at (a) Whiteface Mountain, NY and 

(b) the Mountain Cloud Chemistry Program Shenandoah National 

Park site for May to September 1987 ............................... AX3-96

AX3-61a 3-h Seasonal variations in O concentrations as indicated by the 1-h 

maximum in each month at selected sites, 2002 . . . . . . . . . . . . . . . . . . . . . . AX3-97

AX3-62a 3-f Diurnal variability in 1-h average O concentrations in EPA’s 12 cities . . . . AX3-99

AX3-62g 3-l Diurnal variability in 1-h average O concentrations in EPA’s 12 cities . . . AX3-100

AX3-63a 3-f Diurnal variability in 8-h average O concentrations in EPA’s 12 cities . . . AX3-101

AX3-63g 3-l Diurnal variability in 8-h average O concentrations in EPA’s 12 cities . . . AX3-102

AX3-64 Yea 3r-to-year variability in nationwide mean daily maximum 8-h O

concentrations ................................................ AX3-105

AX3-65 Year-to-year variability in nationwide 95th percentile value of the 

da 3ily maximum 8-h O concentrations ............................. AX3-106

AX3-66a 3-h Year-to-year variability in mean daily maximum 8-h O concentrations

at selected national park (NP), national wildlife refuge (NWR), and 

national monument (NM) sites ................................... AX3-107
II-xxvii

List of Figures

(cont’d)

Number Page

AX3-66 3i-p Year-to-year variability in mean daily maximum 8-h O concentrations

at selected national park (NP), national wildlife refuge (NWR), and 

national monument (NM) sites ................................... AX3-108

AX3-66q-v Yea 3r-to-year variability in mean daily maximum 8-h O concentrations

at selected national park (NP), national wildlife refuge (NWR), and 

national monument (NM) sites ................................... AX3-109

AX3-67a 3-h Year-to-year variability in 95th percentile of daily maximum 8-h O

concentrations at selected national park (NP), national wildlife refuge 

(NWR), and national monument (NM) sites . . . . . . . . . . . . . . . . . . . . . . . . AX3-110

AX3-67i-p Yea 3r-to-year variability in 95th percentile of daily maximum 8-h O

concentrations at selected national park (NP), national wildlife refuge 

(NWR), and national monument (NM) sites . . . . . . . . . . . . . . . . . . . . . . . . AX3-111

AX3-67q-v Yea 3r-to-year variability in 95th percentile of daily maximum 8-h O

concentrations at selected national park (NP), national wildlife refuge 

(NWR), and national monument (NM) sites . . . . . . . . . . . . . . . . . . . . . . . . AX3-112

AX3 3-68a-d Measured O (ppbv) versus PAN (pptv) in Tennessee, including 

(a) aircraft measurements, and (b, c, and d) suburban sites near 

Nashville .................................................... AX3-117

AX3-69 Measured cor yrelation between benzene and NO at a measurement site 

in Boulder, CO ............................................... AX3-118

AX3-70 Binned mean PM2.5 3 concentrations versus binned mean O

concentrations observed at Fort Meade, MD from July 1999 to 

July 2001.................................................... AX3-121

AX3-71 The co-occurrence pa 3 2 ttern for O and NO . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-124

AX3-72 The 3 2 co-occurrence pattern for O and NO using 2001 data from 

the AQS .................................................... AX3-125

AX3-73 The 3 2 co-occurrence pattern for O and SO . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-126

AX3-74 The co-occurrence pa 3 2 ttern for O and SO using 2001 data from AQS . . . . AX3-127

AX3-75 The co-occurrence pa 3 2.5 ttern for O and PM using 2001 data from AQS . . . AX3-128
II-xxviii

List of Figures

(cont’d)

Number Page

AX3-76a Monthly 3 maximum hourly average O concentrations at Yellowstone 

National Park, Wyoming in 1998, 1999, 2000, and 2001 . . . . . . . . . . . . . . AX3-133

AX3-76b Hourly 3 average O concentrations at Yellowstone National Park, 

Wyoming for the period January to December 2001 . . . . . . . . . . . . . . . . . . AX3-133

AX3-77 (a) Contour plot of CO mixing ratios (ppbv) observed in and near the

June 15, 1985, mesoscale convective complex in eastern Oklahoma . . . . . AX3-135

AX3-78 Maximum hourly 3 average O concentrations at rural monitoring sites in 

Canada and the United States in February from 1980 to 1998 . . . . . . . . . . . AX3-143

AX3-79 Schematic diagram of a meteorological mechanism involved in high 

concentrations of O3 found in spring in the lower troposphere off the 

American East Coast .......................................... AX3-145

AX3-80 Ozone vertical profile at Boulder, Colorado on May 6, 1999 at 1802 

UTC (1102 LST) ............................................. AX3-148

AX3-81 CASTNet stations in the continental United States for 2001 . . . . . . . . . . . . AX3-152

AX3-82 Monthly mean afternoon (1300 to 1700 hours LT) concentrations

(ppbv) in surface air averaged over the CASTNet stations

(Figure AX3-81) in each U.S. quadrant for March to October 2001 . . . . . . AX3-153

AX3-83 Probability distributions of daily mean afternoon (1300 to 1700 LT) 

O3 concentrations in surface air for March through October 2001 at 

U.S. CASTNet sites (Figure AX3-83): observations (thick solid line) 

are compared with model results (thin solid line) . . . . . . . . . . . . . . . . . . . . AX3-157

AX3-84 Daily 3 mean afternoon (13 to 17 LT) O concentrations in surface air

at Voyageurs National Park (NP), Minnesota in mid-May through 

June of 2001 ................................................. AX3-157

AX3-85 Same as Figure AX3-84 but for Yellowstone National Park, Wyoming 

in March to May 2001 ......................................... AX3-159

AX3-86 Same as Figure AX3-84 but for March of 2001 at selected western 

(left column) and southeastern (right column) sites . . . . . . . . . . . . . . . . . . . AX3-160

AX3-87a Detailed diagram illustrating components of an exposure model . . . . . . . . AX3-170
II-xxix

List of Figures

(cont’d)

Number Page

AX3-87b Detailed diagram illustrating components of an exposure model . . . . . . . . AX3-171

AX3-88 Measured outdoor O3 concentrations (thin line) and modeled indoor 

concentrations (bold line) ....................................... AX3-185

AX3 3-89 Air exchange rates and outdoor and indoor O concentrations during 

the summer at a telephone switching station in Burbank, CA . . . . . . . . . . . AX3-200

AX3 3-90 Air exchange rates and outdoor and indoor O concentrations during 

the fall at a telephone switching station in Burbank, CA . . . . . . . . . . . . . . . AX3-201

AX3-91 Diurna 3l variation of indoor and outdoor O and PAN concentrations

measured in a private residence, Freising, Germany, August 11-12, 1995 . . AX3-203

AX3-92 3Indoor and outdoor O concentration in moving cars . . . . . . . . . . . . . . . . . . AX3-205

AX3-93 Indoor/outdoor concentration ratios for PAN at 10 southern 

California museums ........................................... AX3-206

AX3-94 Ozone decay processes versus time measured for several indoor rooms . . . AX3-212

AX6-1 FEV1 3 decrements as a function of O concentration following a 2 h 

exposure with incremental exercise (15 min intervals) or rest . . . . . . . . . . . . . AX6-8

AX6-2 Average FEV1 decrements (±SE) for prolonged 6.6 h exposures to 

0.12 ppm O3 E as a function of exercise V . . . . . . . . . . . . . . . . . . . . . . . . . . .

0 AX6-15

AX6-3 The forced expiratory 1 volume in 1 s (FEV ) is shown in relation to 

exposure duration (hours) under three exposure conditions . . . . . . . . . . . . . . AX6-18

AX6-4a,b Recovery of spirometric responses following a 2 h exposure to 0.4 ppm 

O3 with IE .................................................... AX6-23

AX6-5 Plo 1t of the mean FEV (% baseline) vs. time for ozone exposed cohorts . . . AX6-26

AX6-6 F 1requency distributions of FEV decrements following 6.6-h exposures 

3

to O or filtered air ............................................. AX6-42

AX6-7 Effect of O3 1 exposure (0.42 ppm for 1.5 h with IE) on FEV as a function

of subject age ................................................. AX6-50
II-xxx

List of Figures

(cont’d)

Number Page

AX6-8 Reg 1ression curves were fitted to day-by-day postexposure FEV values 

obtained af 3ter repeated daily acute exposures to O for 2 to 3 h with 

E

intermittent exercise at a V of 24 to 43 L/min (adaptation studies) . . . . . . . AX6-81

AX7-1 Density 3 curves of the O -associated excess risk of cardiovascular 

mortality in the warm season per standardized increment . . . . . . . . . . . . . . AX7-127

AX7-2 Fitted derivative curve of the Gompertz model to the regression 

coefficients ($ = log relative risk per 1,000 ppb) for the association 

be 3tween mortality and acute exposure to O plotted against community3

specific long-term average 24-h avg O concentrations using data from 

the U.S. 95 communities study ................................... AX7-131
II-xxxi

Authors, Contributors, and Reviewers

CHAPTER 2 ANNEX (ATMOSPHERIC PHYSICS/CHEMISTRY)

Principal Author

Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Russell Dickerson—Department of Atmospheric and Oceanic Sciences, University of

Maryland, College Park, MD

Contributing Authors

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Daniel Jacob—Department of Earth and Planetary Sciences, Harvard University,

Cambridge, MA

Dr. William Keene—Department of Environmental Sciences, University of Virginia,

Charlottesville, VA

Dr. Tadeusz Kleindienst—National Exposure Research Laboratory, U.S. Environmental

Protection Agency, Research Triangle Park, NC

Dr. Jennie Moody—Department of Environmental Sciences, University of Virginia,

Charlottesville, VA

Mr. Charles Piety—Department of Atmospheric and Oceanic Sciences, University of Maryland,

College Park, MD

Dr. Sandy Sillman—Department of Atmospheric, Oceanic, and Space Sciences, University of

Michigan, Ann Arbor, MI

Dr. Jeffrey Stehr—Department of Atmospheric and Oceanic Sciences, University of Maryland,

College Park, MD

Dr. Bret Taubman—Department of Atmospheric Sciences, Pennsylvania State University,

State College, PA
II-xxxii

Authors, Contributors, and Reviewers

(cont’d)

Contributors and Reviewers

Dr. Christoph Bruhl—Max Planck Institute for Atmospheric Chemistry, Mainz, Germany

Dr. Mohammed Elshahawy—Department of Meteorology and Astronomy, Cairo University,

Giza, Egypt.

Dr. Arlene Fiore—National Oceanic and Atmospheric Administration/Geophysical Fluid Dynamics

Laboratory, Princeton, NJ 

Mr. Chris Geron—National Risk Management Research Laboratory, U.S. Environmental Protection

Agency, Research Triangle Park, NC

Dr. David Golden—Department of Chemistry, Stanford University, Palo Alto, CA

Dr. John Merrill—Graduate School of Oceanography, University of Rhode Island, Kingston, RI

Dr. Sam Oltmans—National Oceanic and Atmospheric Administration/Climate Monitoring and

Diagnostic Laboratory, Boulder, CO

Dr. David Parrish—National Oceanic and Atmospheric Administration/Aeronomy Laboratory,

Boulder, CO

Dr. Perry Samson—Department of Atmospheric, Ocean, and Space Sciences, University of

Michigan, Ann Arbor, MI

Dr. Sandy Sillman—Department of Atmospheric, Ocean, and Space Sciences, University of

Michigan, Ann Arbor, MI

Dr. Melvin Shapiro—National Center for Atmospheric Research, Boulder, CO

CHAPTER 3 ANNEX (AIR QUALITY AND EXPOSURE)

Principal Authors

Ms. Beverly Comfort—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
II-xxxiii

Authors, Contributors, and Reviewers

(cont’d)

Principal Authors

(cont’d)

Dr. Arlene Fiore—National Oceanic and Atmospheric Administration/Geophysical Fluid Dynamics

Laboratory, Princeton, NJ

Dr. Daniel Jacob—Department of Earth and Planetary Sciences, Harvard University,

Cambridge, MA 

Dr. Alan S. Lefohn—ASL &Associates, Helena, MT

Dr. Clifford Weisel—Environmental and Occupational Health Sciences Institute, Rutgers

University, New Brunswick, NJ

Contributing Authors

Dr. Jee Young Kim——National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Mr. Thomas McCurdy—National Exposure Research Laboratory, U.S. Environmental Protection

Agency, Research Triangle Park, NC

Contributors and Reviewers

Dr. Christoph Bruehl—Max Planck Institute for Atmospheric Chemistry, Mainz, Germany

Dr. Russell Dickerson—Department of Atmospheric and Oceanic Sciences, University of

Maryland, College Park, MD

Dr. Judith Graham—American Chemistry Council, Washington, D.C.

Dr. Laszlo Horvath—Hungarian Meteorological Service, Budapest, Hungary

Dr. Ted Johnson—TRJ Associates, Durham, NC
II-xxxiv

Authors, Contributors, and Reviewers

(cont’d)

Contributors and Reviewers

(cont’d)

Dr. John Merrill—Graduate School of Oceanography, University of Rhode Island, Kingston, RI

Dr. Jennie Moody—Department of Environmental Sciences, University of Virginia,

Charlottesville, VA

Dr. Sam Oltmans—National Oceanic and Atmospheric Administration/Climate Monitoring and

Diagnostic Laboratory, Boulder, CO

Dr. Michiel G.M. Roemer—TNO, The Netherlands

Dr. Sandy Sillman—Department of Atmospheric, Ocean, and Space Sciences, University of

Michigan, Ann Arbor, MI

Dr. Tamas Weidinger—Department of Meteorology, University of Budapest, Budapest, Hungary

CHAPTER 4 ANNEX (DOSIMETRY)

Principal Authors

Dr. John Overton—U.S. Environmental Protection Agency, National Health and Environmental

Effects Research Laboratory-Research Triangle Park, NC 27711 (retired)

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Lori White—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Contributors and Reviewers

Dr. Gary Hatch—U.S. Environmental Protection Agency, National Health and Environmental

Effects Research Laboratory, NC
II-xxxv

Authors, Contributors, and Reviewers

(cont’d)

CHAPTER 5 ANNEX (ANIMAL TOXICOLOGY)

Principal Authors

Dr. Lori White—National Center for Environmental Assessment (B243-01), U.S. Environmental

Protection Agency, Research Triangle Park, NC 27711

Mr. James Raub—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (Retired)

Dr. Deepak Bhalla—Department of Occupational and Environmental Health Sciences, 

Wayne State University, Detroit, MI

Dr. Carroll Cross—School of Medicine, University of California, Davis, CA

Dr. Mitch Cohen—NYU School of Medicine, New York University, New York, NY 

Contributors and Reviewers

Dr. Steven Kleeberger—National Institute of Environmental Health Sciences, Research

Triangle Park, NC 27711

Dr. George Liekauf—Department of Environmental Health, University of Cincinnati,

Cincinnati, OH

Dr. David Basset—Department of Occupational and Environmental Health Sciences, Wayne State

University, Detroit, MI

Dr. E.M. Postlethwait—Department of Environmental Health Sciences, University of Texas

Medical Branch, Galveston, TX

Dr. Kent Pinkerton—Center for Health and the Environment, University of California, Davis, CA

Dr. Edward Schelegle—Department of Anatomy, Physiology, and Cell Biology, University of

California, Davis, CA

Dr. Judith Graham—American Chemical Council, Arlington, VA

Dr. Paul Reinhart—National Center for Environment (B243-03), U.S. Environmental Protection

Agency, Research Triangle Park, NC 27711
II-xxxvi

Authors, Contributors, and Reviewers

(cont’d)

CHAPTER 6 ANNEX (CONTROLLED HUMAN EXPOSURE)

Principal Authors

Dr. James S. Brown—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Mr. James Raub—National Center for Environmental Assessment (B243-01), U.S. Environmental

Protection Agency, Research Triangle Park, NC 27711 (Retired)

Dr. William C. Adams—Human Performance Laboratory, University of California, Davis, CA

(retired)

Dr. Milan J. Hazucha—Center for Environmental Medicine, Asthma, and Lung Biology,

University of North Carolina, Chapel Hill, NC

Dr. E. William Spannhake—Department of Environmental Health Sciences, Johns Hopkins

University, Baltimore, MD

Contributors and Reviewers

Dr. Edward Avol—Department of Preventive Medicine, University of Southern California,

Los Angeles, CA

Dr. Jane Q. Koenig—Department of Environmental and Occupational Health, University of

Washington, Seattle, WA

Dr. Michael Madden—National Health and Environmental Effects Research Laboratory,

U.S. Environmental Protection Agency, Chapel Hill, NC

Dr.William McDonnell—National Health and Environmental Effects Research Laboratory,

U.S. Environmental Protection Agency, Chapel Hill, NC
II-xxxvii

Authors, Contributors, and Reviewers

(cont’d)

CHAPTER 7 ANNEX (EPIDEMIOLOGY)

Principal Authors

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Kazuhiko Ito—New York University School of Medicine, Nelson Institute of 

Environmental Medicine, Tuxedo, NY

Dr. Patrick Kinney—Columbia University, Mailman School of Public Health, New York, NY

Reviewers

Dr. Richard Burnett—Health Canada, Ottawa, Canada

Dr. Vic Hasselblad—Duke University, Durham, NC

Dr. Lucas Neas—National Health and Environmental Effects Research Laboratory,

U.S. Environmental Protection Agency, Chapel Hill, NC
II-xxxviii

U.S. Environmental Protection Agency Project Team

for Development of Air Quality Criteria for Ozone

and Related Photochemical Oxidants

Executive Direction

Dr. Lester D. Grant (Director)—National Center for Environmental Assessment-RTP Division,

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Scientific Staff

Dr. Lori White(Ozone Team Leader)—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Ms. Beverly Comfort—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), 

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Dr. Timothy Lewis—National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 

Dr. William Hogsett—National Health and Environmental Effects Research Laboratory,

U.S. Environmental Protection Agency, Corvallis, OR
II-xxxix

U.S. Environmental Protection Agency Project Team

for Development of Air Quality Criteria for Ozone

and Related Photochemical Oxidants

(cont’d)

Scientific Staff

(cont’d)

Dr. Christian Andersen—National Health and Environmental Effects Research Laboratory,

U.S. Environmental Protection Agency, Corvallis, OR

Dr. Jay Garner—National Center for Environmental Assessment (B243-01), U.S. Environmental

Protection Agency, Research Triangle Park, NC 27711 (retired)

Mr. Bill Ewald—National Center for Environmental Assessment (B243-01), U.S. Environmental

Protection Agency, Research Triangle Park, NC 27711 (retired)

Mr. James Raub—National Center for Environmental Assessment (B243-01), U.S. Environmental

Protection Agency, Research Triangle Park, NC 27711 (retired)

Technical Support Staff

Ms. Nancy Broom—Information Technology Manager, National Center for Environmental

Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Mr. Douglas B. Fennell—Technical Information Specialist, National Center for Environmental

Assessment (B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment 

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Ms. Diane H. Ray—Program Specialist, National Center for Environmental Assessment

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

Ms. Donna Wicker—Administrative Officer, National Center for Environmental Assessment

(B243-01), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (retired)

Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01),

U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
II-xl

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. Carolyn T. Perry—Manager, Computer Sciences Corporation, 2803 Slater Road, Suite 220,

Morrisville, NC 27560

Mr. John A. Bennett—Technical Information Specialist, Library Associates of Maryland,

11820 Parklawn Drive, Suite 400, Rockville, MD 20852

Mr. William Ellis—Records Management Technician, InfoPro, Inc., 8200 Greensboro Drive,

Suite 1450, McLean, VA 22102

Ms. Sandra L. Hughey—Technical Information Specialist, Library Associates of Maryland,

11820 Parklawn Drive, Suite 400, Rockville, MD 20852

Mr. Matthew Kirk—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road, Suite 220,

Morrisville, NC 27560

Dr. Barbara Liljequist—Technical Editor, Computer Sciences Corporation, 2803 Slater Road,

Suite 220, Morrisville, NC 27560

Ms. Rosemary Procko—Senior Word Processor, TekSystems, 1201 Edwards Mill Road, Suite 201,

Raleigh, NC 27607

Ms. Faye Silliman—Publication/Graphics Specialist, InfoPro, Inc., 8200 Greensboro Drive, Suite

1450, McLean, VA 22102

Mr. Carlton Witherspoon—Graphic Artist, Computer Sciences Corporation, 2803 Slater Road,

Suite 220, Morrisville, NC 27560
II-xli

U.S. Environmental Protection Agency Science Advisory Board (SAB)

Staff Office Clean Air Scientific Advisory Committee (CASAC)

Ozone Review Panel

Chair

Dr. Rogene Henderson*, Scientist Emeritus, Lovelace Respiratory Research Institute, 2425

Ridgecrest Drive SE, Albuquerque, NM, 87108, Phone: 505-348-9464, Fax: 505-348-8541,

(rhenders@lrri.org) (FedEx: Dr. Rogene Henderson, Lovelace Respiratory Research Institute,

2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, Phone: 505-348-9464)

Members

Dr. John Balmes, Professor, Department of Medicine, University of California San Francisco,

University of California - San Francisco, San Francisco, California, 94143, Phone: 415-206-8953,

Fax: 415-206-8949, (jbalmes@itsa.ucsf.edu)

Dr. Ellis Cowling*, University Distinguished Professor-at-Large, North Carolina State University,

Colleges of Natural Resources and Agriculture and Life Sciences, North Carolina State University,

1509 Varsity Drive, Raleigh, NC, 27695-7632, Phone: 919-515-7564 , Fax: 919-515-1700,

(ellis_cowling@ncsu.edu)

Dr. James D. Crapo*, Professor, Department of Medicine, National Jewish Medical and Research

Center. 1400 Jackson Street, Denver, CO, 80206, Phone: 303-398-1436, Fax: 303- 270-2243,

(crapoj@njc.org)

Dr. William (Jim) Gauderman, Associate Professor, Preventive Medicine, University of

Southerm California, 1540 Alcazar #220, Los Angeles, CA, 91016, Phone: 323-442-1567,

Fax: 323-442-2349, (jimg@usc.edu)

Dr. Henry Gong, Professor of Medicine and Preventive Medicine, Medicine and Preventive

Medicine, Keck School of Medicine, University of Southern California, Environmental Health

Service, MSB 51, Rancho Los Amigos NRC, 7601 East Imperial Highway, Downey, CA, 90242,

Phone: 562-401-7561, Fax: 562-803-6883, (hgong@ladhs.org)

Dr. Paul J. Hanson, Senior Research and Development Scientist , Environmental Sciences Division,

Oak Ridge National Laboratory (ORNL), Bethel Valley Road, Building 1062, Oak Ridge, TN,

37831-6422, Phone: 865-574-5361, Fax: 865-576-9939, (hansonpz@comcast.net)

Dr. Jack Harkema, Professor, Department of Pathobiology, College of Veterinary Medicine,

Michigan State University, 212 Food Safety & Toxicology Center, East Lansing, MI, 48824,

Phone: 517-353-8627, Fax: 517-353-9902, (harkemaj@msu.edu)
II-xlii

U.S. Environmental Protection Agency Science Advisory Board (SAB)

Staff Office Clean Air Scientific Advisory Committee (CASAC)

Ozone Review Panel

(cont’d)

Members

(cont’d)

Dr. Philip Hopke, Bayard D. Clarkson Distinguished Professor, Department of Chemical

Engineering, Clarkson University, Box 5708, Potsdam, NY, 13699-5708, Phone: 315-268-3861,

Fax: 315-268-4410, (hopkepk@clarkson.edu) (FedEx: 8 Clarkson Avenue, Potsdam, NY

136995708) 

Dr. Michael T. Kleinman, Professor, Department of Community & Environmental Medicine, 100

FRF, University of California - Irvine, Irvine, CA, 92697-1825, Phone: 949-824-4765, Fax:

949-824-2070, (mtkleinm@uci.edu) 

Dr. Allan Legge, President, Biosphere Solutions, 1601 11th Avenue NW, Calgary, Alberta,

CANADA, T2N 1H1, Phone: 403-282-4479, Fax: 403-282-4479, (allan.legge@shaw.ca) 

Dr. Morton Lippmann, Professor, Nelson Institute of Environmental Medicine, New York

University School of Medicine, 57 Old Forge Road, Tuxedo, NY, 10987, Phone: 845-731-3558,

Fax: 845-351-5472, (lippmann@env.med.nyu.edu) 

Dr. Frederick J. Miller*, Consultant, 911 Queensferry Road, Cary, NC, 27511, Phone:

919-467-3194, (fjmiller@nc.rr.com) 

Dr. Maria Morandi, Assistant Professor of Environmental Science & Occupational Health,

Department of Environmental Sciences, School of Public Health, University of Texas - Houston

Health Science Center, 1200 Herman Pressler Street, Houston, TX, 77030, Phone: 713-500-9288,

Fax: 713-500-9249, (mmorandi@sph.uth.tmc.edu) (FedEx: 1200 Herman Pressler, Suite 624) 

Dr. Charles Plopper, Professor, Department of Anatomy, Physiology and Cell Biology, School of

Veterinary Medicine, University of California - Davis, Davis, California, 95616, Phone:

530-752-7065, (cgplopper@ucdavis.edu) 

Mr. Richard L. Poirot*, Environmental Analyst, Air Pollution Control Division, Department of

Environmental Conservation, Vermont Agency of Natural Resources, Bldg. 3 South, 103 South

Main Street, Waterbury, VT, 05671-0402, Phone: 802-241-3807, Fax: 802-241-2590,

(rich.poirot@state.vt.us) 

Dr. Armistead (Ted) Russell, Georgia Power Distinguished Professor of Environmental

Engineering, Environmental Engineering Group, School of Civil and Environmental Engineering,

Georgia Institute of Technology, 311 Ferst Drive, Room 3310, Atlanta, GA, 30332-0512, Phone:

404-894-3079, Fax: 404-894-8266, (trussell@ce.gatech.edu) 
II-xliii

U.S. Environmental Protection Agency Science Advisory Board (SAB)

Staff Office Clean Air Scientific Advisory Committee (CASAC)

Ozone Review Panel

(cont’d)

Members

(cont’d)

Dr. Elizabeth A. (Lianne) Sheppard, Research Associate Professor, Biostatistics and Environmental

& Occupational Health Sciences, Public Health and Community Medicine, University of

Washington, Box 357232, Seattle, WA, 98195-7232, Phone: 206-616-2722, Fax: 206 616-2724,

(sheppard@u.washington.edu) 

Dr. Frank Speizer*, Edward Kass Professor of Medicine, Channing Laboratory, Harvard Medical

School, 181 Longwood Avenue, Boston, MA, 02115-5804, Phone: 617-525-2275, Fax:

617-525-2066, (frank.speizer@channing.harvard.edu) 

Dr. James Ultman, Professor, Chemical Engineering, Bioengineering program, Pennsylvania State

University, 106 Fenske Lab, University Park, PA, 16802, Phone: 814-863-4802, Fax:

814-865-7846, (jsu@psu.edu) 

Dr. Sverre Vedal, Professor of Medicine, Department of Environmental and Occupational Health

Sciences, School of Public Health and Community Medicine, University of Washington, 4225

Roosevelt Way NE, Suite 100, Seattle, WA, 98105-6099, Phone: 206-616-8285, Fax:

206-685-4696, (svedal@u.washington.edu) 

Dr. James (Jim) Zidek, Professor, Statistics, Science, University of British Columbia, 6856

Agriculture Rd., Vancouver, BC, Canada, V6T 1Z2, Phone: 604-822-4302, Fax: 604-822-6960,

(jim@stat.ubc.ca) 

Dr. Barbara Zielinska*, Research Professor , Division of Atmospheric Science, Desert Research

Institute, 2215 Raggio Parkway, Reno, NV, 89512-1095, Phone: 775-674-7066, Fax:

775-674-7008, (barbz@dri.edu)

Science Advisory Board Staff

Mr. Fred Butterfield, CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W.,

Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov)

(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff

Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington,

DC 20004, Telephone: 202-343-9994)

*Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by

 the EPA Administrator 
II-xliv

ABBREVIATIONS AND ACRONYMS

AA arachidonic acid

AA ascorbic acid

a1-AT a1-antitrypsin

AC air conditioning

ACh acetylcholine

ADSS aged and diluted sidestream cigarette smoke

AED aerodynamic diameter

AER air exchange rate

AEROCE Atmospheric/Ocean Chemistry Experiment

AF adsorbed fraction

AGL above ground level

AH2 ascorbic acid

AHCs aromatic hydrocarbons

AHR airway hyperreactivity

AirPEX Air Pollution Exposure (model)

AirQUIS Air Quality Information System (model)

AIRS Aerometric Information Retrieval System

ALI air-liquid interface

AM alveolar macrophage

ANOVA analysis of variance

AP alkaline phosphatase

AP-CIMS Atmospheric Pressure Chemical Ionization Mass Spectrometer

APEX Air Pollutants Exposure (model)

APHEA Air Pollution on Health: European Approach (study)

AQCD Air Quality Criteria Document

AQS Air Quality System

ASC ascorbate

ASTM American Society for Testing and Materials

ATLAS atmospheric model (by Kurucz)
II-xlv

A/V surface-to-volume ratio

$ log relative risk

$2-AR beta-2-adrenergic receptor

BAL bronchoalveolar lavage

BALF bronchoalveolar lavage fluid

BALT bronchus-associated lymphoid tissue

B[a]P benzo[a]pyrene

BC black carbon

BEIS Biogenic Emission Inventory System

BERLIOZ Berlin Ozone Experiment

BF black female

BHC biogenic hydrocarbons

BM black male

BME Bayesian Maxim Eutropy

BMZ basement membrane zone

BP blood pressure

bpm breaths per minute

BrdU bromodeoxyuridine

BS black smoke

BSA body surface area

BSA bovine serum albumin

Bscatter back scatter

C concentration

C3a complement protein fragment

CAAA Clean Air Act Amendments of 1990

CADS Cincinnati Activity Diary Study

CAPMoN Canadian Air and Precipitation Monitoring Network

CAPs concentrated ambient particles

CAR centriacinar region

CARB California Air Resources Board
II-xlvi

CASTNet, CASTNET Clean Air Status and Trends Network

CAT catalase

CB carbon black

CBL convective boundary layer

CBU cumulative breath units

% C/C percent carbon of total carbon

CC16 Clara cell secretory protein

CCh carbachol

CCSP Clara cell secretory protein

Cdyn dynamic lung compliance

CE continuous exercise

CEPEX Central Equatorial Pacific Experiment

CFD computational fluid dynamics

CFR Code of Federal Regulations

CG cloud-to-ground (flash)

CH3 ammonia

CH4 methane

C2H4 ethene

C5H8 isoprene

C6H6 benzene

CHAD Consolidated Human Activities Database

CH2=C(CH3)–CHO methacrolein

CH3–CCl3 methyl chloroform

C6H5CH3 toluene

CH3–CHO acetaldehyde

CH3CH(ONO2)CHO 2-nitratopropanol

CHCl3 chloroform

CH3CN acetonitrile

CH3–CO acetyl

CH3–C(O)–CH=CH2 methyl vinyl ketone
II-xlvii

CH3C(O)CH2ONO2 1-nitratopropanone

CH3–C(O)O2,

CH3–C(O)OO

acetyl peroxy, peroxyacetyl

CHO Chinese hamster ovary (cells)

CH3O methoxy

CH3O2 methyl peroxy

CH3OH methanol

CH3–O(O)CH3 acetone

CH3OOH methyl hydroperoxide

CI confidence interval

CIMS Chemical Ionization Mass Spectroscopy

CINC cytokine-induced neutrophil chemoattractant

CIU cumulative inhalation units

CL chemiluminescence

CMAQ Community Model for Air Quality

CMBO chloromethylbutenone

CMD count mean diameter

CMSA consolidated metropolitan statistical area

CN condensation nuclei

CO carbon monoxide

CO2 carbon dioxide

COD coefficient of divergence

ConA concanavalin A

COPD chronic obstructive pulmonary disease

CSA consolidated statistical area

CTM chemistry transport model

CV coefficient of variation

CYP cytochrome P-450

cyt. cytochrome

) delta; change in a variable

2-D two-dimensional
II-xlviii

DA dopamine

DA dry airstream

DD doubling dose

DHBA 2,3-dihydroxybenzoic acid

DI dry intrusion

DIAL differential absorption lidar (system)

DNA deoxyribonucleic acid

DOAS differential optical absorption spectroscopy

DOC dissolved organic carbon

DOE Department of Energy

DOPAC 3,4-dihydroxyphenylacetic acid

DPPC dipalmitoylglycero-3-phosphocholine

DR disulfide reductase

DTPA diethylenetriaminepentaacetic acid

EBC exhaled breath condensate (fluid)

EC elemental carbon

EC0.05% 0.05% excess risk in mortality

ECG electrocardiographic

EC-SOD extracellular superoxide dismutase

EDMAS Exposure and Dose Modeling and Analysis System

EE energy expenditure

eGPx extracellular glutathione peroxidase

ELF epithelial lining fluid

EM electron microscopy

ENA-78 epithelial cell-derived neutrophil-activating peptide 78

eNOS endothelial nitric oxide synthase

EOFs empirical orthogonal functions

EPA U.S. Environmental Protection Agency

EPEM Event Probability Exposure Model

EPR electron paramagnetic resonance (spectroscopy)
II-xlix

EPRI Electric Power Research Institute

ER emergency room

ERAQS Eastern Regional Air Quality Study

ESR electron spin resonance (spectroscopy)

ET endotracheal

ETS environmental tobacco smoke

EVR equivalent ventilation rate

F female

f, f, fB frequency of breathing

F344 Fischer 344 (rat)

FA filtered air

FA fractional absorption; absorbed fraction

FAA Federal Aviation Administration

FEF forced expiratory flow

FEF25-75, FEF25%-75% forced expiratory flow between 25 and 75% of vital capacity

FEFx forced expiratory flow after X% vital capacity (e.g., after 25, 50, or

75% vital capacity)

FEV1 forced expiratory volume in 1 second

FGFR fibroblast growth factor receptor

FIVC forced inspiratory vital capacity

Fn fibronectin

FP fluticasone propionate

FRC functional residual capacity

FS field stimulation

FTIR Fourier Transform Infrared Spectroscopy 

FVC forced vital capacity

GAM General Additive Model

GCE Goddard Cumulus Ensemble (model)

GC-FID gas chromatography-flame ionization detection

GCM general circulation model

GC/MS gas chromatography-mass spectrometry
II-l

GDT glutathione-disulfide transhydrogenase

GEE Generalized Estimating Equations

GEOS-CHEM three-dimensional model of atmospheric composition driven by

assimilated Goddard Earth Orbiting System observations

GEOS-1 DAS NASA Goddard Earth Orbiting System Data Assimilation System

GM-CSF granulocyte-macrophage colony stimulating factor

GMT Greenwich mean time

G6PD glucose-6-phosphate dehydrogenase

GSH glutathione; reduced glutathione

GSHPx, GPx glutathione peroxidase

GSSG glutathione disulfide

GSTM1 glutathione S-transferase μ-1 (genotype)

GSTM1null glutathione S-transferase μ-1 null (genotype)

H+ hydrogen ion; symbol for acid

3

H radiolabeled hydrogen

HCO formyl

H2CO, HCHO formaldehyde

HDMA house dust mite allergen

HF Howland Forest site

H2O2 hydrogen peroxide

H2SO4 sulfuric acid

HCs hydrocarbons

HHP-C9 1-hydroxy-1-hydroperoxynonane

5-HIAA 5-hydroxyindolacetic acid

HIST histamine

HLA human leukocyte antigen

HNE 4-hydroxynonenal

HNO2 nitrous acid

HNO3 nitric acid

HNO4 pernitric acid

HO hydroxy
II-li

HO2 hydroperoxy

H2O2 hydrogen peroxide

H3O+ protonated water

HOCH2OOH hydroxymethylhydroperoxide

HONO nitrous acid

HOONO pernitrous acid

HO2NO2 peroxynitric acid

HOx hydrogen oxides

HPLC high-pressure liquid chromatography

HR heart rate

HRmax maximum heart rate

HRV heart rate variability

5-HT 5-hydroxytryptamine

hv solar ultraviolet proton

HVAC heating, ventilaltion, and air conditioning

IAS interalveolar septum

IBM individual-based model or modeling

IC inspiratory capacity

IC intracloud (flash)

ICAM intracellular adhesion molecule

ICEM Indoor Chemistry and Exposure Model

ICS inhaled steroids

ID# identification number

IE intermittent exercise

IFN interferon

Ig immunoglobulin (e.g., IgA, IgE, IgG, IgM)

IL interleukin (e.g., IL-1, IL-6, IL-8)

IN intranasal

INF interferon

inh inhalation
II-lii

iNOS inducible nitric oxide synthase

I/O indoor-to-outdoor ratio

ip intraperitoneal

IPCC Intergovernmental Panel on Climate Change

IPMMI International Photolysis Frequency Measurement and

Modeling Intercomparison

IQR interquartile range

ISCCP International Satellite Cloud Climatology Project

IT intratracheal

IU International Units

iv intravenous

j(NO2) photolysis rate coefficient for O3 to NO2

j(O3) photolysis rate coefficient for O3 to O(1D)

Ka intrinsic mass transfer coefficient/parameter

KM particle optical reflectance

KO knockout

KTB tracheobronchial region overall mass transfer coefficient

LDH lactate dehydrogenase

LFHFR low frequency/high frequency (ratio)

LFT lower free troposphere

LI labeling index

LIDAR LIght Detection And Ranging

LIF laser-induced fluorescence

LIS lateral intercellular space

LLJ low-level jet

LM light microscopy

LOESS locally estimated smoothing splines

LPS lipopolysaccharide

LST local standard time

LT leukotriene (e.g., LTB4, LTC4, LTD4, LTE4)

LT local time
II-liii

LTA lymphotoxin-alpha

LWC liquid water content

M air molecule

M male

MAQSIP Multiscale Air Quality Simulation Platform

MBL marine boundary layer

NBTH 3-methyl-2-benzothiazolinone acetone azine

MCCP Mountain Cloud Chemistry Program

MCh methacholine

MCM master chemical mechanism

MCP monocyte chemotactic protein

MEF50 maximal expiratory flow at 50% of vital capacity

MENTOR Modeling Environment for Total Risk Studies

MET metabolic equivalent of work

MHC major histocompatibility

MI myocardial infarction

MIESR matrix isolation electron spin resonance (spectroscopy)

MIP macrophage inflammatory protein

MLN mediastinal lymph node

MM Mt. Mitchell site

MM5 National Center for Atmospheric Research/Penn State Mesoscale

Model

MMAD mass median aerodynamic diameter

MMEF maximal midexpiratory flow

MMMD mean maximum mixing height depth

MoOx molybdenum oxides

MOZAIC Measurement of Ozone and Water Vapor by Airbus

In-Service Aircraft

MPAN methacryloylperoxynitrate; peroxy-methacrylic nitric anhydride

mRNA messenger ribonucleic acid

MS mass spectrometry
II-liv

MS Mt. Moosilauke site

MSA metropolitan statistical area

MS/MS tandem mass spectrometry

MT, Mt metallothionein

Mtn mountain

MW molecular weight

n, N number

N100 number of hours $0.10 ppm

NA noradrenaline

NA, N/A not available

NAAQS National Ambient Air Quality Standards

NADH reduced nicotinamide adenine dinucleotide

NADP National Atmospheric Deposition Program

NADPH reduced nicotinamide adenine dinucleotide phosphate

NADPH-CR reduced nicotinamide adenine dinucleotide phosphatecytochrome c reductase 

NAMS/SLAMS National Ambient Monitoring Stations and State and Local Air

Monitoring Stations

NAPBN National Air Pollution Background Network

NARE North Atlantic Regional Experiment

NASA National Aeronautics and Space Administration

NBS National Bureau of Standards

NCICAS National Cooperative Inner-City Asthma Study

NCLAN National Crop Loss Assessment Network

ND not detectable

NEM National Ambient Air Quality Standards Exposure Model

NESCAUM Northeast States for Coordinated Air Use Management

NF national forest

NF-6B nuclear factor kappa B

NH3 ammonia

NH4

+ ammonium ion
II-lv

NHAPS National Human Activity Pattern Survey

NHBE cultured human bronchial epithelial (cells)

(NH4)2SO4 ammonium sulfate

NIH National Institutes of Health

NIST National Institute of Standards and Technology

NK natural killer (cells)

NL nasal lavage

NLF nasal lavage fluid

NM national monument

NMHCs nonmethane hydrocarbons

NMMAPS National Morbidity, Mortality and Air Pollution Study

NMOCs nonmethane organic compounds

NMVOCs nonmethane volatile organic compounds

NNK 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone

nNOS neuronal nitric oxide synthase

NO nitric oxide

NO2 nitrogen dioxide

NO3 nitrate (radical)

NO3

! nitrate (ion)

N2O5 dinitrogen pentoxide

NOAA National Oceanic and Atmospheric Administration

NOAEL non-observable-adverse-effect level

NOS nitric oxide synthase

NOx nitrogen oxides

NOy total reactive nitrogen; sum of NOx and NOz; odd nitrogen species

NOz nitrogen-containing species, the sum of the products of the

oxidation of NOx

NP national park

NQO1 NAD(P)H-quinone oxidoreductase (genotype)

NQO1wt NAD(P)H-quinone oxidoreductase wild type (genotype)

NR not reported
II-lvi

NRC National Research Council

NS national seashore

NS nonsignificant

NS nonsmoker

NSAID non-steroidal anti-inflammatory agent

NSBR nonspecific bronchial responsiveness

NTE nasal trubinate epithelial (cells)

NTRMs NIST Traceable Reference Materials

NWR national wildlife refuge

NZW New Zealand white (rabbit)

O2 molecular oxygen

O2

! superoxide

O3 ozone

18O radiolabeled oxygen atom

OC organic carbon

OAQPS Office of Air Quality Planning and Standards

OBMs observationally based methods

O(1D) electronically excited oxygen atom

OH hydroxy

8-OHdG 8-hydroxy-2N-deoxyguanosine

OLS ordinary least squares

O(3

P) ground-state oxygen atom

OPE ozone production efficiency

OVA ovalbumin

Ox odd oxygen species; total oxidants

p probability

P90 values of the 90th percentile absolute difference in concentrations

PAF platelet-activating factor

PAHs polycyclic aromatic hydrocarbons

PAMS, PAMs Photochemical Aerometric Monitoring System
II-lvii

PAN peroxyacetyl nitrate

PaO2 partial pressure of arterial oxygen

PAR proximal alveolar region

p-ATP para-acetamidophenol

PBL peripheral blood lymphocytes

PBL planetary boundary layer

PBM population-based model or modeling

PBN C-phenyl N-tert-butyl nitrone

PBPK physiologically based pharmacokinetic (approach)

PC20 provocative concentration that produces a 20% decrease in forced

expiratory volume in 1 second

PC50 provocative concentration that produces a 50% decrease in forced

expiratory volume in 1 second

PCA principal component analysis

PC-ALF 1-palmitoyl-2-(9-oxonononoyl)-sn-glycero-3-phosphocholine

pCNEM Canadian version of National Ambient Air Quality Standards

Exposure Model

pCO2 partial pressure of carbon dioxide

PD20, PD20FEV1 provovative dose that produces a 20% decrease in FEV1

PC20FEV1 provovative concentration that produces a 20% decrease in FEV1

PD100SRaw provocative dose that produces a 100% increase in SRaw

PE postexposure

PEF peak expiratory flow

PEF0.75 peak expiratory flow in 0.75 second

PEFR peak expiratory flow rate

PEG-CAT polyethylene glycol-catalase

PEG-SOD polyethylene glycol-superoxide dismutase

PEM personal exposure monitor

PG prostaglandin (e.g., PGD2, PGE, PGE1, PGE2 PGF1", PGF2")

6PGD 6-phosphogluconate dehydrogenase

PGHS-2 prostaglandin endoperoxide G/H synthase 2
II-lviii

PHA phytohemagglutinin

PIF peak inspiratory flow

PK pharmacokinetics

PM particulate matter

Pm0.1 pressure at mouth at 0.1 second of inspiration against a transiently

occluded mouthpiece (an index of inspiratory drive)

PM2.5 fine particulate matter (mass median aerodynamic diameter

#2.5 μm)

PM10 combination of coarse and fine particulate matter (mass median

aerodynamic diameter #10 μm)

PM10-2.5 coarse particulate matter (mass median aerodynamic diameter

between 10 and 2.5 μm)

PM15 combination of coarse and fine particulate matter (mass median

aerodynamic diameter #15 μm)

PM-CAMx Particulate Matter Comprehensive Air Quality Model with

Extensions

PMNs polymorphonuclear leukocytes; neutrophils

PMT photomultiplier tube

PND postnatal day

pNEM Probabilistic National Ambient Air Quality Standard Exposure

Model

PNN50 proportion of adjacent N-N intervals differing by more than 50 ms

POC particulate organic carbon

polyADPR poly(adenosinediphosphate-ribose)

ppb parts per billion

ppbv parts per billion by volume

pphm parts per hundred million

ppm parts per million

ppmv parts per million by volume

PPN peroxypropionyl nitrate

PPPs power plant plumes

pptv parts per trillion by volume

PRB policy relevant background
II-lix

PTR-MS proton-transfer-reaction mass spectroscopy

PU, PUL pulmonary

PUFAs polyunsaturated fatty acids

PV potential vorticity

PVOCs photochemical volatile organic compounds

PWM pokeweed mitogen

R intraclass correlation coefficient

r correlation coefficient

R2 multiple correlation coefficient

r

2 correlation coefficient

RACM Regional Air Chemistry Mechanism

RADM Regional Acid Deposition Model

rALP recombinant antileukoprotease

RAMS Regional Atmospheric Modeling System

RANTES regulated on activation, normal T cell-expressed and -secreted (cells)

Raw, Raw airway resistance

RB respiratory bronchiole

RBC red blood cell

RDBMS Relational Database Management Systems

REHEX Regional Human Exposure Model

RER rough endoplasmic reticulum

RH relative humidity

RIOPA Relationship of Indoor, Outdoor, and Personal Air (study)

RL total pulmonary resistance

RMR resting metabolic rate

rMSSD square root of the mean of the squared difference between adjacent

normal R-R intervals

RO2 organic peroxy

ROI reactive oxygen intermediate/superoxide anion

RONO2 organic nitrate

ROONO2, RO2NO2 peroxy nitrate
II-lx

ROS reactive oxygen species

RR relative risk

RRMS relatively remote monitoring sites

RT respiratory tract

RT transepithelial resistance

Fg sigma-g; geometric standard deviation

S smoker

SAC Staphylococcus aureus Cowan 1 strain

SAI Systems Applications International

SaO2 oxygen saturation of arterial blood

SAPRC Statewide Air Pollution Research Center, University of

California, Riverside

SAROAD Storage and Retrieval of Aerometric Data (U.S. Environmental

Protection Agency centralized database; superseded by Aerometric

Information Retrieval System [AIRS])

SAWgrp small airway function group

SC stratum corneum

sc subcutaneous

SCAQS Southern California Air Quality Study

SD Sprague-Dawley

SD standard deviation

SDNN standard deviation of normal R-R intervals

SE standard error

SEM standard error of the mean

SES socioeconomic status

SGaw specific airway conductance

SH Shenandoah National Park site

SHEDS Simulation of Human Exposure and Dose System

sICAM soluble intracellular adhesion molecule

SO2 sulfur dioxide

SO4

2! sulfate
II-lxi

SOA secondary organic aerosol

SOD superoxide dismutase

SOS Southern Oxidant Study

SOx sulfur oxides

SP substance P

SP surfactant protein (e.g., SP-A, SP-D)

SRaw, sRaw specific airway resistance

SRBC sheep red blood cell

SRM standard reference material

STE stratospheric-tropospheric exchange

STEP Stratospheric-Tropospheric-Exchange Project

STPD standard temperature and pressure, dry

STRF Spatio-Temporal Random Field

SUM06 seasonal sum of all hourly average concentrations $0.06 ppm

SUM07 seasonal sum of all hourly average concentrations $0.07 ppm

SUM08 seasonal sum of all hourly average concentrations $0.08 ppm

SURE Sulfate Regional Experiment Program

J tau; atmospheric lifetime

T time (duration of exposure)

t t-test statistical value; t statistic

T3 triiodothyronine

T4 thyroxine

TAR Third Assessment Report

TB terminal bronchiole

TB tracheobronchial (region)

TBA thiobarbituric acid

TBARS thiobarbituric acid reactive substances

99mTc-DTPA radiolabeled diethylenetriaminepentaacetic acid

TCO core temperature

TDLAS tunable-diode laser absorption spectroscopy
II-lxii

Te expiratory time

TEM transmission electron microscopy

Tg teragram

TGF$1 transforming growth factor-beta 1

Ti inspiratory time

TLC total lung capacity

TLR Toll-like receptor

TNF tumor necrosis factor

TOMS Total Ozone Mapping Satellite; total ozone mapping spectrometer

TOPSE Tropospheric Ozone Production About the Spring Equinox

TRIM Total Risk Integrated Methodology (model)

TRIM.EXPO Total Risk Integrated Methodology Exposure Event (model)

TPLIF two-photon laser-induced fluorescence

TSH thyroid-stimulating hormone

TSP total suspended particulate

TTFMS two-tone frequency-modulated spectroscopy

TVA Tennessee Valley Authority

TWA time-weighted average

TX thromboxane (e.g., TXA2, TXB2)

UA uric acid

UAM Urban Airshed Model

ULLI unit length labeling index

URT upper respiratory tract

UT Universal Time

UTC Coordinated Universal Time

UV ultraviolet

UV-A ultraviolet radiation of wavelengths 320 to 400 nm

UV-B ultraviolet radiation of wavelengths 280 to 320 nm

UV-DIAL Ultraviolet Differential Absorption Lidar

VC vital capacity

VCAM vascular cell adhesion molecule
II-lxiii

VD anatomic dead space

VD deposition velocity

V0 E minute ventilation; expired volume per minute

V0 Emax maximum minute ventilation

V0 max25% maximum expiratory flow at 25% of the vital capacity

V0 max50% maximum expiratory flow at 50% of the vital capacity

V0 max75% maximum expiratory flow at 75% of the vital capacity 

VMD volume median diameter

VO0 2 oxygen consumption

VO0 2max maximal oxygen uptake (maximal aerobic capacity)

VOCs volatile organic compounds

VT tidal volume

VTB tracheobronchial region volume

VTmax maximum tidal volume

W126 cumulative integrated exposure index with a sigmoidal

weighting function

WBGT wet bulb globe temperature

WCB warm conveyor belt

WF white female

WF, WFM White Face Mountain site

WM white male

WT White Top Mountain site

WT wild type
AX2-1

ANNEX AX2. PHYSICS AND CHEMISTRY OF OZONE

IN THE ATMOSPHERE

AX2.1 INTRODUCTION

This annex (Annex AX2) provides detailed supporting information for Chapter 2 on the

physics and chemistry of ozone (O3) in the atmosphere. The organization of the material in this

annex follows that used in prior Air Quality Criteria Documents, i.e., material is presented in

sections and subsections. This annex provides material supporting Chapter 2 of the current draft

Air Quality Criteria Document for Ozone. 

Section AX2.2 focuses on the chemistry of O3 formation. A very brief overview of

atmospheric structure is presented in Section AX2.2.1. An overview of O3 chemistry is given in

Section AX2.2.2. Information about reactive chemical species that initiate the oxidation of

VOCs is given in Section AX2.2.3. The chemistry of nitrogen oxides is then discussed briefly in

Section AX2.2.4. The oxidation of methane, the simplest hydrocarbon is outlined in

Section AX2.2.5. 

The photochemical cycles leading to O3 production are best understood by considering the

oxidation of methane, structurally the simplest VOC. The CH4 oxidation cycle serves as a model

which can be viewed as representing the chemistry of the relatively clean or unpolluted

troposphere (although this is a simplification because vegetation releases large quantities of

complex VOCs, such as isoprene, into the atmosphere). Although the chemistry of the VOCs

emitted from anthropogenic and biogenic sources in polluted urban and rural areas is more

complex, a knowledge of the CH4 oxidation reactions aids in understanding the chemical

processes occurring in the polluted atmosphere because the underlying chemical principles are

the same. The oxidation of more complex hydrocarbons (alkanes, alkenes, and aromatic

compounds) is discussed in Sections AX2.2.6, AX2.2.7, and AX2.2.8, respectively. The

chemistry of oxygenated species is addressed in Section AX2.2.9. Greater emphasis is placed on

the oxidation of aromatic hydrocarbons in this section because of the large amount of new

information available since the last Air Quality Criteria for Ozone document (AQCD 96) was

published (U.S. Environmental Protection Agency, 1996) and because of their importance in O3

formation in polluted areas. Multiphase chemical processes influencing O3 are discussed in
AX2-2

Section AX2.2.10. Meteorological processes that control the formation of O3 and other oxidants

and that govern their transport and dispersion, and the sensitivity of O3 to atmospheric

parameters are given in Section AX2.3. Greater emphasis is placed on those processes for which

a large amount of new information has become available since AQCD 96. The role of

stratospheric-tropospheric exchange in determining O3 in the troposphere is presented in Section

AX2.3.1. The importance of deep convection in redistributing O3 and its precursors and other

oxidants throughout the troposphere is given in Section AX2.3.2. The possible importance of

nocturnal low-level jets in transporting O3 and other pollutants is presented in Section AX2.3.3. 

Information about the mechanisms responsible for the intercontinental transport of pollutants and

for the interactions between stratospheric-tropospheric exchange and convection is given in

Section AX2.3.4. Much of the material in this section is based on results of field programs

examining atmospheric chemistry over the North Atlantic ocean. The sensitivity of O3 to solar

ultraviolet radiation and temperature is given in Section AX2.3.5. The relations of O3 to its

precursors and to other oxidants based on field and modeling studies are discussed in Section

AX2.4. Methods used to calculate relations between O3 its precursors and other oxidants are

given in Section AX2.5. Chemistry-transport models are discussed in Section AX2.5.1. 

Emissions of O3 precursors are presented in Section AX2.5.2. Issues related to the evaluation of

chemistry-transport models and emissions inventories are presented in Section AX2.5.3. 

Measurement methods are summarized in Section AX2.6. Methods used to monitor groundlevel O3 are given in Section AX2.6.1, NO and NO2 in Section AX2.6.2, HNO3 in

Section AX2.6.3 and some important VOCs in Section AX2.6.4. 

AX2.2 TROPOSPHERIC OZONE CHEMISTRY

AX2.2.1 Atmospheric Structure

The atmosphere can be divided into several distinct vertical layers, based primarily on the

major mechanism by which that portion of the atmosphere is heated or cooled. The lowest major

layer is the troposphere, which extends from the earth’s surface to about 8 km above polar

regions and to about 16 km above tropical regions. The troposphere is heated by convective

transport from the surface, and by the absorption of infrared radiation emitted by the surface,

principally by water vapor and CO2. The planetary boundary layer (PBL) is the sublayer of the
AX2-3

troposphere that mixes with surface air on time scales of a few hours or less. It typically extends

to 1-2 km altitude and is often capped by a temperature inversion. The sublayer of the

troposphere above the PBL is called the free troposphere. Ventilation of the PBL with free

tropospheric air takes place on a time scale of a week. Vertical mixing of the whole troposphere

takes place on a time scale of a month or two. The stratosphere extends from the tropopause, or

the top of the troposphere, to about 50 km in altitude. The upper stratosphere is heated by the

absorption of solar ultraviolet radiation by O3, while dissipation of wave energy transported

upwards from the troposphere is a primary heating mechanism in the lower stratosphere. 

Heating of the stratosphere is balanced by radiative cooling due to infrared emissions to space

by CO2, H2O, and O3. As a result of heating of the upper stratosphere, temperatures increase

with height, inhibiting vertical mixing. A schematic overview of the major chemical cycles

involved in O3 formation and destruction in the stratosphere and troposphere is shown in Figure

AX2-1. The figure emphasizes gas phase processes, but the importance of multiphase processes

is becoming apparent. The sequences of reactions shown in the lower right quadrant of the

figure will be discussed in Section AX2.2. The reader is referred to any of the large number of

texts on atmospheric chemistry, such as Wayne (2000) or Seinfeld and Pandis (1998), for an

introduction to stratospheric photochemistry, including the impact of O3-destroying compounds. 

AX2.2.2 Overview of Ozone Chemistry

Ozone is found not only in polluted urban atmospheres but throughout the troposphere,

including remote areas of the globe. Even without ground-level production, some O3 would be

found in the troposphere due to downward transport from the stratosphere. Tropospheric

photochemistry leading to the formation of O3 and other photochemical air pollutants is

complex, involving thousands of chemical reactions and thousands of stable and reactive

intermediate products. Other photochemical oxidants, such as peroxyacetyl nitrate (PAN), are

among the reactive products. Ozone can be photolyzed in the presence of water to form

hydroxyl radical (OH), which is responsible for the oxidation of NOx and SOx to form

nitric (HNO3) and sulfuric acid (H2SO4), respectively. Ozone participates directly in the

oxidation of unsaturated hydrocarbons, via the ozonolysis mechanism, yielding secondary

organic compounds that contribute to aerosol formation and mass, as well as formaldehyde

(H2CO) and other carbonyl compounds, such as aldehydes and ketones. 
AX2-4

Figure AX2-1. Schematic overview of O3 photochemistry in the stratosphere

and troposphere.

There is a rapid photochemical cycle in the troposphere that involves the photolysis of

nitrogen dioxide (NO2) by solar UV-A radiation to yield nitric oxide (NO) and a ground-state

oxygen atom, O(3P),

O(3

P) then reacts with molecular oxygen to form O3: A molecule from the surrounding air

collides with the newly-formed O3 molecule, removing excess energy to allow it to stabilize.

(AX2-1)
AX2-5

(AX2-4)

Reaction AX2-2 is the only significant reaction forming O3 in the troposphere. 

NO and O3 react to reform NO2:

This reaction is responsible for O3 decreases found near sources of NO (e.g., highways)

especially at night. The oxidation of reactive VOCs leads to the formation of reactive radical

species that allow the conversion of NO to NO2 without the participation of O3 (as in

reaction AX2-3).

O3 can, therefore, accumulate as NO2 photolyzes as in reaction AX2-1 followed by reaction

AX2-2. 

It is often convenient to speak about families of chemical species that are defined in terms

of members which interconvert rapidly among themselves on time scales that are shorter than

that for formation or destruction of the family as a whole. For example, an “odd oxygen” (Ox)

family can be defined as 3 (O(3P) +O(1D)+ O3 + NO2) in much the same way as the NOx

(NO + NO2) family is defined. We can then see that production of Ox occurs by the schematic

reaction AX2-4, and that the sequence of reactions given by reactions AX2-1 through AX2-3

represents no net production of Ox. Definitions of species families and methods for constructing

families are discussed in Jacobson (1999) and references therein. Other families that include

nitrogen containing species, and will be referred to later in this chapter, are NOz, which is the

sum of the products of the oxidation of NOx = 3 (HNO3 + PAN (CH3CHO-OO-NO2) + HNO4 +

other organic nitrates + particulate nitrate); and NOy, which is the sum of NOx and NOz. 

(AX2-2)

(AX2-3)
AX2-6

AX2.2.3 Initiation of the Oxidation of VOCs

The key reactive species in the troposphere is the OH radical. OH radicals are

responsible for initiating the photochemical oxidation of CO and most anthropogenic and

biogenic VOCs, including those responsible for depleting stratospheric O3 (e.g., CH3Br,

hydroclorofluorocarbons), and those which contribute to the greenhouse effect (e.g., CH4). 

Because of their role in removing so many potentially damaging species, OH radicals have

sometimes been referred to as the atmosphere’s detergent. In the presence of NO, reactions of

OH with VOCs lead to the formation of O3. In addition to OH radicals, there are several other

atmospheric species such as NO3, Cl, and Br radicals and O3 that are capable of initiating VOC

oxidation. Rate coefficients and estimated atmospheric lifetimes (the e-folding time) for

reactions of a number of alkanes, alkenes and dienes involved in O3 formation with these

oxidants at concentrations characteristic of the relatively unpolluted planetary boundary layer are

given in Table AX2-1. As can be seen from Table AX2-1, there is a wide range of lifetimes

calculated for the different species. However, under certain conditions the relative importance of

these oxidants can change from those shown in the table. For hydrocarbons whose atmospheric

lifetime is much longer than a day, diurnally averaged concentrations of oxidant concentrations

can be used, but for those whose lifetime is much shorter than a day it is more appropriate to use

either daytime or nighttime averages depending on when the oxidant is at highest concentrations. 

During these periods, these averages are of the order of twice the values used in Table AX2-1. 

The main source of OH radicals is the photolysis of O3 by solar ultraviolet radiation at

wavelengths < 340 nm (solar radiation at wavelengths < 320 nm is also referred to as UV-B) to

generate electronically excited O(1

D) atoms (Jet Propulsion Laboratory, 2003), 

The O(1

D) atoms can either be deactivated to the ground state O(3P) atom by collisions with N2

and O2, or they react with water vapor to form two OH radicals:

(AX2-5)

(AX2-6)
Table AX2-1. Comparison of the Atmospheric Lifetimes (

J) of Low Molecular Weight Hydrocarbons D

OH, NO3, Cl, Br, and O3

Hydrocarbon

k, cm3 molecule!1 s!1

OH NO3 Cl Br 

k × 1012 J k ×1012 J k × 1010 J k × 1012 J 

Alkanes

Ethane 0.24 48 d < 1.0 x 10!5 > 13 y 0.57 6.7 mo 3.1 × 10!7 1.0 × 106 y

Propane 1.1 11 d 0.00021 > 0.60 1.3 90 d 0 6.5 × 103 y2-Methylpropane 2.1 5.6 d < 0.00007 > 18 y 1.3 90 d < 1.0 × > 3.2 × 107 n-Butane 2.3 5.2 d 0.000046 2.8 y 2.3 50 d < 1.0 × > 3.2 × 107 2-Methylbutane 4 2.9 d 0.00016 0.79 y 2 60 d NA NA n-Pentane 3.8 3.0 d 0.000081 1.6 y 2.5 46 d NA NA 2,2-Dimethylbutane 2.7 4.3 d NA NA NA NA NA NA 

2,3-Dimethylbutane 6.4 1.8d 0.00041 110 d 2 60 d 0.0064 50 y 

2-Methylpentane 5.6 2.1 d 0.000017 7.5 y 2.5 47 d NA NA 3-Methylpentane 5.8 2.0 d 0.00002 6.3 y 2.5 46d NA NA n-Hexane 5.2 2.2 d 0.00011 1.2 y 3.1 38 d NA NA 2,2,4-Trimethylpentane 3.8 3.0 d 0.000075 1.7 y 2.3 50 d 0.0068 47 y 

AX2-7
Table AX2-1 (cont’d). Comparison of the Atmospheric Lifetimes (

J) of Low Molecular Weight Hydr

Reaction with OH, NO3, Cl, Br and O3

Hydrocarbon

k, cm3 molecule!1 s!1

OH NO3 Cl Br 

k × 1012 J k × 1012 J k × 1010 J k × 1012 J 

Alkenes

Ethene 8.5 33 h 0 230 d 0.99 3.8 m 0.18 1.8 y Propene 26 11 h 0.01 4.9 d 2.3 50 d 5.3 22 d 2-Methylpropene 51 5.4 h 0.34 3.3 h 0.42 9.0 m NA NA 1-Butene 31 9.0 h 0.013 3.6 d 1.4 65 d 3.4 34 d trans-2-Butene 64 4.3 h 0.39 2.8 h NA NA 0.23 1.4 y cis-2-Butene 56 5.0 h 0.35 3.2 h NA NA 6.3 18 d 

1,3-Butadiene 67 4.1 h 0.1 11 h 4.2 28 d 57 2.0 d Isoprene 100 2.8 h 0.68 1.6 h 5.1 23 d 74 1.6 d 2-Methyl-2-butene 87 3.2 h 9.4 0.12 h NA NA 19 6.1 d 1-Pentene 31 9.0 h 0.7 1.6 h NA NA NA NA trans-2-Pentene 67 4.1 h 1.6 0.69 h NA NA NA NA 

cis-2-Pentene 65 4.3 h 1.4 0.79 h NA NA NA NA 

2,4,4-Trimethyl-1-pentene 65 4.3 h 0.51 2.2 h NA NA NA NA 

Notes: NA = Reaction rate coefficient not available. Rate coefficients were calculated at 298k and 1 atmosphere. y = year. d = day.

OH = 1 × 106/cm3; NO3 = 2.5 × 108/cm3; Cl = 1 × 103/cm3; Br = 1 × 105/cm3; O3 = 1 × 1012/cm3. Value for Br calculated based on equ

1 Rate Coefficients were Obtained from the NIST Online Kinetics Database for Reactions of Alkanes and for all Cl and Br Reactions. 

 All Other Rate Coefficients were Obtained from the Evaluation of Calvert et al. (2000).

2 Lifetimes should be regarded as lower limits.

Sources: NIST online kinetics database (http://kinetics.nist.gov/index.php).

AX2-8
AX2-9

The O(3

P) atoms formed directly in the photolysis of O3 in the Huggins and Chappuis bands or

formed from deactivation of O(1D) atoms reform O3 through reaction AX2-2. Hydroxyl radicals

produced by reactions AX2-5 and AX2-6 can react further with species such as carbon monoxide

and with many hydrocarbons (for example, CH4) to produce HO2 radicals. 

Measurements of OH radical concentrations in the troposphere (Poppe et al., 1995; Eisele

et al., 1997; Brune et al., 1999; Martinez et al., 2003; Ren et al., 2003) show that, as expected,

the OH radical concentrations are highly variable in space and time, with daytime maximum

concentrations of > 3 × 106

 molecules /cm3 in urban areas. A global, mass-weighted mean

tropospheric OH radical concentration also can be derived from the estimated emissions and

measured atmospheric concentrations of methylchloroform (CH3CCl3) and the rate constant for

the reaction of the OH radical with CH3CCl3. Krol et al. (1998) derived a global average OH

concentration of 1.07 × 106 molecules /cm3 for 1993 along with an upward trend of about

0.5%/yr between 1978 and 1993. Using an integrated data set of observed O3, H2O, NOy, CO,

VOCs, temperature and cloud optical depth, Spivakovsky et al. (2000) calculated a global annual

mean OH concentration of 1.16 × 106 molecules cm-3, consistent to within 10% of the value

obtained by Krol et al. (1998). 

HO2 radicals do not initiate the oxidation of hydrocarbons, but serve to recycle OH mainly

by way of reaction with NO, O3, and itself (the latter produces H2O2, which can photolyze to

yield OH). The HO2 radicals also react with organo-peroxy radicals produced during the

oxidation of VOCs to form organo-peroxides (cf., Section AX2.2.5, reaction AX2-20). Organoperoxides undergo wet or dry deposition (Wesely and Hicks, 2000) or degrade further by

photolysis and reaction with OH (Jet Propulsion Laboratory, 2003). 

At night, NO3 assumes the role of primary oxidant (Wayne et al., 1991). Although it is

generally less reactive than OH, its high abundance in the polluted atmosphere compensates for

its lower reactivity. For several VOCs, however, including dimethylsulfide, isoprene, some

terpenes ("-pinene, limonene, linalool) and some phenolic compounds (phenol, o-cresol),

oxidation by NO3 at night is competitive with oxidation by OH during the day, making it an

important atmospheric removal mechanism for these compounds (Wayne et al., 1991) (see

Table AX2-1). The role of NO3 radicals in the chemistry of the remote marine boundary layer

has been examined recently by Allen et al., (2000) and in the polluted continental boundary layer

by Geyer and Platt (2002). 
AX2-10

Cl atoms, derived from products of multiphase processes can initiate the oxidation of most

of the same VOCs as OH radicals, however, the rate coefficients for the reactions of alkanes with

Cl atoms are usually much higher. Cl will also oxidize alkenes and aromatic compounds, but

with a significantly lower rate constant than for OH reactions. Following the initial reaction

with Cl, the degradation of the hydrocarbon proceeds as with OH and NO3, generating an

enhanced supply of odd hydrogen radicals leading to O3 production in the presence of

sufficient NOx. The corresponding reactions of Br with hydrocarbons proceed in a similar

manner, but with rate coefficients that can be substantially lower or higher. 

Chlorine and bromine radicals will also react directly with O3 to form ClO and BrO

radicals, providing a sink for odd oxygen if they do not react with NO to form NO2 (e.g.,

Pszenny et al., 1993). As with other oxidants present in the atmosphere, Cl chemistry provides a

modest net sink for O3 when NOx is less than 20 pptv, and is a net source at higher NOx. Kasting

and Singh (1986) estimated that as much as 25% of the loss of nonmethane hydrocarbons in the

nonurban atmosphere can occur by reaction with Cl atoms, based on the production of Cl atoms

from gas phase photochemical reactions involving chlorine containing molecules (HCl, CH3Cl,

CHCl3, etc.). Elevated concentrations of atomic Cl and other halogen radicals can be found in

polluted coastal cities where precursors are emitted directly from industrial sources and/or are

produced via acid-catalyzed reactions involving sea-salt particles (Tanaka et al., 2000; Spicer

et al., 2001). 

Substantial chlorine-VOC chemistry has been observed in the cities of Houston and

Beaumont/Port Arthur, Texas (Tanaka et al., 2000; Chang et al., 2002; Tanaka et al., 2003). 

Industrial production activities in those areas frequently result in large releases of chlorine gas

(Tanaka et al., 2000). Chloromethylbutenone (CMBO), the product of the oxidation of isoprene

by atomic Cl and a unique marker for chlorine radical chemistry in the atmosphere (Nordmeyer

et al., 1997), has been found at significant mixing ratios (up to 145 pptv) in ambient Houston air

(Riemer and Apel, 2001). However, except for situations in which there are strong local sources

such as these, the evidence for the importance of Cl as an oxidizing agent is mixed. Parrish et al.

(1992, 1993) argued that ratios of selected hydrocarbons measured at Pt. Arena, CA were

consistent with loss by reaction with OH radicals and that any deviations could be attributed to

mixing processes. Finlayson-Pitts (1993), on the other hand had suggested that these deviations

could have been the result of Cl reactions. McKeen et al. (1996) suggested that hydrocarbon 
AX2-11

(AX2-8)

ratios measured downwind of anthropogenic source regions affecting the western Pacific Basin

are consistent with loss by reaction with OH radicals only. Rudolph et al. (1997), based on data

for several pairs of hydrocarbons collected during a cruise in the western Mediterranean Sea, the

eastern mid- and North Atlantic Ocean and the North Sea during April and May of 1991, also

found that ratios of hydrocarbons to each other are consistent with their loss given mainly by

reaction with OH radicals without substantial contributions from reactions with Cl. Their best

estimate, for their sampling conditions was a ratio of Cl to OH of about 10!3

, implying a

concentration of Cl of about 103/cm3 using the globally averaged OH concentration of

about 106

/cm3 given above. In contrast Wingenter et al. (1996) and Singh et al. (1996a) inferred

significantly higher concentrations of atomic Cl (104

 to 105 cm-3) based on relative concentration

changes in VOCs measured over the eastern North Atlantic and Pacific Oceans, respectively. 

Similar approaches employed over the high-latitude southern ocean yielded lower estimates of

Cl concentrations (103

 cm-3; Wingenter et al., 1999). Taken at face value, these observations

indicate substantial variability in Cl concentrations and uncertainty in “typical” values. 

AX2.2.4 Chemistry of Nitrogen Oxides in the Troposphere

In the troposphere, NO, NO2, and O3 are interrelated by the following reactions: 

The reaction of NO2 with O3 leads to the formation of the nitrate (NO3) radical,

(AX2-7)

which in the lower troposphere is nearly in equilibrium with dinitrogen pentoxide (N2O5):

(AX2-3)

(AX2-1)

(AX2-2)
AX2-12

(AX2-10)

(AX2-11)

However, because the NO3 radical photolyzes rapidly (with a lifetime of .5 s for an overhead

sun [Atkinson et al., 1992]), 

its concentration remains low during daylight hours, but can increase after sunset to nighttime

concentrations of < 5 × 107

 to 1 × 1010 molecules cm-3 (< 2 to 430 ppt) over continental areas

influenced by anthropogenic emissions of NOx (Atkinson et al., 1986). This leads to an increase

of N2O5 concentrations during the night by reaction (AX2-8). 

The tropospheric chemical removal processes for NOx involve the reaction of NO2 with the

OH radical and the hydrolysis of N2O5 in aqueous aerosol solutions to produce HNO3. 

The gas-phase reaction of the OH radical with NO2 initiates the major and ultimate removal

process for NOx in the troposphere. This reaction removes radicals (OH and NO2) and competes

with hydrocarbons for OH radicals in areas characterized by high NOx concentrations, such as

urban centers (see Section AX2.4). In addition to gas-phase nitric acid, Golden and Smith

(2000) have concluded that, pernitrous acid (HOONO) is also produced by the reaction of NO2

and OH radicals on the basis of theoretical studies. However, a recent assessment (Jet

Propulsion Laboratory, 2003) has concluded that this channel represents a minor yield

(approximately 15% at the surface). HOONO will thermally decompose or photolyze. 

Gas-phase HNO3 formed from reaction AX2-10 undergoes wet and dry deposition to the surface

and uptake by ambient aerosol particles. The tropospheric lifetime of NOx due to reaction

AX2-10 ranges from a few hours to a few days. Geyer and Platt (2002) concluded that reaction

AX2-11 constituted about 10% of the removal of NOx at a site near Berlin, Germany during

 (AX2-9a)

 (AX2-9b)
AX2-13

(AX2-12)

spring and summer. However, during winter the relative importance of reaction AX2-11 could

be much higher because of the much lower concentration of OH radicals and the enhanced

stability of N2O5 due to lower temperatures and intensity of sunlight. Note that reaction AX2-11

surely proceeds as a heterogeneous reaction. 

OH radicals also can react with NO to produce nitrous acid (HNO2):

In the daytime, HNO2 is rapidly photolyzed back to the original reactants:

(AX2-13)

At night, HNO2 can be formed by heterogeneous reactions of NO2 in aerosols or at the earth’s

surface (Lammel and Cape, 1996; Jacob, 2000; Sakamaki et al., 1983; Pitts et al., 1984;

Svensson et al., 1987; Jenkin et al., 1988; Lammel and Perner, 1988; Notholt et al., 1992a,b). 

This results in accumulation of HNO2 during nighttime. Modeling studies suggest that

photolysis of this HNO2 following sunrise, could provide an important early-morning source of

OH radicals to drive O3 formation (Harris et al., 1982). 

Another important process controlling NOx concentrations is the formation of organic

nitrates. Oxidation of VOCs produces organic peroxy radicals (RO2), as discussed in the

hydrocarbon chemistry subsections to follow. Reaction of these RO2 radicals with NO and NO2

produces organic nitrates (RONO2) and peroxynitrates (RO2NO2):

Reaction (AX2-14) is a minor branch for the reaction of RO2 with NO (the major branch

produces RO and NO2, as discussed in the next section). The organic nitrate yield increases with

carbon number (Atkinson, 2000).

(AX2-14)

(AX2-15)
AX2-14

The organic nitrates may react further, depending on the functionality of the R group, but

they will typically not return NOx and can therefore be viewed as a permanent sink for NOx. 

This sink is usually small compared to HNO3 formation, but the formation of isoprene nitrates

may be a significant sink for NOx in the United States in summer (Liang et al., 1998). 

The peroxynitrates produced by (AX2-15) are thermally unstable and most have very short

lifetimes (less than a few minutes) against thermal decomposition to the original reactants. They

are thus not effective sinks of NOx. Important exceptions are the peroxyacylnitrates (PANs)

arising from the peroxyacyl radicals RC(O)OO produced by oxidation and photolysis of

carbonyl compounds. PANs have lifetimes ranging from ~1 hour at room temperature to several

weeks at 250K. They can thus provide an effective sink of NOx at cold temperatures, but also a

reservoir allowing eventual release of NOx as air masses warm, in particular by subsidence. By

far the most important of these PANs compounds is peroxyacetylnitrate (PAN), with formula

CH3C(O)OONO2. PAN is a significant product in the oxidation of most VOCs. It is now well

established that PAN decomposition provides a major source of NOx in the remote troposphere

(Staudt et al., 2003). PAN decomposition in subsiding Asian air masses over the eastern Pacific

could make an important contribution to O3 enhancement in the U.S. from Asian pollution

(Hudman et al., 2004).

AX2.2.5 The Methane Oxidation Cycle

The photochemical cycles leading to O3 production are best understood by considering the

oxidation of methane, structurally the simplest VOC. The CH4 oxidation cycle serves as a model

which describes the chemistry of the relatively clean or unpolluted troposphere (although this is

a simplification because vegetation releases large quantities of complex VOCs into the

atmosphere). Although the chemistry of the VOCs emitted from anthropogenic and biogenic

sources in polluted urban and rural areas is more complex, a knowledge of the CH4 oxidation

reactions aids in understanding the chemical processes occurring in the polluted atmosphere

because the underlying chemical principles are the same. 

Methane is emitted into the atmosphere as the result of anaerobic microbial activity in

wetlands, rice paddies, the guts of ruminants, landfills, and from mining and combustion of

fossil fuels (Intergovernmental Panel on Climate Change, 2001). The major tropospheric

removal process for CH4 is by reaction with the OH radical,
AX2-15

(AX2-17)

(AX2-18)

(AX2-19)

(AX2-20)

(AX2-21a)

(AX2-16)

In the troposphere, the methyl radical reacts solely with O2 to yield the methyl peroxy (CH3O2A)

radical (Atkinson et al., 1992):

In the troposphere, the methyl peroxy radical can react with NO, NO2, HO2 radicals, and

other organic peroxy (RO2 ) radicals, with the reactions with NO and HO2 radicals being the most

important (see, for example, World Meteorological Organization, 1990). The reaction with NO

leads to the formation of the methoxy (CH3O

.

) radical, 

The reaction with the HO2 radical leads to the formation of methyl hydroperoxide

(CH3OOH),

which can photolyze or react with the OH radical (Atkinson et al., 1992):

or

(AX2-21b)
AX2-16

(AX2-22)

Methyl hydroperoxide is much less soluble than hydrogen peroxide (H2O2), and so wet

deposition after incorporation into cloud droplets is much less important as a removal process

than it is for H2O2. CH3OOH can also be removed by dry deposition to the surface or transported

by convection to the upper troposphere. The lifetime of CH3OOH in the troposphere due to

photolysis and reaction with the OH radical is estimated to be .2 days. Methyl hydroperoxide is

then a temporary sink of radicals, with its wet or dry deposition representing a loss process for

tropospheric radicals. 

The only important reaction for the methoxy radical (CH3O

.

) is

The HO2 radicals produced in (AX2-22) can react with NO, O3, or other HO2 radicals according

to,

Formaldehyde (H2CO) produced in reaction AX2-22 can be photolyzed:

Formaldehyde also reacts with the OH radical,

(AX2-23)

(AX2-25)

(AX2-24)

(AX2-26a)

(AX2-26b)

(AX2-27)
AX2-17

The H atom and HˆO (formyl) radical produced in these reactions react solely with O2 to form

the HO2 radical:

The lifetimes of H2CO due to photolysis and reaction with OH radicals are .4 h and 1.5 days,

respectively, leading to an overall lifetime of slightly less than 4 hours for H2CO for overhead

sun conditions (Rogers, 1990). 

The final step in the oxidation of CH4 involves the oxidation of CO by reaction with the

OH radical to form CO2:

The lifetime of CO in the lower troposphere is .2 months at midlatitudes. 

NO and HO2 radicals compete for reaction with CH3O2 and HO2 radicals, and the reaction

route depends on the rate constants for these two reactions and the tropospheric concentrations

of HO2 and NO. The rate constants for the reaction of the CH3O2A radicals with NO (reaction

AX2-18) and HO2 radicals (reaction AX2-19) are of comparable magnitude (e.g., Jet Propulsion

Laboratory, 2003). Based on expected HO2 radical concentrations in the troposphere, Logan

et al. (1981) calculated that the reaction of the CH3O2A radical with NO dominates for NO mixing

ratios of >30 ppt. For NO mixing ratios <30 ppt, the reaction of the CH3O2A radical with HO2

dominates. The overall effects of methane oxidation on O3 formation for the case when

NO >30 ppt can be written as: 

(AX2-28)

(AX2-29)

(AX2-30)

(AX2-29)
AX2-18

Further O3 formation occurs, based on the subsequent reactions of H2CO, e.g.,

Reactions in the above sequence lead to the production of two OH radicals which can further

react with atmospheric constituents (e.g., Crutzen, 1973). There is also a less important

pathway:

(AX2-16, AX2-17)

 (AX2-18)

 (AX2-22)

 (AX2-23)

 (AX2-1)

 (AX2-2)

 (AX2-31)

(AX2-26b; AX2-28; AX2-29)

 (AX2-23)

 (AX2-1)

 (AX2-2)

 (AX2-32)
AX2-19

These reaction sequences are important for tropospheric chemistry because formaldehyde is an

intermediate product of the oxidation of most VOCs. The reaction of O3 and HO2 radicals leads

to the net destruction of tropospheric O3:

Using the rate constants reported for reactions AX2-23 and AX2-24 (Atkinson et al., 1992) and

the background tropospheric O3 mixing ratios given above, the reaction of HO2 radicals with NO

dominates over reaction with O3 for NO mixing ratios >10 ppt. The rate constant for

reaction AX2-25 is such that an NO mixing ratio of this magnitude also means that the HO2

radical reaction with NO will be favored over the self-reaction of HO2 radicals. 

Consequently, there are two regimes in the “relatively clean” troposphere, depending on

the local NO concentration: (1) a “very low-NOx” regime in which HO2 and CH3O2 radicals

combine (reaction AX2-19), and HO2 radicals undergo self-reaction (to form H2O2) and react

with O3 (reactions AX2-25 and AX2-24), leading to net destruction of O3 and inefficient OH

radical regeneration (see also Ehhalt et al., 1991; Ayers et al., 1992); and (2) a “low-NOx”

regime (by comparison with much higher NOx concentrations found in polluted areas) in

which HO2 and CH3O2 radicals react with NO to convert NO to NO2, regenerate the OH radical,

(AX2-26a)

(AX2-30)

(AX2-28)

(AX2-23)

(AX2-1)

(AX2-2)

(AX2-33)

(AX2-24)
AX2-20

and, through the photolysis of NO2, produce O3. In the “low NOx” regime there still may be

significant competition from peroxy-peroxy reactions, depending on the local NO concentration.

Nitric oxide mixing ratios are sufficiently low in the remote marine boundary layer

relatively unaffected by transport of NOx from polluted continental areas (< 15 ppt) that

oxidation of CH4 will lead to net destruction of O3, as discussed by Carroll et al. (1990) and

Ayers et al. (1992). In continental and marine areas affected by transport of NOx from

combustion sources, NO mixing ratios are high enough (of the order of ~one to a few hundred

ppt) for the oxidation of CH4, nonmethane hydrocarbons (NMHCs) and CO to lead to net O3

formation (e.g., Carroll et al., 1990; Dickerson et al., 1995). Generally, NO mixing ratios

increase with altitude and can be of the order of fifty to a few hundred ppt in the upper

troposphere depending on location. The oxidation of peroxides, carbon monoxide and acetone

transported upward by convection, in the presence of this NO, can lead to local O3 formation

(e.g., Singh et al., 1995; McKeen et al., 1997; Wennberg et al., 1998; Brühl et al., 2000). 

AX2.2.6 The Atmospheric Chemistry of Alkanes

The same basic processes by which CH4 is oxidized occur in the oxidation of other, even

more reactive and more complex VOCs. As in the CH4 oxidation cycle, the conversion of NO

to NO2 during the oxidation of VOCs results in the production of O3 and the efficient

regeneration of the OH radical, which in turn can react with other VOCs (Figure AX2-2). The

chemistry of the major classes of VOCs important for O3 formation such as alkanes, alkenes

(including alkenes from biogenic sources), and aromatic hydrocarbons will be summarized in

turn. 

Reaction with OH radicals represents the main loss process for alkanes and as also

mentioned earlier, reaction with nitrate and chlorine radicals are additional sinks for alkanes. 

For alkanes having carbon-chain lengths of four or less, the chemistry is well understood and the

reaction rates are slow in comparison to alkenes and other VOCs of similar structure and

molecular weight. See Table AX2-1 for a comparison of reaction rate constants for several

small alkanes and their alkene and diene homologues. For alkanes larger than C5, the situation

is more complex because the products generated during the degradation of these compounds are

usually not well characterized. Branched alkanes have rates of reaction that are highly 
AX2-21

Figure AX2-2. General chemical mechanism for the oxidative degradation of VOCs. 

Source: Atkinson (2000).

dependent on carbon backbone structure. Stable products of alkane photooxidation are known to

include carbonyl compounds, alkyl nitrates, and hydroxycarbonyls. 

Alkyl nitrates form primarily as an alternate product of reaction AX2-34 (below). Several

modeling studies have predicted that large fractions of NOy exist as alkyl and hydroxy alkyl

nitrates (Calvert and Madronich, 1987; Atherton and Penner, 1988; Trainer et al., 1991). 

In NOx- and VOC-rich urban atmospheres, 100 different alkyl and 74 different hydroxy alkyl

nitrate compounds have been predicted and identified (Calvert and Madronich, 1987; Schneider

and Ballschmiter, 1999; Schneider et al., 1998). Uncertainties in the atmospheric chemistry of

the alkanes include the branching ratio of reaction AX2-34, i.e., the extent to which alkyl nitrates

form versus RO and NO2. These uncertainties affect modeling predictions of NOx

concentrations, NO-to-NO2 conversion and O3 formation during photochemical degradation of

the VOCs. Discrepancies between observations and theory have been found in aircraft

measurements of NOy (Singh et al., 1996b). Recent field studies conducted by Day et al. (2003)

have shown that large fractions of organic nitrates, which may be associated with isoprene
AX2-22

oxidation products, are present in urban and rural atmosphere that have not been previously

measured and considered in NOy calculations to date. 

Alcohols and ethers in ambient air react almost exclusively with the OH radical, with the

reaction proceeding primarily via H-atom abstraction from the C–H bonds adjacent to the

oxygen-containing function group in these compounds (Atkinson and Arey, 2003). 

The following list of general reactions, analogous to those described for methane,

summarizes the role of alkane oxidation in tropospheric O3 formation. 

The oxidation of alkanes can also be initiated by other oxidizing agents such as NO3 and Cl

radicals. In this case, there is net production of an OH radical which can reinitiate the oxidation

sequence. The reaction of OH radicals with aldehydes forms acyl (R'CO) radicals, and acyl

peroxy radicals (R'C(O)O2) are formed by the addition of O2. As an example, the oxidation of

ethane (C2H5–H) yields acetaldehyde (CH3–CHO). Acetyl (CH3–CO) and acetylperoxy

(CH3–C(O)O2) radicals can then be formed. Acetylperoxy radicals can combine with NO2 to

form peroxyacetyl nitrate (PAN) via:

(AX2-34)

(AX2-35)

(AX2-36)

(AX2-23)

(AX2-37)

(AX2-1)

(AX2-2)

(AX2-38)

(AX2-39)
AX2-23

PAN can act as a temporary reservoir for NO2. Upon the decomposition of PAN, either locally

or elsewhere, NO2 is released to participate in the O3 formation process again. During the

oxidation of propane, the relatively long-lived intermediate acetone (CH3–C(O) CH3) is formed,

as shown in Figure AX2-3. The photolysis of acetone can be an important source of OH

radicals, especially in the upper troposphere (e.g., Singh et al., 1995). Examples of oxidation

mechanisms of more complex alkanes and other classes of hydrocarbons can be found in

comprehensive texts such as Seinfeld and Pandis (1998). 

AX2.2.7 The Atmospheric Chemistry of Alkenes

As shown in Figure AX2-3, the presence of a double carbon-carbon bond, i.e., > C = C <,

in a VOC can greatly increase the range of potential reaction intermediates and products,

complicating the prediction of O3 production. The alkenes emitted from anthropogenic sources

are mainly ethene, propene, and the butenes, with lesser amounts of the $ C5 alkenes. The major

biogenic alkenes emitted from vegetation are isoprene (2-methyl-1,3-butadiene) and C10H16

monoterpenes (Atkinson and Arey, 2003), and their tropospheric chemistry is currently the focus

of much attention (Zhang et al., 2002; Sauer et al., 1999; Geiger et al., 2003; Sprengnether et al.,

2002; Witter et al., 2002; Bonn and Moortgat, 2003; Berndt et al., 2003; Fick et al., 2003;

Kavouras et al., 1999; Atkinson and Arey, 2003). 

Alkenes react in ambient air with OH and NO3 radicals and with O3. The mechanisms

involved in their oxidation have been discussed in detail by Calvert et al. (2000). All three

processes are important atmospheric transformation processes, and all proceed by initial addition

to the > C = C < bonds or, to a much lesser extent, by H atom extraction. Products of alkene

photooxidation include carbonyl compounds, hydroxy alkyl nitrates and nitratocarbonyls, and

decomposition products from the high energy biradicals formed in alkene-O3 reactions. 

Table AX2-2 provides estimated atmospheric lifetimes for biogenic alkenes with respect to

oxidation by OH, NO3 and O3. The structures of most of the compounds given in Table AX2-2

are shown in Figure AX2-4.

Uncertainties in the atmospheric chemistry of the alkenes concern the products and

mechanisms of their reactions with O3, especially the yields of OH radicals, H2O2, and secondary

organic aerosol in both outdoor and indoor environments. However, many product analyses of

important biogenic and anthropogenic alkenes in recent years have aided in the narrowing of 
AX2-24

Figure AX2-3. Hydroxyl radical initiated oxidation of a) propane and b) propene. 

Source: Calvert et al. (2000).
AX2-25

Table AX2-2. Calculated Atmospheric Lifetimes of Biogenic Volatile Organic

Compounds (adapted from Atkinson and Arey, 2003) a

Biogenic VOC

Lifetime for Reaction with

OH b O3

 c NO3 d

Isoprene l.4 h 0.92 d l.6 h

Monoterpenes

Camphene 2.6 h 13 d l.7 h

2-Carene l.7 h l.2 h 4 min

3-Carene 16 h 8.0 h 7 min

Limonene 49 min 1.4 h 5 min

Myrcene 39 min 35 min 6 min

cis-/trans-Ocimene 33 min 31 min 3 min

"-Phellandrene 27 min 5.6 min 0.9 min

$-Phellandrene 50 min 5.9 h 8 min

"-Pinene 2.6 h 3.2 h 11 min

$-Pinene l.8 h 0.77 d 27 min

Sabinene l.2 h 3.4 h 7 min

"-Terpinene 23 min 0.7 min 0.5 min

(-Terpinene 47 min 2.0 h 2 min

Terpinolene 37 min 9.1 min 0.7 min

Sesquiterpenes

$-Caryophyllene 42 min 1.4 min 3 min

"-Cedrene 2.l h 9.8 h 8 min

"-Copaene 1.5 h 1.8 h 4 min

"-Humulene 28 min 1.4 min 2 min

Longifolene 2.9 h > 23 d 1.6 h

Oxygenates

Acetonee 61 d f > 3.2 y g > 8 y f

Camphor 2.5 d h > 165 d h > 300 d h

1,8-Cineole 1.0 d i > 77 d j 1.5 y i

cis-3-Hexen-1-ol 1.3 h k 4.3 h k 4.l h k

cis-3-Hexenyl acetate l8 h k 5.1 h k 4.S h k

Linalool 52 min k 39 min k 6 min k
AX2-26

Table AX2-2 (cont’d). Calculated Atmospheric Lifetimes of Biogenic Volatile Organic

Compounds (adapted from Atkinson and Arey, 2003)a

Biogenic VOC

Lifetime for Reaction with

OH b O3

 c NO3 d

Oxygenates (cont’d)

Methanol l2 d f > 3.2 y g 2.0 y f

2-Methyl-3-buten-2-ol 2.4 hl 1.2 d m 7.7 d n

6-Methyl-5-hepten-2-one 53 min o 0.7 h o 9 min o

a Rate coefficients from Calvert et al. (2000) unless noted otherwise. b Assumed OH radical concentration: 1.0 × 106

 molecule cm-3. c Assumed O3 concentration: 1 × 1012 molecule cm-3, 24-h average. d Assumed NO3 radical concentration: 2.5 × 108

 molecule cm-3, 12-h nighttime average. e Photolysis will also occur with a calculated photolysis lifetime of ~60 day for the lower troposphere, July, 40° N

 (Meyrahn et al., 1986).

f Atkinson et al. (1999).

g Estimated.

h Reissell et al. (2001).

i Corchnoy and Atkinson (1990).

j Atkinson et al. (1990).

k Atkinson et al. (1995).

l Papagni et al. (2001).

m Grosjean and Grosjean (1994).

n Rudich et al. (1996).

o Smith et al. (1996).

these uncertainties. The reader is referred to extensive reviews by Calvert et al. (2000) and

Atkinson and Arey (2003) for detailed discussions of these products and mechanisms.

Oxidation by OH

As noted above, the OH radical reactions with the alkenes proceed mainly by OH radical

addition to the > C = C < bonds. As shown in Figure AX2-3, for example, the OH radical

reaction with propene leads to the formation of two OH-containing radicals. The subsequent

reactions of these radicals are similar to those of the alkyl radicals formed by H-atom abstraction

from the alkanes. Under high NO conditions, CH3CHCH2OH continues to react — producing

several smaller, “second generation,” reactive VOCs. 
AX2-27

Figure AX2-4. Structures of a selected number of terpene and sesquiterpene compounds.

Source: Atkinson and Arey (2003).
AX2-28

For the simple #C4 alkenes, the intermediate OH-containing radicals appear to undergo

mainly decomposition at room temperature and atmospheric pressure. Hence, for propene, the

“first-generation” products of the OH radical reaction in the presence of NO are HCHO and

CH3CHO, irrespective of which OH-containing radical is formed. 

For the more complex alkenes of biogenic origin, multiple products may be possible from

the initial oxidation step. Each product will further react, following a distinct degradation

pathway. Formaldehyde (HCHO), methacrolein (CH2 = C(CH3)-CHO) and methyl vinyl

ketone (CH3-C(O)-CH=CH2 have been identified as the major products of the OH-isoprene

reaction. These products also react with OH radicals and undergo photolysis. Yields of these

products(and others) are sensitive to the concentration of NOx used in laboratory experiments. 

For NOx ~100 ppt, methacrolein, methyl vinyl ketone and formaldehyde are formed with yields

of roughly 20%, 16%, and 33% and yields of other carbonyl compounds are about 17%, based

on the results of Ruppert and Becker (2000) and references therein. Ruppert and Becker also

observed much lower yields of C5-unsaturated diols (2 to 5%), methanol and methyl

hydroperoxide indicating the presence of peroxy radical interactions. For NOx ~1 ppb, the yields

of methacrolein are similar to those for NOx ~100 ppb, but the yields of methyl vinyl ketone

(~33%), formaldehyde (~60%) are much higher and the diols, methanol and methyl

hydroperoxide were not observed. Orlando et al. (1999) found that the major products of the

oxidation of methacrolein were CO, CO2, hydroxyacetone, formaldehyde and

methacryloylperoxynitrate (MPAN) in their experiment. Horowitz et al. (1998) suggested that

isoprene may be the principal precursor of PAN over the United States in summer. Hydroperoxy

and organic peroxy radicals formed during the oxidation of isoprene and its products can oxidize

NO to NO2, initiating photochemical O3 formation. It should be noted that only about two-thirds

of the carbon in isoprene can be accounted for on a carbon atom basis for NOx $1 ppb. The

values are much lower for lower NOx concentrations. The situation is much better for

methacrolein. Observed products can account for more than 90% of the reacted carbon. 

The rates of formation of condensible, oxidation products of biogenic compounds that may

contribute to secondary organic aerosol formation is an important matter for the prediction of

ambient aerosol concentrations. Claeys et al. (2004a,b) found that 2-methyltetrols are formed

from the oxidation of isoprene in yields of about 0.2% on a molar basis, or 0.4% on a mass basis. 
AX2-29

These are semivolatile compounds that can condense on existing particles. On the other hand,

pinene oxidation leads to substantial organic aerosol formation. 

Oxidation by Nitrate Radical

NO3 radical reacts with alkenes mainly by addition to the double bond to form a

b-nitrooxyalkyl radical (Atkinson 1991, 1994, 1997). The abstraction pathway may account for

up to 20% of the reaction. For propene, the initial reaction is followed by a series of reactions 

that (Atkinson, 1991) to lead to the formation of, among others, carbonyls and nitrato-carbonyls

including formaldehyde (HCHO), acetaldehyde (CH3CHO), 2-nitratopropanal

(CH3CH(ONO2)CHO), and 1-nitratopropanone (CH3C(O)CH2ONO2). By analogy to OH,

conjugated dienes like butadiene and isoprene will react with NO3 to form d-nitrooxyalkyl

radicals (Atkinson, 2000). If NO3 is available for reaction in the atmosphere, then NO

concentrations will be low, owing to the rapid reaction between NO3 and NO. Consequently,

nitrooxyalkyl peroxy radicals are expected to react primarily with NO2, yielding thermally

unstable peroxy nitrates, NO3, HO2, and organoperoxy radicals (Atkinson, 2000). 

Several studies have undertaken the quantification of the products of NO3

!

 initiated

degradation of several of the important biogenic alkenes in O3 and secondary organic aerosol

formation, including isoprene, "- and $-pinene, 3-carene, limonene, linalool, and 2-methyl-3-

buten-2-ol. See Figure AX2-4 for the chemical structures of these and other biogenic

compounds. The results of these studies have been tabulated by Atkinson and Arey (2003). 

Oxidation by Ozone

Unlike other organic compounds in the atmosphere, alkenes react at significant rates

with O3. Ozone initiates the oxidation of alkenes by addition across carbon-carbon double

bonds, at rates that are competitive with reaction with OH (see Table AX2-1). The addition

(AX2-40)
AX2-30

Figure AX2-5. Products from the reaction of terpenes with O3.

Source: Atkinson and Arey (2003).

of O3 across the double bond yields an unstable ozonide, a 5-member ring including a single

carbon-carbon bond linked to the three oxygen atoms, each singly bound. The ozonide

rearranges spontaneously and then fragments to form an aldehyde or ketone, depending on the

original position of the double bond, and a high energy Criegee biradical. Collisional energy

transfer may stabilize the radical, preventing it from decomposing. Low pressure studies of the

decomposition of the Criegee biradical have shown high yields of the OH radical. 

At atmospheric pressures, the rates of OH production have not been reliably established, due to

complications arising from subsequent reactions of the OH produced with the ozonide fragments

(Calvert et al., 2000). 

The ozonolysis of larger biogenic alkenes yields high molecular weight oxidation products

with sufficiently low vapor pressures to allow condensation into the particle phase. Many

oxidation products of larger biogenic alkenes have been identified in ambient aerosol,

eliminating their further participation in O3 production. Figure AX2-5 shows the chemical

structures of the oxidation products of "-pinene and illustrates the complexity of the products. 

Carbonyl containing compounds are especially prevalent. A summary of the results of product

yield studies for several biogenic alkenes can be found in Atkinson and Arey (2003). 
AX2-31

NO2 also participates to a very small degree in the oxidation of alkenes by addition to

double bonds in a manner similar to O3. Rate constants for reactions of this type range

from 10!18 to 10!24 for dienes and monoalkenes (King et al., 2002). It should also be noted

that O3 reacts with terpenoid compounds released from household products such as air fresheners

and cleaning agents in indoor air to produce ultrafine particles (Wainman et al., 2000; Sarwar

et al., 2002)

AX2.2.8 The Atmospheric Chemistry of Aromatic Hydrocarbons

Aromatic hydrocarbons represent a major class of compounds found in gasoline and other

liquid fuels. Upon vaporization, most of these compounds react rapidly in the atmosphere

(Davis et al., 1975) and following a series of complex processes, involving molecular oxygen

and oxides of nitrogen, produce O3. Reaction with OH radicals serves as the major atmospheric

loss process of aromatic hydrocarbons. Atmospheric losses of alkyl aromatic compounds by O3

and nitrate radicals have been found to be minor processes for most monocyclic aromatic

hydrocarbons. (However, the reaction with of the nitrate radical with substituted

hydroxybenzenes, such as phenol or o-, m-, p-cresol, can be an important atmospheric loss

process for these compounds.) Much of the early work in this field focused on the temperature

dependence of the OH reactions (Perry et al., 1977; Tully et al., 1981) using absolute rate

techniques. Typically two temperature regions were observed for a large number of aromatic

compounds and the complex temperature profile suggested that two mechanisms were operative. 

In the high temperature region, hydrogen (H)-atom abstraction from the aromatic ring

dominates, and in the temperature regime less than 320K, OH addition to the aromatic ring is the

dominant process. Thus, at normal temperatures and pressures in the lower troposphere, ring

addition is the most important reactive process followed by H-atom abstraction from any alkyl

substituents. The kinetics of monocyclic aromatic compounds are generally well understood and

there is generally broad consensus regarding the atmospheric lifetimes for these compounds. By

contrast, there is generally a wide range of experimental results from product studies of these

reactions. This leads to a major problem in model development due to a general lack of

understanding of the product identities and yields for even the simplest aromatic compounds,

which is due to the complex reaction paths following initial reaction with OH, primarily by the

addition pathway. 
AX2-32

Two comprehensive reviews, which provide a detailed understanding of the current stateof-science of aromatic hydrocarbons have been written in the past five years. Atkinson (2000)

reviewed the atmospheric chemistry of volatile organic compounds, of which aromatic

hydrocarbons are included in one section of the review. More recently Calvert et al. (2002)

conducted a highly comprehensive examination of the reaction rates, chemical mechanisms,

aerosol formation, and contributions to O3 formation for monocyclic and polycyclic aromatic

hydrocarbons. 

AX2.2.8.1 Chemical Kinetics and Atmospheric Lifetimes of Aromatic Hydrocarbons

Rate constants for the reaction of species in the atmosphere with aromatic hydrocarbons

vary widely depending on the number of aromatic rings and substituent groups. Reactions of O3

with aromatic hydrocarbons (AHCs) are generally slow except for monocyclic aromatic

hydrocarbons having unsaturated substituent groups. For example, indene and styrene have

atmospheric lifetimes of 3.3 h and 23 h with respect to reaction with O3, which are much longer

than that due to reactive loss with either OH or NO3. Thus, the atmospheric lifetimes and

reaction products of O3 and aromatic hydrocarbons will be ignored in this discussion. In

addition to chemical reaction, some organic compounds photolyze in the lower atmosphere. 

Virtually all aromatic precursors are not subject to photolysis, although many of the ring

fragmentation products having multiple carbonyl groups can photolyze in the troposphere. 

The reaction rates and atmospheric lifetimes of monocyclic aromatic compounds due to

reaction with OH radicals are generally dependent on the number and types of substituent groups

associated with the ring. These reaction rates have been found to be highly temperature and

pressure dependent. The temperature regimes are governed by the processes involved and show

a quite complex appearance. At room temperature (-300 K), both addition to the aromatic ring

and H-atom abstraction occur with the addition reaction being dominant. For the two smallest

monocyclic aromatic hydrocarbons, the initial addition adduct is not completely stabilized at

total pressures below 100 torr. 

Numerous studies have been conducted to measure the OH + benzene rate constant over

a wide range of temperatures and pressures. An analysis of absolute rate data taken at

approximately 100 torr argon and not at the high pressure limit yielded a value of 1.2 × 10!12 cm3
AX2-33

molec!1

 s!1. Atkinson (1989) recommended a value of 1.4 × 10!12 cm3molec!1 s!1 at room

temperature and atmospheric pressure. This recommendation has been refined only slightly and

is reflected in the recent value recommended by Calvert et al. (2002) which is given as

1.39 × 10!12 cm3

 molec!1s

!1

. This recommended value for the reaction of OH + benzene together

with values for other monocyclic aromatic hydrocarbons is given in Table AX2-3. 

In general, it is observed that the OH rate constants with monocyclic alkyl aromatic

hydrocarbons are strongly influenced by the number of substituent groups found on the aromatic

ring. (That is, the identity of the alkyl substituent groups has little influence on the overall

reactions rate constant.) Single substituent single-ring aromatic compounds which include

toluene, ethyl benzene, n-propylbenzene, isopropylbenzene, and t-butylbenzene have average

OH reaction rate constants ranging from 4.5 to 7.0 × 10!12 cm3

 molec!1 s!1 at room temperature

and atmospheric pressure. These rate constants lead to atmospheric lifetimes (see below) that

are still greater than 1 day. Rate constants for monocyclic aromatic compounds with greater

than 10 carbon atoms or more are generally not available. 

The dominant monocyclic aromatic compounds with two substituents are m-, o-, and

p-xylene. Their recommended OH rate constants range from 1.4 to 2.4 × 10!11 cm3 molec!1 s!1. 

Similarly, the three isomers of ethyltoluene have recommended OH rate constants ranging from

1.2 to1.9 × 10!11 cm3

 molec!1 s!1. The only other two substituent single-ring aromatic compound

for which the OH rate constant has been measured is p-cymene (para-isopropyltoluene), giving a

value of 1.5 × 10!11 cm3 molec!1 s!1. 

OH rate constants for the C9 trimethyl substituted aromatic hydrocarbons (1,2,3-; 1,2,4-;

1,3,5-trimethylbenzene) are higher by a factor of approximately 2.6 over the di-substituted

compounds. Rate constants for the three isomers range from 3.3 to 5.7 × 10!11 cm3

 molec!1 s!1. 

While concentrations for numerous other trisubstituted benzene compounds have been reported

(e.g., 1,2-dimethyl-4-ethylbenzene), OH rate constants for trimethylbenzene isomers are the only

trisubstituted aromatic compounds that have been reported. 

Aromatic hydrocarbons having substituent groups with unsaturated carbon groups have

much higher OH rate constants than their saturated analogues. The smallest compound in this

group is the C8 AHC, styrene. This compound reacts rapidly with OH and has a recommended

rate constant of 5.8 × 10!11 cm3

 molec!1 s!1 (Calvert, 2002). Other methyl substituted styrene-
AX2-34

Table AX2-3. Hydroxyl Rate Constants and Atmospheric Lifetimes of Mono- and 

Di-cyclic Aromatic Hydrocarbons (adapted from Atkinson 2000)

Compound

OH Rate Constant

(×1012)

JOH

(as indicated)

Benzene 1.4 8.3 d*

Toluene 5.6 2.1 d

Ethylbenzene 7 1.7 d

n-Propylbenzene 5.8 2.0 d

Isopropylbenzene 6.3 1.8 d

t-Butylbenzene 4.5 2.6 d

o-Xylene 14 20 h

m-Xylene 23 12 h

p-Xylene 14 19 h

o-Ethyltoluene 12 23 h

m-Ethyltoluene 19 15 h

p-Ethyltoluene 12 24 h

p-Cymene 14 19 h

1,2,3-Trimethylbenzene 33 8.4 h

1,2,4-Trimethylbenzene 33 8.6 h

1,3,5-Trimethylbenzene 57 4.8 h

Indan 19 15 h

Styrene3 58 4.8 h

"-Methylstyrene 51 5.4 h

Napthalene 23 12 h

1-Methylnapthalene 53 4.8 h

2-Methylnapthalene 52 8.8 h

1 Rate coefficients given as cm3

/molec-sec. 2 Lifetime for zero and single alkyl substituted aromatic based on OH concentration of 1× 106

 molec cm!3. 3 Lifetime for reaction of styrene with NO3 is estimated to be 44 min based on a nighttime NO3 concentration

 of 2.5 × 108

 molec cm!3 and a rate coefficient of 1.5 × 10!12 cm3/molec-sec.
AX2-35

type compounds (e.g., "-methylstyrene) have OH rate constants within a factor of two of that

with styrene. However, for unsaturated monocyclic aromatic hydrocarbons other processes

including atmospheric removal by NO3 radicals can also be important, particularly at night when

photolysis does not substantially reduce the NO3 radical concentration (see below). 

Polycyclic aromatic hydrocarbons are found to a much lesser degree in the atmosphere

than are the monocyclic aromatic hydrocarbons. For example, measurements made in Boston

during 1995 (Fujita et al., 1997) showed that a single PAH (napthalene) was detected in the

ambient morning air at levels of approximately 1% (C/C) of the total monocyclic aromatic

hydrocarbons. 1-methyl and 2-methylnaphthalene have sufficient volatility to be present in the

gas phase. Other higher molecular weight PAHs (# 3 aromatic rings), if present, are expected to

exist in the gas phase at much lower concentrations than napthalene and are not considered here. 

OH rate constants for napthalene and the two methyl substituted napthalene compounds have

been reviewed by Calvert et al. (2002). The values recommended (or listed) by Calvert et al.

(2002) are given in Table AX2-3. As seen in the monocyclic aromatic hydrocarbons, the

substitution of methyl groups on the aromatic ring increases the OH rate constant, in this case by

a factor of 2.3. 

Some data is available for the reaction of OH with aromatic oxidation products. (In this

context, aromatic oxidation products refer to those products which retain the aromatic ring

structure.) These include the aromatic carbonyl compound, benzaldehyde, 2,4-; 2,5-; and

3,4-dimethyl-benzaldehyde, and t-cinnamaldehyde. Room temperature rate constants for these

compounds range from 1.3 × 10!11 cm3

 molec!1 s!1 (benzaldehyde) to 4.8 × 10!11 cm3 molec!1 s!1

(t-cinnamaldehyde). While the yields for these compounds are typically between 2 to 6%, they

can contribute to the aromatic reactivity for aldehydes having high precursor concentration (e.g.,

toluene, 1,2,4-trimethylbenzene). OH also reacts rapidly with phenolic compounds. OH

reaction rates with phenols and o-, m-, and p-cresol are typically rapid (2.7 to 6.8 × 10!11 cm3

molec!1 s!1) at room temperature. Five dimethylphenols and two trimethylphenols have OH

reaction rates ranging between 6.6 × 10!11 and 1.25 × 10-10 cm3 molec!1 s!1. Finally, unlike the

aromatic aldehydes and phenols, reaction rates for OH + nitrobenzene and OH + m-nitrotoluene

are much lower than the parent molecules, given their electron withdrawing behavior from the

aromatic ring. The room temperature rate constants are 1.4 × 10-13 and 1.2 × 10!12, respectively.
AX2-36

The NO3 radical is also known to react with selected AHCs and aromatic photooxidation

products. Reaction can either occur by hydrogen atom abstraction or addition to the aromatic

ring. However, these reactions are typically slow for alkyl aromatic hydrocarbons and the

atmospheric removal due to this process is considered negligible. For AHCs having substituent

groups with double bonds (e.g., styrene, "-methylstyrene), the reaction is much more rapid, due

to the addition of NO3 to the double bond. For these compounds, NO3 rate constants are on the

order of 10!12 cm3 molec!1 s!1. This leads to atmospheric lifetimes on the order of about 1 h for

typical night time atmospheric NO3 levels of 2.5 × 108 molec cm-3 (Atkinson, 2000). 

The most important reactions of NO3 with AHCs are those which involve phenol and

methyl, dimethyl, and trimethyl analogs. These reactions can be of importance due to the high

yields of phenol for the atmospheric benzene oxidation and o-, m-, p-cresol from toluene

oxidation. The NO3 + phenol rate has been given as 3.8 × 10!12 cm3

 molec!1 s!1. Similarly, the

cresol isomers each has an extremely rapid reaction rate with NO3 ranging from 1.1 to

1.4 × 10!11 cm3

 molec!1 s!1. As a result, these compounds, particularly the cresol isomers, can

show rapid nighttime losses due to reaction with NO3 with nighttime lifetimes on the order of a

few minutes. There is little data for the reaction of NO3 with dimethylphenols or

trimethylphenols which have been found as products of the reaction of OH + m-, p-xylene and

OH + 1,2,4-; 1,3,5-trimethylbenzene. 

AX2.2.8.2 Reaction Products and Mechanisms of Aromatic Hydrocarbon Oxidation

An understanding of the mechanism of the oxidation of AHCs is important l if O3 is to be

accurately predicted in urban atmospheres through modeling studies. As noted above, most

monocyclic aromatic hydrocarbons are removed from the atmosphere through reaction with OH. 

Thus, product studies of the OH + AHC should provide the greatest information regarding the

AHC oxidation products. However, the effort to study these reactions has been intractable over

the past two decades due to a number of difficulties inherent in the OH-aromatic reaction

system. There are several reasons for the slow progress in understanding these mechanisms. 

(1) Product yields for OH-aromatic systems are poorly understood; for the most studied system,

OH-toluene, approximately 50% of the reaction products have been identified under conditions

where NO2 reactions do not dominate the removal of the OH-aromatic adduct. (2) As noted, the

reaction mechanism can change as the ratio of NO2 to O2 changes in the system (Atkinson and
AX2-37

Aschmann, 1994). Thus, reaction product distributions that may be measured in the laboratory

at high NO2 (or NOx) concentrations may not be applicable to atmospheric conditions. This also

limits the usefulness of models to predict O3 formation to the extent that secondary aromatic

reactions are not completely parameterized in the system. (3) Aromatic reactions produce highly

polar compounds for which there are few calibration standards available. In most cases,

surrogate compounds have to be used in GC/MS calibrations. Moreover, it is not at all clear

whether the present sampling techniques or analytical instruments are appropriate to measure the

highly polar products produced in these systems. (4) Finally for benzene and toluene in

particular, reaction rates of the products are substantially faster than that of the parent

compounds. Thus, it is difficult to measure yields accurately without substantial interferences

due to secondary reactions. Even given these difficulties, over the past decade a body of

knowledge has been developed whereby the initial steps in the OH-initiated photooxidation have

been established and a wide range of primary products from each of the major reaction systems

have been catalogued. 

Benzene is one of the most important aromatic hydrocarbons released into the atmosphere

and is a recognized carcinogen. However, its reaction with OH is extremely slow and its

contribution to urban O3 formation is generally recognized to be negligible (Carter, 1994). As a

result, relatively few studies have been conducted on the OH reaction mechanism of benzene. 

Major products of the oxidation of benzene have been found to be phenol and glyoxal (Berndt

et al., 1999; Tuazon et al., 1986). 

Most of the product analysis and mechanistic work on alkyl aromatic compounds in the gas

phase has focused on examining OH reactions with toluene. The primary reaction of OH with

toluene follows either of two paths, the first being an abstraction reaction from the methyl group

and the second being addition to the ring. It has previously been found that H-atom abstraction

from the aromatic ring is of minor importance (Tully et al., 1981). A number of studies have

examined yields of the benzyl radical formed following OH abstraction from the methyl group. 

This radical forms the benzyl peroxy radical, which reacts with nitric oxide (NO) leading to the

stable products benzaldehyde, with an average yield of 0.06, and benzyl nitrate, with an average

yield less than 0.01 (Calvert et al., 2002). Thus, the overall yield for the abstraction channel is

less than approximately 7%. 
AX2-38

It is now generally recognized that addition of OH to the aromatic ring is the major process

removing toluene from the atmosphere and appears to account for more than 90% of the reaction

yield for OH + toluene. The addition of OH to the ring leads to an intermediate OH-toluene

adduct that can be stabilized or can redissociate to the reactant compounds. For toluene, OH

addition can occur at any of the three possible positions on the ring (ortho, meta, or para) to form

the adduct. Addition of OH to the toluene has been shown to occur predominately at the ortho

position (yield of 0.81) with lesser amounts at the meta (0.05) and para (0.14) positions (Kenley

et al., 1981). The initial steps for both the abstraction and addition pathways in toluene have

been shown in Figure AX2-6; only the path to form the ortho-adduct is shown, viz. reaction (2). 

The OH-toluene adduct formed is an energy-rich intermediate that must be stabilized by

third bodies in the system to undergo further reaction. Stabilization has been found to occur at

pressures above 100 Torr for most third bodies (Perry et al., 1977; Tully et al., 1981). Therefore,

at atmospheric pressure, the adduct will not substantially decompose back to its reactants as

indicated by reaction (!2). The stabilized adduct (I) is removed by one of three processes: 

H-atom abstraction by O2 to give a cresol, as in reaction (5); an addition reaction with O2, as in

reaction (6); or reaction with NO2 to give m-nitrotoluene as in reaction (7). 

The simplest fate for the adduct (I) is reaction with O2 to form o-cresol. Data from a

number of studies (e.g., Kenley et al., 1981; Atkinson et al., 1980; Smith et al., 1998; Klotz

et al., 1998; summarized by Calvert et al., 2002) over a wide range of NO2 concentrations

(generally above 1 ppmv) show an average yield of approximately 0.15 for o-cresol. Most of the

measurements suggest the o-cresol yield is independent of total pressure, identity of the third

body, and NO2 concentration (Atkinson and Aschmann, 1994; Moschonas et al., 1999), but the

data tend to be scattered. This finding suggests that the addition of NO2 to the hydroxy

methylcyclo-hexadienyl radical does not contribute to the formation of phenolic-type

compounds. Fewer studies have been conducted for m and p-cresol yields, but the results of two

studies indicate the yield is approximately 0.05 (Atkinson et al., 1980; Gery et al., 1985; Smith

et al., 1998). The data suggests good agreement between the relative yields of the cresols from

the product studies at atmospheric pressure and studies at reduced pressures. Thus, H-atom

abstraction from adducts formed at all positions appears to represent approximately 20% of the

total yield for toluene. 
AX2-39

Figure AX2-6. Initial steps in the photooxidation mechanism of toluene initiated by its

reaction with OH radicals. 
AX2-40

The OH-toluene adduct also reacts with O2 to form a cyclohexadienyl peroxy radical (III),

shown as a product of reaction (6) after rearrangement. This radical can undergo a number of

possible processes. Most of these processes lead to ring fragmentation products, many of which

have been seen in several studies (Dumdei and O’Brien, 1984; Shepson et al., 1984). 

Ring-fragmentation products are frequently characterized by multiple double bonds and/or

multiple functional groups. As such, these products are highly reactive and extremely difficult

to detect and quantify. 

Klotz et al. (1997; 1998) have suggested that the intermediate could also follow through a

mechanism where toluene oxide/oxepin could be formed following the addition of O2 to the

OH-aromatic adduct. Recent experiments suggest that the formation of o-cresol through the

photolysis of toluene oxide/oxepin is only a minor contributor to the overall o-cresol that has

been measured (Klotz et al., 1998). This result contrasts to the high yield observed for the

formation of phenol from the photolysis of benzene oxide/oxepin (Klotz et al., 1997). Recently,

Berndt et al. (1999) used a flow tube to test the hypothetical formation of benzene oxide/oxepin

from the OH + benzene reaction at pressures below 100 torr. They saw very little evidence for

its formation. 

A few studies have been conducted to identify fragmentation products using a variety of

instruments. Several approaches have been used that employ structural methods, particularly

mass spectrometry (MS), to identify individual products formed during the photooxidation. 

In one approach (Dumdei and O’Brien, 1984), the walls of the reaction chamber were extracted

following an extended irradiation. In this study, the analysis was conducted by tandem mass

spectrometry (MS/MS), which allowed products to be separated without the use of a

chromatographic stationary phase. The investigators reported 27 photooxidation products from

toluene, with 15 reportedly from ring fragmentation processes. However, the study was purely

qualitative and product yields could not be obtained. No distinction could be made between

primary and secondary products from the reaction because extended irradiations and species in

various isotopic forms could not be differentiated. More refined approaches using atmospheric

pressure ionization-tandem mass spectrometry has been used to study toluene (Dumdei et al.,

1988) and m- and p-xylene (Kwok et al., 1997) photooxidation. 

In another study, Shepson et al. (1984) demonstrated that a number of these fragmentation

products could be analyzed by gas chromatography. Fragmentation products detected in two 
AX2-41

investigations (Dumdei and O’Brien, 1984; Shepson et al., 1984) included glyoxal, methyl

glyoxal, butenedial, 4-oxo-2-pentenal, hydroxybutenedial, 1-pentene-3,4-dione, 1-butene-3,4-

dione, and methyl vinyl ketone. Additional evidence (Shepson et al., 1984) for fragmentation

processes came from the detection of 2-methylfuran and furfural. These compounds, although

cyclic in structure, result from a bridged oxygen intermediate. Yields of the detected

fragmentation products were subsequently measured in a number of studies (e.g., Bandow et al.,

1985a,b; Tuazon et al., 1986; Smith et al., 1998), were typically under 15% on a reacted carbon

basis. 

An additional possible pathway for reaction of the OH-toluene adduct is by reaction

with NO2 to give isomers of nitrotoluene. A yield of approximately 0.015 at NO2 concentrations

of about 1 ppmv has been measured (Atkinson et al., 1991). Although this yield itself is fairly

minor, the investigators reported a positive intercept in plotting the nitrotoluene concentration

against the NO2 concentration; however, the data were considerably scattered. The positive

intercept has been interpreted as suggesting that the OH-toluene adduct does not add O2. This

finding would require, therefore, another mechanism than that described above to be responsible

for the fragmentation products. 

The results of this study can be compared to experiments which directly examined the OH

radical loss in reactions of OH with toluene and other aromatic compounds. Knipsel and coworkers (Knispel et al., 1990) have found a double exponential decay for toluene loss in the

presence of added O2, a rapid decay reflective of the initial adduct formation and a slower decay

reflecting loss of the adduct by O2 or other scavengers. From the decay data in the presence

of O2, they determine a loss rate for the OH-toluene of 5.4 × 10-16 cm3

 molec-1 s

!1

. Use of this

rate constant suggests that the loss rate of 2500 s!1

 for the adduct in the presence of air at

atmospheric pressure. This loss rate compares to a loss due to NO2 (with a nominal atmospheric

concentration of 0.1 ppmv) of about 100 s!1

. This finding suggests that removal of the OHtoluene adduct by O2 is a far more important loss process than removal by NO2 under

atmospheric conditions which is in contrast other findings (Atkinson et al., 1991). This finding

was confirmed by the recent experiments from Moschonas et al. (1999). 

Therefore, studies on the disposition of toluene following OH reaction can be summarized

as follows. It is generally accepted that H-atom abstraction from the methyl group by OH is a

relatively minor process accounting for a 6 to 7% yield in the OH reaction with toluene. 
AX2-42

Addition of OH to toluene to form an intermediate OH-toluene adduct is the predominant

process. At atmospheric pressure, ring-retaining products such as the cresol and nitrotoluenes

account for another 20% of the primary reaction products (Smith et al., 1999). The remaining

70 to 75% of the products are expected to be ring fragmentation products in the gas phase,

having an uncertain mechanism for formation. Many of these fragmentation products have been

detected, but appear to form at low yields, and relatively little quantitative information on their

formation yields exists. As noted earlier, some of these products contain multiple double bonds,

which are likely to be highly reactive with OH or photolyze which enhances the reactivity of

systems containing aromatics. Mechanisms that cannot adequately reflect the formation of

fragmentation products are likely to show depressed reactivity for the oxidation of toluene and

other aromatic compounds. 

The number of studies of the multiple-substituted alkyl aromatics, such as the xylenes or

the trimethylbenzenes, is considerably smaller than for toluene. Kinetic studies have focused on

the OH rate constants for these compounds. For the xylenes, this rate constant is typically a

factor of 2 to 5 greater than that for OH + toluene. Thus, the OH reactivity of the fragmentation

products is similar to that of the parent compounds, potentially making the study of the primary

products of the xylenes less prone to uncertainties from secondary reactions of the primary

products than is the case for toluene. 

Products from the OH reaction with the three xylenes have been studied most

comprehensively in a smog chamber using long-path FTIR (Bandow and Washida, 1985a) and

gas chromatography (Shepson et al., 1984; Atkinson and Aschmann, 1994; Smith et al., 1999). 

Ring-fragmentation yields of 41, 55, and 36% were estimated for o-, m-, and p-xylene,

respectively, based on the dicarbonyl compounds, glyoxal, methyl glyoxal, biacetyl, and 3-

hexene-2,5-dione detected during the photooxidation. These values could be lower limits, given

that Shepson et al. (1984) report additional fragmentation products from o-xylene, including

1-pentene-4,5-dione, butenedial, 4-oxo-pentenal, furan, and 2-methylfuran. In the earlier

studies, aromatic concentrations were in the range of 5 to 10 ppmv with NOx at 2 to 5 ppmv. 

At atmospheric ratios of NO2 and O2, the observed yields could be different. Smith et al. (1999)

examined most of the ring retaining products in the OH + m-xylene and OH + p-xylene systems. 

In each case, tolualdehyde isomers, dimethylphenol isomers, and nitro xylene isomers specific

for each system were detected. The total ring retaining yield for OH + m-xylene was 16.3%; the
AX2-43

yield for OH + p-xylene it was 24.5%. A mass balance approach suggests that respective ringfragmentation yields of 84% and 76%, respectively. Kwok et al. (1997) also measured products

from the OH + m- and p-xylene systems using atmospheric pressure ionization-tandem mass

spectrometry. Complementary ring-fragmentation products to glyoxal, methylglyoxal, and

biacetyl were detected from the parent ion peaks, although the technique did not permit the

determination of reaction yields. 

Smith et al. (1999) also studied ring fragmentation products from the reaction of OH

with 1,2,4- and 1,3,5-trimethylbenzene. Ring-retaining products from the reaction with

1,2,4-trimethylbenzene gave three isomers each of dimethylbenzaldehyde and trimethylphenol

as expected by analogy with toluene. However, the ring-retaining products only accounted for

5.8% of the reacted carbon. Seven additional ring-fragmentation products were also detected

from the reaction, although the overall carbon yield was 47%. For 1,3,5-trimethylbenzene, its

reaction with OH leads to only two ring-retaining products, 3,5-dimethyl-benzaldehyde and

2,4,6-trimethylphenol, given its molecular symmetry. Only a single fragmentation product was

detected, methyl glyoxal, at a molar yield of 90%. The overall carbon yield in this case was

61%. The formation of relatively low yields of aromatic aldehydes and methylphenols suggests

that NOx removal by these compound in these reaction systems will be minimized (see below). 

In recent years, computational chemistry studies have been applied to reaction dynamics of

the OH-aromatic reaction systems. Bartolotti and Edney (1995) used density functional-based

quantum mechanical calculations to help identify intermediates of the OH-toluene adduct. These

calculations were consistent with the main addition of OH to the ortho position of toluene

followed by addition of O2 to the meta position of the adduct. The reaction energies suggested

the formation of a carbonyl epoxide which was subsequently detected in aromatic oxidation

systems by Yu and Jeffries, (1997). Andino et al. (1996) conducted ab initio calculations using

density functional theory with semiempirical intermediate geometries to examine the energies of

aromatic intermediates and determine favored product pathways. The study was designed to

provide some insight into the fragmentation mechanism, although only a group additivity

approach to calculate )Hrxn was used to investigate favored reaction pathways. However, the

similarity in energies of the peroxy radicals formed from the O2 reaction with the OH-aromatic

adduct were very similar in magnitude making it difficult to differentiate among structures. 
AX2-44

A detailed analysis of toluene oxidation using smog chamber experiments and chemical

models (Wagner et al., 2003) shows that there are still large uncertainties in the effects of

toluene on O3 formation. A similar situation is likely to be found for other aromatic

hydrocarbons. 

AX2.2.8.3 The Formation of Secondary Organic Aerosol as a Sink for Ozone Precursors

Aromatic hydrocarbons are known to generate secondary organic aerosol (SOA) following

their reaction with OH or other reactive oxidants. Secondary organic aerosol refers to the

formation of fine particulate matter either through nucleation processes or through condensation

onto existing particles. Over the last 12 years numerous experiments have been conducted in

environmental chambers to determine the yield of secondary organic aerosol as a function of the

reacted aromatic hydrocarbon. A review of the results of these studies can be found in the latest

Air Quality for Particulate Matter Document (U.S. Environmental Protection Agency, 2003). 

The extent to which aromatic reaction products are removed from the gas phase and

become incorporated in the particle phase will influence the extent to which oxygenated organic

compounds will not be available for participation in the aromatic mechanisms that lead to O3

formation. However, this may be overstated to some degree for products of aromatic precursors. 

First, at atmospheric loading levels of organic particulate matter, the SOA yields of the major

aromatic hydrocarbons are in the low percent range. Second, the aromatic products that are

likely to condense on particles are likely to be highly oxygenated and have OH reaction rates

that make them largely unreactive. Thus, while there may be some reduction of O3 formation, it

is not expected to be large. 

AX2.2.9 Importance of Oxygenated VOCs

The role of oxygenated VOCs in driving O3 production has generated increasing interest

over the past decade. These VOCs include carbonyls, peroxides, alcohols, and organic acids.

They are produced in the atmosphere by oxidation of hydrocarbons, as discussed above, but are

also directly emitted to the atmosphere, in particular by vegetation (Guenther et al., 2000). 

In rural and remote atmospheres, oxygenated VOCs often dominate over nonmethane

hydrocarbons in terms of total organic carbon mass and reactivity (Singh et al., 2004). The most

abundant by mass of these oxygenated VOCs is usually methanol, which is emitted by
AX2-45

vegetation and is present in U.S. surface air at concentrations of typically 1-10 ppbv (Heikes

et al., 2002). 

Most oxygenated VOCs react with OH to drive O3 production in a manner similar to the

hydrocarbon chemistry discussed in the previous sections. In addition, carbonyl compounds

(aldehydes and ketones) photolyze to produce peroxy radicals that can accelerate O3 production,

thus acting as a chemical amplifier (Jaeglé et al., 2001). Photolysis of formaldehyde by

(AX2-26b) was discussed in section AX2.2.5. Also of particular importance is the photolysis of

acetone (Blitz et al., 2004):

producing organic peroxy radicals that subsequently react with NO to produce O3. The

peroxyacetyl radical CH3C(O)OO can also react with NO2 to produce PAN, as discussed in

Section AX2.2.4. Photolysis of acetone are a minor but important source of HO2 radicals in the

upper troposphere (Arnold et al., 2004). 

AX2.2.10 Influence of Multiphase Chemical Processes

In addition to reactions occurring in the gas phase, reactions occurring on the surfaces of or

within cloud droplets and airborne particles also occur. Their collective surface area is huge,

implying that collisions with gas phase species occur on very short time scales. The integrated

aerosol surface area ranges from 4.2 × 10!7

 cm2/cm3 for clean continental conditions to

1.1 × 10!5 cm2/cm3 for urban average conditions (Whitby, 1978). There have been substantial

improvements in air quality especially in urban areas since the time these measurements were

made and so the U.S. urban values should be scaled downward by roughly a factor of two to

four. The resulting surface area is still substantial and the inferred collision time scale of a

gaseous molecule with a particle ranges from a few seconds or less to a few minutes. These

inferred time scales imply that heterogenous reactions will generally be much less important than

gas phase reactions for determining radical concentrations especially when reaction probabilities

much less then unity are considered. A large body of research has accumulated recently

(AX2-41)
AX2-46

regarding chemical processes in cloud droplets, snow and ice crystals, wet (deliquesced)

inorganic particles, mineral dust, carbon chain agglomerates and organic carbon-coated particles.

Jacob’s (2000) comprehensive review of the potential influences of clouds and aerosols on

tropospheric O3 cycling provides the starting point for this section. Updates to that review will

also be provided. Jacob’s review evaluates the literature available through late 1999, discusses

major areas of uncertainty, recommends experiments to reduce uncertainties, and (based on then

current information) recommends specific multiphase pathways that should be considered in

models of O3 cycling. In regard to the latter, Jacob’s recommendations should be viewed as

conservative. Specifically, only reasonably well constrained pathways supported by strong

observational evidence are recommended for inclusion in models. Several poorly resolved

and/or controversial pathways that may be significant in the ambient troposphere lack sufficient

constraints for reliable modeling. Some of these areas are discussed in more detail below. 

It should be noted at the outset that many of the studies described in this section involve either

aerosols that are not found commonly throughout the United States (e.g., marine aerosol) or

correspond to unaged particles (e.g., soot, mineral dust). In many areas of the United States,

particles accrete a layer of hydrated H2SO4 which will affect the nature of the multiphase

processes occurring on particle surfaces. 

Major conclusions from this review are summarized as follows (comments are given in

parentheses):

.HOx Chemistry

(1) Catalytic O3 loss via reaction of O2

!

 + O3(aq) in clouds appears to be inefficient.

(2) Aqueous-phase loss of HCHO in clouds appears to be negligible (see also Lelieveld and

Crutzen, 1990).

(3) Scavenging of HO2 by cloud droplets is significant and can be acceptably parameterized

with a reaction probability of (HO2 = 0.2, range 0.1 to 1, for HO2 6 0.5 H2O2. However,

this approach may overestimate HO2 uptake because the influence of HO2(aq) on the

magnitude (and direction) of the flux is ignored.

(4) The uptake of alkyl peroxy radicals by aerosols is probably negligible.

(5) Hydrolysis of CH3C(O)OO in aqueous aerosols may be important at night in the

presence of high PAN and aerosol surface area; (CH3C(O)OO = 4 × 10!3

 is recommended. 
AX2-47

.NOx Chemistry

(6) Hydrolysis of N2O5 to HNO3 in aqueous aerosols is important (Section AX2.2.4)

(and can be parameterized with (HNO3 = 0.01 to 0.1 [Schutze and Herrmann, 2002;

Hallquist et al., 2003]).

(7) Although the mechanism is uncertain, heterogeneous conversion of NO2 to HONO

on aerosol surfaces should be considered with (NO2

 = 10!4 (range 10!6 to 10!3) for

NO2 ÷ 0.5 HONO + 0.5 HNO3. (This reaction also occurs on snow, Crawford et al.,

2001). Wet and dry deposition sinks for HONO should also be considered although

scavenging by aerosols appears to be negligible. 

(8) There is no evidence for significant multiphase chemistry involving PAN.

(9) There is no evidence for significant conversion of HNO3 to NOx in aerosols. 

.Heterogeneous ozone loss

(10) There is no evidence for significant loss of O3 to aerosol surfaces (except during

dust storms observed in East Asia, e.g., Zhang and Carmichael, 1999).

.Halogen radical chemistry

(11) There is little justification for considering BrOx and ClOx chemistry (except perhaps

in limited areas of the United States and nearby coastal areas).

Most of the above conclusions remain valid but, as detailed below, some should be

qualified based on recently published findings and on reevaluation of results form earlier

investigations. 

AX2.2.10.1 HOx and Aerosols

Field measurements of HOx reviewed by Jacob (2000) correspond to regions with

relatively low aerosol concentrations (e.g., Mauna Loa [Cantrell et al., 1996]; rural Ontario

[Plummer et al., 1996]; and the upper troposphere [Jaeglé et al., 1999]). In all cases, however,

significant uptake of HO2 or HO2 + RO2 radicals by aerosols was inferred based on imbalances

between measured concentrations of peroxy radicals and photochemical models of gas-phase

chemistry. Laboratory studies using artificial aerosols (both deliquesced and solid) confirm

uptake but the actual mechanism remains unclear. Several investigations report significant HOx

and H2O2 production in cloud water (e.g., Anastasio et al., 1994). However the potential

importance of this source is considered unlikely because measurements in continental air show
AX2-48

no evidence of missing sources for HOx or H2O2. No investigations involving the potential

influences of marine aerosols as sources or sinks for HOx were considered in the above analysis. 

Relative to conservative seawater tracers such as Mg2+ and Na+, organic C associated with

sea-salt aerosols is typically enriched by 2 to 3 orders of magnitude in both polluted (e.g.,

Hoffman and Duce, 1976, 1977; Turekian et al., 2003) and remote regions (Chesselet et al.,

1981). This organic C originates from three major sources: 1) organic surfactants concentrated

from bulk seawater on walls of subsurface bubbles (Tseng et al., 1992), 2) the surface microlayer

of the ocean (Gershey, 1983), and 3) condensation of organic gases (Pun et al., 2000). 

Coagulation of chemically distinct aerosols (e.g., via cloud processing) may also contribute

under some conditions. 

Resolving chemical processes involving particles in the marine boundary layer (MBL) is

constrained by the relative scarcity of measurements of particulate organic carbon (POC)

(Penner, 1995) and its molecular composition (Saxena et al., 1995). In MBL regions impacted

by direct continental outflow, POC may constitute more that half of the total dry aerosol mass

(Hegg et al., 1997). Carbon isotopic compositions in the polluted North Atlantic MBL indicate

that, on average, 35% to 40% of POC originates from primary (direct injection) and secondary

(condensation of gases) marine sources (Turekian et al., 2003). 

The photolysis of dissolved organic compounds is a major source for OH, H2O2, and

C-centered radicals in both the surface ocean (e.g., Blough and Zepp, 1995; Blough, 1997;

Mopper and Kieber, 2000) and in marine aerosols (e.g., McDow et al., 1996). Relative to the

surface ocean, however, production rates in the aerosol are substantially greater per unit volume

because organic matter is highly enriched (Turekian et al., 2003) and aerosol pH is much lower

(Keene et al., 2002). Lower pHs increase rates of many reactions including acid-catalyzed

pathways such as the breakdown of the HOCl-

 radical (King et al., 1995), the formation of H2O2

from the photolysis of phenolic compounds (Anastasio et al., 1997), and the photolysis of organic

acids. 

To provide a semi-quantitative context for the potential magnitude of this source, we

assume a midday OH production rate in surface seawater of 10!11 M sec!1

 (Zhou and Mopper,

1990) and a dissolved organic carbon enrichment of 2 to 3 orders of magnitude in sea-salt

aerosols. This yields an estimated OH production rate in fresh (alkaline) sea-salt aerosols of 10!9

to 10!8 M sec!1. As discussed above, rapid (seconds to minutes) acidification of the aerosol
AX2-49

should substantially enhance these production rates. Consequently, the midday OH production

rates from marine-derived organic matter in acidified sea-salt aerosols may rival or perhaps

exceed midday OH scavenging rates from the gas phase (approximately 10!7

 M sec!1; [Chameides

and Stelson, 1992]). Scavenging is the only significant source for OH in acidified sea-salt

aerosols considered by many current models. 

Limited experimental evidence indicates that these pathways are important sources of HOx

and ROx in marine air and possibly in coastal cities. For example, the absorption of solar energy

by organic species dissolved in cloud water (e.g., Faust et al., 1993; Anastasio et al., 1997) and in

deliquesced sea-salt aerosols (Anastasio et al., 1999) produces OH, HO2, and H2O2. In addition,

Fe(III) complexation by oxalate and similar ligands to metal such as iron can greatly enhance

radical production through ligand to metal charge transfer reactions (Faust, 1994; Hoigné et al.,

1994). Oxalate and other dicarboxylic anions are ubiquitous components of MBL aerosols in

both polluted (e.g., Turekian et al., 2003) and remote regions (Kawamura et al., 1996). 

Substantial evidence exists for washout of peroxy radicals. Near solar noon, mixing ratios

of total HOx plus ROx radicals generally fall in the 50 ppt range, but during periods of rain these

values dropped to below the detection limit of 3 to 5 ppt (Andrés Hernández et al., 2001; Burkert

et al., 2001a,b, 2003). Such low concentrations cannot be explained by loss of actinic radiation,

because nighttime radical mixing ratios were higher. 

Burkert et al. (2003) investigated the diurnal behavior of the trace gases and peroxy radicals

in the clean and polluted MBL by comparing observations to a time dependant, zero-dimensional

chemical model. They identified significant differences between the diurnal behavior of RO2

*

derived from the model and that observed possibly attributable to multiphase chemistry. The

measured HCHO concentrations differed from the model results and were best explained by

reactions involving low levels of Cl. 

Finally, photolytic NO3

!

 reduction is important in the surface ocean (Zafiriou and True,

1979) and could contribute to OH production in sea-salt aerosols. Because of the

pH-dependence of HNO3 phase partitioning, most total nitrate (HNO3 + particulate NO3

!

) in

marine air is associated with sea salt (e.g., Huebert et al., 1996; Erickson et al., 1999). At high

mM concentrations of NO3

!

 in sea-salt aerosols under moderately polluted conditions (e.g.,

Keene et al., 2002) and with quantum yields for OH production of approximately 1% (Jankowski

et al., 2000), this pathway would be similar in magnitude to that associated with scavenging
AX2-50

from the gas phase and with photolysis of dissolved organics. Experimental manipulations of

marine aerosols sampled under relatively clean conditions on the California coast confirms that

this pathway is a major source for OH in sea-salt solutions (Anastasio et al., 1999). 

Although largely unexplored, the potential influences of these poorly characterized radical

sources on O3 cycling in marine air are probably significant. At minimum, the substantial

inferred concentrations of HO2 in aerosol solutions would diminish and perhaps reverse HO2

scavenging by marine aerosols and thereby increase O3 production relative to models based on

Jacob’s (2000) recommended reaction probability. 

AX2.2.10.2 NOx Chemistry

Jacob (2000) recommended as a best estimate, (N2O5

 = 0.1 for the reaction probability

of N2O5 on aqueous aerosol surfaces with conversion to HNO3. Recent laboratory studies on

sulfate and organic aerosols indicates that this reaction probability should be revised downward,

to a range 0.01-0.05 (Kane et al., 2001; Hallquist et al., 2003; Thornton et al., 2003). Tie et al.

(2003) found that a value of 0.04 in their global model gave the best simulation of observed NOx

concentrations over the Arctic in winter. A decrease in N2O5 slows down the removal of NOx

and thus increases O3 production. Based on the consistency between measurements of NOy

partitioning and gas-phase models, Jacob (2000) considers it unlikely that significant HNO3 is

recycled to NOx in the lower troposphere. However, only one of the reviewed studies (Schultz

et al., 2000) was conducted in the marine troposphere and none were conducted in the MBL. 

An investigation over the equatorial Pacific reported discrepancies between observations and

theory (Singh et al., 1996b) that might be explained by HNO3 recycling. It is important to

recognize that both Schultz et al. (2000) and Singh et al. (1996b) involved aircraft sampling

which, in the MBL, significantly under represents sea-salt aerosols and thus most total NO3

(HNO3 + NO3

!

) and large fractions of NOy in marine air (e.g., Huebert et al., 1996). 

Consequently, some caution is warranted when interpreting constituent ratios and NOy budgets

based on such data. 

Recent work in the Arctic has quantified significant photochemical recycling of NO3

!

to NOx and perturbations of OH chemistry in snow (Honrath et al., 2000; Dibb et al., 2002;

Domine and Shepson, 2002), which suggests the possibility of similar multiphase pathways

occurring in aerosols. As mentioned above, recent evidence also indicates that NO3

!

 is
AX2-51

photolytically reduced to NO2

!

 (Zafariou and True, 1979) in acidic sea-salt solutions (Anastasio

et al., 1999). Further photolytic reduction of NO2

-

 to NO (Zafariou and True, 1979) could

provide a possible mechanism for HNO3 recycling. Early experiments reported production

of NOx during the irradiation of artificial seawater concentrates containing NO3

!

 (Petriconi and

Papee, 1972). Based on the above, we believe that HNO3 recycling in sea-salt aerosols is

potentially important and warrants further investigation. Other possible recycling pathways

involving highly acidic aerosol solutions and soot are reviewed by Jacob (2000). 

Ammann et al. (1998) reported the efficient conversion of NO2 to HONO on fresh soot

particles in the presence of water. They suggest that interaction between NO2 and soot particles

may account for high mixing ratios of HONO observed in urban environments. Conversion

of NO2 to HONO and subsequent photolysis to NO + OH would constitute an NOx-catalyzed O3

sink involving snow. High concentrations of HONO can lead to the rapid growth in OH

concentrations shortly after sunrise, giving a “jump start” to photochemical smog formation. 

Prolonged exposure to ambient oxidizing agents appears to deactivate this process. Broske et al.

(2003) studied the interaction of NO2 on secondary organic aerosols and concluded that the

uptake coefficients were too low for this reaction to be an important source of HONO in the

troposphere. 

Choi and Leu (1998) evaluated the interactions of nitric acid on a model black carbon soot

(FW2), graphite, hexane and kerosene soot. They found that HNO3 decomposed to NO2

and H2O at higher nitric acid surface coverages, i.e., P(HNO3) > = 10!4 Torr. None of the soot

models used were reactive at low nitric acid coverages, at P(HNO3) = 5 × 10!7

 Torr or at lower

temperatures (220K). They conclude that it is unlikely that aircraft soot in the upper

troposphere/lower stratosphere reduces HNO3. 

Heterogeneous production on soot at night is believed to be the mechanism by which

HONO accumulates to provide an early morning source of HOx in high NOx environments

(Harrison et al., 1996; Jacob, 2000). HONO has been frequently observed to accumulate to

levels of several ppb overnight, and has been attributed to soot chemistry (Harris et al., 1982;

Calvert et al., 1994; Jacob, 2000). 

Longfellow et al. (1999) observed the formation of HONO when methane, propane, hexane

and kerosene soots were exposed to NO2. They estimate that this reaction may account for some

part of the unexplained high levels of HONO observed in urban areas. They comment that
AX2-52

without details about the surface area, porosity and amount of soot available for this reaction,

reactive uptake values cannot reliably be estimated. They comment that soot and NO2 are

produced in close proximity during combustion, and that large quantities of HONO have been

observed in aircraft plumes. 

Saathoff et al. (2001) studied the heterogeneous loss of NO2, HNO3, NO3/N2O5,

HO2/HO2NO2 on soot aerosol using a large aerosol chamber. Reaction periods of up to several

days were monitored and results used to fit a detailed model. They derived reaction probabilities

at 294 K and 50% RH for NO2, NO3, HO2 and HO2NO2 deposition to soot, HNO3 reduction

to NO2, and N2O5 hydrolysis. When these probabilities were included in photochemical box

model calculations of a 4-day smog event, the only noteworthy influence of soot was a 10%

reduction in the second day O3 maximum, for a soot loading of 20 μg m-3, i.e., a factor of 2 to

10 times observed black carbon loadings seen during extreme U.S. urban pollution events,

although such concentrations are observed routinely in the developing world. 

Muñoz and Rossi (2002) conducted Knudsen cell studies of HNO3 uptake on black and

grey decane soot produced in lean and rich flames, respectively. They observed HONO as the

main species released following nitric acid uptake on grey soot, and NO and traces of NO2 from

black soot. They conclude that these reactions would only have relevance in special situations in

urban settings where soot and HNO3 are present in high concentrations simultaneously. 

AX2.2.10.3 Halogen Radical Chemistry

Barrie et al. (1988) first suggested that halogen chemistry on snow surfaces in the Arctic

could lead to BrOx formation and subsequent O3 destruction. More recent work suggests that

halogen radical reactions may influence O3 chemistry in mid latitudes as well. 

The weight of available evidence supports the hypothesis that halogen radical chemistry

significantly influences O3 cycling over much of the marine boundary layer at lower latitudes

and in at least some other regions of the troposphere. However, proposed chemical mechanisms

are associated with substantial uncertainties and, based on available information, it appears

unlikely that a simple parameterization (analogous to those recommended by Jacob (2000) for

other multiphase transformations) would adequately capture major features of the underlying

transformations. 
AX2-53

Most of the Cl and Br in the marine boundary layer are produced in association with

sea-salt aerosols by wind stress at the ocean surface (e.g., Gong et al., 1997). Fresh aerosols

rapidly dehydrate towards equilibrium with ambient water vapor and undergo other chemical

processes involving the scavenging of reactive gases, aqueous-phase transformations, and

volatilization of products. Many of these processes are strongly pH-dependent (Keene et al.,

1998). Throughout most of the marine boundary layer, sea-salt alkalinity is tritrated rapidly

(seconds to minutes) by ambient acids (Chameides and Stelson, 1992; Erickson et al., 1999) and,

under a given set of conditions, the pHs of the super-μm, sea-salt size fractions are buffered to

similar values via HCl phase partitioning (Keene and Savoie, 1998; 1999; Keene et al., 2002). 

Model calculations based on the autocatalytic halogen activation mechanism (Vogt et al.,

1996; Keene et al., 1998; Sander et al., 1999; von Glasow et al., 2002a,b; Pszenny et al., 2004;

Sander et al., 2003) predict that most particulate Br!

 associated with acidified sea-salt aerosol

would react to form Br2 and BrCl, which subsequently volatilize and photolyze in sunlight to

produce atomic Br and Cl. Most Br atoms recycle in the gas phase via 

and thereby catalytically destroy O3, analogous to Br cycling in the stratosphere (e.g.,

Mozurkewitch, 1995; Sander and Crutzen, 1996). Side reactions with HCHO and other

compounds produce HBr, which is either scavenged and recycled through the aerosol or lost to

the surface via wet and dry deposition (Dickerson et al., 1999). 

Cl-radical chemistry influences O3 in two ways (e.g., Pszenny et al., 1993). Some atomic

Cl in marine air reacts directly with O3 initiating a catalytic sequence analogous to that of Br

(AX2-42 through AX2-44 above). However, most atomic Cl in the MBL reacts with

hydrocarbons (which, relative to the stratosphere, are present at high concentrations) via

hydrogen extraction to form HCl vapor. The enhanced supply of odd hydrogen radicals from

(AX2-42)

(AX2-43)

(AX2-44)
AX2-54

hydrocarbon oxidation leads to O3 production in the presence of sufficient NOx. Thus, Cl

chemistry represents a modest net sink for O3 when NOx is less than 20 pptv and a net source at

higher NOx. Although available evidence suggest that significant Cl-radical chemistry occurs in

clean marine air, its net influence on O3 appears to be small relative to that of Br and I. 

In addition to Br and Cl, several lines of recent evidence suggests that an autocatalytic

cycle also sustains I-radical chemistry leading to significant net O3 destruction in marine air

(Vogt et al., 1996, 1999; von Glasow et al., 2002a). The cycle is initiated by photolysis of

organoiodine compounds emitted from the ocean surface to generate atomic I (Carpenter et al.,

1999). Iodine atoms react almost exclusively with O3 to form IO. Most IO photodissociates in

sunlight to generate I and atomic O, which rapidly recombines with O2 to form O3. 

Consequently, this cycle has no net effect on O3 (Stutz et al., 1999). However, alternative

reaction pathways analogous to reactions AX2-42 through AX2-44 above lead to catalytic O3

destruction. Model calculations suggest that HOI recycles via acid-catalyzed aerosol scavenging

to form ICl and IBr, which subsequently volatilize and photolyze to form halogen atoms. The

net effect of this multiphase pathway is to increase concentrations of volatile reactive I. The self

reaction of IO to form I and OIO may further enhance O3 destruction (Cox et al., 1999;

Ashworth et al., 2002). IO also reacts with NO2 to form INO3, which can be scavenged by

aqueous aerosols. This pathway has been suggested as a potentially important sink for NOx in

the remote MBL and would, thus, contribute indirectly to net O3 destruction (McFiggans et al.,

2000). 

Various lines of observational evidence support aspects of the above scenarios. Most

measurements of particulate Br in marine air reveal large depletions relative to conservative seasalt tracers (e.g., Sander et al., 2003) and, because HBr is highly soluble in acidic solution, these

deficits cannot be explained by simple acid-displacement reactions (e.g., Ayers et al., 1999). 

Observed Br depletions are generally consistent with predictions based on the halogen activation

mechanism. In contrast, available, albeit limited, data indicate that I is highly enriched in marine

aerosols relative to bulk seawater (e.g., Sturges and Barrie, 1988), which indicates active

multiphase iodine chemistry. 

Direct measurements of BrO in marine air by differential optical absorption spectroscopy

(DOAS) reveal mixing ratios that are near or below analytical detection limits of about 1 to 3 ppt

(Hönninger, 1999; Pszenny et al., 2003; Leser et al., 2003) but within the range of model
AX2-55

predictions. Column-integrated DOAS observations from space reveal substantial mixing ratios

of tropospheric BrO (e.g., Wagner and Platt, 1998). Although the relative amounts in the MBL

cannot be resolved, these data strongly suggest active destruction of tropospheric O3 via the

reaction sequence of AX2-42 through AX2-44. Similarly, measurements of IO (McFiggans

et al., 2000) and OIO (Allan et al., 2001) indicate active O3 destruction by an analogous pathway

involving atomic I. In addition, anticorrelations on diurnal time scales between total volatile

inorganic Br and particulate Br and between volatile inorganic I and particulate I have been

reported (e.g., Rancher and Kritz, 1980; Pszenny et al., 2004). Although the lack of speciation

precludes unambiguous interpretation, these relationships are also consistent with predictions

based on the halogen activation mechanism. 

Large diurnal variabilities in O3 measured over the remote subtropical Atlantic and Indian

Oceans (Dickerson et al., 1999; Burkert et al., 2003) and early morning depletions of O3

observed in the remote temperate MBL (Galbally et al., 2000) indicate that only about half of the

inferred O3 destruction in the MBL can be explained by conventional HOx/NOx chemistry. 

Model calculations suggest that Br! and I! radical chemistry could account for a “missing” O3

sink of this magnitude (Dickerson et al., 1999; Stutz et al., 1999; McFiggans et al., 2000; von

Glasow et al., 2002b). In addition to the pathway for O3 destruction given by R AX2-39 to R

AX2-41, in areas with high concentrations of halogen radicals the following generic loss

pathways for O3 can occur in the Arctic at the onset of spring and also over salt flats near the

Dead Sea (Hebestreit et al., 1999) and the Great Salt Lake (Stutz et al., 2002) analogous to their

occurrence in the lower stratosphere (Yung et al., 1980). 

Note that the self reaction of ClO radicals is likely to be negligible in the troposphere. There are

three major reaction pathways involved in reaction AX2-47. Short-lived radical species are

(AX2-45)

(AX2-46)

(AX2-47)

(AX2-48)
AX2-56

produced. These radicals rapidly react to yield monoatomic halogen radicals. In contrast to the

situation in marine air, where DOAS measurements indicate BrO concentrations of 1 to 3 ppt,

Stutz et al. (2002) found peak BrO concentrations of about 6 ppt and peak ClO concentrations of

about 15 ppt. They also derived a correlation coefficient of !0.92 between BrO and O3 but much

smaller values of r between ClO and O3. Stutz et al. attributed the source of the reactive

halogens to concentrated high molality solutions or crystalline salt around salt lakes, conditions

that do not otherwise occur in more dilute or ocean salt water. They also suggest that halogens

may be released from saline soils. The inferred atmospheric concentrations of Cl are about

105

/cm3, or about a factor of 100 higher than found in the marine boundary layer by Rudolph

et al. (1997) indicating that, under these conditions, the Cl initiated oxidation of hydrocarbons

could be substantial. 

Most of the well-established multiphase reactions tend to reduce the rate of O3 formation in

the polluted troposphere. Direct reactions of O3 and atmospheric particles appears to be too slow

to reduce smog significantly. Removal of HO2 onto hydrated particles will decrease the

production of O3 by the reaction of HO2 with NO. The uptake of NO2 and HNO3 will also result

in the production of less O3. Conditions leading to high concentrations of Br, Cl, and I radicals

can lead to O3 loss. The oxidation of hydrocarbons (especially alkanes) by Cl radicals,

in contrast, may lead to the rapid formation of peroxy radicals and faster smog production in

coastal environments where conditions are favorable for the release of gaseous Cl from the

marine aerosol. There is still considerable uncertainty regarding the role of multiphase processes

in tropospheric photochemistry and so results should be viewed with caution and an appreciation

of their potential limitations. 

AX2.2.10.4 Reactions on the Surfaces of Crustal Particles

Field studies have shown that O3 levels are reduced in plumes containing high particle

concentrations (e.g., DeReus et al.; 2000; Berkowitz et al., 2001; Gaffney et al., 2002). 

Laboratory studies of the uptake of O3 on untreated mineral surfaces (Hanisch and Crowley,

2003; Michel et al., 2002, 2003) have shown that O3 is lost by reaction on these surfaces and this

loss is catalytic. Values of ( of 1.2 ± 0.4 × 10!4 were found for reactive uptake on "-Al2O3

and 5 ± 1 × 10!5 for reactive uptake on SiO2 surfaces. Usher et al. (2003) found mixed behavior

for O3 uptake on coated surfaces with respect to untreated surfaces. They found that ( drops 
AX2-57

from 1.2 ± 0.4 × 10!4

 to 3.4 ± 0.6 × 10!5 when "-Al2O3 surfaces are coated with NO3 derived

from HNO3, whereas they found that ( increases to 1.6 ± 0.2 × 10!4 after these surfaces have

been pretreated with SO2. Usher et al. also pretreated surfaces of SiO2 with either a C8-alkene or

a C8-alkane terminated organotrichlorosilane. They found that ( increased to 7 ± 2 × 10!5

 in the

case of treatment with the alkene, but that it decreased to 3 ± 1 × 10!5

 for treatment with the

alkane. Usher et al. (2003) suggested, on the basis of these results that mineral dust particles

coated with nitrates or alkanes will affect O3 less than dust particles that have accumulated

coatings of sulfite or alkenes. These studies indicate the importance of aging of airborne

particles on their ability to take up atmospheric gases. Reactions such as these may also be

responsible for O3 depletions observed in dust clouds transiting the Pacific Ocean. 

Underwood et al. (2001) studied the uptake of NO2 and HNO3 on the surfaces of dry

mineral oxides (containing Al, Ca, Fe, Mg, Si and Ti) and naturally occurring mineral dust.

A wide range of values of ((NO2) were found, ranging from < 4 × 10-10 for SiO2 to 2 × 10!5

 for

CaO, with most other values ~10!6

. Values of ( for Chinese loess and Saharan dust were also of

the order of 10!6. They found that as the reaction of NO2 proceeds on the surfaces that reduction

to NO occurs. They recommended a value of ( for HNO3 of about 1 × 10!3

. Not surprisingly,

the values of ( increased from those given above if the surfaces were wetted. Underwood et al.

(2001) also suggested that the uptake of NO2 was likely to be only of marginal importance but

that uptake of HNO3 could be of significance for photochemical oxidant cycles. 

Li et al. (2001) examined the uptake of acetaldehyde, acetone and propionaldehyde on the

same mineral oxide surfaces listed above. They found that these compounds weakly and

reversibly adsorb on SiO2 surfaces. However, on the other oxide surfaces, they irreversibly

adsorb and can form larger compounds. They found values of ( ranging from 10!6

 to 10!4. 

These reactions may reduce O3 production efficiency in areas of high mineral dust concentration

such as the American Southwest or in eastern Asia as noted earlier. 

AX2.2.10.5 Reactions on the Surfaces of Aqueous H2SO4 Solutions

The most recent evaluation of Photochemical and Chemical Data by the Jet Propulsion

Laboratory (Jet Propulsion Laboratory, 2003) includes recommendations for uptake coefficients

of various substances on a variety of surfaces including aqueous H2SO4 solutions. Although

much of the data evaluated have been obtained mainly for stratospheric applications, there are
AX2-58

studies in which the range of environmental parameters is compatible with those found in the

troposphere. In particular, the uptake of N2O5 on the surface of aqueous H2SO4 solutions has

been examined over a wide range of values. Typical values of ( are of the order of 0.1 (e.g., Jet

Propulsion Laboratory, 2003). Values of ( for NO2 are much lower (5 × 10-7 to within a factor

of three) and thus the uptake of NO2 on the surface of aqueous H2SO4 solutions is unlikely to be

of importance for oxidant cycles. The available data indicate that uptake of OH and HO2

radicals could be significant under ambient conditions with values of ( of the order of 0.1 or

higher for OH, and perhaps similar values for HO2. 

AX2.2.10.6 Oxidant Formation in Particles

Water is a major component of submicron particles in the atmosphere. However,

photochemical reactions in particles have not been studied to the same extent as they have in

hydrometeors (e.g., Lelieveld and Crutzen, 1991). Friedlander and Yeh (1998) point out

that H2O2 and hydroxymethylhydroperoxide (HOCH2OOH) are especially likely to be found in

the aqueous component of atmospheric particles, based on observed gas-phase concentrations

and Henry’s law solubility data; the concentrations in particles could be higher if the condensed

hydroperoxides form peroxyhydrate complexes (Wexler and Sarangapani, 1998). Laboratory

studies have found that UV irradiation of dissolved organic carbon (DOC) in collected

cloudwater samples is a source of free radicals to the aqueous phase (Faust et al., 1992, 1993)

but the mechanisms involved and the atmospheric fate of these radicals are unclear. Chemical

reactions involving dissolved transition metal ions could also provide significant sources of

radicals in particles (Jacob, 2000). However, only about 10 to 15% of the mass of organic

compounds in particles are quantified typically, but many of the compounds, in particular

aldehydes, could photolyze to produce free radicals. There are three basic mechanisms for the

formation of SOA (Pandis et al., 1992; Seinfeld and Pankow, 2003). These are (1) condensation

of oxidized end-products of photochemical reactions (e.g., ketones, aldehydes, organic acids, and

hydroperoxides), (2) adsorption of semivolatile organic compounds (e.g., polycyclic aromatic

hydrocarbons) onto existing organic particles, and (3) dissolution of water-soluble gases that can

then undergo subsequent reactions in particles (e.g., aldehydes). The first and third mechanisms

are expected to be of major importance during the summer when photochemistry is at its peak. 

Information about the chemistry of formation of secondary organic aerosol (SOA) was reviewed
AX2-59

in Section 3.3.1 and available information about the composition of organic compounds in

particles was summarized in Appendix 3C of the latest PM AQCD (U.S. Environmental

Protection Agency, 2004). It should be noted that reactive oxygen species (ROS) are also

formed during the production of SOA. In addition, polymerization of the products of the

reaction of "-pinene with O3 occurs (Tolocka et al., 2004).

Recent measurements of aerosol-phase ROS in Rubidoux, CA and New York City have

revealed relatively high concentrations, of the order of 5 to 6 × 10!7 in Rubidoux and 1 × 10!7 M

m!3 in New York City, expressed as equivalent H2O2 (Venkatachari et al., 2005a,b). The ROS

were found in particles of all sizes, with particularly high concentrations in the ultrafine range. 

However, this finding could result from the condensation of vapors onto particles occurring

during adiabatic expansion in the nano stages of the sampler. A weak correlation was found

with O3, but large ROS concentrations were still found at night and in winter. The composition

and sources of the ROS are not clear. Millimolar concentrations of hydroperoxides, as estimated

by Friedlander and Yeh (1998), would contribute only 10!12 M m!3 based on a typical liquid

water volume fraction in air of 10!9. Formation of peroxyhydrates would lead to higher values

but would have to be very large to account for the ROS observations. Ozone and PAN are

orders of magnitude less water-soluble than the hydroperoxides (Jacob, 2000) and would not

contribute significantly to the ROS. Radical oxidants (e.g., OH or the superoxide ion O2

!

) do not

seem to be present in sufficient abundance in the atmosphere to possibly account for the ROS

(Jacob, 2000). Low-volatility organic peroxides produced from the oxidation of large

substituted organic compounds could possibly make a major contribution. Formation of these

peroxides in the aerosol phase could be facilitated by photochemical reactions of dissolved

organic components (Anastasio et al., 1997) and by reactions of transition metals (Jacob, 2000). 

Transition metals participate in the Haber-Weiss set of reactions, including Fenton’s reaction,

generating free radicals from hydrogen peroxide even in the dark. ROS would also be formed in

the reaction of isoprene with O3 (Claeys et al., 2004b). 

Reactions of ozone with monoterpenes have been shown to produce oxidants in the aerosol

phase. Docherty et al. (2005) found evidence for the substantial production of organic

hydroperoxides in SOA resulting from the reaction of monoterpenes with O3. Analysis of the

SOA formed in their environmental chamber indicated the SOA was mainly organic

hydroperoxides. In particular, they obtained yields of 47% and 85% of organic peroxides from
AX2-60

the oxidation of "- and $-pinene. The hydroperoxides then react with aldehydes in particles to

form peroxyhemiacetals, which can either rearrange to form other compounds such as alcohols,

esters, and acids or revert back to the hydroperoxides. The aldehydes may be produced in

addition to the hydroperoxides during the oxidation of the monoterpenes. Monoterpenes also

react with OH radicals resulting, however, in the production of more lower molecular weight

products than in their reaction with O3. Bonn et al. (2004) estimated that hydroperoxides lead to

63% of global SOA formation from the oxidation of terpenes. The oxidation of anthropogenic

aromatic hydrocarbons by OH radicals may also produce organic hydroperoxides in SOA

(Johnson et al., 2004). Although the results of chamber and modeling studies indicate

substantial production of organic hydroperoxides, it should be noted that data for organic

hydroperoxides in ambient aerosol samples are sparse. 

AX2.2.10.7 Ozone Reaction Indoors

Ozone chemical reactions indoors are analogous to those occurring in ambient air. Ozone

reacts with unsaturated VOCs in the indoor environment, primarily terpenes or terpene-related

compounds from cleaning products, air fresheners, and wood products. The reactions are

dependent on the O3 indoor concentration, the indoor temperature and, in most cases, the air

exchange rate/ventilation rate. Some of the reaction products may more negatively impact

human health and artifacts in the indoor environment than their precursors (Wolkoff et al., 1999;

Wilkins et al., 2001; Weschler et al., 1992; Weschler and Shields, 1997; Rohr et al., 2002;

Nøjgaard et al., 2005). Primary reaction products are Criegee biradicals, nitrate radicals, and

peroxyacetyl radicals. Secondary reaction products are hydroxy, alkyl, alkylperoxy,

hydroperoxy, and alkoxy radicals. Reactions with alkenes can produce aldehydes, ketones, and

organic acids (Weschler and Shields, 2000; Weschler et al., 1992).

AX2.3 PHYSICAL PROCESSES INFLUENCING THE ABUNDANCE 

OF OZONE

The abundance and distribution of O3 in the atmosphere is determined by complex

interactions between meteorology and chemistry. This section will address these interactions,

based mainly on the results of field observations. The importance of a number of transport 
AX2-61

mechanisms, whose understanding has undergone significant advances since the last AQCD

for O3, will be discussed in this section. 

Major episodes of high O3 concentrations in the eastern United States and in Europe are

associated with slow moving, high pressure systems. High pressure systems during the warmer

seasons are associated with the sinking of air, resulting in warm, generally cloudless conditions,

with light winds. The sinking of air results in the development of stable conditions near the

surface which inhibit or reduce the vertical mixing of O3 precursors. The combination of

inhibited vertical mixing and light winds minimizes the dispersal of pollutants emitted in urban

areas, allowing their concentrations to build up. Photochemical activity involving these

precursors is enhanced because of higher temperatures and the availability of sunlight. In the

eastern United States, high O3 concentrations during a large scale episode can extend over a

hundred thousand square kilometers for several days. These conditions have been described in

greater detail in AQCD 96. The transport of pollutants downwind of major urban centers is

characterized by the development of urban plumes. However, the presence of mountain barriers

can limit mixing as in Los Angeles and Mexico City and will result in even longer periods and a

higher frequency of days with high O3 concentrations. Ozone concentrations in southern urban

areas, such as Houston, TX and Atlanta, GA tend to follow this pattern and they tend to decrease

with increasing wind speed. In northern cities, like Chicago, IL; New York, NY; and Boston,

MA the average O3 concentrations over the metropolitan areas increase with wind speed

indicating that transport of O3 and its precursors from upwind areas is important (Husar and

Renard, 1998; Schichtel and Husar, 2001). 

Aircraft observations indicate that there can be substantial differences in mixing ratios of

key species between the surface and the atmosphere above (Fehsenfeld et al., 1996a; Berkowitz

and Shaw, 1997). Convective processes and small scale turbulence transport O3 and other

pollutants both upward and downward throughout the planetary boundary layer and the free

troposphere. Ozone and its precursors were found to be transported vertically by convection into

the upper part of the mixed layer on one day, then transported overnight as a layer of elevated

mixing ratios and then entrained into a growing convective boundary layer downwind and

brought back down to the surface. High concentrations of O3 showing large diurnal variations at

the surface in southern New England were associated with the presence of such layers

(Berkowitz et al., 1998). Because of wind shear, winds several hundred meters above the ground
AX2-62

can bring pollutants from the west, even though surface winds are from the southwest during

periods of high O3 in the eastern United States (Blumenthal et al., 1997). Low level nocturnal

jets can also transport pollutants hundreds of kilometers. Turbulence associated with them can

bring these pollutants to the surface and in many locations result in secondary O3 maxima in the

early morning (Corsmeier et al., 1997). Based on analysis of the output of model studies

conducted by Kasibhatla and Chameides (2000), Hanna et al. (2001) concluded that O3 can be

transported over thousands of kilometers in the upper boundary layer of the eastern half of the

United States during specific O3 episodes. 

Stratospheric-tropospheric exchange (STE) will be discussed in Section AX2.3.1. The

vertical redistribution of O3 and other pollutants by deep, or penetrating convection is discussed

in Section AX2.3.2. The potential importance of transport of O3 and precursors by low-level jets

is the topic of Section AX2.3.3. Issues related to the transport of O3 from North America are

presented in Section AX2.3.4. Relations of O3 to solar ultraviolet radiation and temperature will

then be discussed in Section AX2.3.5. 

AX2.3.1 Stratospheric-Tropospheric Ozone Exchange (STE)

In the stratosphere, O3 formation is initiated by the photodissociation of molecular

oxygen (O2) by solar ultraviolet radiation at wavelengths less than 242 nm. Almost all of this

radiation is absorbed in the stratosphere (except for regions near the tropical tropopause),

preventing this mechanism from occurring in the troposphere. Some of the O3 in the

stratosphere is transported downward into the troposphere. The potential importance of this

source of tropospheric O3 has been recognized since the early work of Regener (1941), as cited

by Junge (1963). Stratospheric-tropospheric exchange (STE) of O3 and stratospheric

radionuclides produced by the nuclear weapons tests of the 1960s is at a maximum during late

winter and early spring (e.g., Ludwig et al., 1977). Since AQCD 96 on O3 substantial new

information from numerical models, field experiments and satellite-based observations has

become available. The following sections outline the basic atmospheric dynamics and

thermodynamics of stratosphere/troposphere exchange and review these new developments. 

There are several important mechanisms for injecting stratospheric O3 into the troposphere,

they include tropopause folds (Reed, 1955; Danielsen, 1968), cutoff lows (Price and Vaughan,

1993), clear air turbulence, mesoscale convective complexes and thunderstorms, breaking
AX2-63

gravity waves (Poulida et al., 1996; Langford and Reid, 1998; Stohl et al., 2003) and streamers. 

Streamers are dry, stratospheric intrusions visible in satellite water vapor imagery that are

sheared into long filamentary structures that often roll into vortices and exhibit visible evidence

of the irreversible mixing of moist subtropical tropospheric and dry polar stratospheric air

(Appenzeller et al., 1996; Wimmers et al., 2003). They are often present at a scale that eludes

capture in large scale dynamical models of the atmosphere that cannot resolve features less than

1 degree (~100 km). Empirical evidence for stratospheric intrusions comes from observations of

indicators of stratospheric air in the troposphere. These indicators include high potential

vorticity, low water vapor mixing ratios, high potential temperature, enhancements in the ratio

of 7

Be to 10Be in tropospheric aerosols, as well as enhancements in O3 mixing ratios and total

column amounts. These quantities can be observed with in situ aircraft and balloons, as well as

remotely sensed from aircraft and ground-based lidars and both geostationary and polar (low

earth orbiting) space platforms. 

The exchange of O3 between the stratosphere and the troposphere in middle latitudes

occurs to a major extent by tropopause folding events (Reiter, 1963, 1975; Reiter and Mahlman,

1965; Danielsen, 1968, 1980; Danielsen and Mohnen, 1977). The term, tropopause folding is

used to describe a process in which the tropopause intrudes deeply into the troposphere along a

sloping frontal zone bringing air from the lower stratosphere with it. Tropopause folds occur

with the formation of upper level fronts associated with transverse circulations that develop

around the core of the polar jet stream. South of the jet stream core, the tropopause is higher

than to the north of it. The tropopause can be imagined as wrapping around the jet stream core

and folding beneath it and extending into the troposphere (cf., Figure AX2-7a). Although drawn

as a heavy solid line, the tropopause should not be imagined as a material surface, through which

there is no exchange. Significant intrusions of stratospheric air occur in “ribbons” ~200 to 1000

km in length, 100 to 300 km wide and about 1 to 4 km thick (Hoskins, 1972; Wimmers et al.,

2003). These events occur throughout the year and their location follows the seasonal

displacement of the polar jet stream. 

The seasonal cycle of O3 exchange from the stratosphere into the troposphere is not caused

by a peak in the seasonal cycle of upper tropospheric cyclone activity. Instead, it is related to the

large scale pattern of tracer transport in the stratosphere. During winter in the Northern

Hemisphere, there is a maximum in the poleward, downward transport of mass, which moves O3
AX2-64

from the tropical upper stratosphere to the lower stratosphere of the polar- and midlatitudes. 

This global scale pattern is controlled by the upward propagation of large-scale and small-scale

waves generated in the troposphere. As the energy from these disturbances dissipates, it drives

this stratosphere circulation. As a result of this process, there is a springtime maximum in the

total column abundance of O3 over the poles. The concentrations of O3 (and other trace

Figure AX2-7a. Cross section through a tropopause folding event on March 13, 1978 at

0000 GMT. Potential temperatures (K) are represented by thin solid

lines. Wind speeds (m s!1) are given by thin dashed lines. The hatched

area near the center of the figure indicates the location of the jet stream

core. The tropopause defined by a potential vorticity of 100 × 10!7

 K

mb!1

 s!1 is shown as the heavy solid line. The two Sabreliner flight tracks

through this cross section are shown as a heavy solid line with filled

arrows and heavy dashed line with open arrows. Longitude is shown

along the x-axis . Upper air soundings were taken at Vandenberg AFB,

CA (VBG); San Diego, CA (SAN); Winnemucca, NV (UCC); and Ely, NV

(ELY).

Source: Adapted from Shapiro (1980).
AX2-65

substances) build up in the lower stratosphere until their downward fluxes into the lower

stratosphere are matched by increased fluxes into the troposphere. Thus, there would be a

springtime maximum in the flux of O3 into the troposphere even if the flux of stratospheric air

through the tropopause by tropopause folding remained constant throughout the year (Holton

et al., 1995). Indeed, cyclonic activity in the upper troposphere is active throughout the entire

year in transporting air from the lower stratosphere into the troposphere (Mahlman, 1997). 

Oltmans et al. (1996) and Moody et al. (1996) provide evidence that stratospheric intrusions

contribute to the O3 abundance in the upper troposphere over the North Atlantic even during

the summer. 

There are a number of techniques that have been used to quantify the amount of O3 in the

free troposphere or even the amount of O3 reaching the surface that can be attributed to

downward transport from the stratosphere. Earlier work, cited in AQCD 96 relied mainly on the

use of 7

Be as a tracer of stratospheric air. However, its use is ambiguous because it is also

formed in the upper troposphere. Complications also arise because its production rate is also

sensitive to solar activity (Lean, 2000). The ratio of 7Be to 10Be provides a much more sensitive

tracer of stratospheric air than the use of 7

Be alone (Jordan et al., 2003). More recent work than

cited in AQCD 96 has focused on the use of potential vorticity (PV) as a tracer of stratospheric

air. Potential vorticity is a dynamical tracer used in meteorology. Generally, PV is calculated

from wind and temperature observations and represents the rotational tendency of a column of

air weighted by the static stability, which is just the distance between isentropic surfaces. This

quantity is a maximum in the lower stratosphere where static stability is great and along the jet

stream where wind shear imparts significant rotation to air parcels. As air moves from the

stratosphere to the troposphere, PV is conserved, and therefore it traces the motion of O3. The

static stability is lower in the troposphere, so to preserve PV, fluid rotation will increase. This is

why STE is associated with cyclogenesis, or the formation of storms along the polar jet stream. 

Dynamical models clearly capture this correspondence between the location of storm tracks and

preferred regions for STE. However, because PV is destroyed at a faster rate with increasing

depth, it is not useful as a tracer of stratospheric air reaching the surface. Appenzeller et al.

(1996) found that maps of PV coupled with satellite images of humidity can provide indications

of the intrusion of stratospheric air into the troposphere, however, they had no measurements of

O3. Even if measurements of O3 were available, the extrapolation of any relations to other events
AX2-66

would still be problematic as Olsen et al. (2002) have noted that there are seasonal and

geographic variations in the relation between O3 and PV. Recent flights of the NCAR C130

during the TOPSE campaign measured in situ O3, and curtains of O3 above and below the

aircraft observed with a lidar and clearly showed a correspondence between high PV and

stratospheric levels of O3 and satellite depictions of dry air indicating the presence of tropopause

folding (Wimmers and Moody, 2004a,b). 

Detailed cross sections through a tropopause folding event showing atmospheric structure,

O3 mixing ratios and condensation nuclei (CN) counts are given in Figures AX2-7a, AX2-7b,

and AX2-7c (Shapiro, 1980). Flight tracks of an NCAR Sabreliner obtaining data through the

tropopause fold are also shown. The core of the jet stream is indicated by the hatched area near

the center of Figure AX2-7a. As can be seen from Figure AX2-7 a and b, there is a strong

relation between the folding of the tropopause, indicated by the heavy solid line and O3. CN

counts during the portions of the flights in the lower troposphere were tropospheric were

typically of the order of several × 10 3 cm-3 and 100 or less in the stratospheric portion. 

However, it is clear that CN counts in the fold are much higher than in the stratosphere proper,

suggesting that there was active mixing between tropospheric and stratospheric air in the fold. 

Likewise, it can also be seen from Figure AX2-7b that O3 is being mixed outside the fold into the

middle and upper troposphere. The two data sets shown in Figures AX2-7b and 7c indicate that

small scale turbulent processes were occurring to mediate this exchange and that the folds are

mixing regions whose chemical characteristics lie between those of the stratosphere and the

troposphere (Shapiro, 1980). Chemical interactions between stratospheric and tropospheric 

constituents are also possible within tropopause folds. These considerations also imply that in

the absence of turbulent mixing, tropopause folding can be a reversible process. 

Several recent papers have attempted to demonstrate that the atmosphere is a fluid

composed of relatively distinct airstreams with characteristic three-dimensional motions and

corresponding trace gas signatures. Based on aircraft observations, satellite imagery, and back

trajectories, it has been shown that dry airstreams, or dry intrusions (DA or DI) always advect

stratospheric O3 into the middle and upper troposphere (Cooper et al, 2001; Cooper et al.,

2002a), however the seasonal cycle of O3 in the lowermost stratosphere allows greater quantities

of O3 to enter the troposphere during spring (Cooper et al., 2002b). Other work has focused on

the signatures of PV to show specific instances of STE (Olsen and Stanford, 2001). This
AX2-67

correlation between TOMS gradients and PV was also used to derive the annual mass flux of O3

from STE and generated an estimate somewhat higher (500 Tg/yr over the Northern

Hemisphere) than the estimates of most general circulation models. The IPCC has reported a

large range of model estimates of STE, expressed as the net global flux of O3 in Tg/yr, from a

low of 390 to a high of 1440 (reproduced as Table AX3-15). A few other estimates have been

made based on chemical observations in the lower stratosphere, or combined chemistry and

dynamics (450 Tg/yr Murphy and Fahey, 1994; 510 Tg/yr extratropics only, Gettleman et al.,

1997; and 500 Tg/yr midlatitude NH only (30 to 60N) (Olsen et al., 2002). These values

illustrate the large degree of uncertainty that remains in quantifying this important source of O3.

Figure AX2-7b. Ozone mixing ratios pphm (parts per hundred million) corresponding

to Figure AX2-7a. The two Sabreliner flight tracks through this cross

section are shown as a heavy solid line with filled arrows and a heavy

dashed line with open arrows. Longitude is shown along the x-axis. 

Upper air soundings were taken at Vandenberg AFB, CA (VBG);

San Diego, CA (SAN); Winnemucca, NV (UCC); and Ely, NV (ELY).

Source: Adapted from Shapiro (1980).
AX2-68

Based on the concept of tracing airstream motion, a number of Lagrangian model studies

have resulted in climatologies that have addressed the spatial and temporal variability in

stratosphere to troposphere transport (Stohl, 2001; Wernli and Borqui, 2002; Seo and Bowman,

2002; James et al., 2003a,b; Sprenger and Wernli, 2003; Sprenger et al., 2003). Both Stohl

(2001) and Sprenger et al. (2003) produced one year climatologies of tropopause folds based on 

a 1° by 1° gridded meteorological data set. They each found the probability of deep folds

(penetrating to the 800 hPa level) was a maximum during winter (December through February).

The highest frequency of folding extended from Labrador down the east coast of North America. 

Figure AX2-7c. Condensation nuclei concentrations (particles cm-3) corresponding to

Figure AX2-7a. The two flight Sabreliner flight tracks through this cross

section are shown as a heavy solid line with filled arrows and a heavy

dashed line with open arrows. Longitude is shown along the x-axis. 

Upper air soundings were taken at Vandenberg AFB, CA (VBG);

San Diego, CA (SAN); Winnemucca, NV (UCC); and Ely, NV (ELY).

Source: Adapted from Shapiro (1980).
AX2-69

However, these deep folds occurred less than 1% of the six hour intervals for which

meteorological data is assimilated for grid points in the United States. They observed a higher

frequency of more shallow folds (penetrating to the upper troposphere) and medium folds

(penetrating to levels between 500 and 600 hPa) of about 10% and 1 to 2% respectively. These

events occur preferentially across the subtropics and the southern United States. At higher

latitudes other mechanisms such as the erosion of cutoff lows and the breakup of stratospheric

streamers are likely to play an important role in STE. Stohl (2001) also described the region of

strong stirring in the upper extratropical troposphere related to the midlatitude storm tracks. 

Stohl (2001) demonstrated that airstreams with strong vertical motion are all highly incoherent,

they stir their air parcels into a new environment, producing filamentary tracer structures and

paving the way for subsequent mixing. A 15-year climatology by Sprenger and Wernli (2003)

shows the consistent pattern of STE occurring over the primary storm tracks in the Pacific and

Atlantic along the Asian and North American coasts. This climatology, and the one of James

et al. (2003a,b) both found that recent stratospheric air associated with deep intrusions are

relatively infrequent occurrences in these models. Thus, stratospheric intrusions are most likely

to directly affect the middle and upper troposhere and not the planetary boundary layer. 

However, this O3 can still exchange with the planetary boundary layer through convection as

described later in this subsection and in Section AX2.3.2, AX2.3.3 and AX2.3.4. 

Interannual variations in STE are related to anomalies in large-scale circulation such as the

North Atlantic Oscillation which causes changes in storm track positions and intensities, and the

El Niño-Southern Oscillation, which results in anomalous strong convection over the eastern

Pacific (James et al., 2003a,b). It should also be remembered that the downward flux of O3 into

the troposphere is related to the depletion of O3 within the wintertime stratospheric polar

vortices. The magnitude of this depletion and the transport of O3 depleted air to midlatitudes in

the stratosphere (Mahlman et al., 1994; Hadjinicolaou and Pyle, 2004) shows significant

interannual variability which may also be reflected in the downward flux of O3 into the

troposphere. All of these studies, from the analysis of individual events to multiyear

climatologies are based on the consideration of the three-dimensional motion of discrete

airstreams in the atmosphere. However, there is a significant body of work that reports that

airstreams are not entirely independent of each other (Cooper et al., 2004a,b). Midlatitude

cyclones typically form in a sequential manner, some trailing in close proximity along a
AX2-70

quasi-stationary frontal boundary, with each system influenced by remnants of other systems. 

For example, a rising stream of air ahead of a cold front (also known as a warm conveyor belt or

WCB) on the back (western) side of a surface anticyclone may entrain air that has subsided

anticyclonically into the surface high pressure system from the upper troposphere and the lower

stratosphere (also known as a Dry Airstream or DA) that intruded into the mid-troposphere in a

cyclone that is further downstream. Convective mixing of the boundary layer in the WCB will

distribute this enhanced O3 throughout the lower troposphere and down to the surface (Davies

and Shuepbach, 1994; Cooper and Moody, 2000). The net effect is that the DA of one cyclone

may feed into the WCB of the system immediately upwind. Similarly, the lofting of warm moist

air in the WCB may inject surface emissions into the upper troposphere adjacent to the western

side of the subsiding Dry Airstream of the storm system immediately downwind, with

subsequent interleaving of these two airstreams (Prados et al., 1999; Parrish et al., 2000; Cooper

et al., 2004a,b) as illustrated schematically in Figure AX2-8. The ultimate mixing of these

airstreams, which inevitably occurs at a scale that is not resolved by current models confounds

our ability to attribute trace gases to their sources. 

These studies suggest that both downward transport from the stratosphere and upward

transport from the atmospheric boundary layer act in concert with their relative roles determined

by the balance between the amount of O3 in the lower stratosphere and the availability of free

radicals to initiate the photochemical processes forming O3 in the boundary layer. Dickerson

et al. (1995) pointed out that springtime maxima in O3 observed in Bermuda correlate well with

maxima in carbon monoxide. Carbon monoxide, O3 and its photochemical precursors may have

been transported into the upper troposphere from the polluted continental boundary layer by

deep convection. The photochemical processes involve the buildup of precursors during the

winter at Northern mid- and high latitudes. Parrish et al. (1999) have noted that reactions

occurring during the colder months may tend to titrate O3. However, as NOx and its reservoirs

are transported sourthward they can initiate O3 formation through reactions described in

Section AX2.2 (see also Stroud et al., 2003). 
AX2-71

Figure AX2-8. Schematic diagram of a meteorological mechanism involved in high

concentrations of O3 found in spring in the lower troposphere off the

American east coast. Subsidence behind the first cold front meets

convection ahead of a second cold front such that polluted air and O3

from the upper troposphere/lower stratosphere are transported in close

proximity (or mixed) and advected over the north Atlantic Ocean. The

vertical scale is about 10 km; the horizontal scale about 1500 km.

(Note that not all cold fronts are associated with squall lines and that

mixing occurs even in their absence.)

Source: Prados (2000).

AX2.3.2 Deep Convection in the Troposphere

Much of the upward motion in the troposphere is driven by convergence in the boundary

layer and deep convection. Deep convection, as in developing thunderstorms can transport

pollutants rapidly to the middle and upper troposphere (Dickerson et al., 1987). The outflow

from these systems results in the formation of layers with distinctive chemical properties in the

middle troposphere. In addition, layers are formed as the result of stratospheric intrusions. 

Layers ranging in thickness typically from 0.3 to about 2 km in the middle troposphere (mean

altitudes between 5 and 7 km) are ubiquitous and occupy up to 20% of the troposphere to 12 km

(Newell et al., 1999). The origin of these layers can be judged by analysis of their chemical
AX2-72

composition (typically by comparing ratios of H2O, O3 and CO to each other) or dynamical

properties (such as potential vorticity). Thus, pollutants that have been transported into the

middle and upper troposphere at one location can then be transported back down into the

boundary layer somewhere else. 

Crutzen and Gidel (1983), Gidel (1983), and Chatfield and Crutzen (1984) hypothesized

that convective clouds played an important role in rapid atmospheric vertical transport of trace

species and first tested simple parameterizations of convective transport in atmospheric chemical

models. At nearly the same time, evidence was shown of venting of the boundary layer by

shallow fair weather cumulus clouds (e.g., Greenhut et al., 1984; Greenhut, 1986). Field

experiments were conducted in 1985, which resulted in verification of the hypothesis that deep

convective clouds are instrumental in atmospheric transport of trace constituents (Dickerson

et al., 1987; Luke, 1997). Once pollutants are lofted to the middle and upper troposphere, they

typically have a much longer chemical lifetime and with the generally stronger winds at these

altitudes they can be transported large distances from their source regions. Photochemical

reactions occur during this long-range transport. Pickering et al. (1990) demonstrated that

venting of boundary layer pollutants by convective clouds (both shallow and deep) causes

enhanced O3 production in the free troposphere. Therefore, convection aids in the

transformation of local pollution into a contribution to global atmospheric pollution. Downdrafts

within thunderstorms tend to bring air with less pollution from the middle troposphere into the

boundary layer. 

Field studies have established that downward transport of larger O3 and NOx mixing ratios

from the free troposphere to the boundary layer is an important process over the remote oceans

(e.g., Piotrowicz et al., 1991), as well as the upward transport of very low O3 mixing ratios from

the boundary layer to the upper troposphere (Kley et al., 1996). Global modeling by Lelieveld

and Crutzen (1994) suggests that the downward mixing of O3 into the boundary layer (where it is

destroyed) is the dominant global effect of deep convection. Some indications of downward

transport of O3 from higher altitudes (possibly from the stratosphere) in the anvils of

thunderstorms have been observed (Dickerson et al., 1987; Poulida et al., 1996; Suhre et al.,

1997). Ozone is most effective as a greenhouse gas in the vicinity of the tropopause. Therefore,

changes in the vertical profile of O3 in the upper troposphere caused by deep convection have

important radiative forcing implications for climate. 
AX2-73

Other effects of deep convection include perturbations to photolysis rates, which include

enhancement of these rates in the upper portion of the thunderstorm anvil. In addition,

thunderstorms are effective in the production of NO by lightning and in wet scavenging of

soluble species. 

AX2.3.2.1 Observations of the Effects of Convective Transport

Some fraction of shallow fair weather cumulus clouds actively vent boundary layer

pollutants to the free troposphere (Stull, 1985). The first airborne observations of this

phenomenon were conducted by Greenhut et al. (1984) over a heavily urbanized area, measuring

the in-cloud flux of O3 in a relatively large cumulus cloud. An extension of this work was

reported by Greenhut (1986) in which data from over 100 aircraft penetrations of isolated

nonprecipitating cumulus clouds over rural and suburban areas were obtained. Ching and

Alkezweeny (1986) reported tracer (SF6) studies associated with nonprecipitating cumulus (fair

weather cumulus and cumulus congestus). Their experiments showed that the active cumulus

clouds transported mixed layer air upward into the overlying free troposphere and suggested that

active cumuli can also induce rapid downward transport from the free troposphere into the mixed

layer. A UV-DIAL (Ultraviolet Differential Absorption Lidar) provided space-height cross

sections of aerosols and O3 over North Carolina in a study of cumulus venting reported by Ching

et al. (1988). Data collected on evening flights showed regions of cloud debris containing

aerosol and O3 in the lower free troposphere in excess of background, suggesting that significant

vertical exchange had taken place during afternoon cumulus cloud activity. Efforts have also

been made to estimate the vertical transport by ensembles of nonprecipitating cumulus clouds in

regional chemical transport models (e.g., Vukovich and Ching, 1990). 

The first unequivocal observations of deep convective transport of boundary layer

pollutants to the upper troposphere were documented by Dickerson et al. (1987). 

Instrumentation aboard three research aircraft measured CO, O3, NO, NOx, NOy, and

hydrocarbons in the vicinity of an active mesoscale convective system near the

Oklahoma/Arkansas border during the 1985 PRE-STORM experiment. Anvil penetrations about

two hours after maturity found greatly enhanced mixing ratios of all of the aforementioned

species compared with outside of the cloud. Among the species measured, CO is the best tracer

of upward convective transport because it is produced primarily in the boundary layer and has an
AX2-74

atmospheric lifetime much longer than the timescale of a thunderstorm. In the observed storm,

CO measurements exceeded 160 ppbv as high as 11 km, compared with ~70 ppbv outside of the

cloud (Figure AX2-9a). Cleaner middle tropospheric air appears to have descended in

downdrafts forming a pool of lower mixing ratio CO beneath the cloud. Nonmethane

hydrocarbons (NMHC) with moderate lifetimes can also serve as tracers of convective transport

from the boundary layer. Ozone can also be an indicator of convective transport. In the polluted

troposphere large O3 values will indicate upward transport from the boundary layer, but in the

clean atmosphere such values are indicative of downward transport from the uppermost

troposphere or lowermost stratosphere. In this case measured O3 in the upper rear portion of the

anvil peaked at 98 ppbv, while boundary layer values were only ~65 ppbv (Figure AX2-9b). It is

likely that some higher-O3 stratospheric air mixed into the anvil. 

The large amount of vertical trace gas transport noted by Dickerson et al. (1987) cannot,

however, be extrapolated to all convective cells. Pickering et al. (1988) reported airborne

measurements of trace gases taken in the vicinity of a line of towering cumulus and

cumulonimbus clouds that also occurred during PRE-STORM. In this case trace gas mixing

ratios in the tops of these clouds were near ambient levels. Meteorological analyses showed that

these clouds were located above a cold front, which prevented entry of air from the boundary

layer directly below or near the clouds. Instead, the air entering these clouds likely originated in

the layer immediately above the boundary layer which was quite clean. Luke et al. (1992)

summarized the air chemistry data from all 18 flights during PRE-STORM by categorizing each

case according to synoptic flow patterns. Storms in the maritime tropical flow regime

transported large amounts of CO, O3, and NOy into the upper troposphere with the

midtroposphere remaining relatively clean. During frontal passages a combination of stratiform

and convective clouds mixed pollutants more uniformly into the middle and upper levels; high

mixing ratios of CO were found at all altitudes. 

Prather and Jacob (1997) and Jaeglé et al. (1997) noted that in addition to the primary

pollutants (e.g., NOx, CO, VOCs), precursors of HOx are also transported to the upper

troposphere by deep convection. Precursors of most importance are water vapor, formaldehyde,

hydrogen peroxide, methylhydroperoxide, and acetone. HOx is critical for oxidizing NO to NO2

in the O3 production process. 
AX2-75

Figure AX2-9a,b. (a) Contour plot of CO mixing ratios (ppbv) observed in and near the

June 15, 1985, mesoscale convective complex in eastern Oklahoma. 

Heavy line shows the outline of the cumulonimbus cloud. Dark shading

indicates high CO and light shading indicates low CO. Dashed contour

lines are plotted according to climatology since no direct measurements

were made in that area. (b) Same as (a) but for O3 (ppbv). 

Source: Dickerson et al. (1987).
AX2-76

Over remote marine areas the effects of deep convection on trace gas distributions differ

from that over moderately polluted continental regions. Chemical measurements taken by the

NASA ER-2 aircraft during the Stratosphere-Troposphere Exchange Project (STEP) off the

northern coast of Australia show the influence of very deep convective events. Between

14.5 and 16.5 km on the February 2 to 3, 1987 flight, perturbations in the chemical profiles were

noted that included pronounced maxima in CO, water vapor, and CCN and minima of NOy,

and O3 (Pickering et al., 1993). Trajectory analysis showed that these air parcels likely were

transported from convective cells 800 to 900 km upstream. Very low boundary layer mixing

ratios of NOy and O3 in this remote region were apparently transported upward in the convection. 

A similar result was noted in CEPEX (Central Equatorial Pacific Experiment; Kley et al., 1996)

where a series of ozonesonde ascents showed very low upper tropospheric O3 following deep

convection. It is likely that similar transport of low-O3 tropical marine boundary layer air to the

upper troposphere occurs in thunderstorms along the east coast of Florida. Convection over the

Pacific will likely transport halogens to the upper troposphere where they may aid in the

destruction of O3. This low-O3 convective outflow will likely descend in the subsidence region

of the eastern Pacific, leading to some of the cleanest air that arrives at the west coast of the

United States. 

AX2.3.2.2 Modeling the Effects of Convection

The effects of deep convection may be simulated using cloud-resolving models, or in

regional or global models in which the convection is parameterized. The Goddard Cumulus

Ensemble (GCE) model (Tao and Simpson, 1993) has been used by Pickering et al. (1991,

1992a,b, 1993, 1996), Scala et al. (1990) and Stenchikov et al. (1996) in the analysis of

convective transport of trace gases. The cloud model is nonhydrostatic and contains detailed

representation of cloud microphysical processes. Two- and three-dimensional versions of the

model have been applied in transport analyses. The initial conditions for the model are usually

from a sounding of temperature, water vapor and winds representative of the region of storm

development. Model-generated wind fields can be used to perform air parcel trajectory analyses

and tracer advection calculations. Once transport calculations are performed for O3 precursors, a

1-D photochemical model was employed to estimate O3 production rates in the outflow air from
AX2-77

the convection. These rates were then compared with those prior to convection to determine an

enhancement factor due to convection. 

Such methods were used by Pickering et al. (1992b) to examine transport of urban plumes

by deep convection. Transport of the Oklahoma City plume by the 10–11 June 1985

PRE-STORM squall line was simulated with the 2-D GCE model. In this event forward

trajectories from the boundary layer at the leading edge of the storm showed that almost 75% of

the low level inflow was transported to altitudes exceeding 8 km. Over 35% of the air parcels

reached altitudes over 12 km. Tracer transport calculations were performed for CO, NOx, O3,

and hydrocarbons. The 3-D version of the GCE model has also been run for the 10–11 June

1985 PRE-STORM case. Free tropospheric O3 production enhancement of a factor of 2.5 for

Oklahoma rural air and ~4 for the Oklahoma City case were calculated. 

Stenchikov et al. (1996) used the 2-D GCE model to simulate the North Dakota storm

observed by Poulida et al. (1996). This storm showed the unusual feature of an anvil formed

well within the stratosphere. The increase of CO and water vapor above the altitude of the

preconvective tropopause was computed in the model. The total mass of CO across the model

domain above this level increased by almost a factor of two during the convective event. VOCs

injected into the lower stratosphere could enhance O3 production there. Downward transport of

O3 from the stratosphere was noted in the simulation in the rear anvil. 

Regional estimates of deep convective transport have been made through use of a traveling

1-D model, regional transport models driven by parameterized convective mass fluxes from

mesoscale meteorological models, and a statistical-dynamical approach. Pickering et al. (1992c)

developed a technique which uses a combination of deep convective cloud cover statistics from

the International Satellite Cloud Climatology Project (ISCCP) and convective transport statistics

from GCE model simulations of prototype storms to estimate the amount of CO vented from the

planetary boundary layer (PBL) by deep convection. This statistical-dynamical approach was

used by Thompson et al. (1994) to estimate the convective transport component of the boundary

layer CO budget for the central United States (32.5°–50° N, 90°–105° W) for the month of June. 

They found that the net upward deep convective flux (~18 × 105

 kg-CO/month) and the shallow

convective flux (~16 × 105 kg-CO/month) to the free troposphere accounted for about 80% of the

loss of CO from the PBL. These losses roughly balanced horizontal transport of CO (~28 × 105

kg-CO/month), the oxidation of hydrocarbons (~8 × 105 kg-CO/month) and anthropogenic and
AX2-78

biogenic emissions (~8 + ~1 × 105

 kg-CO/month) into the PBL in the central United States. 

In this respect the central United States acts as a “chimney” for venting CO and other pollutants. 

Regional chemical transport models have been used for applications such as simulations of

photochemical O3 production, acid deposition, and fine particulate matter. Walcek et al. (1990)

included a parameterization of cloud-scale aqueous chemistry, scavenging, and vertical mixing

in the chemistry model of Chang et al. (1987). The vertical distribution of cloud microphysical

properties and the amount of subcloud-layer air lifted to each cloud layer are determined using a

simple entrainment hypothesis (Walcek and Taylor, 1986). Vertically-integrated O3 formation

rates over the northeast U.S. were enhanced by ~50% when the in-cloud vertical motions were

included in the model. 

Wang et al. (1996) simulated the 10–11 June 1985 PRE-STORM squall line with the

NCAR/Penn State Mesoscale Model (MM5; Grell et al., 1994; Dudhia et al., 1993). Convection

was parameterized as a subgrid-scale process in MM5 using the Kain and Fritsch (1993) scheme. 

Mass fluxes and detrainment profiles from the convective parameterization were used along with

the 3-D wind fields in CO tracer transport calculations for this convective event. The U.S.

Environmental Protection Agency has developed a Community Multiscale Air Quality (CMAQ)

modeling system that uses MM5 with the Kain-Fritsch convective scheme as the dynamical

driver (Ching et al., 1998). 

Convective transport in global chemistry and transport models is treated as a subgrid-scale

process that is parameterized typically using cloud mass flux information from a general

circulation model or global data assimilation system. While GCMs can provide data only for a

“typical” year, data assimilation systems can provide “real” day-by-day meteorological

conditions, such that CTM output can be compared directly with observations of trace gases. 

The NASA Goddard Earth Observing System Data Assimilation System (GEOS-1 DAS and

successor systems; Schubert et al., 1993; Bloom et al., 1996) provides archived global data sets

for the period 1980 to present, at 2° × 2.5° or better resolution with 20 layers or more in the

vertical. Convection is parameterized with the Relaxed Arakawa-Schubert scheme (Moorthi and

Suarez, 1992). Pickering et al. (1995) showed that the cloud mass fluxes from GEOS-1 DAS are

reasonable for the 10–11 June 1985 PRE-STORM squall line based on comparisons with the

GCE model (cloud-resolving model) simulations of the same storm. In addition, the GEOS-1

DAS cloud mass fluxes compared favorably with the regional estimates of convective transport
AX2-79

for the central U.S. presented by Thompson et al. (1994). However, Allen et al. (1997) have

shown that the GEOS-1 DAS overestimates the amount and frequency of convection in the

tropics and underestimates the convective activity over midlatitude marine storm tracks. 

AX2.3.3 Nocturnal Low-Level Jets

Nocturnal low-level jets (LLJ) are coincident with synoptic weather patterns involved with

high O3 episodes implying that they may play an important role in the formation of severe O3

events (Rao and Zurbenko, 1994). LLJ can transport pollutants hundreds of kilometers from

their sources. Figure AX2-10 shows the evolution of the planetary boundary layer (PBL) over

land during periods when high-pressure weather patterns prevail (Stull, 1988). During synoptic

weather patterns with stronger zonal flow, a schematic of the boundary layer could look quite

different with generally more uniform mixing present. As can be seen from Figure AX2-10, the

PBL can be divided into three sublayers: a turbulent mixed layer (typically present during

daylight hours), a less turbulent residual layer which occupies space that was formerly the mixed

layer, and a nocturnal, stable boundary layer that has periods of sporadic turbulence (Stull,

1988). The LLJ forms in the residual layer. It is important to note, that during the nighttime, the

PBL often comprises thin, stratified layers with different physical and chemical properties

(Stull, 1988). 

At night, during calm conditions, the planetary boundary layer is stably stratified and as a

result verticle mixing is inhibited. On cloud-free evenings the LLJ begins to form shortly after

sunset. The wedge of cool air in the stable nocturnal boundary layer decouples the surface layer

from the residual layer and acts like a smooth surface allowing the air just above it (in the

residual layer) to flow rapidly past the inversion mostly unencumbered by surface friction (Stull,

1988). As the sun rises, its energy returns to heat the land and the lower atmosphere begins to

mix as the warm air rises. The jet diminishes as the nocturnal temperature inversion erodes and

surface friction slows wind speeds. If stable synoptic conditions persist, the same conditions the

next night could allow the low-level jet to reform with equal strength and similar consequences. 

LLJ formation results in vertical wind shear that induces mixing between the otherwise stratified

layers. 
AX2-80

Figure AX2-10. The diurnal evolution of the planetary boundary layer while high

pressure prevails over land. Three major layers exist (not including the

surface layer): a turbulent mixed layer; a less turbulent residual layer

which contains air formerly in the mixed layer; and a nocturnal, stable

boundary layer which is characterized by periods of sporadic turbulence.

Source: Adapted from Stull (1988) Figures 1.7 and 12.1.

LLJs are often associated with mountain ranges. Mountains and pressure gradients on

either side of a developing LLJ help concentrate the flow of air into a corridor or horizontal

stream (Hobbs et al., 1996). Figure AX2-11 shows that LLJs commonly form east of the Rocky

Mountains and east of the Appalachian Mountains (Bonner, 1968). There may be other locations

in the U.S. where LLJs occur. The width of the jet can vary from location to location and from

one weather pattern to another, but is typically less than several hundred km not greater than

1000 km long. In extreme cases, winds in a LLJ can exceed 60 ms!1

 but average speeds are

typically in the range of 10 to 20 ms!1. 

Nocturnal low-level jets are not unique to the United States; they have been detected in

many other parts of the world (Corsmeier, 1997, Reitebuch, et al., 2000). Corsmeier et al.

(1997) observed secondary maxima in surface O3 at nighttime at a rural site in Germany,

supporting the notion that downward transport from the residual layer was occurring. The

secondary maxima were, on average, 10% of the next day’s O3 maximum but at times could be

as much as 80% of the maximum (Corsmeier et al., 1997). The secondary O3 maxima were well 
AX2-81

Figure AX2-11. Locations of low-level jet occurrences in decreasing order of prevalence

(most frequent, common, observed). These locations are based on 2-years

radiosonde data obtained over limited areas. With better data coverage,

other low-level jets may well be observed elsewhere in the United States.

Source: Bonner (1968).

correlated with an increase in wind speed and wind shear. The increased vertical shear over the

very thin layer results in mechanical mixing that leads a downward flux of O3 from the residual

to the near surface layer (see Low-level jets AX2-12 and AX2-13). Analysis of wind profiles

from aerological stations in northeastern Germany revealed the spatial extent of that particular

LLJ was up to 600 km in length and 200 km in width. The study concluded the importance of O3

transport by low-level jets was twofold: O3 and other pollutants could be transported hundreds

of kilometers at the jet core level during the night and then mixed to the ground far from their

source region. Salmond and McKendry (2002) also observed secondary O3 maxima (in the

Lower Fraser Valley, British Columbia) associated with low-level jets that occasionally

exceeded half the previous day’s maximum O3 concentration. The largest increases in surface

O3 concentration occurred when boundary layer turbulence coincided with O3 levels greater than

80 parts per billion were observed aloft. In addition, the study suggests horizontal transport

efficiency during a low-level jet event could be as much as six times greater than transport with

light winds without an LLJ. Reitebuch et al. (2000) observed secondary O3 maxima associated

with low-level jet evolution in an urban area in Germany. The notion that O3 was transported 
AX2-82

Figure AX2-13. The nocturnal low-level jet occupies a thin slice of the atmosphere near

the Earth’s surface. Abrupt changes in wind speed and wind direction

with height associated with the low-level jet create conditions favorable

for downward transport of air to the surface layer. 

Source: Singh et al. (1997); Corsmeier et al. (1997).

Figure AX2-12. Schematic diagram showing the diurnal behavior of O3 and the

development of secondary O3 maxima resulting from downward

transport from the residual layer when a low-level jet is present. 

Source: Adapted from Reitbuch et al. (2000); Corsmeier et al. (1997); and Salmond and McKendry (2002).
AX2-83

downward from the residual layer to the surface was supported by observed decreases in

concentrations of NO, NO2 and CO in the residual layer during secondary O3 maxima. Unlike

O3 in the residual layer, concentrations of NO, NO2, and CO should be lower than those found

nearer the surface (Reitebuch et al., 2000; Seinfeld and Pandis, 1998). As in other studies, wind

speed and directional shear were detected during these events. Calculations of the average wind

speed and duration of the LLJ suggested that pollutants were transported several hundred

kilometers. A study of the PBL and the vertical structure of O3 observed at a costal site in Nova

Scotia described how temperature and differences of surface roughness in a marine environment

can induce LLJ formation and pollution transport (Gong et al., 2000). In this case, rather strong

horizontal sea surface temperature gradients provided the necessary baroclinic forcing. 

While the studies mentioned above have shed light on the possible role of the LLJ in the

transport of O3 and its precursors, quantitative statements about the significance of the LLJ in

affecting local and regional O3 budgets cannot yet be made. This inability reflects the lack of

available data for wind profiles in the planetary boundary layer in areas where LLJ are likely to

occur and because of the inadequacy of numerical models in simulating their occurrence. 

AX2.3.4 Intercontinental Transport of Ozone and Other Pollutants

AX2.3.4.1 The Atmosphere/Ocean Chemistry Experiment, AEROCE

The AEROCE experiment, initiated in the early 1990s set out to examine systematically

the chemistry and meteorology leading to the trace gas and aerosol composition over the North

Atlantic Ocean. One particular focus area was to determine the relative contribution of

anthropogenic and natural processes to the O3 budget and oxidizing capacity of the troposphere

over the North Atlantic Ocean. Early results using isentropic back trajectories suggested that

periodic pulses of O3 mixing ratios up to 80 ppb were associated with large-scale subsidence

from the mid-troposphere, favoring a natural source (Oltmans and Levy, 1992). Moody et al.

(1995) extended this work with a five-year seasonal climatology and found the highest

concentrations of O3 were always associated with synoptic scale postfrontal subsidence off the

North American continent behind cold fronts, and this pattern was most pronounced in the

April-May time frame. These postfrontal air masses had uniformly low humidity and high

concentrations of 7

Be, a cosmogenic tracer produced in the upper troposphere and lower

stratosphere. However, the pulsed occurrence of these postfrontal air masses also frequently
AX2-84

delivered enhanced concentrations of species such as SO4

2-, NO3!

, 210Pb, etc. suggesting a

component originating in North America. In a subsequent analysis of data from one year (1992)

when CO observations were available, Dickerson et al. (1995) concluded that anthropogenic

sources made a significant contribution to surface O3, and using a simple mixing model they

determined that 57% of the air had a continental boundary layer origin. 

Based on these observations of the synoptically modulated concentrations, AEROCE

conducted an aircraft and ozonesonde intensive in the spring of 1996. The intention was to

adopt a meteorologically informed sampling strategy to clearly distinguish the characteristics of

air masses ahead of and behind eastward progressing cold fronts. Sixteen research flights were

conducted with the University of Wyoming King Air research aircraft. The goal was to

differentiate the sources of enhanced O3 mixing ratios observed on Bermuda after the passage of

cold fronts, and to identify the major processes controlling the highly variable O3 mixing ratios

in the mid-to-upper troposphere over eastern North America and the North Atlantic Ocean

during April and May. In addition to aircraft flights, near-daily ozonesondes were launched in a

quasi-zonal transect from Purdue, Indiana, to Charlottesville, Virginia to Bermuda. An effort

was made to time the release of ozonesondes to cleanly differentiate pre- and postfrontal air

masses. 

In several aircraft flights, the presence at altitude of distinct layers of air with elevated

concentrations of nonmethane hydrocarbons (NMHCs) attested to the dynamic vertical mixing

associated with springtime frontal activity. Layers of mid-tropospheric air of high O3 (140 ppb)

and low background NMHC mixing ratios (1.44 ppbv ethane, 0.034 ppbv propene, 0.247 ppbv

propane, and 0.034 ppbv isobutene, 0.041 ppbv n-butane, 0.063 ppbv benzene, 0.038 ppbv

toluene) were indicative of descending, stratospherically influenced air on a flight to the east of

Norfolk, VA on April 24 (alt 4600m). However layers of elevated NMHC concentrations

(1.88 ppbv ethane, 0.092 ppbv propene, 0.398 ppbv propane, 0.063 ppbv isobutene, 0.075 ppbv

n-butane, 0.106 ppbv benzene, 0.0102 ppbv toluene) occurred along with 60-70 ppbv of O3 on a

flight west of Bermuda April 28 (alt. 4100m), indicating air had been lofted from the continental

boundary layer. Meteorological evidence, supported by ozonesonde observations and earlier

King Air flights, indicated that stratosphere/troposphere exchange associated with an upstream

frontal system had injected and advected dry, O3-rich air into the mid-troposhere region over the

continent. This subsiding air mass provided deep layers of enhanced O3 in the offshore,
AX2-85

postfrontal area. Convection from a developing (upwind) system lifted continental boundary

layer air into the proximity of the dry, subsiding air layer (Prados, et al., 1999). This resulted in

a mixture of high concentrations of anthropogenic pollutants along with naturally enhanced O3. 

Ozone mixing ratios exceeded those attributable to boundary layer venting or in-transit

photochemical production. These meteorological processes led to pollution and stratospherically

enhanced O3 co-occurring in postfrontal air masses over the North Atlantic Ocean. A similar

event in February 1999 was observed by Parrish et al. (2000). It confirmed the occurrence of

thin layers of anthropogenic and stratospheric air that subsequently mix. These results, along

with recent modeling studies suggest that North American pollution clearly does contribute to

the periodic influx of less-than-pristine air observed in the marine boundary layer over Bermuda

(e.g., Li et al., 2002) and yet these incursions are not inconsistent with observing enhancements

in O3 due to stratospheric exchange. 

The ozonesonde climatology of AEROCE clearly established that O3 mixing ratios were

always enhanced and increased with height in postfrontal air masses. Postfrontal O3 in the lower

troposphere over Bermuda originates in the postfrontal midtroposphere over the continent,

supporting the hypothesis that naturally occurring stratospheric O3 makes a contribution to air in

the marine boundary layer (Cooper et al., 1998). A schematic of the meteorological processes

responsible for the close proximity of natural and man-made O3 can be seen in Figure AX2-8

from Prados (2000). Cold fronts over North America tend to be linked in wave-like patterns

such that the subsidence behind one front may occur above with intrusions of convection ahead

of the next cold front. Pollutants, including VOC and NOx, precursors to O3, may be lofted into

the mid-to-upper troposphere where they have the potential to mix with layers of air descending

from O3-rich but relatively unpolluted upper troposphere and lower stratosphere. Through this

complex mechanism, both stratospheric and photochemically produced O3 may be transported to

the remote marine environment where they have large-scale impacts on the radiative and

chemical properties of the atmosphere. Recent three-dimensional modeling studies of air mass

motion over the Pacific provide further evidence that these complex mechanisms are indeed

active (Cooper et al., 2004b). 
AX2-86

AX2.3.4.2 The North Atlantic Regional Experiment, NARE

NARE was established by the International Global Atmospheric Chemistry Project to study

the chemical processes occurring in the marine troposphere of the North Atlantic, the marine

region expected to be the most impacted by industrial emissions from eastern North America and

western Europe. Surface measurements from several surface sites were initiated in 1991, with

major field intensives in summer 1993, spring 1996, early autumn 1997 and a few winter flights

in 1999. In the summer of 1993, airborne and ground-based measurements of O3 and O3

precursors were made in the North Atlantic region by an international team of scientists to

determine how the continents that rim the North Atlantic are affecting atmospheric composition

on a hemispheric scale (Fehsenfeld et al., 1996a,b). The focus of NARE was to investigate the

O3 budget of the North Atlantic region. Previous observations indicated that the O3 produced

from anthropogenic sources is greater than that reaching the lower troposphere from the

stratosphere and that O3 derived from anthropogenic pollution has a hemisphere wide effect at

northern mid latitudes. This study was performed to better quantify the contribution of

continental sources to the O3 levels over the North Atlantic. 

Buhr et al. (1996) measured O3, CO, NO, and NOy as well as meteorological parameters

aboard the NCAR King Air in August 1993 during 16 flights over and near the Gulf of Maine. 

They found that O3 produced from anthropogenic precursors was dominant throughout the

experimental region below 1500 m, in altitude. 

The National Research Council of Canada Twin Otter aircraft was used to measure the O3

and related compounds in the summertime atmosphere over southern Nova Scotia (Kleinman

et al., 1996a,b). Forty-eight flights were performed, primarily over the surface sampling site in

Chebogue Point, Nova Scotia, or over the Atlantic Ocean. They found that a wide variety of air

masses with varying chemical content impact Nova Scotia. The effect depends on flow

conditions relative to the locations of upwind emission regions and the degree of photochemical

processing associated with transport times ranging from about 1 – 5 d. Moist continental

boundary layer air with high concentrations of O3 and other anthropogenic pollutants was

advected to Nova Scotia in relatively thin vertical layers, usually with a base altitude of several

hundred meters. Dry air masses with high concentrations of O3 often had mixed boundary layer

and upper atmosphere source regions. When a moist and dry air mass with the same

photochemical age and O3 concentration were compared, the dry air mass had lower
AX2-87

concentrations of NOy and aerosol particles, which was interpreted as evidence for the selective

removal of soluble constituents during vertical lifting. 

Due to strong, low-level temperature inversions over the North Atlantic, near surface air is

often unrepresentative of the eastward transport of the North American plume because of a

decoupling from the air transported aloft (Kleinman et al., 1996a; Daum et al., 1996; Angervine

et al., 1996). Pollution plumes were observed in distinct strata up to 1 km. Plume chemical

compositions were consistent with the occurrence of considerable photochemical processing

during transit from source regions over the eastern seaboard of the U.S. Ozone concentrations

reached 150 ppbv, NOx conversion to its oxidation products exceeded 85%, and high hydrogen

peroxide concentrations were observed (median 3.6 ppbv, maximum 11 ppbv). CO and O3

concentrations were well correlated (R2 = 0.64) with a slope (0.26) similar to previous

measurements in photochemically aged air (Parrish et al., 1998). Ozone depended nonlinearly

on the NOx oxidation product concentration, but there was a correlation (r2

 = 0.73) found

between O3 and the concentration of radical sink species as represented by the quantity

((NOy – NOx) + 2H2O2). 

Banic et al. (1996) determined that the average mass of O3 transported through an area

1 m in horizontal extent and 5 km in the vertical over the ocean near Nova Scotia to be 2.8 g s!1,

moving from west to east. Anthropogenic O3 accounted for half of the transport below 1 km,

35 to 50% from 1 to 3 km, 25 to 50% from 3 to 4 km, and only 10% from 4 to 5 km. Merrill and

Moody (1996) analyzed the meteorological conditions during the NARE intensive period

(August 1 to September 13, 1993). They determined the ideal meteorological scenario for

delivering pollution plumes from the U.S. East Coast urban areas over the Gulf of Maine to the

Maritime Provinces of Canada to be warm sector flow ahead of an advancing cold front. In the

winter phase of NARE, O3 and CO were measured from the NOAA WP-3D Orion aircraft from

St. John’s, Newfoundland, Canada, and Keflavik, Iceland, from February 2 to 25, 1999 (Parrish

et al., 2000). In the lower troposphere over the western North Atlantic Ocean, the close

proximity of air masses with contrasting source signatures was remarkable. High levels of

anthropogenic pollution immediately adjacent to elevated O3 of stratospheric origin were

observed, similar to those reported by Prados et al. (1999). In air masses with differing amounts

of anthropogenic pollution, O3 was negatively correlated with CO, which indicates that
AX2-88

emissions from surface anthropogenic sources had reduced O3, in this wintertime period, even in

air masses transported into the free troposphere. 

The influence of the origin and evolution of airstreams on trace gas mixing ratios has been

studied in great detail for NARE aircraft data. The typical midlatitude cyclone is composed of

four major component airstreams, the warm conveyor belt, the cold conveyor belt, the post coldfront airstream and the dry airstream (Cooper et al., 2001). The physical and chemical

processing of trace species was characterized for each airstream, and a conceptual model of a

midlatitude cyclones was developed (Cooper et al., 2002a). This showed how airstreams within

midlatitude cyclones drew and exported trace gases from the polluted continental boundary

layer, and the stratospherically enhanced mid-troposphere. Using back trajectories, airstream

composition was related to the origin and transport history of the associated air mass. The

lowest O3 values were associated with airstreams originating in Canada or the Atlantic Ocean

marine boundary layer; the highest O3 values were associated with airstreams of recent

stratospheric origin. The highest NOy values were seen in polluted outflow from New England

in the lower troposphere. A steep and positive O3/NOy slope was found for all airstreams in the

free troposphere regardless of air mass origin. Finally, the seasonal variation of photochemistry

and meteorology and their impact on trace gas mixing ratios in the conceptual cyclone model

was determined (Cooper et al., 2002b). Using a positive O3/CO slope as an indicator of

photochemical O3 production, O3 production during late summer-early autumn is associated with

the lower troposphere post-cold-front airstream and all levels of the WCB, especially the lower

troposphere. However, in the early spring, there is no significant photochemical O3 production

for airstreams at any level, and negative slopes in the dry air airstream indicate STE causes the

O3 increase in the mid- and upper troposphere. 

Stohl et al. (2002) analyzed total odd nitrogen (NOy) and CO data taken during NARE in

spring 1996 and fall 1997. They studied the removal timescales of NOy originating from surface

emissions of NOx and what fraction reached the free troposphere. NOx limits O3 production in

the free troposphere and can be regenerated from NOy after the primary NOx has been

exhausted. It was determined that < 50% of the NOy observed above 3 km came from

anthropogenic surface emissions. The rest had to have been emitted in situ. 

Several studies (e.g., Stohl and Trickl, 1999; Brunner et al., 1998; Schumann et al., 2000;

Stohl et al., 2003; Traub et al., 2003) have identified plumes that have originated in North
AX2-89

America over Europe and over the eastern Mediterranean basin (e.g., Roelofs et al., 2003; Traub

et al., 2003). Modeling studies indicate that North American emissions contribute roughly 20%

to European CO levels and 2 to 4 ppb to surface O3, on average. Episodic events, such as forest

fires in North America have also been found to result in elevated CO and O3 levels and visible

haze layers in Europe (Volz-Thomas, et al., 2003). The O3 is either transported from North

America or formed during transport across the North Atlantic Ocean, perhaps as the result of

interactions between the photochemical degradation products of acetone with emissions of NOx

from aircraft (Bruhl et al., 2000; Arnold et al., 1997). In addition, North American and European

pollution is exported to the Arctic. Eckhardt et al. (2003) show that this transport is related to

the phase of the North Atlantic Oscillation which has a period of about 20 years. 

AX2.3.5 Small-Scale Circulation Systems

Sub-synoptic scale circulation systems are especially important for determining pollution

levels. These systems include sea-land breezes, mountain-valley breezes and circulations driven

by the urban heat island. The circulations associated with these phenomena typically occur on

spatial scales of tens of kilometers. 

AX2.3.5.1 Land-Sea Breeze

Of particular interest is the sea-land breeze, as many urban areas such as those in the

Northeast Corridor (Washington, Baltimore, Philadelphia, New York and Boston), Chicago,

Houston, and Los Angeles in which high O3 values are found (see Chapter 3) are located in or

near coastal zones. 

During the day, heating of the land surface results in upward motion that is compensated

by air flowing in from the adjacent water body, i.e., the sea breeze. Winds gradually rotate with

height to produce a return flow aloft. This circulation generally reaches maximum strength in

late afternoon. Afterwards, the sense of the circulation is reversed and a land breeze develops,

which reaches maximum strength shortly after the land-sea temperature contrast is largest. This

also implies that winds are rotating at the surface as the sense of the circulation changes. The

circulation can interact with the larger synoptic scale flow pattern to either attenuate surface

winds or to increase them.
AX2-90

Because of these effects, sea-land breezes can exert significant effects on concentrations of

pollutants emitted in coastal areas. If there is onshore flow (sea breeze) when there is opposing

large scale flow, a transition zone (sometimes called a sea breeze front) in which convergence of

the opposing flows forms. In this zone, horizontal winds are weak. Furthermore, air pollutants

are concentrated and are transported upwards. This situation was found during O3 episodes

occurring in Houston in August 2000, in which a “wall of pollution” formed (Banta et al., 2005). 

If the sea breeze is dominant, it can transport pollutants well inland, even to central-eastern

Texas. During the land breeze phase, pollutants at the surface tend to be transported out over the

adjacent water body, resulting in dilution and dispersion of pollutants. Observational studies of

the effects of small scale circulations on O3 concentrations are lacking. 

AX2.3.6 The Relation of Ozone to Solar Ultraviolet Radiation, Aerosols,

and Air Temperature

AX2.3.6.1 Solar Ultraviolet Radiation and Ozone

The effects of sunlight on photochemical oxidant formation, aside from the role of solar

radiation in meteorological processes, are related to its intensity and its spectral distribution. 

Intensity varies diurnally, seasonally, and with latitude, but the effect of latitude is strong only in

the winter. Ultraviolet radiation from the sun plays a key role in initiating the photochemical

processes leading to O3 formation and affects individual photolytic reaction steps. However,

there is little empirical evidence in the literature, directly linking day-to-day variations in

observed UV radiation levels with variations in O3 levels. 

In urban environments the rate of O3 formation is sensitive to the rate of photolysis of

several species including H2CO, H2O2, O3, and especially NO2. Monte Carlo calculations

suggest that model calculations of photochemical O3 production are most sensitive to uncertainty

in the photolysis rate coefficient for NO2 (Thompson and Stewart, 1991; Baumann et al., 2000). 

The International Photolysis Frequency Measurement and Modeling Intercomparison (IPMMI)

hosted recently by NCAR in Boulder, CO brought together more than 40 investigators from

8 institutions from around the world (Bais et al., 2003; Cantrell et al., 2003 and Shetter et al.,

2003). They compared direct actinometric measurements, radiometric measurements, and

numerical models of photolysis rate coefficients, focusing on O3 to O(1

D) and NO2, referred to as

j(O3) and j(NO2). 
AX2-91

The combination of direct measurements and comparisons to model calculations indicated

that for clear skies, zenith angles less than 70°, and low aerosol loadings, the absolute value of

the j(NO2) at the Earth’s surface is known to better than 10% with 95% confidence. The results

suggest that the cross sections of Harder et al. (1997a) may yield more accurate values when

used in model calculations of j(NO2). Many numerical models agreed among themselves and

with direct measurements (actinometers) and semi-direct measurements (radiometers) when

using ATLAS extraterrestrial flux from Groebner and Kerr (2001). The results of IPMMI

indicate numerical models are capable of precise calculation of photolysis rates at the surface

and that uncertainties in calculated chemical fields arise primarily from uncertainties in the

variation of actinic flux with altitude in addition to the impact of clouds and aerosols on

radiation. 

AX2.3.6.2 Impact of Aerosols on Radiation and Photolysis Rates and

Atmospheric Stability

Because aerosol particles influence the UV flux there is a physical link between particles

and gases that depends on the concentration, distribution, and refractive index of the particles. 

Scattering of UV radiation by tropospheric aerosol particles can strongly impact photolysis rates

and thus photochemical O3 production or destruction. The effect shows high sensitivity to the

properties of the aerosol. Particles in the boundary layer can accelerate photochemistry if the

single scattering albedo is near unity, such as for sulfate and ammoniated sulfate aerosols, or

inhibit O3 production if the single scattering albedo is low, such as for mineral dust or soot

(Dickerson et al., 1997; Jacobson, 1998; Liao et al., 1999; Castro et al., 2001; Park et al., 2001). 

Any aerosol layer in the free troposphere will reduce photolysis rates in the boundary layer. 

The interaction of aerosols, photochemistry, and atmospheric thermodynamic processes

can impact radiative transport, cloud microphysics, and atmospheric stability with respect to

vertical mixing. Park et al. (2001) developed a single-column chemical transport model that

simulates vertical transport by convection, turbulent mixing, photochemistry, and interactive

calculations of radiative fluxes and photolysis rates. Results from simulations of an episode over

the eastern United States showed strong sensitivity to convective mixing and aerosol optical

depth. The aerosol optical properties observed during the episode produced a surface cooling of

up to 120 W/m2

 and stabilized the atmosphere suppressing convection. This suggests two
AX2-92

possible feedbacks mechanisms between aerosols and O3-reduced vertical mixing would tend to

increase the severity of O3 episodes, while reduced surface temperatures would decrease it. 

AX2.3.6.3 Temperature and Ozone

An association between surface O3 concentrations and temperature has been demonstrated

from measurements in outdoor smog chambers and from measurements in ambient air. 

Numerous ambient studies done over more than a decade have reported that successive

occurrences or episodes of high temperatures characterize high O3 years (Clark and Karl, 1982;

Kelly et al., 1986). The relation of daily maximum 8-h average O3 concentration to daily

maximum temperature from May to September 1994 to 2004 is illustrated in Figure AX2-14 for

the Baltimore Air Quality Forecast Area. The relation, based on daily maximum 1-h average O3

concentration is illustrated in Figure AX2-15. The relations are very similar in the two figures,

reflecting the high degree of correlation (r = 0.98) between the daily maximum 1-h and 8-h O3

concentrations. The relation of daily maximum 8-h average O3 to daily maximum temperature

from May to September 1994 to 2004 is illustrated in Figure AX2-15 for the three sites

downwind of Phoenix, AZ on high O3 days (cf., Figure AX3-32). As can be seen from a

comparison of Figures AX2-14 and AX2-16, O3 concentrations in the Phoenix area are not as

well correlated with daily maximum temperature (r = 0.14) as they are in the Baltimore Area

(r = 0.74). There appears to be an upper-bound on O3 concentrations that increases with

temperature. Likewise, Figure AX2-16 shows that a similar qualitative relationship exists

between O3 and temperature even at a number of nonurban locations. 

The notable trend in these plots is the apparent upper-bound to O3 concentrations as a

function of temperature. It is clear that, at a given temperature, there is a wide range of possible

O3 concentrations because other factors (e.g., cloudiness, precipitation, wind speed) can reduce

O3 production rates. The upper edge of the curves may represent a practical upper bound on the

maximum O3 concentration achieved under the most favorable conditions. Relationships

between peak O3 and temperature also have been recorded by Wunderli and Gehrig (1991) for

three locations in Switzerland. At two sites near Zurich, peak O3 increased 3 to 5 ppb/°C for

diurnal average temperatures between 10 and 25 °C, and little change in peak O3 occurred for

temperatures below 10 °C. At the third site, a high-altitude location removed from

anthropogenic influence, a much smaller variation of O3 with temperature was observed. 
AX2-93

Figure AX2-14. A scatter plot of daily maximum 8-h O3 concentration versus daily

maximum temperature in the Baltimore, MD Air Quality Forecast Area.

Source: Piety (2005)

Figure AX2-15. A scatter plot of daily maximum 1-h average O3 concentration versus

daily maximum temperature in the Baltimore, MD Air Quality Forecast

Area.

Source: Piety (2005)
AX2-94

Figure AX2-16. A scatter plot of daily maximum 8-h average O3 concentrations versus

daily maximum temperature downwind of Phoenix, AZ.

Source: Piety (2005)

Some possible explanations for the correlation of O3 with temperature include:

(1) Increased photolysis rates under meterological conditions associated with higher

temperatures;

(2) Increased H2O concentrations with higher temperatures as this will lead to greater OH

production via R(2-6);

(3) Enhanced thermal decomposition of PAN and similar compounds to release NOx at

higher temperatures;

(4) Increase of anthropogenic hydrocarbon (e.g., evaporative losses) emissions or NOx,

emissions with temperature or both;

(5) Increase of natural hydrocarbon emissions (e.g., isoprene) with temperature; and

(6) Relationships between high temperatures and stagnant circulation patterns.

(7) Advection of warm air enriched with O3.
AX2-95

Cardelino and Chameides (1990) and Sillman and Samson (1995) both identified the

temperature-dependent thermal decomposition of PAN as the primary cause of the observed

O3-temperature relationship. When temperatures are low, PAN is relatively stable. Formation of

PAN represents a significant sink for NOx (in low NOx rural areas) and radicals (in high NOx

urban areas). This has the effect of slowing the rate of O3 production. Sillman and Samson

found that the impact of the PAN decomposition rate could explain roughly half of the observed

correlation between O3 and temperature. Jacob et al. (1993) found that warm events in summer

in the United States were likely to occur during stagnant meteorological conditions, and the

concurrence between warm temperatures and meteorological stagnation also explained roughly

half of the observed O3-temperature correlation. Other possible causes include higher solar

radiation during summer, the strong correlation between biogenic emission of isoprene and

temperature, and the somewhat weaker tendency for increased anthropogenic emissions

coinciding with warmer temperatures. 

However, it should also be noted that a high correlation of O3 with temperature does not

necessarily imply a causal relation. Extreme episodes of high temperatures (a heat wave) are

often multiday events, high O3 episodes are also multiday events, concentrations build,

temperatures rise, but both are being influenced by larger-scale regional or synoptic

meteorological conditions. It also seems apparent, that while there is a trend for higher O3

associated with higher temperatures, there is also much greater variance in the range of O3

mixing ratios at higher temperatures. 

AX2.4 THE RELATION OF OZONE TO ITS PRECURSORS AND

OTHER OXIDANTS

Ozone is unlike many other species whose rates of formation vary directly with the

emissions of their precursors. Ozone changes in a nonlinear fashion with the concentrations of

its precursors. At the low NOx concentrations found in most environments, ranging from remote

continental areas to rural and suburban areas downwind of urban centers the net production of O3

increases with increasing NOx. At the high NOx concentrations found in downtown metropolitan

areas, especially near busy streets and roadways, and in power plant plumes there is net

destruction (titration) of O3 by reaction with NO. In between these two regimes there is a
AX2-96

transition stage in which O3 shows only a weak dependence on NOx concentrations. In the high

NOx regime, NO2 scavenges OH radicals which would otherwise oxidize VOCs to produce

peroxy radicals, which in turn would oxidize NO to NO2. In the low NOx regime, the oxidation

of VOCs generates, or at least does not consume, free radicals and O3 production varies directly

with NOx. Sometimes the terms VOC limited and NOx limited are used to describe these two

regimes. However, there are difficulties with this usage because (1) VOC measurements are not

as abundant as they are for nitrogen oxides, (2) rate coefficients for reaction of individual VOCs

with free radicals vary over an extremely wide range, and (3) consideration is not given to CO

nor to reactions that can produce free radicals without invoking VOCs. The terms NOx-limited

and NOx-saturated (e.g., Jaeglé et al., 2001) will be used wherever possible to describe these two

regimes more adequately. However, the terminology used in original articles will also be kept. 

The chemistry of OH radicals, which are responsible for initiating the oxidation of hydrocarbons,

shows behavior similar to that for O3 with respect to NOx concentrations (Hameed et al., 1979;

Pinto et al., 1993; Poppe et al., 1993; Zimmerman and Poppe, 1993). These considerations

introduce a high degree of uncertainty into attempts to relate changes in O3 concentrations to

emissions of precursors. 

Various analytical techniques have been proposed that use ambient NOx and VOC

measurements to derive information about O3 production and O3-NOx-VOC sensitivity. It has

been suggested that O3 formation in individual urban areas could be understood in terms of

measurements of ambient NOx and VOC concentrations during the early morning (e.g., National

Research Council, 1991). In this approach, the ratio of summed (unweighted by chemical

reactivity) VOC to NOx is used to determine whether conditions were NOx-sensitive or VOC

sensitive. This procedure is inadequate because it omits many factors that are recognized as

important for O3 production: the impact of biogenic VOCs (which are not present in urban

centers during early morning); important individual differences in the ability of VOCs to

generate free radicals (rather than just total VOC) and other differences in O3 forming potential

for individual VOCs (Carter, 1995); the impact of multiday transport; and general changes in

photochemistry as air moves downwind from urban areas (Milford et al., 1994). 

Jacob et al. (1995) used a combination of field measurements and a chemistry-transport

model (CTM) to show that the formation of O3 changed from NOx-limited to NOx-saturated as

the season changed from summer to fall at a monitoring site in Shenandoah National Park, VA. 
AX2-97

Photochemical production of O3 generally occurs simultaneously with the production of various

other species: nitric acid (HNO3), organic nitrates, and hydrogen peroxide. The relative rate of

production of O3 and other species varies depending on photochemical conditions, and can be

used to provide information about O3-precursor sensitivity. 

There are no hard and fast rules governing the levels of NOx at which the transition from

NOx-limited to NOx-saturated conditions occurs. The transition between these two regimes is

highly spatially and temporally dependent. Similar responses to NOx additions from commercial

aircraft have also been found for the upper troposphere (Bruhl et al., 2000). Bruhl et al. (2000)

found that the NOx levels for O3 production versus loss are highly sensitive to the radical sources

included in model calculations. They found that the inclusion of only CH4 and CO oxidation

leads to a decrease in net O3 production in the North Atlantic flight corridor due to NO emissions

from aircraft. However, the inclusion of acetone photolysis was found to shift the maximum in

O3 production to higher NOx mixing ratios, thereby reducing or eliminating areas in which there

is a decrease in O3 production rates due to aircraft emissions. 

Trainer et al. (1993) suggested that the slope of the regression line between O3 and

summed NOx oxidation products (NOz, equal to the difference between measured total reactive

nitrogen, NOy, and NOx) can be used to estimate the rate of O3 production per NOx (also known

as the O3 production efficiency, or OPE). Ryerson et al. (1998, 2001) used measured

correlations between O3 and NOz to identify different rates of O3 production in plumes from

large point sources. 

Sillman (1995) and Sillman and He (2002) identified several secondary reaction products

that show different correlation patterns for NOx-limited conditions and NOx-saturated conditions. 

The most important correlations are for O3 versus NOy, O3 versus NOz, O3 versus HNO3, and

H2O2 versus HNO3. The correlations between O3 and NOy, and O3 and NOz are especially

important because measurements of NOy and NOx are widely available. Measured O3 versus

NOz (Figure AX2-17) shows distinctly different patterns in different locations. In rural areas and

in urban areas such as Nashville, TN, O3 shows a strong correlation with NOz and a relatively

steep slope to the regression line. By contrast, in Los Angeles O3 also increases with NOz, but

the rate of increase of O3 with NOz is lower and the O3 concentrations for a given NOz value are

generally lower. 
AX2-98

Figure AX2-17. Measured values of O3 and NOz (NOy–NOx) during the afternoon at rural

sites in the eastern United States (gray circles) and in urban areas and

urban plumes associated with Nashville, TN (gray dashes), Paris, FR

(black diamonds) and Los Angeles, CA (X’s). 

Sources: Trainer et al. (1993), Sillman et al. (1997, 1998, 2003). 

The difference between NOx-limited and NOx-saturated regimes is also reflected in

measurements of hydrogen peroxide (H2O2). Hydrogen peroxide production is highly sensitive

to the abundance of free radicals and is thus favored in the NOx-limited regime, typical of

summer conditions. Differences between these two regimes are also related to the preferential

formation of sulfate during summer and to the inhibition of sulfate and hydrogen peroxide

during winter (Stein and Lamb, 2003). Measurements in the rural eastern United States (Jacob

et al., 1995) Nashville (Sillman et al., 1998), and Los Angeles (Sakugawa and Kaplan, 1989)

show large differences in H2O2 concentrations between likely NOx-limited and NOx-saturated

locations. 

The discussion in Section AX2.4.1 centers mainly on the relations among O3, NOx and its

oxidation products, represented as NOz (NOy–NOx) and VOCs derived from the results of field

studies. Most of these studies examined processes occurring in power plant and urban plumes. 
AX2-99

AX2.4.1 Summary of Results for the Relations Among Ozone, its Precursors

and Other Oxidants from Recent Field Experiments

AX2.4.1.1 Results from the Southern Oxidant Study and Related Experiments

The Southern Oxidant Study (SOS) was initiated to describe the sources, variation, and

distribution of O3 and its precursors in the southeastern United States during the summer season

(Hübler et al., 1998; Meagher et al., 1998; Goldan et al., 2000). Specific issues that were

addressed included: (1) the role of biogenic VOC and NOx emissions on local and regional O3

production, (2) the effect of urban-rural exchange/interchange on local and regional O3

production, (3) sub-grid-scale photochemical and meteorological processes, and (4) the

provision of a high-quality chemical and meteorological data set to test and improve observation

and emission-based air quality forecast models. Some of the more significant findings of the

1994 to 1995 studies include the following: (1) Ozone production in Nashville was found to be

close to the transition between NOx-limited and NOx-saturated regimes. (2) The number of

molecules of O3 produced per molecule of NOx oxidized in power plant plumes, or the O3

production efficiency (OPE) was found to be inversely proportional to the NOx emission rate,

with the plants having the highest NOx emissions exhibiting the lowest OPE. (3) During

stagnant conditions, winds at night dominated pollutant transport and represent the major

mechanism for advecting urban pollutants to rural areas—specific findings follow. 

As part of SOS, the Tennessee Valley Authority’s instrumented helicopter conducted

flights over Atlanta, Georgia to investigate the evolution of the urban O3 plume (Imhoff et al.,

1995). Ozone peak levels occurred at 20 – 40 km downwind of the city center. The OPE

obtained from five afternoon flights ranged between 4 and 10 molecules of O3 per molecule

of NOx. 

Berkowitz and Shaw (1997) measured O3 and its precursors at several altitudes over a

surface site near Nashville during SOS to determine the effects of turbulent mixing on

atmospheric chemistry. Early morning measurements of O3 aloft revealed values near 70 ppb,

while those measured at the surface were closer to 25 ppb. As the daytime mixed layer

deepened, surface O3 values steadily increased until they reached 70 ppb. The onset of

turbulence increased isoprene mixing ratios aloft by several orders of magnitude and affected the

slope of O3 as a function of NOy for each of the flight legs. Measurements from nonturbulent

flight legs yielded slopes that were considerably steeper than those from measurements made in
AX2-100

turbulence. This study shows that the concentration of O3 precursors aloft is dependent on the

occurrence of turbulence, and turbulent mixing could explain the evolution of O3 concentrations

at the surface. In general, conclusions regarding pollutant concentrations must account for both

chemical and local dynamic processes. 

Gillani et al. (1998) analyzed data from instrumented aircraft during SOS that flew through

the plumes of three large, tall-stack, base-load, Tennessee Valley Authority (TVA) coal-fired

power plants in northwestern Tennessee. They determined that plume chemical maturity and

peak O3 and NOz production occurred within 30 to 40 km and 4 hours of summer daytime

convective boundary layer (CBL) transport time for a coal-fired power plant in the Nashville,

TN urban O3 nonattainment area (Gallatin). For a rural coal-fired power plant in an isoprenerich forested area about 100 km west of Nashville (Cumberland), plume chemical maturity and

peak O3 and NOz production were realized within approximately 100 km and 6 hours of CBL

transport time. Their findings included approximately 3 molecules of O3 and more than

0.6 molecules of NOz may be produced in large isolated rural power plant plumes (PPPs) per

molecule of NOx release; the corresponding peak yields of O3 and NOz may be significantly

greater in urban PPPs. Both power plants can contribute as much as 50 ppb of excess O3 to the

Nashville area, raising the local levels to well above 100 ppb. Also using aircraft data collected

during SOS, Ryerson et al. (1998) concluded that the lower and upper limits to O3 production

efficiency in the Cumberland and Paradise PPPs (located in rural Tennessee) were 1 and

2 molecules of O3 produced per molecule of NOx emitted. The estimated lower and upper limits

to O3 production efficiency in the Johnsonville PPP (also located in rural Tennessee) were

higher, at 3 and 7. 

The NOAA airborne O3 lidar provided detailed, three-dimensional lower tropospheric O3

distribution information during June and July 1995 in the Nashville area (Senff et al., 1998;

Alvarez et al., 1998). The size and shape of power plant plumes as well as their impacts on O3

concentration levels as the plume is advected downwind were studied. Specific examples

include: the July 7 Cumberland plume that was symmetrical and confined to the boundary layer,

and the July 19 Cumberland plume that was irregularly shaped with two cores, one above and

the other within the boundary layer. The disparate plume characteristics on these two days were

the result of distinctly different meteorological conditions. Ozone in the plume was destroyed at

a rate of 5 to 8 ppbv h!1

 due to NOx titration close to the power plant, while farther downwind,
AX2-101

O3 was produced at rates between 1.5 and 4 ppbv h!1

. The lidar O3 measurements compared

reasonably well with in situ values, with the average magnitude of the offsets over all the flights

at 4.3 ppbv (7%). 

The highest O3 concentrations observed during the 1995 SOS in middle Tennessee

occurred during a period of strong, synoptic-scale stagnation from July 11 through July 15. This

massive episode covered most of the eastern United States (e.g., Ryan et al., 1998). During this

time, the effects of vertical wind profiles on the buildup and transport of O3 were studied by

Banta et al. (1998) using an airborne differential absorption lidar (DIAL) system. Vertical cross

sections showed O3 concentrations exceeding 120 ppb extending to nearly 2 km above ground

level, but that O3 moved little horizontally. Instead, it formed a dome of pollution over or near

Nashville. Due to the stagnant daytime conditions (boundary layer winds ~1 to 3 m s!1

),

nighttime transport of O3 became disproportionately important. At night, in the layer between

100 and 2000 m AGL (which had been occupied by the daytime mixed layer), the winds could

be accelerated to 5 to 10 m s!1 as a result of nocturnal decoupling from surface friction. Data

from surface and other aircraft measurements taken during this period suggest that the

background air and the edges of the urban plume were NOx sensitive and the core of the urban

plume was hydrocarbon sensitive (Valente et al., 1998). Also revealed was the fact that the

surface monitoring network failed to document the maximum surface O3 concentrations. Thus,

monitoring networks, especially in medium-sized urban areas under slow transport conditions,

may underestimate the magnitude and frequency of urban O3 concentrations greater than

120 ppb. 

Nunnermacker et al. (1998) used both aircraft and surface data from SOS to perform a

detailed kinetic analysis of the chemical evolution of the Nashville urban plume. The analysis

revealed OH concentrations around 1.2 x 107

 cm-3 that consumed 50% of the NOx within

approximately 2 hours, at an OPE of 2.5 to 4 molecules for each molecule of NOx. 

Anthropogenic hydrocarbons provided approximately 44% of the fuel for O3 production by the

urban plume. 

Surface and aircraft observations of O3 and O3 precursors were compared during SOS to

assess the degree to which midday surface measurements may be considered representative of

the larger planetary boundary layer (PBL) (Luke et al., 1998). Overall agreement between

surface and aircraft O3 measurements was excellent in the well-developed mixed layer
AX2-102

(r2

 = 0.96), especially in rural-regional background air and under stagnant conditions, where

surface concentrations change only slowly. Vertical variations in trace gas concentrations were

often minimal in the well-mixed PBL, and measurements at the surface always agreed well with

aircraft observations up to the level of measurements (460 m above ground level). Under

conditions of rapidly varying surface concentrations (e.g., during episodes of power plant plume

fumigation and early morning boundary layer development), agreement between surface and

aloft was dependent upon the spatial (aircraft) and temporal (ground) averaging intervals used in

the comparison. Under these conditions, surface sites were representative of the PBL only to

within a few kilometers horizontally. 

On four days during SOS, air samples were taken in the plume of the Cumberland Power

Plant in central Tennessee using an instrumented helicopter to investigate the evolution of

photochemical smog (Luria et al., 1999, 2000). Twelve crosswind air-sampling traverses were

made between 35 and 116 km from this Power Plant on 16 July 1995. Winds, from the westnorthwest during the sampling period, directed the plume toward Nashville. Ten of the traverses

were performed upwind of Nashville, where the plume was isolated, and two were made

downwind of the city. The results indicated that even six hours after the plume left the stacks,

excess O3 production was limited to the edges of the plume. Excess O3 production within the

plume was found to vary from 20 ppb up to 55 ppb. It was determined that this variation

corresponded to differences in ambient isoprene levels. Excess O3 (up to 109 ppbv, 50 to

60 ppbv above background), was produced in the center of the plume when there was sufficient

mixing upwind of Nashville. The power plant plume apparently mixed with the urban plume

also, producing O3 up to 120 ppbv 15 to 25 km downwind of Nashville. 

Nunnermacker et al. (2000) used data from the DOE G-1 aircraft to characterize emissions

from a small power plant plume (Gallatin) and a large power plant plume (Paradise) in the

Nashville region. Observations made on July 3, 7, 15, 17, and 18, 1995, were compiled, and a

kinetic analysis of the chemical evolution of the power plant plumes was performed. OPEs were

found to be 3 in the Gallatin and 2 in the Paradise plumes. Lifetimes for NOx (2.8 and 4.2 hours)

and NOy (7.0 and 7.7 hours) were determined in the Gallatin and Paradise plumes, respectively. 

These NOx and NOy lifetimes imply rapid loss of NOz (assumed to be primarily HNO3), with a

lifetime determined to be 3.0 and 2.5 hours for the Gallatin and Paradise plumes, respectively. 
AX2-103

AX2.4.1.2 Results from Studies on Biogenic and Anthropogenic Hydrocarbons and

Ozone Production

Williams et al. (1997) made the first airborne measurements of peroxy-methacrylic nitric

anhydride (MPAN), which is formed from isoprene-NOx chemistry and is an indicator of recent

O3 production from isoprene and therefore biogenic hydrocarbons (BHC). They also measured

peroxyacetic nitric anhydride (PAN), peroxypropionic nitric anhydride (PPN), and O3 to estimate

the contributions of anthropogenic hydrocarbons (AHC) and BHC to regional tropospheric O3

production. 

Airborne measurements of MPAN, PAN, PPN, and O3 were made during the 1994 and

1995 Nashville intensive studies of SOS to determine the fraction of O3 formed from

anthropogenic NOx and BHC (Roberts et al., 1998). It was found that PAN, a general product of

hydrocarbon-NOx photochemistry, could be well represented as a simple linear combination of

contributions from BHC and AHC as indicated by MPAN and PPN, respectively. The

PAN/MPAN ratios, characteristic of BHC-dominated chemistry, ranged from 6 to 10. The

PAN/PPN ratios, characteristic of AHC-dominated chemistry, ranged from 5.8 to 7.4. These

ratios were used to estimate the contributions of AHC and BHC to regional tropospheric O3

production. It was estimated that substantial O3 (50 to 60 ppbv) was produced from BHC when

high NOx from power plants was present in areas of high BHC emission. 

AX2.4.1.3 Results of Studies on Ozone Production in Mississippi and Alabama

Aircraft flights made in June 1990 characterized the variability of O3 and reactive nitrogen

in the lower atmosphere over Mississippi and Alabama. The variety and proximity of sources

and the photochemical production and loss of O3 were found to be contributing factors (Ridley

et al., 1998). Urban, biomass burning, electrical power plant, and paper mill plumes were all

encountered during these flights. Urban plumes from Mobile, AL had OPEs as high as 6 to

7 ppbv O3 per ppbv of NOx. Emissions measured from biomass burning had lower efficiencies

of 2 to 4 ppbv O3 per ppbv of NOx, but the average rate of production of O3 was as high as

58 ppbv hr!1

 for one fire where the plume was prevented from vertical mixing. Near-source

paper mill and power plant plumes showed O3 titration, while far-field observations of power

plant plumes showed net O3 production. Early morning observations below a nocturnal

inversion provided evidence for the nighttime oxidation of NOx to reservoir species. 
AX2-104

Aircraft measurements of O3 and oxides of nitrogen were made downwind of Birmingham,

AL to estimate the OPE in the urban plume (Trainer et al., 1995). NOx emission rates were

estimated at 0.6 x 1025 molecules s!1 with an uncertainty of a factor of 2. During the

summertime it was determined that approximately seven O3 molecules could be formed for

every molecule of NOx emitted by the urban and proximately located power plant plumes. The

regional O3, the photochemical production of O3 during the oxidation of the urban emissions, and

wind speed and direction all combined to dictate the magnitude and location of the peak O3

concentrations observed in the vicinity of the Birmingham metropolitan area. 

Aircraft observations of rural U.S. coal-fired power plant plumes in the middle Mississippi

and Tennessee Valleys were used to quantify the nonlinear dependence of tropospheric O3

formation on plume NOx concentration, determined by plant NOx emission rate and atmospheric

dispersion (Ryerson et al., 2001). The ambient availability of reactive VOCs, primarily biogenic

isoprene, was also found to affect O3 production rate and yield in these rural plumes. Plume O3

production rates and yields as a function of NOx and VOC concentrations differed by a factor of

2 or more. These large differences indicate that power plant NOx emission rates and geographic

locations play a large role in tropospheric O3 production. 

AX2.4.1.4 The Nocturnal Urban Plume over Portland, Oregon

Aircraft observations of aerosol surface area, O3, NOy and moisture were made at night in

the Portland, Oregon urban plume (Berkowitz et al., 2001). Shortly after sunset, O3, relative

humidity, NOy and aerosol number density were all positively correlated. However, just before

dawn, O3 mixing ratios were highly anti-correlated with aerosol number density, NOy and

relative humidity. Back-trajectories showed that both samples came from a common source to

the northwest of Portland. The predawn parcels passed directly over Portland, while the other

parcels passed to the west of Portland. Several hypotheses were put forward to explain the loss

of O3 in the parcels that passed over Portland, including homogeneous gas-phase mechanisms

and a heterogeneous mechanism on the aerosol particle surface. 

AX2.4.1.5 Effects of VOCs in Houston on Ozone Production

Aircraft Observations of O3 and O3 precursors over Houston, TX, Nashville, TN; New

York, NY; Phoenix, AZ, and Philadelphia, PA showed that despite similar NOx concentrations,
AX2-105

high concentrations of VOCs in the lower atmosphere over Houston led to calculated O3

production rates that were 2 to 5 times higher than in the other 4 cities (Kleinman et al., 2002). 

Concentrations of VOCs and O3 production rates are highest in the Ship Channel region of

Houston, where one of the largest petrochemical complexes in the world is located. As a result,

Houston lays claim to the highest recorded hourly average O3 concentrations in the United States

within the last 5 years (in excess of 250 ppb). 

AX2.4.1.6 Chemical and Meteorological Influences on the Phoenix Urban Ozone Plume

The interaction of chemistry and meteorology for western cities can contrast sharply with

that of eastern cities. A 4-week field campaign in May and June of 1998 in the Phoenix area

comprised meteorological and chemical measurements (Fast et al., 2000). Data from models and

observations revealed that heating of the higher terrain north and east of Phoenix produced

regular, thermally driven circulations during the afternoon from the south and southwest through

most of the boundary layer, advecting the urban O3 plume to the northeast. Deep mixed layers

and moderate winds aloft ventilated the Phoenix area during the study period so that multiday

buildups of locally produced O3 did not appear to contribute significantly to O3 levels. 

Sensitivity simulations estimated that 20% to 40% of the afternoon surface O3 mixing ratios

(corresponding to 15 to 35 ppb) was due to the entrainment of O3 reservoirs into the growing

convective boundary layer. The model results also indicated that O3 production in this arid

region is NOx-saturated, unlike most eastern U.S. sites. 

AX2.4.1.7 Transport of Ozone and Precursors on the Regional Scale

Instrumented aircraft flights by the University of Maryland in a Cessna 172 and Sonoma

Technology, Inc. in a Piper Aztec measured the vertical profiles of trace gases and

meteorological parameters in Virginia, Maryland, and Pennsylvania on July 12–15, 1995 during

a severe O3 episode in the mid-Atlantic region (Ryan et al., 1998). Ozone measured upwind of

the urban centers reached 80 to 110 ppbv. Layers of high O3 aloft were associated with local

concentration maxima of SO2 and NOy, but not CO or NOx. This, together with a back trajectory

analysis, implicated coal-fired power plants in the industrialized Midwest as the source of the

photochemically aged air in the upwind boundary of the urban centers. When the PBL over the

Baltimore-Washington area deepened, the O3 and O3 precursors that had been transported from
AX2-106

the west and northwest mixed with the local emissions and O3 in excess of 125 ppbv was

measured at the surface. 

During the blackout of August 14, 2003 Marufu et al. (2004) measured profiles of O3, SO2

and CO over areas in western Pennsylvania, Maryland and Virginia. They found notable

decreases in O3, SO2, and NOx, over areas affected by the blackout but not over those that were

not affected. They also found that CO concentrations aloft were comparable over areas affected

and not affected by the blackout. They attributed the differences in concentrations between what

was observed and what was expected to the reduction in emissions from power plants mainly in

the Ohio Valley. They also reasoned that the CO concentrations were relatively unaffected

because they arise from traffic emissions, which may have been largely unaffected by the

blackout. However, the blackout also disrupted many industries, small scale emission sources,

and rail and air transportation.

The Department of Energy G-1 aircraft flew in the New York City metropolitan area in

the summer of 1996 as part of the North American Research Strategy for Tropospheric

Ozone-Northeast effort to ascertain the causes leading to high O3 levels in the northeastern

United States (Kleinman et al., 2000). Ozone, O3 precursors, and other photochemically active

trace gases were measured upwind and downwind of New York City to characterize the O3

formation process and its dependence on NOx and VOCs. During two flights, the wind was

south southwesterly and O3 levels reached 110 ppb. On two other flights, the wind was from the

north-northwest and O3 levels were not as high. When the G-1 observed O3 around 110 ppb, the

NOx/NOy ratio measured at the surface was between 0.20 and 0.30, indicating an aged plume. 

AX2.4.1.8 Model Calculations and Aircraft Observations of Ozone Over Philadelphia

Regional-scale transport and local O3 production over Philadelphia was estimated using a

new meteorological-chemical model (Fast et al., 2002). Surface and airborne meteorological and

chemical measurements made during a 30-day period in July and August of 1999 as part of the

Northeast Oxidant and Particulate Study were used to evaluate the model performance. Both

research aircraft and ozonesondes, during the morning between 0900 and 1100 LST, measured

layers of O3 above the convective boundary layer. The model accounted for these layers through

upwind vertical mixing the previous day, subsequent horizontal transport aloft, and NO titration

of O3 within the stable boundary layer at night. Entrainment of the O3 aloft into the growing
AX2-107

convective boundary contributed to surface O3 concentrations. During the study period, most of

the O3 appeared to result from local emissions in the vicinity of Philadelphia and the Chesapeake

Bay area, but during high O3 episodes, up to 30 to 40% of the O3 was due to regional transport

from upwind sources. 

AX2.4.1.9 The Two-Reservoir System

Studies described above and over 500 aircraft flights over the mid-Atlantic region show

that a two-reservoir system illustrated schematically in Figure AX2-18 may represent both the

dynamics and photochemistry of severe, multiday haze and O3 episodes over the eastern United

States (Taubman et al., 2004, 2005). The first reservoir is the PBL, where most precursor

species are injected, and the second is the lower free troposphere (LFT), where photochemical

processes are accelerated and removal via deposition is rare. Bubbles of air lifted from urban

and industrial sources were rich in CO and SO2, but not O3, and contained greater numbers of

externally mixed primary sulfate and black carbon (BC) particles. Correlations among O3, air

parcel altitude, particle size, and relative humidity suggest that greater O3 concentrations and

relatively larger particles are produced in the LFT and mix back down into the PBL. Backward

trajectories indicated source regions in the Midwest and mid-Atlantic urban corridor, with

southerly transport up the urban corridor augmented by the Appalachian lee trough and nocturnal

low-level jet (LLJ). This concept of two-reservoirs may facilitate the numerical simulation of

multiday events in the eastern United States. A relatively small number of vertical layers will be

required if accurate representation of the sub-gridscale transport can be parameterized to

represent the actual turbulent exchange of air between the PBL and lower free troposphere. 

AX2.5 METHODS USED TO CALCULATE RELATIONS BETWEEN

OZONE AND ITS PRECURSORS

Atmospheric chemistry and transport models are the major tools used to calculate the

relations between O3, its precursors, and other oxidation products. Other techniques, involving

statistical relations between O3 and other variables have also been used. Chemistry-transport

models (CTM) are driven by emissions inventories for O3 precursor compounds and by

meterological fields. Emissions of precursor compounds can be divided into anthropogenic and 
AX2-108

Figure AX2-18. Conceptual two-reservoir model showing conditions in the PBL and

in the lower free troposphere during a multiday O3 episode. The dividing

line, the depth of the mixed layer, is about 1000 m. Emissions occur in

the PBL, where small, unmixed black carbon, sulfate, and crustal

particles in the PM2.5 size range are also shown. Ozone concentrations as

well as potential temperature (2) and actinic flux are lower in the PBL

than in the lower free troposphere, while RH is higher. Larger, mixed

sulfate and carbonaceous particles (still in the PM2.5 size range) and more

O3 exist in the lower free troposphere.

Source: Taubman et al. (2004, 2005).

natural source categories. Natural sources can be further divided into biotic (vegetation,

microbes, animals) and abiotic (biomass burning, lightning) categories. However, the distinction

between natural sources and anthropogenic sources is often difficult to make as human activities

affect directly, or indirectly, emissions from what would have been considered natural sources

during the preindustrial era. Emissions from plants and animals used in agriculture are usually

referred to as anthropogenic. Wildfire emissions may be considered natural, except that forest

management practices may have led to the buildup of fuels on the forest floor, thereby altering

the frequency and severity of forest fires. Needed meteorological quantities such as winds and
AX2-109

temperatures are taken from operational analyses, reanalyses, or circulation models. In most

cases, these are off-line analyses, i.e., they are not modified by radiatively active species such as

O3 and particles generated by the model. 

A brief overview of atmospheric chemistry-transport models is given in Section AX2.5.1. 

A discussion of emissions inventories of precursors that are used by these models is given in

Section AX2.5.2. Uncertainties in emissions estimates have also been discussed in Air Quality

Criteria for Particulate Matter (U.S. Environmental Protection Agency, 2000). So-called

“observationally based models” which rely more heavily on observations of the concentrations

of important species are discussed in Section AX2.5.3. Chemistry-transport model evaluation

and an evaluation of the reliability of emissions inventories are presented in Section AX2.5.4. 

AX2.5.1 Chemistry-Transport Models

Atmospheric chemistry-transport models (CTMs) are used to obtain better understanding

of the processes controlling the formation, transport, and destruction of O3 and other air

pollutants; to understand the relations between O3 concentrations and concentrations of its

precursors such as NOx and VOCs; and to understand relations among the concentration patterns

of O3 and other oxidants that may also exert health effects. Detailed examination of the

concentrations of short-lived species in a CTM can provide important insights into how O3 is

formed under certain conditions and can suggest likely avenues for data analysis and future

experiments and field campaigns. The dominant processes leading to the formation of O3 in a

particular time period, questions about whether NOx or VOCs were more important, the

influence of meteorology and of emissions from a particular geographic region, and the

transformation or formation of other pollutants could be examined using a CTM. 

CTMs are also used for determining control strategies for O3 precursors. However, this

application has met with varying degrees of success because of the highly nonlinear relations

between O3 and emissions of its precursors. CTMs include mathematical descriptions of

atmospheric transport, emissions, the transfer of solar radiation through the atmosphere,

chemical reactions, and removal to the surface by turbulent motions and precipitation for

chemical species of interest. Increasingly, the trend is for these processes to be broken down and

handled by other models or sub-models, so a CTM will likely use emissions and meteorological

data from at least two other models. 
AX2-110

There are two major formulations of CTMs in current use. In the first approach,

grid-based, or Eulerian, air quality models, the region to be modeled (the modeling domain) is

subdivided into a three-dimensional array of grid cells. Spatial derivatives in the species

continuity equations are cast in finite-difference form over this grid, and a system of equations

for the concentrations of all the chemical species in the model are solved numerically at each

grid point. The modeling domain may be limited to a particular airshed or provide global

coverage and extend through several major atmospheric layers. Time dependent continuity

(mass conservation) equations are solved for each species including terms for transport, chemical

production and destruction, and emissions and deposition (if relevant), in each cell. Chemical

processes are simulated with ordinary differential equations, and transport processes are

simulated with partial differential equations. Because of a number of factors such as the

different time scales inherent in different processes, the coupled, nonlinear nature of the

chemical process terms, and computer storage limitations, all of the terms in the equations are

not solved simultaneously in three dimensions. Instead, a technique known as operator splitting,

in which terms involving individual processes are solved sequentially, is used. In the second

application of CTMs, trajectory or Lagrangian models, a large number of hypothetical air parcels

are specified as following wind trajectories. In these models, the original system of partial

differential equations is transformed into a system of ordinary differential equations. 

A less common approach is to use a hybrid Lagrangian/Eulerian model, in which certain

aspects of atmospheric chemistry and transport are treated with a Lagrangian approach and

others are treaded in a Eulerian manner (e.g., Stein et al., 2000). Both modeling approaches have

their advantages and disadvantages. The Eulerian approach is more general in that it includes

processes that mix air parcels and allows integrations to be carried out for long periods during

which individual air parcels lose their identity. There are, however, techniques for including the

effects of mixing in Lagrangian models such as FLEXPART (e.g., Zanis et al., 2003), ATTILA

(Reithmeir and Sausen, 2002), and CLaMS (McKenna et al., 2002). 

Major modeling efforts within the U.S. Environmental Protection Agency center on the

Models3/Community Modeling for Air Quality (CMAQ, Byun et al., 1998) and the Multi Scale

Air Quality Simulation Platform (MAQSIP, Odman and Ingram, 1996) whose formulations are

based on the regional acid deposition model (RADM, Chang et al., 1987). A number of other

modeling platforms using the Lagrangian and Eulerian frameworks have been reviewed in
AX2-111

AQCD 96. CTMs currently in use are summarized in the review by Russell and Dennis (2000). 

Evaluations of the performance of CMAQ are given in Arnold et al. (2003) and Fuentes and

Raftery (2005). The domains of MAQSIP and CMAQ are flexible and can extend from several

hundred km to the hemispherical scale. In addition, both of these classes of models allow the

resolution of the calculations over specified areas to vary. CMAQ and MAQSIP are both driven

by the MM5 mesoscale meteorological model (Seaman, 2000), though both may be driven by

other meteorological models (e.g., RAMS and Eta). Simulations of regional O3 episodes have

been performed with a horizontal resolution of 4 km. In principle, calculations over limited

domains can be accomplished to even finer scales. However, simulations at these higher

resolutions require better parameterizations of meteorological processes such as boundary layer

fluxes, deep convection and clouds (Seaman, 2000), and knowledge of emissions. Resolution at

finer scales will likely be necessary to resolve smaller-scale features such as the urban heat

island; sea, bay, and land breezes; and the nocturnal low-level jet. 

Currently, the most common approach to setting up the horizontal domain is to nest a finer

grid within a larger domain of coarser resolution. However, a number of other strategies are

currently being developed, such as the stretched grid (e.g., Fox-Rabinowitz et al., 2002) and the

adaptive grid. In a stretched grid, the grid’s resolution continuously varies throughout the

domain, thereby eliminating any potential problems with the sudden change from one resolution

to another at the boundary. One must be careful in using such a formulation, because certain

parameterizations that are valid on a relatively coarse grid scale (such as convection, for

example) are not valid or should not be present on finer scales. Adaptive grids are not set at the

start of the simulation, but instead adapt to the needs of the simulation as it evolves (e.g., Hansen

et al., 1994). They have the advantage that, if the algorithm is properly set up, the resolution is

always sufficient to resolve the process at hand. However, they can be very slow if the situation

to be modeled is complex. Additionally, if one uses adaptive grids for separate meteorological,

emissions, and photochemical models, there is no reason a priori why the resolution of each grid

should match; and the gains realized from increased resolution in one model will be wasted in

the transition to another model. The use of finer and finer horizontal resolution in the

photochemical model will necessitate finer-scale inventories of land use and better knowledge of

the exact paths of roads, locations of factories, and, in general, better methods for locating
AX2-112

sources. The present practice of locating a source in the middle of a county or distributing its

emissions throughout a county if its location is unknown will likely not be adequate in the future.

The vertical resolution of these models continues to improve as more layers are added to

capture atmospheric processes and structures. This trend will likely continue because a model

with 25 vertical layers, for example, may have layers that are 500 m thick at the top of the

planetary boundary layer. Though the boundary layer height is generally determined through

other methods, the chemistry in the model is necessarily confined by such layering schemes. 

Because the height of the boundary layer is of critical importance in simulations of air quality,

improved resolution of the boundary layer height would likely improve air quality simulations. 

The difficulty of properly establishing the boundary layer height is most pronounced when

considering tropopause folding events, which are important in determining the chemistry of the

background atmosphere. In the vicinity of the tropopause, the vertical resolution of most any

large scale model is quite unlikely to be able to capture such a feature. Additionally, any current

model is likely to have trouble adequately resolving fine scale features such as the low-level jet. 

Finally, models must be able to treat emissions, meteorology, and photochemistry differently in

different areas. Emissions models are likely to need better resolution near the surface and

possibly near any tall stacks. Photochemical models, on the other hand, may need better

resolution away from the surface and be more interested in resolving the planetary boundary

layer height, terrain differences, and other higher altitude features. Meteorological models share

some of the concerns of photochemical models, but are less likely to need sufficient resolution to

adequately treat a process such as dry deposition beneath a stable nocturnal boundary layer. 

Whether the increased computational power necessary for such increases in resolution will be

ultimately justified by improved results in the meteorological and subsequent photochemical

simulations remains to be seen. 

CTMs require time dependent, three-dimensional wind fields for the time period of

simulation. The winds may be either generated by a model using initial fields alone or four

dimensional data assimilation can be used to improve the model’s meteorological fields (i.e.,

model equations can be updated periodically [or “nudged”] to bring results into agreement with

observations). Most modeling efforts have focused on simulations of several days duration (a

typical time scale for individual O3 episodes), but there have been several attempts at modeling

longer periods. For example, Kasibhatla and Chameides (2000) simulated a four month period
AX2-113

from May to September of 1995 using MAQSIP. The current trend appears to be toward

simulating longer time periods. This will impose additional strains on computational resources,

as most photochemical modeling until recently has been performed with an eye toward

simulating only summertime episodes of peak O3. With the shift toward modeling an entire year

being driven by the desire to understand observations of periods of high wintertime PM (e.g.,

Blanchard et al., 2002), models will be further challenged to simulate air quality under

conditions for which they may not have been used previously. 

Chemical kinetics mechanisms (a set of chemical reactions) representing the important

reactions that occur in the atmosphere are used in air quality models to estimate the net rate of

formation of each pollutant simulated as a function of time. Chemical mechanisms that

explicitly treat the chemical reactions of each individual reactive species are too lengthy and

demanding of computer resources to be incorporated into three-dimensional atmospheric models. 

As an example, a master chemical mechanism includes approximately 10,500 reactions

involving 3603 chemical species (Derwent et al., 2001). Instead, “lumped” mechanisms, that

group compounds of similar chemistry together, are used. The chemical mechanisms used in

existing photochemical O3 models contain significant uncertainties that may limit the accuracy

of their predictions; the accuracy of each of these mechanisms is also limited by missing

chemistry. Because of different approaches to the lumping of organic compounds into surrogate

groups, chemical mechanisms, can produce somewhat different results under similar conditions. 

The CB-IV chemical mechanism (Gery et al., 1989), the RADM II mechanism (Stockwell et al.,

1990), the SAPRC (e.g., Wang et al., 2000a,b; Carter, 1990) and the RACM mechanisms can be

used in CMAQ. Jimenez et al. (2003) provide brief descriptions of the features of the main

mechanisms in use and they compared concentrations of several key species predicted by seven

chemical mechanisms in a box model simulation over 24 h. The average deviation from the

average of all mechanism predictions for O3 and NO over the daylight period was less than 20%,

and 10% for NO2 for all mechanisms. However, much larger deviations were found for HNO3,

PAN, HO2, H2O2, C2H4 and C5H8 (isoprene). An analysis for OH radicals was not presented. 

The large deviations shown for most species imply differences between the calculated lifetimes

of atmospheric species and the assignment of model simulations to either NOx limited or radical

limited regimes between mechanisms. Gross and Stockwell (2003) found small differences

between mechanisms for clean conditions with differences becoming more significant for
AX2-114

polluted conditions, especially for NO2 and organic peroxy radicals. They caution modelers to

consider carefully the mechanisms they are using.

As CTMs incorporate more processes and knowledge of aerosol- and gas-phase chemistry

improves, a “one atmosphere” approach is evolving. For example, CMAQ and PM-CAMx now

incorporate some aerosol processes, and several attempts are currently underway to study

feedbacks of chemistry on atmospheric dynamics using meteorological models, usually MM5

(e.g., Grell et al., 2000; Liu et al., 2001a; Lu et al., 1997; Park et al., 2001). This coupling may

be necessary to accurately simulate cases such as the heavy aerosol loading found in forest fire

plumes (Lu et al., 1997; Park et al., 2001). 

Spatial and temporal characterizations of anthropogenic and biogenic precursor emissions

must be specified as inputs to a CTM. Emissions inventories have been compiled on grids of

varying resolution for many hydrocarbons, aldehydes, ketones, CO, NH3, and NOx. Emissions

inventories for many species require the application of some algorithm for calculating the

dependence of emissions on physical variables such as temperature. For many species,

information concerning the temporal variability of emissions is lacking, so long term (e.g.,

annual or O3-season) averages are used in short term, episodic simulations. Annual emissions

estimates are often modified by the emissions model to produce emissions more characteristic of

the time of day and season. Significant errors in emissions can occur if an inappropriate time

dependence or a default profile is used. Additional complexity arises in model calculations

because different chemical mechanisms are based on different species, and inventories

constructed for use with another mechanism must be adjusted to reflect these differences. This

problem also complicates comparisons of the outputs of these models because one chemical

mechanism will necessarily produce species that are different from those in another and neither

output will necessarily agree with the measurements. 

The effects of clouds on atmospheric chemistry are complex and introduce considerable

uncertainty into CTM calculations. Thunderstorm clouds are optically very thick and have

major effects on radiative fluxes and thus on photolysis rates. Madronich (1987) provided

modeling estimates of the effects of clouds of various optical depths on photolysis rates. In the

upper portion of a thunderstorm anvil, photolysis is likely to be enhanced (as much as a factor of

2 or more) due to multiple reflections off the ice crystals. In the lower portion of the cloud and

beneath the cloud, photolysis is substantially decreased. Thunderstorm updrafts, which contain
AX2-115

copious amounts of water, are regions where efficient scavenging of soluble species occurs

(Balkanski et al., 1993). Direct field measurements of the amounts of specific trace gases

scavenged in observed storms are sparse. Pickering et al. (2001) used a combination of model

estimates of soluble species that did not include wet scavenging and observations of these

species from the upper tropospheric outflow region of a major line of convection observed near

Fiji. Over 90% of the nitric acid and hydrogen peroxide in the outflow air appeared to have been

removed by the storm. Walcek et al. (1990) included a parameterization of cloud-scale aqueous

chemistry, scavenging, and vertical mixing in the regional scale, chemistry-transport model of

Chang et al. (1987). The vertical distribution of cloud microphysical properties and the amount

of subcloud-layer air lifted to each cloud layer were determined using a simple entrainment

hypothesis (Walcek and Taylor, 1986). Vertically-integrated O3 formation rates over the

northeastern United States were enhanced by ~50% when the in-cloud vertical motions were

included in the model. 

In addition to wet deposition, dry deposition (the removal of chemical species from the

atmosphere by interaction with ground-level surfaces) is an important removal process for

pollutants on both urban and regional scales and must be included in CTMs. The general

approach used in most models is the three-resistance method, in which where dry deposition is

parameterized with a deposition velocity, which is represented as vd = (ra + rb + rc)

!1

 where ra, rb,

and rc represent the resistance due to atmospheric turbulence, transport in the fluid sublayer very

near the elements of surface such as leaves or soil, and the resistance to uptake of the surface

itself. This approach works for a range of substances although it is inappropriate for species

with substantial emissions from the surface or for species whose deposition to the surface

depends on its concentration at the surface itself. The approach is also modified somewhat for

aerosols: the terms rb and rc are replaced with a surface deposition velocity to account for

gravitational settling. In their review, Wesley and Hicks (2000) point out several shortcomings

of current knowledge of dry deposition. Among those shortcomings are difficulties in

representing dry deposition over varying terrain where horizontal advection plays a significant

role in determining the magnitude of ra and difficulties in adequately determining a deposition

velocity for extremely stable conditions such as those occurring at night (e.g., Mahrt, 1998). 

Under the best of conditions, when a model is exercised over a relatively small area where dry

deposition measurements have been made, models still commonly show uncertainties at least as
AX2-116

large as ± 30% (e.g., Massman et al., 1994; Brook et al., 1996; Padro, 1996). Wesley and

Hicks (2000) state that an important result of these comparisons is that the current level of

sophistication of most dry deposition models is relatively low and relies heavily on empirical

data. Still larger uncertainties exist when the surface features are not well known or when the

surface comprises a patchwork of different surface types, as is common in the eastern United

States. 

The initial conditions, i.e., the concentration fields of all species computed by a model, and

the boundary conditions, i.e., the concentrations of species along the horizontal and upper

boundaries of the model domain throughout the simulation must be specified at the beginning of

the simulation. It would be best to specify initial and boundary conditions according to

observations. However, data for vertical profiles of most species of interest are sparse. 

Ozonesonde data have been used to specify O3 fields, but the initial and boundary values of

many other species are often set equal to zero because of a lack of observations. Further,

ozonesondes are thought to be subject to errors in measurement and differences arising from

improper corrections for pump efficiency and the solutions used (e.g., Hilsenrath et al., 1986;

Johnson et al., 2002). The results of model simulations over larger, preferably global, domains

can also be used. As may be expected, the influence of boundary conditions depends on the

lifetime of the species under consideration and the time scales for transport from the boundaries

to the interior of the model domain (Liu et al., 2001b). 

Each of the model components described above has an associated uncertainty, and the

relative importance of these uncertainties varies with the modeling application. The largest

errors in photochemical modeling are still thought to arise from the meteorological and

emissions inputs to the model (Russell and Dennis, 2000). Within the model itself, horizontal

advection algorithms are still thought to be significant source of uncertainty (e.g., Chock and

Winkler, 1994) though more recently those errors are thought to have been reduced (e.g., Odman

et al., 1996). There are also indications that problems with mass conservation continue to be

present in photochemical and meteorological models (e.g., Odman and Russell, 1999); these can

result in significant simulation errors. Uncertainties in meteorological variables and emissions

can be large enough that they would lead one to make the wrong decision when considering

control strategies (e.g., Russell and Dennis, 2000; Sillman et al., 1995). The effects of errors in

initial conditions can be minimized by including several days “spin-up” time in a simulation to
AX2-117

allow species to come to chemical equilibrium with each other before the simulation of the

period of interest begins. 

While the effects of poorly specified boundary conditions propagate through the model’s

domain, the effects of these errors remain undetermined. Many regional models specify constant

O3 profiles (e.g., 35 ppb) at their lateral and upper boundaries; ozonesonde data, however,

indicate that the mixing ratio of O3 increases vertically in the troposphere (to over 100 ppb at the

tropopause) and into the stratosphere (e.g., Newchurch et al., 2003). The practice of using

constant O3 profiles strongly reduces the potential effects of vertical mixing of O3 from above

the planetary boundary layer (via mechanisms outlined in Section AX2.3) on surface O3 levels. 

The use of an O3 climatology (e.g., Fortuin and Kelder, 1998) might reduce the errors that would

otherwise be incurred. Because many meteorological processes occur on spatial scales which

are smaller than the grid spacing (either horizontally or vertically) and thus are not calculated

explicitly, parameterizations of these processes must be used and these introduce additional

uncertainty. 

Uncertainty also arises in modeling the chemistry of O3 formation because it is highly

nonlinear with respect to NOx concentrations. Thus, the volume of the grid cell into which

emissions are injected is important because the nature of O3 chemistry (i.e., O3 production or

titration) depends in a complicated way on the concentrations of the precursors and the OH

radical. The use of ever-finer grid spacing allows regions of O3 titration to be more clearly

separated from regions of O3 production. The use of grid spacing fine enough to resolve the

chemistry in individual power-plant plumes is too demanding of computer resources for this to

be attempted in most simulations. Instead, parameterizations of the effects of subgrid scale

processes such as these must be developed; otherwise serious errors can result if emissions are

allowed to mix through an excessively large grid volume before the chemistry step in a model

calculation is performed. In light of the significant differences between atmospheric chemistry

taking place inside and outside of a power plant plume (e.g., Ryerson et al., 1998 and Sillman,

2000), inclusion of a separate, meteorological module for treating large, tight plumes is

necessary. Because the photochemistry of O3 and many other atmospheric species is nonlinear,

emissions correctly modeled in a tight plume may be incorrectly modeled in a more dilute

plume. Fortunately, it appears that the chemical mechanism used to follow a plume’s

development need not be as detailed as that used to simulate the rest of the domain, as the
AX2-118

inorganic reactions are the most important in the plume (e.g., Kumar and Russell, 1996). The

need to include explicitly plume-in-grid chemistry disappears if one uses the adaptive grid

approach mentioned previously, though such grids are more computationally intensive. The

differences in simulations are significant because they can lead to significant differences in the

calculated sensitivity of O3 to its precursors (e.g., Sillman et al., 1995). 

Because the chemical production and loss terms in the continuity equations for individual

species are coupled, the chemical calculations must be performed iteratively until calculated

concentrations converge to within some preset criterion. The number of iterations and the

convergence criteria chosen also can introduce error. 

The importance of global transport of O3 and its contribution to regional O3 levels in the

United States is slowly becoming apparent. There are presently on the order of 20

three-dimensional global models that have been developed by various groups to address

problems in tropospheric chemistry. These models resolve synoptic meteorology, O3-NOx-COhydrocarbon photochemistry, wet and dry deposition, and parameterize sub-grid scale vertical

mixing such as convection. Global models have proven useful for testing and advancing

scientific understanding beyond what is possible with observations alone. For example, they can

calculate quantities of interest that we do not have the resources to measure directly, such as

export of pollution from one continent to the global atmosphere or the response of the

atmosphere to future perturbations to anthropogenic emissions. 

The finest horizontal resolution at which global simulations are typically conducted is

~200 km2

 although rapid advances in computing power continuously change what calculations

are feasible. The next generation of models will consist of simulations that link multiple

horizontal resolutions from the global to the local scale. Finer resolution will only improve

scientific understanding to the extent that the governing processes are more accurately described

at that scale. Consequently there is a critical need for observations at the appropriate scales to

evaluate the scientific understanding represented by the models. 

Observations of specific chemical species have been useful for testing transport schemes. 

Radon-222 simulations in sixteen global models have been evaluated with observations to show

that vertical mixing is captured to within the constraints offered by the mean observed

concentrations (Jacob et al., 1997). Tracers such as cosmogenic 7

Be and terrigenic 210Pb have

been used to test and constrain model transport and wet deposition (e.g., Liu et al., 2001b). 
AX2-119

Other chemical species obtained from various platforms (surface measurements, aircraft,

satellites) are useful for evaluating the simulation of chemical and dynamical processing in

global models. For example, Emmons et al. (2000) compiled available measurements of

12 species relevant to O3 photochemistry from a number of aircraft campaigns in different

regions of the world and used this data composite to evaluate two global models. They

concluded that one model (MOZART) suffered from weak convection and an underestimate of

nitrogen oxide emissions from biomass burning, while another model (IMAGES) transported too

much O3 from the stratosphere to the troposphere (Emmons et al., 2000). The global coverage

available from satellite observations offers new information for testing models. Recent efforts

are using satellite observations to evaluate the emission inventories of O3 precursors that are

included in global models; such observations should help to constrain the highly uncertain

natural emissions of isoprene and nitrogen oxides (e.g., Palmer et al., 2003; Martin et al., 2003). 

A comparison of numerous global chemistry-transport models developed by groups around

the world was included in Section 4.4 of the recent report of the Intergovernmental Panel on

Climate Change (Prather and Ehhalt, 2001). In that report, monthly mean O3 (O3) and carbon

monoxide (CO) simulated by the various models was evaluated with O3 observations from global

ozonesonde stations at 700, 500, and 300 hPa and with surface CO measurements from

17 selected NOAA/CMDL sites. The relevant figures (Figures AX2-4-10 and AX2-4-11) are

reproduced here (as Figures AX2-19 for O3 and AX2-20 for CO) along with the references in

their Table AX2-10 (as Table AX2-4). Overall, the models capture the general features of the O3

and CO seasonal cycles but meet with varying levels of success at matching the observed

concentrations and the amplitude of the observed seasonal cycle. For O3, the models show less

disagreement in the lower troposphere than in the upper troposphere, reflecting the difficulty of

representing the exchange between the stratosphere and troposphere and the loose constraints on

the net O3 flux that are provided by observations. 

An evaluation of five global models with data from the Measurement of Ozone and Water

Vapor by Airbus In-Service Aircraft (MOZAIC) project over New York City and Miami

indicates that the models tend to underestimate the summer maximum in the middle and lower

troposphere over northern mid-latitude cities such as New York City and to underestimate the

variability over coastal cities such as Miami which are strongly influenced by both polluted

continental and clean marine air masses (Law et al., 2000). Local maxima and minima are 
AX2-120

Figure AX2-19. Seasonal variability in O3 concentrations observed at a number of

pressure surfaces at six ozonesonde sites and the predictions of 13 global

scale chemistry-transport models.

Source: IPCC Third Assessment Report (2001).
AX2-121

Figure AX2-20. Seasonal variability in O3 concentrations observed at a number of

pressure surfaces at six ozonesonde sites and the predictions of 13 global

scale chemistry-transport models.

Source: IPCC Third Assessment Report (2001).

difficult to reproduce with global models because processes are averaged over an entire model

grid cell. Much of the spatial and temporal variability in surface O3 over the United States is

modulated by synoptic meteorology (e.g., Logan, 1989; Eder et al., 1993; Vukovich, 1995, 1997;

Cooper and Moody, 2000) which is resolved in the current generation of global models. 

For example, an empirical orthogonal function analysis on observed and simulated fields over
AX2-122

Table AX2-4. Chemistry-Transport Models (CTM) Contributing to the Oxcomp

Evaluation of Predicting Tropospheric O3 and OH (Prather and Ehhalt, 2001)

CTM Institute Contributing Authors References

GISS GISS Shindell/Grenfell Hansen et al. (1997)

HGEO Harvard U. Bey/Jacob Bey et al. (2001a)

HGIS Harvard U. Mickley/Jacob Mickley et al. (1999)

IASB IAS/Belg. Mülller Müller and Brasseur

(1995, 1999)

KNMI KNMI/Utrecht van Weele Jeuken et al. (1999),

Houweling et al. (2000)

MOZ1 NCAR/CNRS Hauglustaine/Brasseur Brasseur et al. (1998),

Hauglustaine et al. (1998)

MOZ2 NCAR Horowitz/Brasseur Brasseur et al. (1998),

Hauglustaine et al.(1998)

MPIC MPI/Chem Kuhlmann/Lawrence Crutzen et al. (1999),

Lawrence et al. (1999)

UCI UC Irvine Wild Hannegan et al. (1998),

Wild and Prather (2000)

UIO U. Oslo Berntsen Berntsen and Isaksen (1997),

Fuglestvedt et al. (1999)

UIO2 U. Oslo Sundet Sundet (1997)

UKMO UK Met Office Stevenson Collins et al. (1997),

Johnson et al. (1999)

ULAQ U. L. Aquila Pitari Pitari et al. (1997)

UCAM U. Cambridge Plantevin/Johnson

(TOMCAT)

Law et al. (1998, 2000)

the eastern United States in summer has shown that a 2° × 2.5° horizontal resolution global

model (GEOS-CHEM) captures the synoptic-scale processes that control much of the observed 

variability (Fiore et al., 2003). Further evaluation of the same model showed that it can also

capture many of the salient features of the observed distributions of O3 as well as its precursors 

in surface air over the United States in summer, including formaldehyde concentrations and
AX2-123

correlations between O3 and the oxidation products of nitrogen oxides (O3: NOy-NOx), all of

which indicate a reasonable photochemical simulation (Fiore et al., 2002). 

A significant amount of progress in evaluating the performance of three-dimensional

global models with surface, aircraft, and satellite data has been made in recent years. 

Disagreement among model simulations mainly stems from differences in the driving

meteorology and emissions. The largest discrepancies amongst models and between models and

observations occur in the upper troposphere and likely reflect uncertainties in exchange between

the stratosphere and troposphere and photochemical processes there; the models agree better

with observations closer to the surface. Synoptic-scale meteorology is resolved in these models,

enabling them to simulate much of the observed variability in pollutants in the lower

troposphere. 

AX2.5.2 Emissions of Ozone Precursors

Estimated annual emissions of nitrogen oxides, VOCs, CO, and NH3 for 1999 (U.S.

Environmental Protection Agency, 2001) are shown in Tables AX2-5, AX2-6, AX2-7, and

AX2-8. Methods for estimating emissions of criteria pollutants, quality assurance procedures

and examples of emissions calculated by using data are given in U.S. Environmental Protection

Agency (1999). 

Emissions of nitrogen oxides associated with combustion arise from contributions from

both fuel nitrogen and atmospheric nitrogen. Sawyer et al. (2000) have reviewed the factors

associated with NOx emissions by mobile sources. Estimates of NOx emissions from mobile

sources are generally regarded as fairly reliable although further work is needed to clarify this

point (Sawyer et al., 2000). Both nitrifying and denitrifying bacteria in the soil can produce

NOx, mainly in the form of NO. Emission rates depend mainly on fertilization levels and soil

temperature. About 60% of the total NOx emitted by soils occurs in the central corn belt of the

United States. The oxidation of NH3, emitted mainly by livestock and soils, leads to the 

formation of NO. Estimates of emissions from natural sources are less certain than those from

anthropogenic sources. 

Natural sources of oxides of nitrogen include lightning, oceans, and soil. Of these, as

reviewed in AQCD 96, only soil emissions appear to have the potential to impact surface O3 over

the U.S. On a global scale, the contribution of soil emissions to the oxidized nitrogen budget is
AX2-124

Table AX2-5. Emissions of Nitrogen Oxides by Various Sources in the 

United States in 1999

Source

Emissions1

(1012 g/y) Notes

On-road vehicle exhaust 7.8 Gasoline (58%) and diesel (42%) vehicles.

Non-road vehicle exhaust 5 Diesel (49%) and gasoline (3%) vehicles; railroads (22%);

marine vessels (18%); other sources (8%).

Fossil fuel combustion 9.1 Electric utilities (57%); industry (31%); commercial,

institutional and residential combustion (12%).

Industrial Processes 0.76 Mineral products (43%); petrochemical products (17%);

chemical mfg. (16%); metal processing (11%); misc.

industries (12%).

Biomass burning 0.35 Residential wood burning (11%); 

open burning (8%); wildfires (81%).

Waste disposal 0.053 Non-biomass incineration.

Natural sources2 3.1 Lightning (50%); soils(50%).

Total 26

1

Emissions are expressed in terms of NO2. 2

Estimated on the basis of data given in Guenther et al. (2000).

Source: U.S. Environmental Protection Agency (2001).

on the order of 10% (van Aardenne et al., 2001; Finlayson-Pitts and Pitts, 2000; Seinfeld and

Pandis, 1998), but attempts to quantify emissions of NOx from fertilized fields show great

variability. Soil NO emissions can be estimated from the fraction of the applied fertilizer

nitrogen emitted as NOx, but the flux varies strongly with land use and temperature. The fraction

nitrogen. Estimated globally averaged fractional applied nitrogen loss as NO varies from 0.3%

(Skiba et al., 1997) to 2.5% (Yienger and Levy, 1995). Variability within biomes to which

fertilizer is applied, such as shortgrass versus tallgrass prairie, accounts for a factor of three in

uncertainty (Williams et al., 1992; Yienger and Levy, 1995; Davidson and Kingerlee, 1997). 

The local contribution can be much greater than the global average, particularly in summer

especially where corn is grown extensively. Williams et al. (1992) estimated that contributions

from soils in Illinois contribute about 26% of the emissions from industrial and commercial
AX2-125

Table AX2-6. Emissions of Volatile Organic Compounds by Various Sources in the

United States in 1999

Source

Emissions

(1012 g/y) Notes

On-road vehicles 4.8 Exhaust and evaporative losses from gasoline (95%) and

diesel (5%) vehicles.

Non-road vehicles 2.9 Exhaust and evaporative losses from gasoline (80%) and

diesel (12%) vehicles; aircraft and other sources (8%). 

Fossil fuel combustion 0.27 Electrical utilities; industrial, commercial, institutional,

and residential sources.

Chemical industrial

 processes

0.36 Mfg. of organic chemicals, polymers and resins, and misc.

products.

Petroleum industrial

 processes

0.39 Oil and gas production (64%); refining (36%). 

Other industrial

processes

0.48 Metal processing (15%); wood processing (32%); 

agricultural product processing (21%); misc.

processes (18%). 

Solvent volatilization 4.4 Surface coatings (44%); other industrial uses (20%); nonindustrial uses (e.g., pesticide application, consumer

solvents) (36%).

Storage and transport

 of volatile compounds

1.1 Evaporative losses from petroleum products and other

organic compounds.

Biomass burning 1.2 Residential wood combustion (37%); open burning

(22%); agricultural burning (22%); wildfires (19%). 

Waste disposal 0.53 Residential burning (63%); waste water (23%); landfills

(6%); non-biomass incineration (8%).

Biogenic sources1 4.4 Approximately 98% emitted by vegetation. (Isoprene

[35%], monoterpenes [25%], and all other reactive and

non-reactive compounds [40%]).

Total 21

1

Estimated on the basis of data given in Guenther et al. (2000). 

Source: U.S. Environmental Protection Agency (2001).
AX2-126

Table AX2-7. Emissions of Ammonia by Various Sources in the United States in 1999

Source

Emissions

(1012 g/y) Notes

Exhaust from on-road

and non-road engines and

vehicles

0.25 Exhaust from on-road (96%) and non-road (4%) vehicles.

Fossil fuel combustion 0.044 Combustion by electric utilities, industry, commerce,

institutions, residences. 

Industry 0.18 Chemical manufacturing (67%); petroleum refining (9%);

other industries (25%). 

Agriculture 3.9 Livestock (82%); fertilizer application (18%).

Waste disposal and

recycling

0.08 Wastewater treatment (99%).

Natural sources 0.032 Unmanaged soils; wild animals.

Total 4.5

Source: U.S. Environmental Protection Agency (2001).

processes in that State. In Iowa, Kansas, Minnesota, Nebraska, and South Dakota soil emissions

may dominate. Conversion of ammonium to nitrate (nitrification) in aerobic soils appears to be

the dominant pathway to NO. The mass and chemical form of nitrogen (reduced or oxidized)

applied to soils, the vegetative cover, temperature, soil moisture, and agricultural practices such

as tillage all influence the amount of fertilizer nitrogen released as NO. 

As pointed out in the previous AQCD for O3, emissions of NO from soils peak in summer

when O3 formation is at a maximum. A recent NRC report outlined the role of agricultural in

emissions of air pollutants including NO and NH3 (NRC, 2002). That report recommends

immediate implementation of best management practices to control these emissions, and further

research to quantify the magnitude of emissions and the impact of agriculture on air quality. 

Civerolo and Dickerson (1998) report that use of the no-till cultivation technique on a fertilized

cornfield in Maryland reduced NO emissions by a factor of seven. 

Annual global production of NO by lightning is the most uncertain source of reactive

nitrogen. In the last decade literature values of the production rate range from 2 to 20 Tg-N per

year. However, the most likely range is from 3 to 8 Tg-N per year, because the majority of the
AX2-127

Table AX2-8. Emissions of Carbon Monoxide by Various Sources in the 

United States in 1999

Source

Emissions

(1012 g/y) Notes

On-road vehicle exhaust 50 Gasoline-fueled light-duty cars (54%) and trucks (32%),

heavy-duty trucks (9%); diesel vehicles (5%);

motorcycles (0.4%).

Non-road engines and

 vehicle exhaust

25 Gasoline-fueled (lawn and garden [44%], light

commercial [17%], recreational [14%], logging [4%],

industry and construction [6%, other [1%]); diesel-fueled

(5%); aircraft (4%); other (5%).

Fossil fuel combustion 2 Electric utilities (22%); industry (58%); commercial,

institutional and residential combustion (20%).

Industrial Processes 3.7 Metal processing (45%); chemical mfg. (29%);

petrochemical production; (10%); mineral products (5%);

wood products (10%); misc. industries (1%).

Biomass burning 16 Residential wood burning (21%); open burning (21%);

agricultural burning (41%); wildfires (17%).

Waste disposal 0.42 Non-biomass incineration.

Other 0.19 Structural fires (45%); storage and transport (38%);

misc. sources (17%). 

Biogenic emissions1 4.7+ Primary emissions from vegetation and soils;

secondary formation (?).

Total 102+

1

Estimated on the basis of data given in Guenther et al. (2000).

Source: U.S. Environmental Protection Agency (2001).

recent estimates fall in this range. The large uncertainty stems from several factors: (1) a large

range of NO production rates per flash (as much as two orders of magnitude); (2) the open

question of whether cloud-to-ground (CG) flashes and intracloud flashes (IC) produce

substantially different amounts of NO; (3) the global flash rate; and (4) the ratio of the number of

IC flashes to the number of CG flashes. Estimates of the amount of NO produced per flash have

been made based on theoretical considerations (e.g., Price et al., 1997), laboratory experiments

(e.g., Wang et al., 1998a); field experiments (e.g., Stith et al., 1999; Huntrieser et al., 2002), and
AX2-128

through a combination of cloud-resolving model simulations, observed lightning flash rates, and

anvil measurements of NO (e.g., DeCaria et al., 2000). The latter method was also used by

Pickering et al. (1998), who showed that only ~5% to 20% of the total NO production by

lightning in a given storms exists in the boundary layer at the end of a thunderstorm. Therefore,

the direct contribution to boundary layer O3 production by lightning NO is thought to be small. 

However, lightning NO production can contribute substantially to O3 production in the middle

and upper troposphere. DeCaria et al. (2000) estimated that up to 7 ppbv of O3 were produced in

the upper troposphere in the first 24 hours following a Colorado thunderstorm due to the

injection of lightning NO. A major uncertainty in mesoscale and global chemical transport

models is the parameterization of lightning flash rates. Model variables such as cloud top height,

convective precipitation rate, and upward cloud mass flux have been used to estimate flash rates. 

Allen and Pickering (2002) have evaluated these methods against observed flash rates from

satellite, and examined the effects on O3 production using each method. 

Literally tens of thousands of organic compounds have been identified in plant tissues. 

However, most of these compounds either have sufficiently low volatility or are constrained so

that they are not emitted in significant quantities. Less than 40 compounds have been identified

by Guenther et al. (2000) as being emitted in large enough quantities to affect atmospheric

composition. These compounds include terpenoid compounds (isoprene, 2-methyl-3-buten-2-ol,

monoterpenes), compounds in the hexanal family, alkenes, aldehydes, organic acids, alcohols,

ketones and alkanes. As can be seen from Table AX2-6, the major species emitted by plants are

isoprene (35%), 19 other terpenoid compounds (25%) and 17 non-terpenoid compounds (40%)

(Guenther et al., 2000). Of the latter, methanol contributes 12% of total emissions. 

Because isoprene has been identified as the most abundant of biogenic VOCs (Guenther

et al., 1995, 2000; Geron et al., 1994), it has been the focus of air quality model analyses in

many published studies (Roselle, 1994; Sillman et al., 1995). The original Biogenic Emission

Inventory System (BEIS) of Pierce and Waldruff (1991) used a branch-level isoprene emission

factor of 14.7 μg (g-foliar dry mass)!1

 h!1 for high isoprene emitting species (e.g., oaks, or North

American Quercus species). When considering self-shading of foliage within branch enclosures,

this is roughly equivalent to a leaf level emission rate of 20 to 30 μg-C (g-foliar dry mass)!1

 h!1

(Guenther at al, 1995). Geron et al (1994) reviewed studies between 1990 and 1994 and found

that a much higher leaf-level rate of 70 μg-C (g-foliar dry mass)!1

 h!1 + 50% was more realistic,
AX2-129

and this rate was used in BEIS2 for high isoprene emitting tree species. BEIS3 (Guenther et al.,

2000) applied similar emission factors at tree species levels (Geron et al 2000a, 2001) and more

recent canopy environment models to estimate isoprene fluxes. 

The results from several studies of isoprene emission measurements made at leaf, branch,

tree, forest stand, and landscape levels have been used to test the accuracy of BEIS2 and BEIS3. 

These comparisons are documented in Geron et al. (1997) and Guenther et al. (2000). The

results of these studies support the higher emission factors used in BEIS2 and BEIS3. Typically,

leaf emission factors (normalized to standard conditions of PAR = 1000 μmol m!2

 and leaf

temperature of 30 °C) measured at the top of tree canopies equal or exceed those used in 

BEIS2/3, while those in more shaded portions of the canopy tend to be lower than those assumed

in the models, likely due to differences in developmental environments of leaves within the

canopy (Monson et al., 1994; Sharkey et al., 1996; Harley et al., 1996; Geron et al., 2000b). 

Uncertainty in isoprene emissions due to variability in forest composition and leaf area remain in

BVOC emission models and inventories. Seasonality and moisture stress also impact isoprene

emission, but algorithms to simulate these effects are currently fairly crude (Guenther et al,

2000). The bulk of biogenic emissions occur during the summer, because of their dependence

on temperature and incident sunlight. Biogenic emissions are also higher in southern states than

in northern states for these reasons. The uncertainty associated with natural emissions ranges

from about 50% for isoprene under midday summer conditions to about a factor of ten for other

compounds (Guenther et al., 2000). In assessing the relative importance of these compounds, it

should be borne in mind that the oxidation of many of the classes of compounds result in the

formation of secondary organic aerosol and that many of the intermediate products may be

sufficiently long lived to affect O3 formation in areas far removed from where they were emitted. 

The oxidation of isoprene can also contribute about 10% of the source of CO (U.S.

Environmental Protection Agency, 2000). Direct emissions of CO by vegetation is of much

smaller importance. Soil microbes both emit and take up atmospheric CO, however, soil

microbial activity appears to represent a net sink for CO. 

Emissions from biomass burning depend strongly on the stage of combustion. Smoldering

combustion, especially involving forest ecosystems favors the production of CH4, NMHC and

CO at the expense of CO2, whereas active combustion produces more CO2 relative to the other

compounds mentioned above. Typical emissions ratios (defined as moles of compound per
AX2-130

moles of emitted CO2 expressed as a percentage) range from 6 to 14% for CO, 0.6 to 1.6% for

CH4, and 0.3 to 1.1% for NMHCs (Andreae, 1991). Most NMHC emissions are due to

emissions of lighter compounds, containing 2 or 3 carbon atoms. 

AX2.5.3 Observationally-Based Models

As an alternative to chemistry-transport models, observationally-based methods (OBMs),

which seek to infer O3-precursor relations by relying more heavily on ambient measurements,

can be used. Observationally-based methods are intuitively attractive because they provide an

estimate of the O3-precursor relationship based directly on observations of the precursors. These

methods rely on observations as much as possible to avoid many of the uncertainties associated

with chemistry/transport models (e.g., emission inventories and meteorological processes). 

However, these methods have large uncertainties with regards to photochemistry. As originally

conceived, the observation-based approaches were intended to provide an alternative method for

evaluating critical issues associated with urban O3 formation. The proposed OBMs include

calculations driven by ambient measurements (Chameides et al., 1992; Cardelino et al., 1995)

and proposed “rules of thumb” that seek to show whether O3 is primarily sensitive to NOx or to

VOC concentrations (Sillman, 1995; Chang et al., 1997; Tonnesen and Dennis, 2000a,b;

Blanchard et al., 1999; Blanchard, 2000). These methods are controversial when used as

“stand-alone” rules, because significant uncertainties and possible errors have been identified for

all the methods (Chameides et al., 1988, Lu and Chang, 1998, Sillman and He, 2002; Blanchard

and Stoeckenius, 2001). Methods such as these are most promising for use in combination with

chemistry/transport models principally for evaluating the accuracy of model predictions. 

Recent results (Tonnesen and Dennis, 2000a; Kleinman et al., 1997; 2000, 2001;

Kleinman, 2000) suggest that ambient VOC and NOx data can be used to identify the

instantaneous production rate for O3 and how the production rate varies with concentrations of

NOx and VOCs. The instantaneous production rate for O3 is only one of the factors that affect

the total O3 concentration, because O3 concentrations result from photochemistry and transport

over time periods ranging from several hours to several days in regional pollution events. Ozone

concentrations can be affected by distant emissions and by photochemical conditions at upwind

locations, rather than instantaneous production at the site. Despite this limitation, significant

information can be obtained by interpreting ambient NOx and VOC measurements. Kleinman
AX2-131

et al. (1997, 2000, 2001) and Tonnesen and Dennis (2000a) both derived simple expressions that

relate the NOx-VOC sensitivity of instantaneous O3 production to ambient VOC and NOx. These

expressions usually involve summed VOC weighted by reactivity. 

Cardelino et al. (1995, 2000) developed a method that seeks to identify O3-NOx-VOC

sensitivity based on ambient NOx and VOC data. Their method involves an area-wide sum of

instantaneous production rates over an ensemble of measurement sites, which serve to represent

the photochemical conditions associated with O3 production in metropolitan areas. Their

method, which relies on routine monitoring methods, is especially useful because it permits

evaluation for a full season rather than just for individual episodes. 

AX2.5.4 Chemistry-Transport Model Evaluation

The comparison of model predictions with ambient measurements represents a critical task

for establishing the accuracy of photochemical models and evaluating their ability to serve as the

basis for making effective control strategy decisions. The evaluation of a model’s performance,

or its adequacy to perform the tasks for which it was designed can only be conducted within the

context of measurement errors and artifacts. Not only are there analytical problems, but there

are also problems in assessing the representativeness of monitors at ground level for comparison

with model values which represent typically an average over the volume of a grid box. 

Chemistry-transport models for O3 formation at the urban/regional scale have traditionally

been evaluated based on their ability to correctly simulate O3. A series of performance statistics

that measure the success of individual model simulations to represent the observed distribution

of ambient O3, as represented by a network of surface measurements were recommended in U.S.

Environmental Protection Agency (1991; see also Russell and Dennis, 2000). These statistics

consist of the following: 

• Unpaired peak O3 within a metropolitan region (typically for a single day).

• Normalized bias equal to the summed difference between model and measured hourly

concentrations divided by the sum of measured hourly concentrations. 

• Normalized gross error, equal to the summed unsigned (absolute value) difference

between model and measured hourly concentrations divided by the sum of measured

hourly concentrations.
AX2-132

Unpaired peak prediction accuracy, Au;

Normalized bias, D;

Gross error, Ed (for hourly observed values of O3 >60 ppb)

The following performance criteria for regulatory models were recommended in U.S.

Environmental Protection Agency (1991): unpaired peak O3 to within ±15% or ±20%;

normalized bias within ±5% to ±15%; and normalized gross error less than 30% to 35%, but

only when O3 >60 ppb. This can lead to difficulties in evaluating model performance since

nighttime and diurnal cycles are ignored. A major problem with this method of model

evaluation is that it does not provide any information about the accuracy of O3-precursor

relations predicted by the model. The process of O3 formation is sufficiently complex that

models can predict O3 correctly without necessarily representing the O3 formation process

properly. If the O3 formation process is incorrect, then the modeled source-receptor relations

will also be incorrect. 

Studies by Sillman et al. (1995, 2003), Reynolds et al. (1996) and Pierce et al. (1998) have

identified instances in which different model scenarios can be created with very different

O3-precursor sensitivity, but without significant differences in the predicted O3 fields. 

Figures AX2-21a,b provide an example. Referring to the O3-NOx-VOC isopleth plot

(Figure AX2-22), it can be seen that similar O3 concentrations can be found for photochemical

conditions that have very different sensitivity to NOx and VOCs. 

(AX2-49)

(AX2-50)

(AX2-51)
AX2-133

Global-scale chemistry-transport models have generally been evaluated by comparison

with measurements for a wide array of species, rather than just for O3 (e.g., Wang et al., 1998b; 

Emmons et al., 2000; Bey et al., 2001b; Hess, 2001; Fiore et al., 2002). These have included

evaluation of major primary species (NOx, CO, and selected VOCs) and an array of secondary

species (HNO3, PAN, H2O2) that are often formed concurrently with O3. Models for

urban/regional O3 have also been evaluated against a broader ensemble of measurements in a

few cases, often associated with measurement intensives (e.g., Jacobson et al., 1996, Lu et al.,

1997; Sillman et al., 1998). The results of a comparison between observed and computed

concentrations from Jacobson et al. (1996) for the Los Angeles Basin are shown in

Figures AX2-23a,b.

The highest concentrations of primary species usually occur in close proximity to emission

sources (typically in urban centers) and at times when dispersion rates are low. The diurnal

cycle includes high concentrations at night, with maxima during the morning rush hour, and low

concentrations during the afternoon (Figure AX2-23a). The afternoon minima are driven by the

much greater rate of vertical mixing at that time. Primary species also show a seasonal

maximum during winter, and are often high during fog episodes in winter when vertical mixing ,

is suppressed. By contrast, secondary species such as O3 are typically highest during the

afternoon (the time of greatest photochemical activity), on sunny days and during summer. 

During these conditions concentrations of primary species may be relatively low. Strong

correlations between primary and secondary species are generally observed only in downwind

rural areas where all anthropogenic species are high simultaneously. The difference in the

diurnal cycles of primary species (CO, NOx and ethane)and secondary species (O3, PAN and

HCHO) is evident in Figure AX2-23b. 

Models for urban/regional O3 have been evaluated less extensively than global-scale

models in part because the urban/regional context presents a number of difficult challenges.

Global-scale models typically represent continental-scale events and can be evaluated effectively

against a sparse network of measurements. By contrast, urban/regional models are critically

dependent on the accuracy of local emission inventories and event-specific meteorology, and

must be evaluated separately for each urban area that is represented. 
AX2-134

Figure AX2-21a,b. Impact of model uncertainty on control strategy predictions for O3

for two days (August 10[a] and 11[b], 1992) in Atlanta, GA. The

figures show the predicted reduction in peak O3 resulting from 35%

reductions in anthropogenic VOC emissions (crosses) and from 35%

reductions in NOx (solid circles) in a series of model scenarios with

varying base case emissions, wind fields, and mixed layer heights. 

Source: Results are plotted from tabulated values published in Sillman et al. (1995, 1997). 
AX2-135

Figure AX2-22. Ozone isopleths (ppb) as a function of the average emission rate for

NOx and VOC (1012 molec. cm!2 s!1) in zero dimensional box model

calculations. The isopleths (solid lines) represent conditions during

the afternoon following 3-day calculations with a constant emission

rate, at the hour corresponding to maximum O3. The ridge line

(shown by solid circles) lies in the transition from NOx-saturated to

NOx-limited conditions.

The evaluation of urban/regional models is also limited by the availability of data. 

Measured NOx and speciated VOC concentrations are widely available through the EPA PAMs

network, but questions have been raised about the accuracy of those measurements and the data

have not yet been analyzed thoroughly. Evaluation of urban/regional models versus

measurements has generally relied on results from a limited number of field studies in the United

States. Short term research-grade measurements for species relevant to O3 formation, including

VOCs, NOx, PAN, nitric acid (HNO3) and hydrogen peroxide (H2O2) are also widely available at
AX2-136

Figure AX2-23a. Time series for measured gas-phase species in comparison with

results from a photochemical model. The dashed lines represent

measurements, and solid lines represent model predictions (in parts per

million, ppmv) for August 26–28, 1988 at sites in southern California. 

The horizontal axis represents hours past midnight, August 25. Results

represent O3 and NOx at Reseda and CO at Riverside.

Source: Jacobson et al. (1996).
AX2-137

Figure AX2-23b. Time series for measured gas-phase species in comparison with results

from a photochemical model. The circles represent measurements, and

solid lines represent model predictions (in parts per million, ppmv) for

August 26 – 28, 1988 at sites in southern California. The horizontal axis

represents hours past midnight, August 25. Results represent ethane

and formaldehyde at Claremont, and PAN at Los Angeles. 

Source: Jacobson et al. (1996).
AX2-138

rural and remote sites (e.g., Daum et al., 1990, 1996; Martin et al., 1997; Young et al., 1997;

Thompson et al., 2000; Hoell et al., 1996, 1997; Fehsenfeld et al., 1996a; Emmons et al., 2000;

Hess, 2001; Carroll et al., 2001). The equivalent measurements are available for some polluted

rural sites in the eastern United States but only at a few urban locations (Meagher et al., 1998;

Hübler et al., 1998; Kleinman et al., 2000, 2001; Fast et al., 2002; new SCAQS-need reference). 

Extensive measurements have also been made in Vancouver (Steyn et al., 1997) and in several

European cities (Staffelbach et al., 1997; Prévôt et al., 1997, Dommen et al., 1999; Geyer et al.,

2001; Thielman et al., 2001; Martilli et al., 2002; Vautard et al., 2002). 

The results of straightforward comparisons between observed and predicted concentrations

of O3 can be misleading because of compensating errors, although this possibility is diminished

when a number of species are compared. Ideally, each of the main modules of a chemistrytransport model system (for example, the meteorological model and the chemistry and radiative

transfer routines) should be evaluated separately. However, this is rarely done in practice. 

To better indicate how well physical and chemical processes are being represented in the model,

comparisons of relations between concentrations measured in the field and concentrations

predicted by the model can be made. These comparisons could involve ratios and correlations

between species. For example, correlation coefficients could be calculated between primary

species as a means of evaluating the accuracy of emission inventories; or between secondary

species as a means of evaluating the treatment of photochemistry in the model. In addition,

spatial relations involving individual species (correlations, gradients) can also be used as a

means of evaluating the accuracy of transport parameterizations. Sillman and He (2002)

examined differences in correlation patterns between O3 and NOz in Los Angeles, CA, Nashville,

TN and various sites in the rural United States. Model calculations (Figure AX2-24) show

differences in correlation patterns associated with differences in the sensitivity of O3 to NOx

and VOCs. Primarily NOx-sensitive ( NOx-limited) areas in models show a strong correlation

between O3 and NOz with a relatively steep slope, while primarily VOC-sensitive (NOxsaturated) areas in models show lower O3 for a given NOz and a lower O3-NOz slope. They

found that differences found in measured data ensembles were matched by predictions from

chemical transport models. Measurements in rural areas in the eastern U.S. show differences in

the pattern of correlations for O3 versus NOz between summer and autumn (Jacob et al., 1995;
AX2-139

Figure AX2-24. Correlations for O3 versus NOz (NOy–NOx) in ppb from chemical

transport models for the northeast corridor, Lake Michigan, Nashville,

the San Joaquin Valley, and Los Angeles. Each location is classified as

NOx-limited or NOx-sensitive (circles), NOx-saturated or VOC-sensitive

(crosses), mixed or with near-zero sensitivity (squares), and dominated by

NOx titration (asterisks) based on the model response to reduced NOx and

VOC. 

Source: Sillman and He (2002).

Hirsch et al., 1996), corresponding to the transition from NOx-limited to NOx-saturated patterns,

a feature which is also matched by chemistry-transport models. 

The difference in correlations between secondary species in NOx-limited to NOx-saturated

environments can also be used to evaluate the accuracy of model predictions in individual

applications. Figures AX2-25a and AX2-25b show results for two different model scenarios for

Atlanta. As shown in the figures, the first model scenario predicts an urban plume with high

NOy and O3 formation apparently suppressed by high NOy. Measurements show much lower
AX2-140

Figure AX2-25a,b. Evaluation of model versus measured O3 versus NOy for two

model scenarios for Atlanta. The model values are classified as NOxlimited (circles), NOx-saturated (crosses), or mixed or with low

sensitivity to NOx (squares). Diamonds represent aircraft

measurements.

Source: Sillman et al. (1997).
AX2-141

NOy in the Atlanta plume. This error was especially significant because the model locations

with high NOy were not sensitive to NOx, while locations with lower NOy were primarily

sensitive to NOx. The second model scenario (with primarily NOx-sensitive conditions) shows

much better agreement with measured values. Figure AX2-26a,b shows model-measurement

comparisons for secondary species in Nashville, showing better agreement with measured

conditions. Greater confidence in the predictions made by chemistry-transport models will be

gained by the application of techniques such as these on a more routine basis. 

The ability of chemical mechanisms to calculate the concentrations of free radicals under

atmospheric conditions was tested in the Berlin Ozone Experiment, BERLIOZ (Volz-Thomas

et al., 2003) during July and early August at a site located about 50 km NW of Berlin. (This

location was chosen as O3 episodes in central Europe are often associated with SE winds.) 

Concentrations of major compounds such as O3, hydrocarbons, etc., were fixed at observed

values. In this regard, the protocol used in this evaluation is an example of an observationally

based method. Figure AX2-27 compares the concentrations of RO2 (organic peroxy), HO2

(hydroperoxy) and OH (hydroxyl) radicals predicted by RACM (regional air chemistry

mechanism; Stockwell et al., 1997) and MCM (master chemical mechanism; Jenkin et al, 1997

with updates) with observations made by the laser induced fluorescence (LIF) technique and by

matrix isolation ESR spectroscopy (MIESR). Also shown are the production rates of O3

calculated using radical concentrations predicted by the mechanisms and those obtained by

measurements, and measurements of NOx concentrations. As can be seen, there is good

agreement between measurements of organic peroxy, hydroperoxy and hydroxyl radicals with

values predicted by both mechanisms at high concentrations of NOx (>10 ppb). However, at

lower NOx concentrations, both mechanisms substantially overestimate OH concentrations and

moderately overestimate HO2 concentrations. Agreement between models and measurements is

generally better for organic peroxy radicals, although the MCM appears to overestimate their

concentrations somewhat. In general, the mechanisms reproduced the HO2 to OH and RO2 to

OH ratios better than the individual measurements. The production of O3 was found to increase

linearly with NO (for NO <0.3 ppb) and to decrease with NO (for NO >0.5 ppb). 

OH and HO2 concentrations measured during the PM2.5 Technology Assessment and

Characterization Study conducted at Queens College in New York City in the summer of 2001

were also compared with those predicted by RACM (Ren et al., 2003). The ratio of observed to
AX2-142

Figure AX2-26a,b. Evaluation of model versus: (a) measured O3 versus NOz and (b) O3

versus the sum 2H2O2 + NOz for Nashville, TN. The model values are

classified as NOx-limited (gray circles), NOx-saturated (×s), mixed or

with near-zero sensitivity (squares), or dominated by NOx titration

(filled circles). Diamonds represent aircraft measurements. 

Source: Sillman et al. (1998).
AX2-143

Figure AX2-27. Time series of concentrations of RO2, HO2, and OH radicals, local

O3 photochemical production rate and concentrations of NOx from

measurements made during BERLIOZ. Also shown are comparisons

with results of photochemical box model calculations using the RACM

and MCM chemical mechanisms.

Source: Volz-Thomas et al. (2003).
AX2-144

predicted HO2 concentrations over a diurnal cycle was 1.24 and the ratio of observed to

predicted OH concentrations was about 1.10 during the day, but the mechanism significantly

underestimated OH concentrations during the night. 

AX2.5.4.1 Evaluation of Emissions Inventories

Comparisons of emissions model predictions with observations have been performed in a

number of environments. A number of studies of ratios of concentrations of CO to NOx and

NMOC to NOx during the early 1990s in tunnels and ambient air (summarized in Air Quality

Criteria for Carbon Monoxide [U.S. Environmental Protection Agency, 2000]) indicated that

emissions of CO and NMOC were systematically underestimated in emissions inventories. 

However, the results of more recent studies have been mixed in this regard, with many studies

showing agreement to within ± 50% (U.S. Environmental Protection Agency, 2000). 

Improvements in many areas have resulted from the process of emissions model development,

evaluation, and further refinement. It should be remembered that the conclusions from these

reconciliation studies depend on the assumption that NOx emissions are predicted correctly by

emissions factor models. Road side remote sensing data indicate that over 50% of NMHC and

CO emissions are produced by less than about 10% of the vehicles (Stedman et al., 1991). These

“super-emitters” are typically poorly maintained vehicles. Vehicles of any age engaged in offcycle operations (e.g., rapid accelerations) emit much more than if operated in normal driving

modes. Bishop and Stedman (1996) found that the most important variables governing CO

emissions are fleet age and owner maintenance. 

Emissions inventories for North America can be evaluated with comparisons to measured

long-term trends and or ratios of pollutants in ambient air. A decadal field study of ambient CO

at a rural cite in the Eastern U.S. (Hallock-Waters et al., 1999) indicates a downward trend

consistent with the downward trend in estimated emissions over the period 1988 to 1999 (U.S.

Environmental Protection Agency, 1997), even when a global downward trend is accounted for. 

Measurements at two urban areas in the United States confirmed the decrease in CO emissions

(Parrish et al., 2002). That study also indicated that the ratio of CO to NOx emissions decreased

by almost a factor of three over 12 yr (such a downward trend was noted in AQCD 96). 

Emissions estimates (U.S. Environmental Protection Agency, 1997) indicate a much smaller

decrease in this ratio, suggesting that NOx emissions from mobile sources may be
AX2-145

underestimated and/or increasing. The authors conclude that O3 photochemistry in U.S. urban

areas may have become more NOx-limited over the past decade. 

Pokharel et al. (2002) employed remotely-sensed emissions from on-road vehicles and fuel

use data to estimate emissions in Denver. Their calculations indicate a continual decrease in CO,

HC, and NO emissions from mobile sources over the 6 yr study period. Inventories based on the

ambient data were 30 to 70% lower for CO, 40% higher for HC, and 40 to 80% lower for NO

than those predicted by the recent MOBILE6 model. 

Stehr et al. (2000) reported simultaneous measurements of CO, SO2 and NOy at an East

Coast site. By taking advantage of the nature of mobile sources (they emit NOx and CO but little

SO2) and power plants (they emit NOx and SO2 but little CO), the authors evaluated emissions

estimates for the eastern United States. Results indicated that coal combustion contributes 25 to

35% of the total NOx emissions in agreement with emissions inventories (U.S. Environmental

Protection Agency, 1997). 

Parrish et al. (1998) and Parrish and Fehsenfeld (2000) proposed methods to derive

emission rates by examining measured ambient ratios among individual VOC, NOx and NOy. 

There is typically a strong correlation among measured values for these species (e.g., Figure

AX2-14) because emission sources are geographically collocated, even when individual sources

are different. Correlations can be used to derive emissions ratios between species, including

adjustments for the impact of photochemical aging. Investigations of this type include

correlations between CO and NOy (e.g., Parrish et al., 1991), between individual VOC species

and NOy (Goldan et al., 1995, 1997, 2000) and between various individual VOC (Goldan et al.,

1995, 1997; McKeen and Liu, 1993; McKeen et al., 1996). Buhr et al. (1992) derived emission

estimates from principal component analysis (PCA) and other statistical methods. Many of these

studies are summarized in Trainer et al. (2000), Parrish et al. (1998), and Parrish and Fehsenfeld

(2000). Goldstein and Schade (2000) also used species correlations to identify the relative

impacts of anthropogenic and biogenic emissions. Chang et al. (1996, 1997) and

Mendoza-Dominguez and Russell (2000, 2001) used the more formal techniques of inverse

modeling to derive emission rates, in conjunction with results from chemistry-transport models. 

Another concern regarding the use of emissions inventories is that emissions from all significant

sources have been included. This may not always be the case. As an example, hydrocarbon
AX2-146

seeps from offshore oil fields may represent a significant source of reactive organic compounds

in near by coastal areas (Quigley et al., 1999). 

AX2.5.4.2 Availability and Accuracy of Ambient Measurements

The use of methods such as observationally based methods or source apportionment

models, either as stand-alone methods or as a basis for evaluating chemistry/transport models,

is often limited by the availability and accuracy of measurements. Measured speciated VOC and

NOx are widely available in the United States through the PAMS network. However, challenges

have been raised about both the accuracy of the measurements and their applicability. 

Parrish et al. (1998) and Parrish and Fehsenfeld (2000) developed a series of quality

assurance tests for speciated VOC measurements. Essentially these tests used ratios among

individual VOC with common emission sources to identify whether the variations in species

ratios were consistent with the relative photochemical lifetimes of individual species. These

tests were based on a number of assumptions: the ratio between ambient concentrations of

long-lived species should show relatively little variation among measurements affected by a

common emissions sources; and the ratio between ambient concentrations of long-lived and

short-lived species should vary in a way that reflects photochemical aging at sites more different

from source regions. Parrish et al. used these expectations to establish criteria for rejecting

apparent errors in measurements. They found that the ratios among alkenes at many PAMS sites

did not show variations that would be expected due to photochemical aging. 

The PAMs network currently includes measured NO and NOx. However, Cardelino and

Chameides (2000) reported that measured NO during the afternoon was frequently at or below

the detection limit of the instruments (1 ppb), even in large metropolitan regions (Washington,

DC; Houston, TX; New York, NY). NOx measurements are made with commercial

chemilluminescent detectors with molybdenum converters. However these measurements

typically include some organic nitrates in addition to NOx, and cannot be interpreted as a “pure”

NOx measurement (see summary in Parrish and Fehsenfeld, 2000). 

Total reactive nitrogen (NOy) is included in the PAMS network only at a few sites. The

possible expansion of PAMS to include more widespread NOy measurements has been suggested

(McClenny, 2000). A major issue concerning measured NOy is the possibility that HNO3,

a major component of NOy, is sometimes lost in inlet tubes and not measured (Luke et al., 1998;
AX2-147

Parrish and Fehsenfeld, 2000). This problem is especially critical if measured NOy is used to

identify NOx-limited versus NOx-saturated conditions. The correlation between O3 and NOy

differs for NOx-limited versus NOx-saturated locations, but this difference is driven primarily by

differences in the ratio of O3 to HNO3. If HNO3 were omitted from the NOy measurements, than

the measurements would represent a biased estimate and their use would be problematic. 

AX2.6 TECHNIQUES FOR MEASURING OZONE AND ITS 

PRECURSORS

AX2.6.1 Sampling and Analysis of Ozone

Numerous techniques have been developed for sampling and measurement of O3 in the

ambient atmosphere at ground level. As noted above, sparse surface networks tend to

underestimate maximum O3 concentrations. Today, monitoring is conducted almost exclusively

with UV absorption spectrometry with commercial short path (0.15 to 0.3 m) instruments, a

method that has been thoroughly evaluated in clean air. The ultimate reference method is a

relatively long-path (3 m path length) UV absorption instrument maintained under carefully

controlled conditions at NIST (e.g., Fried and Hodgeson, 1982). Episodic measurements are

made with a variety of other techniques based on the principles of chemiluminescence,

electrochemistry, DOAS, and LIDAR. The rationale, history, and calibration of O3

measurements were summarized in AQCD 96, so this section will focus on the current state of

ambient O3 measurement, tests for artifacts, and on new developments. 

Several reports in the reviewed scientific literature have investigated interferences in O3

detection via UV radiation absorption. Kleindienst et al. (1993) investigated the effects of water

vapor and VOCs on instruments based on both UV absorption and chemiluminescence. They

concluded that water vapor had no significant impact on UV absorption-based instruments, but

could cause a positive interference of up to 9% in chemiluminescence-based detectors at high

humidities (dew point of 24 C). In smog chamber studies, aromatic compounds and their

oxidation products were found to generate a positive but small interference in the UV absorption

instruments. Kleindienst et al. concluded that “when the results are scaled back to ambient

concentrations of toluene and NOx, the effect appears to be very minor (ca. 3 percent under the

study conditions).” Arshinov et al. (2002) reported a positive interference in UV absorption
AX2-148

instruments from ambient particles at high concentrations, but this interference is eliminated by

use of particle filters less subject to absorption/adsorption artifacts such as used in the

NAMS/SLAMS network along with replacement of these filters to avoid artifacts associated

with particle loading on the filters. The possibility for substantive interferences in O3 detection

exists, but such interferences have not been observed even in urban plumes. Ryerson et al.

(1998) measured O3 with UV absorption and chemiluminescence instruments operated off a

common inlet on the NOAA WP-3 research aircraft. As reported by Parrish and Fehsenfeld

(2000) “Through five field missions over four years, excellent correlations were found between

the measurements of the two instruments, although the chemiluminescence instrument was

systematically low (5%) throughout some flights. The data sets include many passes through the

Nashville urban plume. There was never any indication (<1%) that the UV instrument measured

systematically higher in the urban plume.” The same group tested the air of Houston, El Paso,

Nashville, Los Angeles, San Francisco, and the East Coast. They observed only one instance of

substantive positive interference defined as the UV absorption technique showing more than a

few ppb more than the CL. This occurred in Laporte, TX under heavily polluted conditions and

a low inversion, at night (Jobson et al., 2004). 

Leston et al. (2005) reported positive and negative interferences in UV absorption

techniques for measuring O3 (relative to the CL technique) in Mexico City and in a smog

chamber study. They suggested that O3 measured in ambient air could be too high by 20 to

40 ppb under specific conditions due to positive interference by a number of organic compounds,

mainly those produced during the oxidation of aromatic hydrocarbons and some primary

compounds such as styrene and naphthalene. However, the concentrations of these compounds

were many times higher in both of these environments than are typically found at ambient air

monitoring sites in the United States. Although Hg is also potentially a strong interfering agent,

because the Hg resonance line is used in this technique, its concentration would also have to be

many times higher than is typically found in ambient air, e.g., as might be found in power plant

plumes. Thus, it seems unlikely that such interferences would amount to more than one or two

ppb (within the design specifications of the FEM), except under conditions conducive to

producing high concentrations of the substances they identified as causing interference. These

conditions might be found next to a plant producing styrene, for example. Leston et al. (2005)
AX2-149

also noted that the use of alternative materials in the scrubber could alleviate many potential

problems under these conditions. 

Ozone can also be detected by differential optical absorption spectroscopy (DOAS) at a

variety of wavelengths in the UV and visible parts of the spectrum. Prior comparisons of DOAS

results to those from a UV absorption instrument showed good agreement, on the order of 10%

(Stevens et al., 1993). Reisinger (2000) reported a positive interference due to an unidentified

absorber in the 279 to 289 nm spectral region used by many commercial short-path DOAS

systems for the measurement of O3. Results of that study suggest that effluent from wood

burning, used for domestic heating, may be responsible. Vandaele et al. (2002) reported good

agreement with other methods in the detection of O3 (and SO2) over the course of several years

in Brussels. While the DOAS method remains attractive due to its sensitivity and speed of

response further intercomparisons and interference tests are recommended. 

Electrochemical methods are commonly employed where sensor weight is a problem, such

as in balloon borne sondes, and these techniques have been investigated for ambient monitoring. 

Recent developments include changes in the electrodes and electrolyte solution (Knake and

Hauser, 2002) and selective removal of O3 for a chemical zero (Penrose et al., 1995). 

Interferences from other oxidants such as NO2 and HONO remain potential problems and further

comparisons with UV absorption are necessary. Because of potential interferences from water

vapor (ASTM, 2003a,b), all instruments should be either calibrated and zeroed with air humidity

near ambient or demonstrated to be insensitive to humidity. 

Change in the vibration frequency of a piezoelectric quartz crystal has been investigated as

a means of detecting O3. Ozone reacts with polybutadiene coated onto the surface of a crystal,

and the resulting change in mass is detected as a frequency change (Black et al., 2000). While

this sensor has advantages of reduced cost power consumption and weight, it is lacks the lifetime

and absolute accuracy for ambient monitoring. 

AX2.6.2 Sampling and Analysis of Nitrogen Oxides

Reactive nitrogen is generally released as NO but quickly converted in ambient air to NO2

and back again, thus these two species are often referred to together as NOx (NO + NO2). The

photochemical interconversion of NO and NO2 leads to O3 formation. Because NO2 is a health

hazard at sufficiently high concentrations, it is itself a criteria pollutant. In EPA documents,
AX2-150

emissions of NOx are expressed in units of mass of NO2 per unit time, i.e., the total mass of NOx

that would be emitted if all the NO were converted to NO2. Ambient air monitors have been

required to demonstrate compliance with the standard for NO2 and thus have focused on

measuring this gas or determining an upper limit for its concentration. 

NOx can be oxidized to species such as nitrous acid (HNO2), nitric acid (HNO3), aerosol

nitrate (NO3

!

), and organo-nitrates such as alkyl nitrates (RONO2) and peroxy acetyl nitrate,

PAN, (CH3C(O)O2NO2). The sum of these species (explicitly excluding N2, N2O, and reduced N

such as NH3 and HCN) is called NOy. Nitrates play important roles in acid rain, and nutrient

cycling including over nitrification of surface ecosystems and in the formation of fine particulate

matter, but are generally inactive photochemically. Some studies refer specifically to the

oxidized or processed NOy species, NOy-NOx, as NOz because this quantity is related to the

degree of photochemical aging in the atmosphere. Several NOz species such as PAN and HONO

can be readily photolyzed or thermally dissociated to NO or NO2 and thus act as reservoirs for

NOx. This discussion focuses on current methods and on promising new technologies, but no

attempt is made here to cover the extensive development of these methods or of methods such as

wet chemical techniques, no longer in widespread use. More detailed discussions of the histories

of these methods may be found elsewhere (U.S. Environmental Protection Agency, 1993, 1996). 

AX2.6.2.1 Calibration Standards

Calibration gas standards of NO, in nitrogen (certified at concentrations of approximately

5 to 40 ppm) are obtainable from the Standard Reference Material (SRM) Program of the

National Institute of Standards and Technology (NIST), formerly the National Bureau of

Standards (NBS), in Gaithersburg, MD. These SRMs are supplied as compressed gas mixtures

at about 135 bar (1900 psi) in high-pressure aluminum cylinders containing 800 L of gas at

standard temperature and pressure, dry (STPD; National Bureau of Standards, 1975; Guenther

et al., 1996). Each cylinder is supplied with a certificate stating concentration and uncertainty. 

The concentrations are certified to be accurate to ±1 percent relative to the stated values. 

Because of the resources required for their certification, SRMs are not intended for use as daily

working standards, but rather as primary standards against which transfer standards can be

calibrated. 
AX2-151

Transfer stand-alone calibration gas standards of NO in N2 (in the concentrations indicated

above) are obtainable from specialty gas companies. Information as to whether a company

supplies such mixtures is obtainable from the company, or from the SRM Program of NIST. 

These NIST Traceable Reference Materials (NTRMs) are purchased directly from industry and

are supplied as compressed gas mixtures at approximately 135 bars (1,900 psi) in high-pressure

aluminum cylinders containing 4,000 L of gas at STPD. Each cylinder is supplied with a

certificate stating concentration and uncertainty. The concentrations are certified to be accurate

to within ±1 percent of the stated values (Guenther et al., 1996). Additional details can be found

in the previous AQCD for O3 (U.S. Environmental Protection Agency, 1996). 

AX2.6.2.2 Measurement of Nitric Oxide

.Gas-Phase Chemiluminescence (CL) Methods

Nitric oxide, NO, can be measured reliably using the principle of gas-phase

chemiluminescence induced by the reaction of NO with O3 at low pressure. Modern commercial

NOx analyzers have sufficient sensitivity and specificity for adequate measurement in urban and

many rural locations (U.S. Environmental Protection Agency, 1996). The physics of the method,

detection limits, interferences, and comparisons under field comparisons have been thoroughly

reviewed in the previous AQCD. Research grade CL instruments have been compared under

realistic field conditions to spectroscopic instruments, and the results indicate that both methods

are reliable (at concentrations relevant to smog studies) to better than 15 percent with 95 percent

confidence. Response times are on the order of 1 minute. For measurements meaningful for

understanding O3 formation, emissions modeling, and N deposition, special care must be taken

to frequently zero and calibrate the instrument. A chemical zero, by reacting the NO up stream

and out of view of the PMT, is preferred because it accounts for unsaturated hydrocarbon or

other interferences. Calibration should be performed with NIST-traceable reference material of

compressed NO in N2. Standard additions of NO at the inlet will account for NO loss or

conversion to NO2 in the lines. In summary CL methods, when operated in an appropriate

manner, can be suitable for measuring or monitoring NO (e.g., Crosley, 1996). 
AX2-152

.Spectroscopic Methods for Nitric Oxide

Nitric oxide has also been successfully measured in ambient air with direct spectroscopic

methods; these include two-photon laser-induced fluorescence (TPLIF), tunable diode laser

absorption spectroscopy (TDLAS), and two-tone frequency-modulated spectroscopy (TTFMS). 

These were reviewed thoroughly in the previous AQCD and will be only briefly summarized

here. The spectroscopic methods demonstrate excellent sensitivity and selectivity for NO with

detection limits on the order of 10 ppt for integration times of 1 min. Spectroscopic methods

compare well with the CL method for NO in controlled laboratory air, ambient air, and heavily

polluted air (e.g., Walega et al., 1984; Gregory et al., 1990; Kireev et al., 1999). These

spectroscopic methods remain in the research arena due to their complexity, size, and cost, but

are essential for demonstrating that CL methods are reliable for monitoring NO concentrations

involved in O3 formation—from 100’s of ppb to around 20 ppt. 

Atmospheric pressure laser ionization followed by mass spectroscopy has also been

reported for detection of NO and NO2. Garnica et al. (2000) describe a technique involving

selective excitation at one wavelength followed by ionization at a second wavelength. They

report good selectivity and detection limits well below 1 ppb. The practicality of the instrument

for ambient monitoring has yet to be demonstrated. 

AX2.6.2.3 Measurements of Nitrogen Dioxide

.Gas-Phase Chemiluminescence Methods

Since the previous AQCD, photolytic reduction followed by CL has been improved and the

.method of laser-induced fluorescence has been developed. Ryerson et al. (2000) developed a

photolytic converter based on a Hg lamp with increased radiant intensity in the region of peak

NO2 photolysis (350 to 400 nm) and producing conversion efficiencies of 70% or more in less

than 1 s. Because the converter produces little radiation at wavelengths less than 350 nm,

interferences from HNO3 and PAN are minimal. 

Alternative methods to photolytic reduction followed by CL are desirable to test the

reliability of this widely used technique. In any detector based on conversion to another species

interferences can be a problem. Several atmospheric species, PAN and HO2NO2 for example,

dissociate to NO2 at higher temperatures. 
AX2-153

Laser induced fluorescence for NO2 detection involves excitation of atmospheric NO2 with

laser light emitted at wavelengths too long to induce photolysis. The resulting excited molecules

relax in a photoemissive mode and the fluorescing photons are counted. Because collisions

would rapidly quench electronically excited NO2, the reactions are conducted at low pressure

(Cohen, 1999; Thornton et al., 2000; Day et al., 2002). For example Cleary et al. (2002)

describe field tests of a system that uses continuous, supersonic expansion followed by

excitation at 640 nm with a commercial cw external-cavity tunable diode laser. Sensitivity is

adequate for measurements in most continental environments (145 ppt in 1 min) and no

interferences have been identified. 

Matsumi et al. (2001) describe a comparison of laser-induced fluorescence with a

photofragmentation chemiluminescence instrument. The laser-induced fluorescence system

involves excitation at 440 nm with a multiple laser system. They report sensitivity of 30 ppt in

10 s and good agreement between the two methods under laboratory conditions at mixing ratios

up to 1.0 ppb. This high-sensitivity laser-induced fluorescence system has yet to undergo longterm field tests. 

NO2 can be detected by differential optical absorption spectroscopy (DOAS) in an open,

long-path system (Kim and Kim, 2001). Vandaele et al. (2002) reported that the DOAS

technique measured higher NO2 concentrations than were reported by other techniques in a

three-year study conducted in Brussels. Harder et al. (1997b) conducted an experiment in rural

Colorado involving simultaneous measurements of NO2 with DOAS and photolysis followed by

chemiluminescence. The found differences of as much as 110% in clean air from the west, but

for NO2 mixing ratios in excess of 300 ppt, the two methods agreed to better than 10%. Stutz

and Platt (1996) report less uncertainty. 

AX2.6.2.4 Monitoring for NO2 Compliance Versus Monitoring for Ozone Formation

Observations of NO2 have been focused on demonstrating compliance with the NAAQS for

NO2. Today, few locations violate that standard, but NO2 and related NOy compounds remain

among the most important atmospheric trace gases to measure and understand. Commercial

instruments for NO/NOx detection are generally constructed with an internal converter for

reduction of NO2 to NO, and generate a signal referred to as NOx. These converters, generally

constructed of molybdenum oxides (MoOx), reduce not only NO2 but also most other NOy
AX2-154

species (Fehsenfeld et al., 1987; Crosley, 1996; Nunnermacker et al., 1998). Thus the NOx

signal is more accurately referred to as NOy. Unfortunately with an internal converter, the

instruments may not give a faithful indication of NOy either — reactive species such as HNO3

will adhere to the walls of the inlet system. Most recently, commercial vendors such as Thermo

Environmental (Franklin, MA) have offered NO/NOy detectors with external Mo converters. 

If such instruments are calibrated through the inlet with a reactive nitrogen species such as

propyl nitrate, they should give accurate measurements of total NOy, suitable for evaluation of

photochemical models. States should be encouraged to make these NOy measurements where

ever possible. 

AX2.6.3 Measurements of Nitric Acid Vapor, HNO3

Accurate measurement of nitric acid vapor, HNO3, has presented a long-standing analytical

challenge to the atmospheric chemistry community. In this context, it is useful to consider the

major factors that control HNO3 partitioning between the gas and deliquesced-particulate phases

in ambient air. In equation form,

where KH is the Henry’s Law constant in M atm-1 and Ka is the acid dissociation constant in M.

Thus, the primary controls on HNO3 phase partitioning are its thermodynamic properties

(KH, Ka, and associated temperature corrections), aerosol liquid water content (LWC), solution

pH, and kinetics. Aerosol LWC and pH are controlled by the relative mix of different acids and

bases in the system, hygroscopic properties of condensed compounds, and meteorological

conditions (RH, temperature, and pressure). It is evident from relationship XX that, in the

presence of chemically distinct aerosols of varying acidities (e.g., super-μm predominantly sea

salt and sub-μm predominantly S aerosol), HNO3 will partition preferentially with the less-acidic

particles, which is consistent with observations (e.g., Huebert et al., 1996; Keene and Savoie,

1998; Keene et al., 2002). Kinetics are controlled by atmospheric concentrations of HNO3 vapor

and particulate NO3

!

 and the size distribution and corresponding atmospheric lifetimes of

particles against deposition. Sub-μm-diameter aerosols typically equilibrate with the gas phase

(AX2-52)
AX2-155

in seconds to minutes while super-um aerosols require hours to a day or more (e.g., Meng and

Seinfeld, 1996; Erickson et al., 1999). Consequently, smaller aerosol size fractions are typically

close to thermodynamic equilibrium with respect to HNO3 whereas larger size fractions (for

which atmospheric lifetimes against deposition range from hours to a few days) are often

undersaturated (e.g., Erickson et al., 1999; Keene and Savioe, 1998). 

Many sampling techniques for HNO3 (e.g., standard filterpack and mist-chamber samplers)

employ upstream prefilters to remove particulate species from sample air. However, when

chemically distinct aerosols with different pHs (e.g., sea salt and S aerosols) mix together on a

bulk filter, the acidity of the bulk mixture will be greater than that of the less acidic aerosols with

which most NO3

!

 is associated. This change in pH may cause the bulk mix to be supersaturated

with respect to HNO3 leading to volatilization and, thus, positive measurement bias in HNO3

sampled downstream. Alternatively, when undersaturated super-um size fractions (e.g., sea salt)

accumulate on a bulk filter and chemically interacts over time with HNO3 in the sample air

stream, scavenging may lead to negative bias in HNO3 sampled downsteam. Because the

magnitude of both effects will vary as functions of the overall composition and thermodynamic

state of the multiphase system, the combined influence can cause net positive or net negative

measurement bias in resulting data. Pressure drops across particle filters can also lead to artifact

volatilization and associated positive bias in HNO3 measured downstream. 

Widely used methods for measuring HNO3 include standard filterpacks configured with

nylon or alkaline-impregnated filters (e.g., Goldan et al., 1983; Bardwell et al., 1990;

respectively) and standard mist chambers (Talbot et al., 1990). Samples are typically analyzed

by ion chromatography. Intercomparisons of these measurement techniques (e.g., Hering et al.,

1988; Tanner et al., 1989; Talbot et al., 1990) report differences of a factor of two or more. 

More recently, sensitive HNO3 measurements based on the principle of Chemical

Ionization Mass Spectroscopy (CIMS) have been reported (e.g., Huey et al., 1998; Mauldin

et al., 1998; Furutani and Akimoto, 2002; Neuman et al., 2002). CIMS relies on selective

formation of ions such as SiF5

-

AHNO3 or HSO4

-

AHNO3 followed by detection via mass

spectroscopy. Two CIMS techniques and a filter pack technique were intercompared in Boulder,

CO (Fehsenfeld et al., 1998). Results indicated excellent agreement (within 15%) between the

two CIMS instruments and between the CIMS and filterpack methods under relatively clean

conditions with HNO3 mixing ratios between 50 and 400 pptv. In more polluted air, the
AX2-156

filterpack technique generally yielded higher values than the CIMS suggesting that interactions

between chemically distinct particles on bulk filters is a more important source of bias in

polluted continental air. Differences were also greater at lower temperature when particulate

NO3

!

 corresponded to relatively greater fractions of total NO3

!

. 

AX2.6.4 Sampling and Analysis of Volatile Organic Compounds

Hydrocarbons can be measured with gas chromatography followed by flame ionization

detection (GC-FID). Detection by mass spectroscopy is sometimes used to confirm species

identified by retention time (Westberg and Zimmerman, 1993; Dewulf and Van Langenhove,

1997). Preconcentration is typically required for less abundant species. Details are available in

AQCD 96. 

Because of their variety, nonmethane hydrocarbons pose special analytical problems,

and several laboratory and field studies have recently addresses the uncertainty of VOC

measurements. An intercomparison conducted with 16 components among 28 laboratories,

showed agreement on the order of 10s of percents (Apel et al., 1994). In a more recent

intercomparison (Apel et al., 1999) 36 investigators from around the world were asked to

identify and quantify C2 to C10 hydrocarbons (HCs) in a mixture in synthetic air. Calibration was

based on gas standards of individual compounds, such as propane in air, and a 16-compound

mixture of C2 to C16 –alkanes, all prepared by NIST and certified to ± 3 percent. The

top-performing laboratories, including several in the United States, identified all the compounds

correctly, and obtained agreement of generally better than 20 percent for the 60 compounds. 

Intercomparison of NMHCs in ambient air has only recently been reported by a European group

of 12 – 14 laboratories (Slemr et al., 2002). Some compounds gave several groups difficulties,

including isobutene, butadiene, methyl pentanes, and trimethyl benzenes. These

intercomparisons illustrated the need for reliable, multicomponent calibration standards. 

AX2.6.4.1 Polar Volatile Organic Compounds

Many of the more reactive oxygen- and nitrogen-containing organic compounds play a role

in O3 formation and are included among the list of 189 hazardous air pollutants specified in the

1990 CAAA (U.S. Congress, 1990). These compounds are emitted directly from a variety of

sources including biogenic processes, biomass burning, industry, vehicles, and consumer
AX2-157

products. Some can also be formed in the atmosphere by photochemical oxidation of

hydrocarbons. Although these compounds have been referred to collectively as PVOCs, their

reactivity and water solubility, rather than just polarity, make sampling and measurement

challenging. As indicated in the earlier AQCD, few ambient data exist for these species, but that

database has grown. The previous AQCD discusses two analytical methods for

PVOCs—cryogenic trapping techniques similar to those used for the nonpolar hydrocarbon

species, and adsorbent material for sample preconcentration. Here we discuss recently

developed methods. 

Several techniques for sampling, preconcentrating and detecting oxygenated volatile

organic compounds were inter-compared during the 1995 Southern Oxidants Study Nashville

Intensive (Apel et al., 1998). Both chemical traps and derivatization followed by HPLC and

preconcentration and gas chromatography followed by mass spectrometric of flame ionization

were investigated. Both laboratory and field tests were conducted for formaldehyde,

acetaldehyde, acetone, and propanal. Substantial differences were observed indicating that

reliable sampling and measurement of PVOCs remains an analytical challenge and high research

priority. 

Chemical ionization-mass spectroscopy, such as proton-transfer-reaction mass

spectroscopy (PTR-MS) can also be used for fast-response measurement of volatile organic

compounds including acetonitrile (CH3CN), methanol (CH3OH), acetone (CH3COCH3),

acetaldehyde (CH3CHO), benzene (C6H6) and toluene (C6H5CH3) (e.g., Hansel et al., 1995a,b;

Lindinger et al., 1998; Leibrock and Huey, 2000; Warneke et al., 2001). The method relies on

gas phase proton transfer reactions between H3O+ primary ions and volatile trace gases with a

proton affinity higher than that of water. Into a flow drift tube continuously flushed with

ambient air, H3O+

 ions (from a hollow cathode ion source) are injected. On collisions between

H3O+

 ions and organic molecules protons H+ are transferred thus charging the reagent. Both

primary and product ions are analyzed in a quadrupole mass spectrometer and detected by a

secondary electron multiplier/pulse counting system. The instrument has been successfully

employed in several field campaigns and compared to other techniques including gas

chromatography and Atmospheric Pressure Chemical Ionization Mass Spectrometer (AP-CIMS)

(Crutzen et al., 2000; Sprung et al., 2001). Sufficient sensitivity was observed for urban and

rural measurements; no interferences were discovered, although care must be exercised to avoid
AX2-158

sampling losses. Commercial instruments are becoming available, but their price still precludes

widespread monitoring. 
AX2-159

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AX3-1

ANNEX AX3. ENVIRONMENTAL CONCENTRATIONS,

PATTERNS, AND EXPOSURE ESTIMATES

AX3.1 INTRODUCTION

Identification and Use of Existing Air Quality Data

Topics discussed in this annex include the characterization of ambient air quality data for

ozone (O3), the uses of these data in assessing the exposure of vegetation to O3, concentrations

of O3 in microenvironments, and a discussion of the currently available human exposure data and

exposure model development. The information contained in this chapter pertaining to ambient

concentrations is taken primarily from the U.S. Environmental Protection Agency (EPA) Air

Quality System (AQS; formerly the AIRS database). The AQS contains readily accessible

detailed, hourly data that has been subject to EPA quality control and assurance procedures. 

Data available in AQS were collected from 1979 to 2001. As discussed in previous versions of

the O3 Air Quality Criteria Document or AQCD (U.S. Environmental Protection Agency, 1986,

1996a), the data available prior to 1979 may be unreliable due to calibration problems and

measurement uncertainties. 

As indicated in the 1996 O3 AQCD (U.S. Environmental Protection Agency, 1996a), O3 is

the only photochemical oxidant other than nitrogen dioxide (NO2) that is routinely monitored

and for which a comprehensive database exists. Data for peroxyacetyl nitrate (PAN), hydrogen

peroxide (H2O2), and other oxidants either in the gas phase or particle phase typically have been

obtained only as part of special field studies. Consequently, no data on nationwide patterns of

occurrence are available for these non-O3 oxidants; nor are extensive data available on the

relationships of levels and patterns of these oxidants to those of O3. However, available data for

gas-phase and particle-phase oxidants will be discussed.

Characterizing Ambient Ozone Concentrations

The “concentration” of a specific air pollutant is typically defined as the amount (mass) of

that material per unit volume of air. However, most of the data presented in this annex are

expressed as “mixing ratios” in terms of a volume-to-volume ratio (parts per million [ppm] or

parts per billion [ppb]). Data expressed this way are often referred to as concentrations, both in
AX3-2

the literature and in the text, following common usage. Human exposures are expressed in units

of mixing ratio times time.

Several different types of indicators are used for evaluating exposures of vegetation to O3. 

The peak-weighted, cumulative exposure indicators used in this chapter for characterizing

vegetation exposures are SUM06 and SUM08 (the sums of all hourly average concentrations

$0.06 and 0.08 ppm, respectively) and W126 (the sum of the hourly average concentrations that

have been weighted according to a sigmoid function that is based on a hypothetical vegetation

response [see Lefohn and Runeckles, 1987]). Further discussion of these exposure indices is

presented in Chapter 9. 

The U.S. Environmental Protection Agency (U.S. EPA) has established “ozone seasons”

for the required monitoring of ambient O3 concentrations for different locations within the

United States and U.S. territories (CFR, 2000). Table AX3-1 shows the O3 seasons during which

continuous, hourly averaged O3 concentrations must be monitored. Note that O3 monitoring is

optional outside of the “ozone season” and is monitored in many locations throughout the year. 

In Section AX3.2, surface O3 concentrations are characterized and the difficulties of

characterizing background O3 concentrations for controlled exposure studies and for assessing

the health benefits associated with setting the NAAQS are discussed. In addition, hourly

averaged concentrations obtained by several monitoring networks have been characterized for

urban and rural areas. Spatial variations that occur within urban areas, between rural and urban

areas, as well as variations with elevation are discussed in Section AX3.3. The diurnal

variations for the various urban and rural locations are found in Section AX3.4, where urban and

rural patterns are described. In Section AX3.5 seasonal variations in 1-h and 8-h average

concentrations are discussed. Section AX3.6 of this annex summarizes the historical trends for

1980 to 2001 on a national scale and for selected cities. The most recent U.S. EPA trends results

are also presented. Section AX3.7 describes available information for the concentrations and

patterns of related photochemical oxidants. Section AX3.8 describes the co-occurrence patterns

of O3 with NO2, sulfur dioxide (SO2), and 24-h PM2.5. Indoor O3 concentrations, including

sources and factors affecting indoor O3 concentrations, are described in Section AX3.9. 

Section AX3.10 describes human population exposure measurement methods, factors

influencing exposure, and exposure models.
AX3-3

Table AX3-1. Ozone Monitoring Seasons by State

State Start Month — End State Start Month — End

Alabama March — October Nevada January — December

Alaska April — October New Hampshire April — September

Arizona January — December New Jersey April — October

Arkansas March — November New Mexico January — December

California January — December New York April — October

Colorado March - September North Carolina April — October

Connecticut April — September North Dakota May — September

Delaware April — October Ohio April — October

District of Columbia April — October Oklahoma March — November

Florida March — October Oregon May — September

Georgia March — October Pennsylvania April — October

Hawaii January — December Puerto Rico January — December

Idaho April — October Rhode Island April — September

Illinois April — October South Carolina April — October

Indiana April — September South Dakota June — September

Iowa April — October Tennessee March — October

Kansas April — October Texas1 January — December

Kentucky March — October Texas1 March — October

Louisiana January — December Utah May — September

Maine April — September Vermont April — September

Maryland April — October Virginia April — October

Massachusetts April — September Washington May — September

Michigan April — September West Virginia April — October

Minnesota April — October Wisconsin April 15 — October 15

Mississippi March — October Wyoming April — October

Missouri April — October American Samoa January — December

Montana June — September Guam January — December

Nebraska April — October Virgin Islands January — December

1

The ozone season is defined differently in different sections of Texas.

Source: CFR (2000).
AX3-4

AX3.2 SURFACE OZONE CONCENTRATIONS

Data for O3 concentrations in a number of different environments, ranging from urban to

remote, are summarized and characterized in this section. The main emphasis is placed on the

characterization of the variability of O3 concentrations in these different environments. Another

important issue relates to the determination of background concentrations. There are a number

of different uses of the term background depending on the context in which it is used. Various

definitions of background have been covered in the 1996 O3 AQCD (U.S. Environmental

Protection Agency, 1996a) and in Air Quality Criteria for Particulate Matter (PM AQCD; U.S.

Environmental Protection Agency, 1996b). This section deals with the characterization of

background O3 concentrations that are used for two main purposes: (1) performing experiments

relating the effects of exposure to O3 on humans, animals, and vegetation; and (2) assessing the

health benefits associated with setting different levels of the NAAQS for O3. Ozone background

concentrations used for NAAQS setting purposes are referred to as policy relevant background

(PRB) concentrations. PRB concentrations are defined by the U.S. EPA Office of Air Quality

Programs and Standards (OAQPS) as those concentrations that would be observed in the United

States if anthropogenic sources of O3 precursors were turned off in continental North America

(the United States, Canada and Mexico), i.e., the definition includes O3 formed from natural

sources everywhere in the world and from anthropogenic O3 precursors outside of North

America. The 1996 O3 AQCD considered two possible methods for quantifying background O3

concentrations for the two purposes mentioned above. The first method relied on mathematical

models and historical data. The second method used the distribution of hourly average O3

concentrations observed at clean, relatively remote monitoring sites (RRMS) in the United States

(i.e., those which experience low maximum hourly concentrations). At the time of the 1996 O3

AQCD, simulations of mathematical models were limited; therefore, the second method was

employed to quantify background O3 concentrations.

Sections AX3.2.1 and AX3.2.2 review data for O3 concentrations in urban and nonurban

(but influenced by urban emissions) environments. Section AX3.2.3 reviews the data from

relatively clean remote sites, addresses the issue of how to use these data to help set background

levels for controlled exposure studies, and presents evidence of trends in O3 concentrations at

these sites. The characterization of PRB O3 concentrations will be the subject of

Section AX3.2.4. Two alternative approaches for establishing PRB concentrations are
AX3-5

presented: the first uses data from relatively clean, remote monitoring sites and the second uses

numerical models. The strengths and weaknesses of each approach are presented in the hopes of

stimulating discussion that will resolve issues related to the use of either of these alternative

methods.

Ozone Air Quality at Urban, Suburban, and Nonurban Sites

Figure AX3-1 shows the mean daily maximum 8-h O3 concentrations and Figure AX3-2

shows the 95th percentile values of the daily maximum 8-h O3 concentrations, based on

countywide site-wise averages across the United States from May to September 2000 to 2004. 

The locations of the monitoring sites, whose data were used in the calculation of background O3

concentrations, are shown in Figure AX3-3. The period from May to September was chosen

because, although O3 was monitored for different lengths of time across the country, all O3

monitors should be operational during these months. Data flagged because of quality control

issues were removed with concurrence of the local monitoring agency. Only days for which

there were 75% complete data (i.e., 18 of 24 hours) were kept, and a minimum of 115 of

153 days were required in each year. Cut points for the tertile distributions on each map were

chosen at the median and 95th percentile values. These cut points were chosen as they represent

standard metrics for characterizing important aspects of human exposure used by the EPA. Any

other percentiles or statistics that are believed to be helpful for characterizing human exposures

could also be used. Blank areas on the maps indicate no data coverage. It should be noted that

county areas can be much larger in the West than in the East, but monitors are not spread evenly

within a county. As a result, the assigned concentration range might not represent conditions

throughout a particular county and so large areas in western counties where there are not any

monitors were blanked out. 

As shown in Figure AX3-1, the median of the countywide, mean daily maximum 8-h O3

concentration across the United States is 49 ppb, and 5% of these site-wise means exceeded

57 ppb. Although the median and 95th percentile value of the countywide means are fairly

close, these results cannot be taken to imply that mean O3 concentrations lie in a relatively

narrow range throughout the United States, because data coverage is not as complete in the West

as it is in the East. High mean daily maximum 8-h O3 concentrations are found in California and

states in the Southwest as well as in several counties in the East. As shown in Figure AX3-2, the
AX3-6

nationwide median of the countywide, 95th percentile value of the daily maximum 8-h O3

concentration is 73 ppb and 5% of these values are above 85 ppb. High values for the 95th

percentiles are found in California, Texas, and in the East, but not necessarily in the same

counties as shown for the mean daily maximum 8-h concentrations in Figure AX3-1. 

Although mean O3 concentrations in Houston, TX were below the nationwide median, its

95th percentile value ranks in the highest 5% nationwide. Conversely, mean O3 concentrations

in southwestern states are among the highest in the United States, but peak values (i.e., 95th or

98th percentile values) in those counties are not among the highest peak values in the United

States. In other areas where the highest mean O3 concentrations occurred, such as California;

Dallas-Fort Worth, TX; and the Northeast Corridor, the highest peak values also were observed. 

Figure AX3-1. Countywide mean daily maximum 8-h O3 concentrations, May to

September 2002 to 2004.

Source: Fitz-Simons et al. (2005).
AX3-7

Although countywide averages are shown, it should be noted that considerable spatial

variability can exist within a county, especially within urban areas as described in

Section AX3.3. In addition, there can also be differences in the diurnal profile of O3 among

monitors within counties.

Box plots showing the percentile distribution of nationwide O3 concentrations for

different averaging periods (1-h daily maximum, 8-h daily maximum and 24-h daily average) are

given in Figures AX3-4 to AX3-6 and the numerical values are given in Table AX3-2. The

differences between the 50th and 95th percentile values indicate the range of O3 levels between

“typical” O3 days and “high” O3 days. These differences are approximately 40, 30, and 25 ppb 

Figure AX3-2. Countywide 95th percentile value of daily maximum 8-h O3 concentrations,

May to September 2002 to 2004. 

Source: Fitz-Simons et al. (2005).
AX3-8

for the daily 1-h, 8-h, maxima and daily averaged O3 concentrations. As might be expected, the

daily maximum 1-h and 8-h O3 concentrations are highly correlated. 

Lehman et al. (2004) have shown that the eastern United States can be divided into five

regions, each of which exhibit spatial, relatively coherent spatial patterns of O3 at nonurban sites. 

Only sites classified as being rural or suburban and with land usage of forest, agriculture, or

residential were included in the analyses. These criteria were chosen to avoid sites where O3 is

scavenged by NO that can be found in high concentrations near major sources, such as traffic in

urban cores. The five regions, shown in Figure AX3-7, are characterized by different patterns 

of O3 properties such as temporal persistence and seasonal variability. Figure AX3-7 shows

nonurban, monthly average, daily maximum 8-h O3 concentrations in the five regions in the

eastern United States from April to October 1993 to 2002. 

Figure AX3-3. Locations of monitoring sites used for calculating countywide averages

across the United States.

Source: Fitz-Simons et al. (2005).
AX3-9

Figure AX3-5. Distribution of nationwide daily maximum 8-h average O3 concentrations

from May to September 2000 to 2004. Medians, interquartile ranges,

minima and maxima and means (as dots) are shown. Numbers above the

boxes are the number of observations.

Source: Fitz-Simons et al. (2005).

Figure AX3-4. Distribution of nationwide daily maximum 1-h average O3 concentrations

from May to September 2000 to 2004. Medians, interquartile ranges,

minima and maxima and means (as dots) are shown. Numbers above the

boxes are the number of observations.

Source: Fitz-Simons et al. (2005).
AX3-10

Regional differences are immediately apparent. Highest concentrations among all the

regions are generally found in the Mid-Atlantic region (mean of 52 ppb) with highest values

throughout the ozone concentration distribution except for the overall maximum. Lowest mean

concentrations (42 ppb) are found in Florida. In the northern regions (the Northeast, Great

Lakes) and the Mid-Atlantic region, highest median and peak concentrations are found in July,

whereas in the Southwest, highest median concentrations are found in August, with highest

peaks in June and September, i.e., outside the warmest summer months. In Florida, highest

monthly averaged median and peak concentrations are found during the spring. High O3

concentrations tend to be most persistent (3-4 days of persistence) in the southern regions, less

persistent in the Mid-Atlantic region (2-3 days) and least persistent in the northern regions (1 or

2 days). Such analyses could not be made for the western United States, in part because of the

presence of more extensive mountain ranges.

Box plots showing the distributions of hourly average O3 concentrations for different types

of rural sites for 2001 are given in Figures AX3-8 (rural-agricultural), AX3-9 (rural-forest),

Figure AX3-6. Distribution of nationwide 24-h average O3 concentrations from May to

September 2000 to 2004. Medians, interquartile ranges, minima and

maxima and means (as dots) are shown. Numbers above the boxes are the

number of observations.

Source: Fitz-Simons et al. (2005).
Table AX3-2. Summary of Percentiles of Data Pooled Across Monitoring Sites for May to Septemb

Concentrations are in ppb.

Percentiles

Pooled Group/Avg. Time

Number

of Values Mean 1 5 10 25 30 50 70 75 9

Daily 1-h Maximum ConcentrationsMonitors inCSAs

367,121 58 20 29 34 44 46 56 66 70 8

Monitors notin CSAs

323,891 55 20 28 33 43 45 54 64 67 7

8-h Daily Maximum ConcentrationsMonitors inCSAs

367,029 50 16 23 28 37 40 49 58 61 7

Monitors notin CSAs

323,815 49 16 23 28 37 39 48 57 59 7

24-h Average ConcentrationsMonitors inCSAs

367,121 33 10 15 18 24 26 32 39 41 5

Monitors notin CSAs

323,891 34 10 15 18 25 27 33 39 41 5

AX3-11
AX3-12

Figure AX3-7. Box plots showing O3 averaged by month from 1993 to 2002 in the five

regions in the eastern United States derived by Lehman et al. (2004). The

boxes define the interquartile range and the whiskers, the extreme values.

Source: Lehman et al. (2004).
AX3-13

and AX3-10 (rural-residential or commercial). Shown below the figures are the number of

observations and various metrics for characterizing vegetation exposures. Note that high O3

concentrations are found at sites that are classified as rural, as in Anne Arundel Co., MD;

Yosemite NP, CA; and Crestline, CA. Land use designations might not give an accurate picture

of exposure regimes in rural areas, because the land use characterization of “rural” does not

necessarily mean that a specific location is isolated from anthropogenic influences. Rather, the

characterization refers only to the current use of the land, not to the presence of sources. 

Since O3 produced from emissions in urban areas is transported to more rural downwind

locations, elevated O3 concentrations can occur at considerable distances from urban centers. 

In addition, major sources of O3 precursors such as power plants and highways are located in

nonurban areas and also produce O3 in these areas. Due to lower rates of chemical scavenging in 

Figure AX3-8. Hourly average O3 concentrations observed at selected rural-agricultural

sites from April to October 2001. The whiskers represent minimum and

maximum concentrations. The boxes represent the 10th and 90th

percentile concentrations.

Source: Fitz-Simons et al. (2005).
AX3-14

nonurban areas, O3 tends to persist longer in nonurban than in urban areas, also tending to lead to

higher exposures in nonurban areas influenced by anthropogenic precursor emissions. 

Ozone Air Quality Data at Relatively Remote Monitoring Sites (RRMS)

RRMS are sites that are located in the national parks that tend to be less affected by

obvious pollution sources than other sites. This does not mean that they are completely

unaffected by local pollution, because of the large number of visitors to these national parks. 

It is important to characterize hourly average O3 concentrations at RRMS so that assessments of

the possible effects of O3 on human health and vegetation, use concentration ranges that mimic

the range found in the United States. Hourly average concentrations used as controls in studies

Figure AX3-9. Hourly average O3 concentrations observed at selected rural-forest sites

from April to October 2001. The whiskers represent minimum and

maximum concentrations. The boxes represent the 10th and 90th

percentile concentrations.

Source: Fitz-Simons et al. (2005).
AX3-15

of human health and vegetation exposures to O3 appear to be lower than those experienced at

RRMS in the United States or in other parts of the world (see Chapter 9). Typically, ambient air

is filtered to remove O3 before being admitted into the exposure chambers. As a result, O3

concentrations might only be a few ppb within these chambers. 

Box plots in Figures AX3-11a-d depicting the distributions of annual hourly average

measured O3 concentrations at four relatively remote monitoring sites (RRMS), show that annual

mean values of the daily 8-h maximum O3 concentration have not changed much over the past

10 years of available data. Mean values range typically from about 0.020 ppm to about

0.040 ppm. Concentrations only rarely exceed 0.080 ppm, in contrast to observations at other

“rural” sites shown in Figures AX3-8 to AX3-10.

Figure AX3-10. Hourly average O3 concentrations observed at selected rural-commercial

or -residential sites from April to October 2001. The whiskers represent

minimum and maximum concentrations. The boxes represent the 10th

and 90th percentile concentrations.

Source: Fitz-Simons et al. (2005).
AX3-16

Figure AX3-11a-d. Daily 8-h maximum O3 concentrations observed at selected national

park sites. The whiskers on the box plot represent the 10th and

90th percentile concentrations. The “X”s above and below the

whiskers are the values that fall below and above the 10th and 90th

percentile concentrations. The dots inside the box represent the

mean. The number of observations is shown above each box plot.

Source: Fitz-Simons et al. (2005).
AX3-17

It is unlikely that distributions found at sites with low maximum hourly average

concentrations in the western United States represent those at sites in the eastern and midwestern

United States because of regional differences in sources of precursors and transport patterns. 

Given the high density of sources in the eastern and midwestern United States, it is unclear

whether a site could be found in either of these regions that would not be influenced by the

transport of O3 from nearby urban areas. Thus, with the exception of the Voyageurs NP site in

Minnesota, observations at RRMS are limited to those obtained in the western United States. 

However, not all national park sites in the West can be considered to be free of strong regional

pollution influences, e.g., Yosemite NP (CA), as can be seen from Figure AX3-9. 

The 1996 O3 AQCD (U.S. Environmental Protection Agency, 1996a) concluded that the

annual average “background” concentration of O3 near sea level ranged from 0.020 to 0.035 ppm

and that, during the summer, the 1-h daily maximum ranged from 0.03 to 0.05 ppm. The 

1996 O3 AQCD also included O3 hourly average concentrations measured at several clean,

RRMS mostly located in the western United States. Table AX3-3 provides a summary of the

characterization of the hourly average concentrations recorded from 1988 to 2001 at some of the

monitoring sites previously analyzed. The percentile distribution of the hourly average

concentrations (April to October), number of hourly average occurrences $0.08 and $0.10 ppm,

seasonal 7-h average concentrations, the SUM06, and W126 values were characterized for those

site years with a data capture of $75%. From 1988 to 2001, no hourly average concentrations

$0.08 ppm were observed at monitoring sites in Redwood NP (CA), Olympic NP (WA), Glacier

NP (MT), Denali NP (AK), Badlands (SD), and Custer NF (MT) during the months of April to

October. There were eight occurrences of hourly average O3 concentrations $0.08 ppm from

April to October of 1997 at the monitoring site in Theodore Roosevelt NP (ND). However, no

hourly average concentrations $0.08 ppm were observed from April to October in any other year

at this site. Except for 1988, the year in which there were major forest fires at Yellowstone NP

(WY), the monitoring site located there experienced no hourly average concentrations

$0.08 ppm. Logan (1989) noted that O3 hourly average concentrations rarely exceed 0.08 ppm

at remote monitoring sites in the western United States. In almost all cases for the above sites,

the maximum hourly average concentration was #0.075 ppm. The top 10 daily maximum 8-h 

average concentrations for sites experiencing low maximum hourly average concentrations with
AX3-18

Table AX3-3. Seasonal (April to October) Percentile Distribution of Hourly Ozone Concentrations (p

Hourly Mean Ozone Occurrences $0.08 and $0.10, Seasonal 7-h Average Concentrations, SUM06, and W

Experiencing Low Maximum Hourly Average Concentrations with Data Capture of $7

Site

Percentiles

Max.

No. of

Obs.

Hours

Se

Year Min. 10 30 50 70 90 95 99 $0.08 $0.10 

Redwood NP060150002(California)235 m

1988 0.002 0.011 0.018 0.023 0.029 0.038 0.041 0.046 0.06 4825 0 0 1989 0.000 0.010 0.017 0.022 0.027 0.034 0.038 0.042 0.047 4624 0 0 1990 0.000 0.011 0.018 0.023 0.028 0.035 0.038 0.043 0.053 4742 0 0 1991 0.001 0.012 0.019 0.025 0.031 0.038 0.041 0.045 0.054 4666 0 0 1992 0.000 0.010 0.017 0.021 0.026 0.035 0.039 0.045 0.055 4679 0 0 1993 0.000 0.010 0.017 0.022 0.027 0.035 0.038 0.042 0.054 4666 0 0 1994 0.001 0.011 0.018 0.024 0.028 0.035 0.038 0.043 0.050 4846 0 0 

Olympic NP(Washington)530090012125 m

1989 0.000 0.003 0.010 0.015 0.022 0.030 0.035 0.046 0.065 4220 0 0 1990 0.000 0.005 0.012 0.018 0.023 0.030 0.034 0.043 0.064 4584 0 0 1991 0.000 0.006 0.014 0.019 0.024 0.033 0.036 0.044 0.056 4677 0 0 1993 0.000 0.004 0.010 0.016 0.021 0.029 0.034 0.041 0.064 4595 0 0 1994 0.000 0.006 0.013 0.019 0.025 0.033 0.038 0.043 0.062 4044 0 0 1995 0.000 0.006 0.014 0.020 0.027 0.037 0.040 0.048 0.077 4667 0 0 1996 0.000 0.006 0.013 0.019 0.025 0.034 0.038 0.043 0.058 4811 0 0 1997 0.000 0.005 0.010 0.015 0.022 0.035 0.040 0.046 0.057 44031998 0.000 0.008 0.014 0.019 0.025 0.033 0.037 0.044 0.063 4792 0 0 1999 0.000 0.006 0.014 0.019 0.026 0.036 0.039 0.044 0.050 4656 0 0 2000 0.000 0.006 0.013 0.019 0.025 0.035 0.039 0.045 0.061 4676 0 0 2001 0.002 0.009 0.017 0.023 0.028 0.036 0.041 0.046 0.055 4643 0 0 
AX3-19

Table AX3-3 (cont’d). Seasonal (April to October) Percentile Distribution of Hourly Ozone Concentrati

of Hourly Mean Ozone Occurrences $0.08 and $0.10, Seasonal 7-h Average Concentrations, SUM06, an

Sites Experiencing Low Maximum Hourly Average Concentrations with Data Capture of 

Site

Percentiles

Max.

No. of

Obs.

Hours

Se

Year Min. 10 30 50 70 90 95 99 $0.08 $0.10 

Glacier NP300298001(Montana)963 m

1989 0.000 0.003 0.015 0.026 0.036 0.046 0.050 0.058 0.067 4770 0 0 1990 0.000 0.003 0.014 0.026 0.035 0.044 0.047 0.052 0.066 5092 0 0 1991 0.000 0.001 0.014 0.027 0.036 0.046 0.049 0.056 0.062 5060 0 0 1992 0.000 0.001 0.013 0.025 0.033 0.043 0.048 0.055 0.077 4909 0 0 1993 0.000 0.000 0.010 0.020 0.029 0.040 0.044 0.050 0.058 5071 0 0 1994 0.000 0.001 0.014 0.026 0.036 0.046 0.050 0.056 0.061 5072 0 0 1995 0.000 0.000 0.010 0.022 0.031 0.041 0.045 0.051 0.066 4744 0 0 1996 0.000 0.002 0.013 0.025 0.035 0.046 0.051 0.058 0.065 4666 0 0 1997 0.000 0.000 0.008 0.017 0.026 0.041 0.045 0.053 0.058 4378 0 0 1998 0.000 0.003 0.013 0.025 0.035 0.047 0.051 0.058 0.064 4649 0 0 1999 0.000 0.002 0.015 0.026 0.035 0.046 0.051 0.058 0.068 4540 0 0 2000 0.000 0.001 0.011 0.023 0.033 0.044 0.048 0.055 0.062 4551 0 0 2001 0.000 0.000 0.013 0.025 0.033 0.042 0.044 0.049 0.057 4643 0 0 

Yellowstone NP(Wyoming)5603910102484 m

1988 0.002 0.020 0.029 0.037 0.044 0.054 0.058 0.070 0.098 4257 17 0 1989 0.002 0.018 0.027 0.036 0.044 0.052 0.057 0.063 0.071 4079 0 0 1990 0.000 0.015 0.023 0.029 0.036 0.043 0.046 0.053 0.061 4663 0 0 1991 0.004 0.020 0.030 0.037 0.042 0.048 0.051 0.057 0.064 4453 0 0 1992 0.001 0.018 0.029 0.036 0.042 0.051 0.056 0.064 0.075 4384 0 0 1993 0.000 0.018 0.028 0.036 0.042 0.047 0.050 0.054 0.060 4399 0 0 1994 0.003 0.022 0.033 0.040 0.046 0.053 0.056 0.062 0.072 4825 0 0 1995 0.004 0.022 0.033 0.040 0.045 0.052 0.055 0.059 0.065 4650 0 0 
AX3-20

Table AX3-3 (cont’d). Seasonal (April to October) Percentile Distribution of Hourly Ozone Concentrati

of Hourly Mean Ozone Occurrences $0.08 and $0.10, Seasonal 7-h Average Concentrations, SUM06, an

Sites Experiencing Low Maximum Hourly Average Concentrations with Data Capture of 

Site

Percentiles

Max.

No. of

Obs.

Hours

Se

Year Min. 10 30 50 70 90 95 99 $0.08 $0.10 

Yellowstone NP(Wyoming)5603910112468 m

1997 0.005 0.026 0.035 0.040 0.045 0.051 0.054 0.060 0.068 4626 0 0 1998 0.004 0.029 0.038 0.043 0.048 0.055 0.058 0.064 0.073 4827 0 0 1999 0.012 0.033 0.040 0.046 0.051 0.059 0.062 0.069 0.079 4733 0 0 2000 0.009 0.031 0.039 0.045 0.050 0.057 0.060 0.065 0.074 4678 0 0 2001 0.012 0.034 0.041 0.046 0.050 0.057 0.060 0.065 0.078 4869 0 0 

Denali NP(Alaska)022900003640 m

1988 0.003 0.018 0.024 0.028 0.033 0.044 0.050 0.053 0.056 4726 0 0 1990 0.003 0.017 0.024 0.029 0.034 0.040 0.043 0.048 0.050 3978 0 0 1991 0.005 0.018 0.024 0.028 0.034 0.041 0.043 0.047 0.057 4809 0 0 1992 0.003 0.016 0.023 0.028 0.034 0.044 0.047 0.050 0.054 4800 0 0 1993 0.002 0.017 0.023 0.028 0.033 0.041 0.043 0.048 0.055 4773 0 0 1994 0.003 0.017 0.022 0.027 0.033 0.042 0.045 0.049 0.053 4807 0 0 1995 0.001 0.013 0.019 0.025 0.032 0.042 0.044 0.052 0.059 4825 0 0 1996 0.002 0.015 0.022 0.028 0.035 0.044 0.047 0.052 0.063 4831 0 0 1997 0.001 0.015 0.023 0.030 0.038 0.045 0.048 0.051 0.084 4053 1 0 1998 0.004 0.018 0.023 0.030 0.036 0.048 0.050 0.055 0.058 4782 0 0 1999 0.002 0.016 0.024 0.029 0.036 0.045 0.048 0.054 0.058 4868 0 0 2000 0.003 0.014 0.019 0.025 0.029 0.034 0.036 0.038 0.049 4641 0 0 2001 0.002 0.016 0.023 0.029 0.036 0.048 0.051 0.055 0.068 4868 0 0 

Badlands NP460711001(South Dakota)730 m

1989 0.006 0.020 0.027 0.034 0.041 0.049 0.053 0.060 0.071 4840 0 0 1990 0.006 0.019 0.027 0.032 0.037 0.044 0.048 0.054 0.063 4783 0 0 1991 0.005 0.020 0.028 0.033 0.040 0.047 0.050 0.056 0.066 4584 0 0 
AX3-21

Table AX3-3 (cont’d). Seasonal (April to October) Percentile Distribution of Hourly Ozone Concentrati

of Hourly Mean Ozone Occurrences $0.08 and $0.10, Seasonal 7-h Average Concentrations, SUM06, an

Sites Experiencing Low Maximum Hourly Average Concentrations with Data Capture of 

Site

Percentiles

Max.

No. of

Obs.

Hours

Se

Year Min. 10 30 50 70 90 95 99 $0.08 $0.10 

Theod. Roos.NP380530002(North Dakota)730 m

1984 0.000 0.017 0.025 0.032 0.039 0.047 0.050 0.059 0.068 4923 0 0 1985 0.000 0.019 0.026 0.032 0.038 0.046 0.049 0.054 0.061 4211 0 0 1986 0.004 0.017 0.027 0.033 0.039 0.047 0.050 0.056 0.062 4332 0 0 1989 0.004 0.023 0.032 0.039 0.045 0.054 0.058 0.065 0.073 4206 0 0 1992 0.005 0.019 0.027 0.033 0.039 0.047 0.050 0.056 0.063 4332 0 0 1993 0.004 0.018 0.025 0.031 0.037 0.045 0.048 0.055 0.064 4281 0 0 1994 0.000 0.018 0.028 0.035 0.041 0.049 0.052 0.058 0.079 4644 0 0 1995 0.000 0.018 0.028 0.035 0.041 0.050 0.053 0.058 0.064 4242 0 0 1996 0.003 0.022 0.031 0.037 0.043 0.051 0.054 0.059 0.064 3651 0 0 1997 0.000 0.016 0.029 0.037 0.044 0.053 0.058 0.069 0.082 4344 8 0 

Theod. Roos.NP380070002(North Dakota)808 m

1999 0.007 0.024 0.031 0.037 0.042 0.049 0.052 0.058 0.070 5105 0 0 2000 0.002 0.021 0.031 0.036 0.043 0.050 0.053 0.058 0.066 5105 0 0 2001 0.002 0.023 0.031 0.036 0.042 0.049 0.052 0.058 0.064 5099 0 0 

Custer NF, MT300870101(Montana)1006 m

1978 0.000 0.010 0.020 0.035 0.040 0.050 0.055 0.060 0.070 4759 0 0 1979 0.010 0.025 0.035 0.040 0.045 0.050 0.055 0.060 0.075 5014 0 0 1980 0.010 0.025 0.035 0.040 0.050 0.055 0.060 0.065 0.070 4574 0 0 1983 0.010 0.025 0.035 0.040 0.045 0.05 0.055 0.060 0.065 4835 0 0 
AX3-22

a data capture of $75% are summarized in Table AX3-4. The highest 8-h daily maximum

concentrations do not necessarily all occur during the summer months. For example, at the

Yellowstone National Park site, the three highest 8-h daily maximum concentrations occurred in

April and May in 1998, and the fourth highest, 8-h daily maximum concentration did not occur

until July of that year. In 1999, the three highest, 8-h daily maximum concentrations were

observed in March and May, and the fourth highest value occurred in April. In 2000, the four

highest values occurred in May, June, July, and August.

The 1996 O3 AQCD (U.S. Environmental Protection Agency, 1996a) noted that the

7-month (April to October) average of the 7-h daily average concentrations (0900 to 1559 hours)

observed at the Theodore Roosevelt National Park monitoring site in North Dakota were 0.038,

0.039, and 0.039 ppm, respectively, for 1984, 1985, and 1986 and concluded that the range of

7-h seasonal averages for the Theodore Roosevelt National Park site was representative of the

range of maximum daily 8-h average O3 concentrations that may occur at other fairly clean sites

in the United States and other locations in the Northern Hemisphere. However, as shown in

Table AX3-4, the representative (as given by the fourth highest) daily maximum 8-h average O3

concentrations at fairly clean sites in the United States are higher than the 0.038 and 0.039 ppm

values cited in the 1996 O3 AQCD, and these updated values should be used to characterize O3 at

these sites. 

As described in the 1996 O3 AQCD, the O3 monitoring site in the Ouachita National Forest,

AR experienced distributions of hourly average concentrations similar to some of the western

sites. However, since 1993, this site has seen significant shifts, both increases and decreases, in

hourly average concentrations. Figure AX3-12 shows the changes that have occurred from 1991

to 2001. The large changes in hourly average O3 concentrations observed at the Ouachita

National Forest may indicate that this rural site is influenced by the transport of pollution. Given

the high density of sources in the eastern and midwestern United States, it is unclear whether a

site could be found in either of these regions that would not be influenced by the transport of O3

from urban areas. Thus, with the exception of the Voyageurs National Park site, observations in

this section are limited to those obtained at relatively clean, remote sites in western North

America. 
AX3-23

Table AX3-4. The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Experiencing 

Hourly Average Concentrations with Data Capture of $75%

Site Year 1 2 3 4 5 6 7 8 Redwood NP060150002(California)235 m

1988 0.061 0.058 0.053 0.052 0.049 0.047 0.046 0.046 1989 0.044 0.043 0.043 0.043 0.042 0.042 0.042 0.042 1990 0.051 0.048 0.048 0.047 0.047 0.046 0.045 0.044 1991 0.048 0.047 0.046 0.045 0.045 0.045 0.044 0.044 1992 0.060 0.053 0.045 0.045 0.045 0.044 0.044 0.043 1993 0.049 0.046 0.043 0.043 0.043 0.042 0.042 0.042 1994 0.048 0.048 0.046 0.046 0.045 0.044 0.044 0.043 

Olympic NP530090012(Washington)125 m

1989 0.054 0.052 0.047 0.044 0.044 0.044 0.042 0.042 1990 0.056 0.048 0.046 0.046 0.043 0.040 0.040 0.039 1991 0.050 0.048 0.045 0.043 0.042 0.041 0.041 0.041 1993 0.055 0.052 0.044 0.042 0.040 0.039 0.038 0.038 1994 0.050 0.046 0.042 0.042 0.042 0.042 0.041 0.041 1995 0.064 0.063 0.050 0.049 0.045 0.045 0.044 0.044 1996 0.046 0.046 0.046 0.046 0.043 0.042 0.041 0.041 1997 0.052 0.051 0.046 0.045 0.045 0.045 0.044 0.043 1998 0.051 0.050 0.049 0.046 0.044 0.043 0.042 0.041 1999 0.045 0.044 0.044 0.043 0.043 0.042 0.042 0.042 2000 0.051 0.051 0.048 0.047 0.045 0.044 0.043 0.042 2001 0.051 0.050 0.047 0.045 0.045 0.044 0.044 0.044 
AX3-24

Table AX3-4 (cont’d). The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Exp

Maximum Hourly Average Concentrations with Data Capture of $75%

Site Year 1 2 3 4 5 6 7 8 Glacier NP300298001(Montana)963 m

1989 0.062 0.061 0.060 0.059 0.058 0.057 0.056 0.056 1990 0.058 0.057 0.055 0.054 0.053 0.053 0.052 0.052 1991 0.060 0.057 0.057 0.057 0.056 0.055 0.055 0.054 1992 0.062 0.056 0.055 0.054 0.054 0.054 0.053 0.053 1993 0.055 0.052 0.051 0.051 0.050 0.050 0.049 0.049 1994 0.057 0.057 0.056 0.056 0.055 0.055 0.055 0.055 1995 0.061 0.055 0.053 0.052 0.052 0.052 0.051 0.051 1996 0.059 0.059 0.058 0.058 0.057 0.057 0.055 0.056 1997 0.056 0.054 0.052 0.052 0.052 0.051 0.050 0.050 1998 0.060 0.059 0.058 0.058 0.056 0.056 0.055 0.055 1999 0.065 0.065 0.060 0.058 0.056 0.055 0.055 0.055 2000 0.059 0.058 0.058 0.056 0.054 0.052 0.051 0.050 2001 0.054 0.052 0.049 0.049 0.049 0.048 0.047 0.047 

Yellowstone NP560391010(Wyoming)2484 m

1988 0.068 0.068 0.067 0.066 0.066 0.066 0.064 0.064 1989 0.067 0.065 0.064 0.063 0.063 0.061 0.061 0.061 1990 0.057 0.056 0.054 0.054 0.053 0.052 0.050 0.050 1991 0.059 0.058 0.058 0.057 0.056 0.056 0.056 0.055 1992 0.066 0.064 0.064 0.063 0.063 0.061 0.061 0.059 1993 0.057 0.054 0.054 0.054 0.053 0.053 0.053 0.052 1994 0.067 0.063 0.063 0.061 0.061 0.061 0.061 0.061 1995 0.064 0.062 0.061 0.060 0.059 0.059 0.059 0.059 
AX3-25

Table AX3-4 (cont’d). The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Exp

Maximum Hourly Average Concentrations with Data Capture of $75%

Site Year 1 2 3 4 5 6 7 8 Yellowstone NP560391011(Wyoming)2468 m

1997 0.065 0.065 0.062 0.061 0.061 0.060 0.057 0.056 1998 0.069 0.068 0.066 0.066 0.063 0.063 0.061 0.061 1999 0.078 0.074 0.073 0.071 0.070 0.070 0.070 0.069 2000 0.070 0.069 0.067 0.065 0.065 0.065 0.064 0.064 2001 0.068 0.068 0.066 0.066 0.065 0.064 0.064 0.064 

Denali NP022900003(Alaska)640 m

1988 0.055 0.054 0.054 0.053 0.053 0.053 0.052 0.052 1990 0.049 0.048 0.048 0.048 0.048 0.047 0.047 0.046 1991 0.054 0.054 0.050 0.050 0.047 0.046 0.046 0.046 1992 0.053 0.052 0.052 0.051 0.050 0.050 0.049 0.049 1993 0.053 0.053 0.051 0.048 0.048 0.047 0.047 0.046 1994 0.053 0.051 0.049 0.049 0.049 0.048 0.048 0.048 1995 0.058 0.056 0.056 0.054 0.051 0.050 0.049 0.046 1996 0.058 0.053 0.053 0.053 0.052 0.052 0.052 0.052 1997 0.054 0.053 0.052 0.051 0.051 0.050 0.050 0.049 1998 0.057 0.056 0.056 0.055 0.054 0.054 0.054 0.054 1999 0.056 0.056 0.054 0.054 0.054 0.053 0.053 0.053 2000 0.046 0.046 0.044 0.044 0.044 0.043 0.043 0.042 2001 0.061 0.058 0.057 0.055 0.055 0.055 0.053 0.053 

Badlands NP460711001(South Dakota)730 m

1989 0.069 0.066 0.064 0.063 0.060 0.058 0.057 0.057 1990 0.061 0.059 0.055 0.055 0.054 0.052 0.052 0.051 1991 0.058 0.058 0.056 0.056 0.056 0.055 0.055 0.054 
AX3-26

Table AX3-4 (cont’d). The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Exp

Maximum Hourly Average Concentrations with Data Capture of $75%

Site Year 1 2 3 4 5 6 7 8 Theod. Roos. NP380530002(North Dakota)730 m

1984 0.064 0.062 0.062 0.062 0.059 0.058 0.057 0.057 1985 0.058 0.055 0.055 0.054 0.054 0.054 0.053 0.053 1986 0.059 0.058 0.057 0.056 0.055 0.055 0.054 0.053 1989 0.073 0.069 0.066 0.065 0.065 0.064 0.063 0.063 1992 0.060 0.059 0.058 0.058 0.056 0.056 0.056 0.054 1993 0.062 0.059 0.056 0.056 0.055 0.053 0.052 0.052 1994 0.066 0.064 0.058 0.058 0.057 0.056 0.056 0.056 1995 0.060 0.059 0.058 0.058 0.058 0.058 0.057 0.057 1996 0.060 0.059 0.059 0.059 0.058 0.058 0.057 0.057 1997 0.080 0.073 0.072 0.071 0.069 0.068 0.066 0.066 

Theod. Roos. NP380070002(North Dakota)808 m

1999 0.063 0.060 0.059 0.058 0.057 0.057 0.057 0.056 2000 0.062 0.061 0.060 0.059 0.059 0.057 0.057 0.057 2001 0.060 0.059 0.059 0.058 0.058 0.057 0.057 0.056 

Custer NF, MT300870101(Montana)1006 m

1978 0.069 0.065 0.063 0.062 0.061 0.061 0.060 0.060 1979 0.073 0.066 0.066 0.065 0.063 0.060 0.060 0.060 1980 0.069 0.069 0.069 0.068 0.067 0.067 0.066 0.066 1983 0.064 0.061 0.060 0.060 0.059 0.058 0.058 0.058 
AX3-27

Figure AX3-12. Seasonal SUM06 and W126 exposure indices for the Ouachita National

Forest for the period of 1991 to 2001.

AX3.2.1 Nationwide Distribution of Metrics for Characterizing Exposures

of Vegetation to Ozone

The previous O3 AQCD (U.S. Environmental Protection Agency, 1996a) concluded that

higher hourly average concentrations ($0.10 ppm) should be given greater weight than mid-level

(0.06 to 0.099 ppm) and lower hourly average concentrations in predicting injury and yield

reduction for agricultural crops and forests. The most recent findings concerning the importance

of the higher hourly average concentrations in comparison to the mid-level and lower values will

be discussed in Chapter 9. Because of a lack of air quality data collected at rural and remote

locations, interpolation techniques, such as kriging, have been applied to the estimation of O3

exposures across the United States (Reagan, 1984; Lefohn et al., 1987; Knudsen and Lefohn,

1988). “Kriging” (Matheron, 1963) has been used in the analyses of air quality data (Grivet,

1980; Faith and Sheshinski, 1979) and was used to provide estimates of seasonal O3 values for

the National Crop Loss Assessment Network (NCLAN) for 1978 through 1982 (May to

September of each year) (Reagan, 1984). These values, along with updated values, coupled with

exposure-response models, were used to predict agriculturally related economic benefits

anticipated by lower O3 levels in the United States (Adams et al., 1985, 1989). It should be

noted that although kriging has been used here to map unmeasured ozone concentrations, it has

shortcomings. In particular, the kriging variance underestimates the uncertainty in spatial
AX3-28

prediction and relies on the assumption of spatial covariance isotropy. Newer methods

overcomes many of these shortcomings (e.g., Le et al., 1992, 1997, 2001). These methodologies

have been tested by Sun et al. (1998), who also show that the uncertainties in spatial fields can

be substantially underestimated using kriging.

Spatiotemporal distributions of O3 concentrations have alternatively been obtained using

methods of the “Spatio-Temporal Random Field” (STRF) theory (Christakos and Vyas,

1998a,b). The STRF approach interpolates monitoring data in both space and time

simultaneously. This method can analyze information on “temporal trends,” which cannot be

incorporated directly in purely spatial interpolation methods such as standard kriging. Further,

the STRF method can optimize the use of data that are not uniformly sampled in either space or

time. The STRF theory was further extended in the Bayesian Maximum Entropy (BME)

framework and applied to O3 interpolation studies (Christakos and Hristopulos, 1998; Christakos

and Kolovos, 1999; Christakos, 2000). The BME framework can use prior information in the

form of “hard data” (measurements), probability law descriptors (type of distribution, mean and

variance), interval estimation (maximum and minimum values) and even constraint from

physical laws. According to these researchers, both STRF and BME were found to successfully

reproduce O3 fields when adequate monitor data are available.

For 2001, ordinary kriging was used to estimate the seasonal W126, SUM06, and number

of hours $0.10 ppm (N100), using hourly average concentrations accumulated over a 24-h

period. As discussed in Chapter 9, the correlation between the number of occurrences of hourly

average concentrations $0.10 ppm and the magnitude of the W126 and SUM06 values is not

strong. Because of this, the N100 was also estimated, along with the W126 and SUM06

exposure indices. For the period of April through September, the estimates of the seasonal

W126, SUM06, and N100 exposure index values were made for each 0.5° by 0.5° cell in the

continuous United States. The kriged values, the variance, and the 95% error bound for each

0.5° by 0.5° cell were estimated. Because of the concern for inner-city depletion caused by NOx

scavenging, data from specific monitoring stations located in large metropolitan areas were not

included in the analysis.

Figure AX3-13 shows the kriged values for the 24-h cumulative seasonal W126 exposure

index and the N100 index for 2001 for the eastern United States. Note that for some of the areas

with elevated W126 values (e.g., >35 ppm-h), the number of hourly average concentrations was 
AX3-29

Figure AX3-13. Six-month (April to September) 24-h cumulative W126 exposure index

with the number of hourly average concentrations $0.10 ppm (N100)

occurring during 2001 for the eastern United States.
AX3-30

estimated to be <22. Figure AX3-14 illustrates the kriged values using the 24-h cumulative

seasonal SUM06 exposure index and the N100 index for 2001 for the eastern United States. 

Figures AX3-15 and AX3-16 show the W126 and SUM06 values, respectively, with the N100

values for the central United States region. For 2001, the number of hourly average

concentrations $0.10 ppm was usually <22 for the 6-month period. Figures AX3-17 and

AX3-18 illustrate the W126 and SUM06 values, respectively, for the western United States

region. Note that in the Southern California and Central California areas, the number of hourly

average concentrations $0.10 ppm was in the range of 48 to 208 for the 6-month period. This is

considerably greater than the frequency of occurrences for the higher hourly average

concentrations observed in the eastern and central United States. 

Due to the scarcity of monitoring sites across the United States, especially in the Rocky

Mountain region, the uncertainty in the estimates for the various exposure indices vary. 

Figures AX3-19 through AX3-27 illustrate the 95% confidence intervals associated with the

indices by region. 

AX3.3 SPATIAL VARIABILITY IN OZONE CONCENTRATIONS

The spatial variability of O3 concentrations in different environments in the United States

occurring across a variety of spatial scales is characterized in this section. This information will

be useful for understanding the influence of regional or altitudinal differences in O3 exposure on

vegetation and for establishing the spatial variations in O3 concentrations as they are used in

epidemiologic studies. Intracity variations in O3 concentrations are described in Section 

AX3.3.1. Small scale horizontal and vertical variations in O3 concentrations are discussed in

Section AX3.3.2. Ozone concentrations at high elevations are characterized in Section AX3.3.3.

AX3.3.1 Spatial Variability of Ozone Concentrations in Urban Areas 

Many processes contribute to spatial variability in O3 concentrations in urban areas. Ozone

formation occurs more or less continuously downwind of sources of precursors, producing a

gradient in O3 concentrations. Ozone “titration” by reaction with NO can deplete O3 levels near

NO sources such as highways and busy streets. Differences in surface characteristics affect the 
AX3-31

Figure AX3-14. Six-month (April to September) 24-h cumulative SUM06 exposure index

with the number of hourly average concentrations $0.10 ppm (N100)

occurring during 2001 for the eastern United States.
AX3-32

Figure AX3-15. Six-month (April to September) 24-h cumulative W126 exposure index

with the number of hourly average concentrations $0.10 ppm (N100)

occurring during 2001 for the central United States.
AX3-33

Figure AX3-16. Six-month (April to September) 24-h cumulative SUM06 exposure index

with the number of hourly average concentrations $0.10 ppm (N100)

occurring during 2001 for the central United States.
AX3-34

Figure AX3-17. Six-month (April to September) 24-h cumulative W126 exposure index

with the number of hourly average concentrations $0.10 ppm (N100)

occurring during 2001 for the western United States.
AX3-35

Figure AX3-18. Six-month (April to September) 24-h cumulative SUM06 exposure index

with the number of hourly average concentrations $0.10 ppm (N100)

occurring during 2001 for the western United States.
AX3-36

Figure AX3-19. The 95% confidence interval for the 6-month (April to September) 24-h

cumulative W126 exposure index for 2001 for the eastern United States.

Figure AX3-20. The 95% confidence interval for the 6-month (April to September)

24-h cumulative SUM06 exposure index for 2001 for the eastern

United States.
AX3-37

Figure AX3-21. The 95% confidence interval for the 6-month (April to September) 24-h

cumulative N100 exposure index for 2001 for the eastern United States.

Figure AX3-22. The 95% confidence interval for the 6-month (April to September) 24-h

cumulative W126 exposure index for 2001 for the central United States.
AX3-38

Figure AX3-23. The 95% confidence interval for the 6-month (April to September)

24-h cumulative SUM06 exposure index for 2001 for the central

United States.

Figure AX3-24. The 95% confidence interval for the 6-month (April to September) 24-h

cumulative N100 exposure index for 2001 for the central United States.
AX3-39

Figure AX3-25. The 95% confidence interval for the 6-month (April to September)

24-h cumulative W126 exposure index for 2001 for the western

United States.

Figure AX3-26. The 95% confidence interval for the 6-month (April to September)

24-h cumulative SUM06 exposure index for 2001 for the western

United States.
AX3-40

rate of deposition of O3. Mixing of O3 from aloft can also lead to local increases in O3

concentration. 

The spatial variability in O3 concentrations in 24 MSAs across the United States is

characterized in this section. These areas were chosen to provide analyses to help guide risk

assessment, to provide a general overview of the spatial variability of O3 over different regions

of the country, and also to provide insight into the spatial distribution of O3 in cities where health

outcome studies have been conducted. Statistical analyses of the human health effects of

airborne pollutants based on aggregate population time-series data have often relied on ambient

concentrations of pollutants measured at one or more central sites in a given metropolitan area. 

In the particular case of ground-level O3 pollution, central-site monitoring has been justified as a

regional measure of exposure partly on grounds that correlations between concentrations at

neighboring sites measured over time are usually high (U.S. Environmental Protection Agency,

1996a). In analyses where multiple monitoring sites provide ambient O3 concentrations, a

Figure AX3-27. The 95% confidence interval for the 6-month (April to September)

24-h cumulative N100 exposure index for 2001 for the western

United States.
(AX3-1)

1 The COD is defined as follows:

where xij and xik represent the 24-h average PM2.5 concentration for day i at site j and site k and p is the number of observations.

AX3-41

summary measure such as an averaged concentration has often been regarded as adequately

characterizing the exposure distribution. Indeed, a number of studies have referred to

multiple-site averaging as the method for estimating O3 exposure (U.S. Environmental

Protection Agency, 1996a). It is hoped that the analyses presented here will shed some light on

the suitability of this practice. Earlier analyses were reported in the previous O3 AQCD (U.S.

Environmental Protection Agency, 1996a). The analyses presented there concluded that the

extent of spatial homogeneity varies with the MSA under study. In particular, cities with low

traffic densities that are located downwind of major sources of precursors are heavily influenced

by long range transport and tend to show smaller spatial variability (e.g., New Haven, CT) than

those source areas with high traffic densities located upwind (e.g., New York, NY). 

Metrics for characterizing spatial variability include the use of Pearson correlation

coefficients (r), values of the 90th percentile (P90) of the absolute difference in concentrations,

and coefficients of divergence (COD)1. These methods of analysis follow those used for

characterizing PM2.5 and PM10-2.5 concentrations in Pinto et al. (2004) and in the latest edition of

the PM AQCD (U.S. Environmental Protection Agency, 2004a). Data were aggregated over

local O3 seasons, whose length varies from state to state. In several southwestern states, it lasts

all year long. However, it typically lasts for 6 months in other areas, such as New England, the

mid-Atlantic states, the Midwest, and the Northwest (see Table AX3-1). 

Table AX3-5 shows the chosen urban areas, the range of 24-h average O3 concentrations

over the local O3 season from 1999 to 2001, the range of intersite correlation coefficients, the

range of P90 differences in O3 concentrations between site pairs, and the range in COD values. A

COD of zero implies that values in both data sets are identical, and a COD of one indicates that

the two data sets are uncorrelated with no identical values from either data set. In general,

statistics were calculated for partial MSAs. This was done so as to obtain reasonable lower

estimates of the spatial variability that is present, as opposed to examining the consolidated

MSAs. In Boston, MA and New York, NY, this could not be readily done, and so statistics were 
Table AX3-5. Summary Statistics for Ozone (in ppm) Spatial Variability in Selected U.S. Urb

Urban Area

Number of

Sites

Minimum

Mean Conc.

Maximum

Mean Conc.

Minimum

Corr. Coeff.

Maximum

Corr. Coeff.

Minimum

P90a

Maximum

P90

M

Boston, MA 18 0.021 0.033 0.46 0.93 0.012 0.041 New York, NY 29 0.015 0.041 0.45 0.96 0.0080 0.044 Philadelphia, PA 12 0.020 0.041 0.79 0.95 0.011 0.036 Washington, DC 20 0.022 0.041 0.72 0.97 0.010 0.032 Charlotte, NC 8 0.031 0.043 0.48 0.95 0.012 0.038 Atlanta, GA 12 0.023 0.047 0.63 0.94 0.013 0.045 Tampa, FL 9 0.024 0.035 0.74 0.94 0.011 0.025 Detroit, MI 7 0.022 0.037 0.74 0.96 0.0090 0.027 Chicago, IL 24 0.015 0.039 0.38 0.96 0.0080 0.043 Milwaukee, WI 9 0.027 0.038 0.73 0.96 0.0090 0.025 St. Louis, MO 17 0.022 0.038 0.78 0.96 0.0090 0.031 Baton Rouge, LA 7 0.018 0.031 0.81 0.95 0.0090 0.029 Dallas, TX 10 0.028 0.043 0.67 0.95 0.011 0.033 Houston, TX 13 0.016 0.036 0.73 0.96 0.0090 0.027 Denver, CO 8 0.022 0.044 0.60 0.92 0.013 0.044 El Paso, TX 4 0.022 0.032 0.81 0.94 0.012 0.023 Salt Lake City, UT 8 0.029 0.048 0.52 0.92 0.012 0.043 Phoenix, AZ 15 0.021 0.058 0.29 0.95 0.011 0.057 Seattle, WA 5 0.015 0.038 0.63 0.94 0.0080 0.024 Portland, OR 5 0.015 0.036 0.73 0.91 0.011 0.025 Fresno, CA 6 0.030 0.047 0.90 0.97 0.0090 0.027 Bakersfield, CA 8 0.028 0.047 0.23 0.96 0.013 0.052 Los Angeles, CA 14 0.010 0.042 0.42 0.95 0.010 0.053 Riverside, CA 18 0.018 0.054 0.38 0.95 0.013 0.057 aP90 = 90th percentile absolute difference in concentrations.bCOD = coefficient of divergence for different site pairs.

AX3-42
AX3-43

calculated for the consolidated MSAs. More detailed calculations for a subset of nine MSAs are

given in Figures AX3-28 through AX3-36. 

As can be seen, there are no clearly discernible regional trends in the ranges of parameters

shown. Additional urban areas would need to be examined to discern broadscale patterns. The

data indicate considerable variability in the concentration fields. Mean O3 concentrations vary

within individual urban areas from factors of 1.4 to 4.0. 

The highest annual mean O3 concentration (0.058 ppm) is found in the Phoenix, AZ MSA

at a site which is located in the mountains well downwind of the main urban area. The lowest

annual mean O3 concentration (0.010 ppm) was found in Lynwood in the urban core of the

Los Angeles MSA. CO and NOx monitors at this site recorded the highest concentrations in

California, indicating that titration of O3 by NO freshly emitted from tail pipes of motor vehicles

is responsible for the low O3 values that are found. Ratios of highest to lowest mean O3

concentrations in these two MSAs are among the highest shown in Table AX3-5. Both of these

MSAs are characterized by sunny, warm climates; sources of precursors that are associated 

with O3 titration to varying degrees in their urban centers; and with maximum O3 found well

downwind of the urban centers. Intersite correlation coefficients show mixed patterns, i.e.,

in some urban areas all pairs of sites are moderately to highly correlated, while other areas show

a very large range of values. As may be expected, those areas which show smaller ratios of

seasonal mean concentrations also exhibit a smaller range of intersite correlation coefficients.

Within the examined urban areas, P90 values were evenly distributed between all site pairs

considered. The CODs indicate variability among site pairs. However, there are a number of

cases where sites in an urban area may be moderately to highly correlated but showed substantial

differences in absolute concentrations. In many cases, values for P90 equaled or exceeded

seasonal mean O3 concentrations. This was reflected in both values for P90 and for the COD.

It is instructive to compare the metrics for spatial variability shown in Table AX3-5 to

those calculated for PM2.5 and PM10-2.5 in the PM AQCD (U.S. Environmental Protection

Agency, 2004a). The values for concentrations and concentration differences are unique to the

individual species, but the intersite correlation coefficients and the COD values can be directly

compared. 
AX3-44

Figure AX3-28. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Charlotte, NC-Gastonia-Rock Hill, SC

MSA. The mean hourly measured O3 concentration at each site is given

above its letter code. For each data pair, the Pearson correlation

coefficient, 90th percentile difference in absolute concentrations, the

coefficient of divergence, and number of observations are given.
AX3-45

Figure AX3-29. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Baton Rouge, LA MSA. The mean hourly

measured O3 concentration at each site is given above its letter code. 

For each data pair, the Pearson correlation coefficient, 90th percentile

difference in absolute concentrations, the coefficient of divergence, and

number of observations are given.
AX3-46

Figure AX3-30. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Detroit-Ann Arbor-Flint, MI CMSA. 

The mean hourly measured O3 concentration at each site is given above

its letter code. For each data pair, the Pearson correlation coefficient,

90th percentile difference in absolute concentrations, the coefficient of

divergence, and number of observations are given.
AX3-47

Figure AX3-31. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the St. Louis, MO-IL MSA. The mean hourly

measured O3 concentration at each site is given above its letter code. 

For each data pair, the Pearson correlation coefficient, 90th percentile

difference in absolute concentrations, the coefficient of divergence, and

number of observations are given.
AX3-48

Figure AX3-31 (cont’d).
AX3-49

Figure AX3-32. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Phoenix-Mesa, AZ MSA. The mean

hourly measured O3 concentration at each site is given above its letter

code. For each data pair, the Pearson correlation coefficient, 90th

percentile difference in absolute concentrations, the coefficient of

divergence, and number of observations are given.
AX3-50

Figure AX3-33. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Fresno, CA MSA. The mean hourly

measured O3 concentration at each site is given above its letter code. For

each data pair, the Pearson correlation coefficient, 90th percentile

difference in absolute concentrations, the coefficient of divergence, and

number of observations are given.

In general, the variability in O3 concentrations is larger than for PM2.5 concentrations and

comparable to that obtained for PM10-2.5. Intersite correlation coefficients in some areas (e.g.,

Philadelphia, PA; Atlanta, GA; Portland, OR) can be very similar for both PM2.5 and for O3. 

However, there is much greater variability in the concentration fields of O3 as evidenced by the

much higher COD values. Indeed, COD values are higher for O3 than for PM2.5 in each of the

urban areas examined. In all of the urban areas examined for O3 some site pairs are always very

highly correlated with each other (i.e., r > 0.9) as seen for PM2.5. These sites also show less
AX3-51

Figure AX3-34. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Bakersfield, CA MSA. The mean hourly

measured O3 concentration at each site is given above its letter code. 

For each data pair, the Pearson correlation coefficient, 90th percentile

difference in absolute concentrations, the coefficient of divergence, and

number of observations are given.

variability in concentration and are probably influenced most strongly by regional production

mechanisms. 
AX3-52

Figure AX3-35. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Los Angeles-Orange County, CA CMSA. 

The mean hourly measured O3 concentration at each site is given above

its letter code. For each data pair, the Pearson correlation coefficient,

90th percentile difference in absolute concentrations, the coefficient of

divergence, and number of observations are given.
AX3-53

Figure AX3-35 (cont’d).
AX3-54

Figure AX3-36. Locations of O3 sampling sites (a) by AQS ID# (b) and intersite

correlation statistics (c) for the Riverside-Orange County, CA CMSA. 

The mean hourly measured O3 concentration at each site is given above

its letter code. For each data pair, the Pearson correlation coefficient,

90th percentile difference in absolute concentrations, the coefficient of

divergence, and number of observations are given.
AX3-55

Figure AX3-36 (cont’d).
AX3-56

AX3.3.2 Small-scale Horizontal and Spatial Variability in Ozone

Concentrations

Ozone concentrations near roadways

Apart from the larger scale variability in surface O3 concentrations, there is also significant

variability on the micro-scale (< a few hundred meters), especially near roadways and other

sources of emissions that react with O3. These sources are not confined to urban areas. Sources

of emissions that react with O3 such as highways and power plants are also found in rural areas. 

Johnson (1995) described the results of studies examining O3 upwind and downwind of

roadways in Cincinnati, OH. In these studies, O3 upwind of the roadway was about 50 ppb and

values as high as this were not found again until distances of about 100 m downwind. The O3

profile varied inversely with that of NO, as might be expected. For peak NO concentrations of

30 ppb, the O3 mixing ratio was about 36 ppb, or about 70% of the upwind value. The

magnitude of the downwind depletion of O3 depends on the emissions of NO, the rate of mixing

of NO from the roadway and ambient temperatures. So depletions of O3 downwind of roadways

are expected, but with variable magnitude, although scavenging of O3 by NO near roadways was

more pronounced before the implementation of stringent NOx emissions controls.

Guidance for the placement of O3 monitors (U.S. Environmental Protection Agency, 1998)

states a separation distance that depends on traffic counts. For example, a minimum separation

distance of 100 m from a road with 70,000 vehicles per day is recommended for siting an O3

monitor to avoid interference that would mean a site is no longer representative of the

surrounding area. An average rate of about 3,000 vehicles per hour passing by a monitoring site

implies a road with rather heavy traffic. As noted earlier in Section AX3.3.1 for the Lakewood,

CA monitoring, O3 levels are lower at sites located near traffic than those located some distance

away and the scavenging of O3 by emissions of NO from roadways is a major source of spatial

variability in O3 concentrations. 

Vertical Variations in Ozone Concentrations

In addition to horizontal variability in O3 concentrations, consideration must also be given

to variations in the vertical profile of O3 in the lowest layers of the atmosphere. The planetary

boundary layer consists of an outer and an inner portion. The inner part extends from the surface

to about one-tenth the height of the planetary boundary layer. Winds and transported pollutants,
AX3-57

such as O3, are especially susceptible to interactions with obstacles, such as buildings and trees

in the inner boundary layer (atmospheric surface layer) (e.g., Garratt, 1992). Inlets to ambient

monitors (typically at heights of 3 to 5 meters) are located in, and human and vegetation

exposures occur in this part of the boundary layer.

Photochemical production and destruction of O3 occurs throughout the planetary boundary

layer. However, O3 is also destroyed on the surfaces of buildings, vegetation, etc. On most

surfaces, O3 is destroyed with every collision. In addition, O3 is scavenged by NO emitted by

motor vehicles and soils. These losses imply that the vertical gradient of O3 should always be

directed downward. The magnitude of the gradient is determined by the intensity of turbulent

mixing in the surface layer.

Most work characterizing the vertical profile of O3 near the surface has been performed in

nonurban areas with the aim of calculating fluxes of O3 and other pollutants through forest

canopies and to crops and short vegetation etc. Corresponding data are sparse for urban areas. 

However, monitoring sites are often set up in open areas such as parks and playgrounds where

surface characteristics may resemble those in rural areas more than those in the surrounding

urban area. The vertical profile of O3 measured over low vegetation is shown in Figure AX3-37. 

These measurements were obtained as part of a field campaign to measure the fluxes of several

gas and aerosol phase pollutants using the gradient-flux technique in a remote area in Hortobagy

National Park in Hungary during late spring of 1994 (Horvath et al., 1995). The labels stable

and unstable in the figure refer to atmospheric stability conditions and average represents the

overall average. Ozone concentrations were normalized relative to their values at a height of

4 m. As can be seen from the figure, there was a decrease of about 20% in going from a height

of 4 m down to 0.5 m above the surface during stable conditions, but O3 decreased by only about

7% during unstable conditions. The average decrease was about 10% for all measurements. As

might be expected, O3 concentrations at all heights were very highly correlated with one another. 

Of course, these values represent averages and there is scatter about them, particularly under

strongly stable conditions. However, these conditions tend to occur mainly during night and the

stability regime during the day in urban areas tends more towards instability because of the

urban heat island effect. Figure AX3-38 shows the vertical profile of O3 obtained in a spruce

forest in northwestern Hungary in late summer 1991 (Horvath et al., 2003). The fall off in O3 for 
AX3-58

this case is due to uptake by trees, reaction with ambient NO and with NO emitted by the soil in

the forest in addition to deposition on the surface. 

AX3.3.3 Ozone Concentrations at High Elevations

The distributions of hourly average concentrations experienced at high-elevation cities are

similar to those experienced in low-elevation cities. For example, the distribution of hourly

average concentrations for several O3 sites located in Denver were similar to distributions

observed at many low-elevation sites elsewhere in the United States. However, the use of

absolute concentrations (e.g., in units of micrograms per cubic meter) in assessing the possible

impacts of O3 on vegetation at high-elevation sites instead of mixing ratios (e.g., parts per

million) may be an important consideration (see Chapter 9, for further considerations about

exposure and effective dose considerations for vegetation assessments). 

Figure AX3-37. Vertical profile of O3 obtained over low vegetation. Values shown are

relative to concentrations at 4 m above the surface. Ozone

concentrations for stable and unstable conditions were 41.3 and 24.1

ppb, and average O3 concentration weighted by stability class was 33.1

ppb at 4 m.

Source. Horvath et al. (1995).
AX3-59

Concentrations of O3 vary with altitude and latitude. Although a number of reports contain

data on O3 concentrations at high altitudes (e.g., Coffey et al., 1977; Reiter, 1977; Singh et al.,

1977; Evans et al., 1985; Lefohn and Jones, 1986), fewer reports present data for different

elevations in the same locality. Monitoring data collected by the Mountain Cloud Chemistry

Project (MCCP) provide useful information about O3 exposure differences at different

elevations. When applying different exposure indices to the MCCP data, there appears to be no

consistency in the relationship between O3 exposure and elevation. 

Lefohn et al. (1990a) summarized the characterization of gaseous exposures at rural sites in

1986 and 1987 at several MCCP high-elevation sites (see Table AX3-6). Aneja and Li (1992)

have summarized the O3 concentrations for 1986 to 1988 (see Table AX3-7). Table AX3-7

summarizes the concentrations and exposures that occurred at several of the sites for the period

1987 to 1988. 

Figure AX3-38. Vertical profile of O3 obtained in a spruce forest. Values shown are

relative to concentrations at 19 m above the surface. Mean tree height is

14.5 m. Ozone concentrations for stable and unstable conditions were

36.7 and 33.8 ppb, and the average O3 concentration weighted by stability

class was 34.6 ppb at 19 m. 

Source: Horvath et al. (2003).
Table AX3-6. Description of Mountain Cloud Chemistry Program Sites

Site Elevation (m) Latitude LoHowland Forest (HF1), ME 65 458° 11' 68° Mt. Moosilauke (MS1), NH 1000 438° 59' 18" 71° Whiteface Mountain (WF1), NY 1483 448° 23' 26" 73° Shenandoah NP (SH1), VA 1015 38° 37' 12" 78° Shenandoah NP (SH2), VA 716 38° 37' 30" 78° Shenandoah NP (SH3), VA 524 38° 37' 45" 78° Whitetop Mountain (WT1), VA 1689 36° 38' 20" 81° Mt. Mitchell (MM1), NC 2006 35° 44' 15" 82° Mt. Mitchell (MM2), NC 1760 35° 45' 82° 

AX3-60
Table AX3-7. Seasonal (April-October) Percentiles, SUM06, SUM08, and W126 Values for the 

Site Year Min. 10 30 50

70

(ppm) 90 95 99 Max.

No.

Obs. S

Howland Forest, ME(HF1)

1987 0.000 0.013 0.021 0.028 0.035 0.046 0.052 0.065 0.076 4766 

1988 0.000 0.012 0.021 0.028 0.036 0.047 0.054 0.076 0.106 4786 

Mt. Moosilauke, NH(MS1)

1987 0.006 0.027 0.036 0.045 0.053 0.065 0.074 0.086 0.102 4077 1988 0.010 0.026 0.033 0.043 0.055 0.076 0.087 0.113 0.127 2835 

Whiteface Mountain,NY (WF1) (36-031-0002)

1987 0.011 0.029 0.037 0.046 0.053 0.067 0.074 0.087 0.104 4703 1988 0.014 0.025 0.033 0.043 0.056 0.078 0.089 0.110 0.135 4675 

Whiteface Mountain,NY (WF3)

1987 0.010 0.025 0.033 0.039 0.047 0.064 0.075 0.091 0.117 4755 

Whiteface Mountain,NY (WF4)

1987 0.000 0.011 0.023 0.031 0.041 0.056 0.065 0.081 0.117 4463 

Mt. Mitchell, NC (MM1)

1987 0.008 0.034 0.044 0.051 0.058 0.067 0.074 0.085 0.105 3539 1988 0.011 0.038 0.054 0.065 0.075 0.095 0.106 0.126 0.145 2989 11989 0.010 0.038 0.047 0.054 0.059 0.068 0.072 0.081 0.147 2788 1992 0.005 0.036 0.043 0.048 0.053 0.063 0.069 0.081 0.096 3971 

Mt. Mitchell, NC (MM2)

1987 0.017 0.032 0.042 0.049 0.056 0.067 0.073 0.083 0.096 3118 1988 0.009 0.029 0.041 0.050 0.060 0.080 0.092 0.110 0.162 2992 

Shenandoah Park,VA (SH1)

1987 0.000 0.023 0.036 0.044 0.054 0.069 0.076 0.085 0.135 3636 

1988 0.006 0.024 0.036 0.047 0.058 0.077 0.087 0.103 0.140 3959 

Shenandoah Park,VA (SH2)

 1987* 0.003 0.027 0.040 0.049 0.059 0.071 0.077 0.086 0.145 2908 

1988 0.006 0.029 0.042 0.054 0.064 0.083 0.095 0.108 0.145 4661 1

AX3-61
Table AX3-7 (cont’d). Seasonal (April-October) Percentiles, SUM06, SUM08, and W126 Values for 

Site Year Min. 10 30 50

70

(ppm) 90 95 99 Max.

No.

Obs. S

Shenandoah Park,VA (SH3)

1987 0.000 0.018 0.029 0.037 0.047 0.061 0.068 0.080 0.108 3030 

1988 0.000 0.020 0.031 0.040 0.051 0.067 0.076 0.097 0.135 4278 

Whitetop Mountain,VA (WT1)

1987 0.01 0.038 0.051 0.059 0.066 0.078 0.085 0.096 0.111 4326 11988 0.000 0.030 0.046 0.058 0.068 0.084 0.094 0.119 0.163 3788 1

*Calculations based on a May-September season.

AX3-62
AX3-63

In 1987, the 7- and 12-h seasonal means were similar at the Whiteface Mountain WF1 and

WF3 sites (Figure AX3-39a). The 7-h mean values were 0.0449 and 0.0444 ppm, respectively,

and the 12-h mean values were 0.0454 and 0.0444 ppm, respectively. Note that, in some cases,

the 12-h mean was slightly higher than the 7-h mean value. In fact, at higher elevations, the 24-h

level was larger still (Table AX3-8). This resulted when the 7-h mean period (0900 to

1559 hours) did not capture the period of the day when the highest hourly mean O3

concentrations were measured. A similar observation was made, using the 1987 data, for the

MCCP Shenandoah National Park sites. The 7-h and 12-h seasonal means were similar for the

SH1 and SH2 sites (Figure AX3-39b). Based on cumulative indices, the Whiteface Mountain

summit (1483-m) site (WF1) experienced a higher exposure than the WF3 (1026-m) site

(Figure AX3-39c). The site at the base of Whiteface Mountain (WF4) experienced the lowest

exposure of the three O3 sites. Among the MCCP Shenandoah National Park sites, marginally

higher O3 exposures were found at the SH2 site, based on the index that sums all of the hourly

average concentrations (referred to as “total dose” in Figure AX3-39c) and sigmoidal values,

than the SH1 high-elevation site (Figure AX3-39d). The reverse was true for concentrations

$0.07 ppm (SUM07) and the number of hourly concentrations $0.07 ppm the sums of the

concentrations $0.07 ppm and the number of hourly concentrations $0.07 ppm. When the Big

Meadows, Dickey Ridge, Sawmill Run, and Shenandoah National Park data for 1983 to 1987

were compared, it again was found that the 7-h and 12-h seasonal means were insensitive to the

different O3 exposure patterns. Cumulative exposures at three sites in Shenandoah National Park

are shown in Figure AX3-40. There was no evidence that the highest elevation site, Big

Meadows, consistently had experienced higher O3 exposures than the other sites. In 2 of the

5 years, the Big Meadows site experienced lower exposures than the Dickey Ridge and Sawmill

Run sites, based on the sum of all concentration or sigmoidal indices. For 4 of the 5 years, the

SUM07 index yielded the same result.

Taylor et al. (1992) indicated that the forests they monitored experienced differences in O3

exposure. The principal spatial factors underlying this variation were elevation, proximity to

anthropogenic sources of oxidant precursors, regional-scale meteorological conditions, and

airshed dynamics between the lower free troposphere and the surface boundary layer. 

Table AX3-8 summarizes the exposure values for the 10 EPRI Integrated Forest Study sites

located in North America. 
AX3-64

Figure AX3-39a-d. Seven- and 12-h seasonal means at (a) Whiteface Mountain and

(b) Shenandoah National Park for May to September 1987,

and integrated exposures at (c) Whiteface Mountain and

(d) Shenandoah National Park for May to September 1987.

Source: Lefohn et al. (1990a).

An important issue for assessing possible impacts of O3 at high-elevation sites requiring

further attention is the use of mixing ratios (e.g., parts per million) instead of absolute

concentration (e.g., in units of micrograms per cubic meter) to describe O3 concentration. 

In most cases, mixing ratios or mole fractions are used to describe O3 concentrations. Lefohn

et al. (1990b) pointed out that the manner in which concentration is reported may be important

when assessing the potential impacts of air pollution on high-elevation forests. Even when partsper-million values at high- and low-elevation sites are equal, the absolute concentrations (i.e.,

micrograms per cubic meter) at the two elevations will be different, because both O3 and ambient

air are gases, and changes in pressure directly affect their volume. According to Boyle’s law, if
AX3-65

Figure AX3-40a-e. Cumulative exposures for three non-Mountain Cloud Chemistry

Program Shenandoah National Park sites, 1983 to 1987.

Source: Lefohn et al. (1990b).
AX3-66

Table AX3-8. Summary Statistics for 11 Integrated Forest Study Sitesa

Site Year Quarter 24-h 12-h 7-h 1-h Max.

SUM06

103 ppb-h

SUM08

103 ppb-h

HIGH ELEVATION SITES

Whiteface Mtn, NY 1987 2 42 43 42 104 13.2 2.5

1987 3 45 44 43 114 30.1 11.8

1988 2 49 50 49 131 33.5 13.9

1988 3 44 43 43 119 22.6 10.4

Great Smoky Mtns NP 1987 2 54 52 49 99 57.1 10.9

1987 3 53 51 49 95 34.3 8.8

1988 2 71 70 68 119 126.3 61.2

1988 3 59 57 55 120 74.7 22.2

Coweeta Hydrologic Lab,

NC

1987 2 50 48 47 85 32.4 2.6

1987 3 47 44 42 95 24.1 2.4

1988 2 61 59 59 104 81.6 18.5

1988 3 57 54 51 100 63.6 19.8

LOW ELEVATION SITES

Huntington Forest, NY 1987 2 36 42 42 88 9.8 0.9

1987 3 24 32 33 76 5.4 0.2

1988 2 40 46 46 106 19.2 6.1

1988 3 37 46 48 91 18.6 2.7

Howland, ME 1987 2 34 39 39 69 1.9 0.0

1987 3 26 32 31 76 3.8 0.0

1988 2 36 41 41 90 8.1 2.9

1988 3 24 30 30 71 1.7 0.0

Oak Ridge, TN 1987 2 42 53 50 112 39.5 13.5

1987 3 29 44 41 105 24.3 9.0

1988 2 40 57 58 104 26.4 9.8

1988 3 32 47 51 122 19.7 7.7

Thompson Forest, WA 1987 2 36 43 41 103 10.7 3.6

1987 3 30 36 34 94 10.3 2.1

1988 2 32 39 37 103 8.1 2.3

1988 3 32 39 36 140 13.5 6.7
AX3-67

Table AX3-8 (cont’d). Summary Statistics for 11 Integrated Forest Study Sitesa

Site Year Quarter 24-h 12-h 7-h 1-h Max.

SUM06

103 ppb-h

SUM08

103 ppb-h

LOW ELEVATION SITES (cont’d)

B.F. Grant Forest, GA 1987 2 32 46 48 99 26.1 5.1

1987 3 33 52 54 102 31.3 10.3

1988 2 47 63 64 127 53.1 21.9

1988 3 32 47 48 116 24.1 7.4

Gainesville, FL 1987 2 42 53 50 bb b

1987 3 29 44 41 bb b

1988 2 35 48 51 84 23.4 0.5

1988 3 20 29 30 70 1.9 0.1

Duke Forest, NC 1987 2 38 48 52 100 29.2 7.8

1987 3 52 59 50 124 b b

1988 2 54 69 75 115 b b

1988 3 38 51 54 141 52.9 23.4

Nordmoen, Norway 1987 2 32 40 41 75 2.4 0.0

1987 3 14 18 20 32 0.0 0.0

1988 2 22 28 29 53 0.0 0.0

1988 3 11 15 16 30 0.0 0.0

a

Concentration in ppb.

b

Data were insufficient to calculate statistic.

Source: Taylor et al. (1992).

the temperature of a gas is held constant, the volume occupied by the gas varies inversely with

the pressure (i.e., as pressure decreases, volume increases). This pressure effect must be

considered when measuring absolute pollutant concentrations. At any given sampling location,

normal atmospheric pressure variations have very little effect on air pollutant measurements. 

However, when mass/volume units of concentration are used and pollutant concentrations

measured at significantly different altitudes are compared, pressure (and, hence, volume)

adjustments are necessary. In practice, the summit site at Whiteface Mountain had a slightly
AX3-68

higher O3 exposure than the two low-elevation sites (Lefohn et al., 1991). However, at

Shenandoah National Park sites, the higher elevation site experienced lower exposures than

lower elevation sites in some years. 

These exposure considerations are relatively unimportant at low-elevation sites. However,

the differences between exposure-effects at high- and low-elevation sites, may be significant

(Lefohn et al., 1990b). In particular, assuming the sensitivity of the biological target to be

identical at low- and high-elevations, some adjustment will be necessary when attempting to link

experimental data obtained at low-elevation sites with air quality data monitored at the highelevation stations. This topic is further discussed in Annex AX9 when considering effective

dose considerations for predicting vegetation effects associated with O3.

AX3.4 DIURNAL PATTERNS IN OZONE CONCENTRATION

AX3.4.1 Introduction

Diurnal variations in O3 at a given location are controlled by a number of factors such as

the relative importance of transport versus local photochemical production and loss rates, the

timing for entrainment of air from the nocturnal residual boundary layer and the diurnal

variability in mixing layer height. 

The form of an average diurnal pattern provides some information on sources, transport,

and chemical formation and destruction effects at various sites (Lefohn, 1992). Atmospheric

conditions leading to limited transportation from source regions will produce early afternoon

peaks. However, long-range transport processes will influence the actual timing of a peak, from

afternoon to evening or early morning hours. Ozone is rapidly depleted near the surface below

the nocturnal inversion layer (Berry, 1964). Mountainous sites, which are above the nocturnal

inversion layer, do not necessarily experience this depletion (Stasiuk and Coffey, 1974). Taylor

and Hanson (1992) reported similar findings, using data from the Integrated Forest Study. The

authors reported that intraday variability was most significant for the low-elevation sites due to

the pronounced daily amplitude in O3 concentration between the predawn minimum and

mid-afternoon-to-early evening maximum. The authors reported that interday variation was

more significant in the high-elevation sites. Ozone trapped below the inversion layer is depleted

by dry deposition and chemical reactions if other reactants are present in sufficient quantities
AX3-69

(Kelly et al., 1984). Above the nocturnal inversion layer, dry deposition does not generally

occur, and the concentration of O3 scavengers is generally lower, so O3 concentrations remain

fairly constant (Wolff et al., 1987). A flat diurnal pattern is usually interpreted as indicating a

lack of efficient scavenging of O3 or a lack of photochemical precursors, whereas a strongly

varying diurnal pattern is taken to indicate the opposite.

An analysis that identified when the highest hourly average concentrations were observed

at rural agricultural and forested sites was described in 1996 O3 AQCD. A review of the hourly

average data collected at all rural agricultural and forested sites in Environmental Protection

Agency’s AQS database for 1990 to 1992 was undertaken to evaluate the percentage of time

hourly average concentrations $0.1 ppm occurred during the period of 0900 to 1559 hours in

comparison with the 24-h period. It was found that 70% of the rural-agricultural and forested

sites used in the analysis experienced at least 50% of the occurrences $0.1 ppm during the period

of 0900 to 1559 hours when compared to the 24-h period. When O3 monitoring sites in

California were eliminated, approximately 73% of the remaining sites experienced at least 50%

of the occurrences $0.10 ppm during the daylight 7-h period when compared with the

24-h period. 

Diurnal Variations in the Nationwide Data Set

Composite urban, diurnal variations in hourly averaged O3 for April through October 2000

to 2004 are shown in Figure AX3-41. As can be seen from Figure AX3-41, daily 1-h O3 maxima

tend to occur in mid-afternoon and daily 1-h O3 minima tend to occur during the early morning. 

However, there is also considerable spread in these times. Therefore, some caution must be

exercised in extrapolating results from one city to another and when attempting to judge the time

of day when the daily 1-h maximum occurs. 

Corresponding data for 8 hour average O3 data are shown in Figure AX3-42. As can be

seen from Figure AX3-42, daily maximum eight hour O3 concentrations tend to occur from

about 10 a.m. to about 6 p.m. As can be seen from Figure AX3-42, they can also occur at

slightly different times and the variation in the 8-h averages is smoother than for the 1-h

averages. The minima in the 8 h averages tend to occur starting at about midnight. 
AX3-70

AX3.4.2 Diurnal Patterns in Urban Areas

Diurnal Variations in EPA’s 12 Cities

The diurnal variability of hourly averaged O3 in the twelve urban areas considered for

inclusion in EPA’s human health exposure assessment-risk assessment for the current review is

illustrated in Figure AX3-43a-l for April to October. Daily maximum 1-h concentrations tend to

occur in mid-afternoon. However, as can be seen from the figures, the diurnal patterns vary

from city to city, with high values ($0.100 ppm) occurring either late in the evening as in

Boston, past midnight as in Los Angeles and Sacramento, or mid-morning as in Houston. 

Typically, high values such as these are found during the daylight hours in mid to late afternoon. 

The reasons for the behavior of O3 during the night at the above mentioned locations are not

clear. Measurement issues may be involved or there may be physical causes such as transport 

Figure AX3-41. Composite, nationwide diurnal variability in hourly averaged O3 in urban

areas. Values shown are averages from April to October 2000 to 2004. 

Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-71

phenomena, as discussed in Chapter 2. As discussed in Chapter 2, and in greater detail in

Section AX2.3.3, nocturnal low level jets are capable of producing secondary O3 maxima

at night. 

The diurnal variability of O3 averaged over 8 hours in the same twelve urban areas is

shown in Figures AX3-44a-l. The diurnal patterns of 1-h O3 averages are broadly similar to 8-h

averages. Typically, although the 8-h daily maximum occurs between 10 a.m to 6 p.m., actual

starting and ending times can differ from these characteristic times, depending on location. For

example, as shown in Figures AX3-44a for Boston and AX3-44k for Sacramento, the highest 8-h

daily maximum values can start in mid-afternoon and extend into late evening. These results

suggest that transport processes are playing the dominant role in determining the timing of the

highest daily maxima in these areas.

Figure AX3-42. Composite, nationwide diurnal variability in 8 hour average O3 in

urban areas. Values shown are averages from April to October 2000 to

2004. Boxes define the interquartile range and the whiskers, the minima

and maxima. The hour refers to the start of the 8-h averaging period. 

Source: Fitz-Simons et al. (2005).
AX3-72

Figure AX3-43a-f. Diurnal variability in hourly averaged O3 in selected urban areas. 

Values shown are averages from April to October 2000 to 2004. 

Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-73

Figure AX3-43g-l. Diurnal variability in hourly averaged O3 in selected urban areas. 

Values shown are averages from April to October 2000 to 2004. 

Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-74

Figure AX3-44a-f. Diurnal variability in 8 hour averaged O3 in selected urban areas. 

Values shown are averages from April to October 2000 to 2004. 

Boxes define the interquartile range and the whiskers, the minima

and maxima. The hour refers to the start of the 8-h averaging period. 

Source: Fitz-Simons et al. (2005).
AX3-75

Figure AX3-44g-l. Diurnal variability in 8 hour averaged O3 in selected urban areas. 

Values shown are averages from April to October 2000 to 2004. 

Boxes define the interquartile range and the whiskers, the minima

and maxima. The hour refers to the start of the 8-h averaging period. 

Source: Fitz-Simons et al. (2005).
AX3-76

On days with high 1-h daily maximum concentrations (e.g., $0.12 ppm) the maxima tend

to occur in a smaller time window centered in the middle of the afternoon, compared to days in

which the maximum is lower. For example, on the high O3 days the 1-h maximum occurs from

about 11 a.m. to about 6 p.m. However, on days in which the 1-h daily maximum is

#0.080 ppm, the daily maximum can occur at any time during the day or night, with only a 50%

probability that it occurs between 1 and 3 p.m., in each of the 12 cities. Photochemical reactions

in combination with diurnal emissions patterns are expected to produce mid-afternoon peaks in

urban areas. These results suggest that transport from outside the urban airshed plays a major

role in determining the timing of the daily maxima for low peak O3 levels. This pattern is more

typical for the Los Angeles-Long Beach-Riverside, CA area even for high O3 days.

The same general timing patterns are found for 1-h daily maximum O3 concentrations as

for the daily maximum 8-h average O3 concentration. As mentioned above, the daily maximum

8-h O3 concentrations are generally found between the hours of 10 a.m and 6 p.m. However,

there are a significant number of days when this is not the case for high values, as in Houston,

TX and Los Angeles, CA, or in general for low values at any of the cities examined. Although

the 8-h average O3 concentration is highly correlated with the daily maximum 1-h average O3

concentration, there are situations where the daily maximum 8-h average O3 concentration may

be driven by very high values in the daily maximum 1-h average O3 concentration as illustrated

in Figure AX3-43j. In cases such as these, the predicted 8-h average might overestimate the

short-term O3 concentration later in the day. 

As an aid to better understanding the nature of the diurnal patterns shown in the figures for

EPA’s 12 cities, Figures AX3-45a-d show the hours in which the 1-h daily maximum O3

concentration occurs in four of the cities. As can be seen from Figures AX3-45a-c for the

Philadelphia, Atlanta, and Houston areas, the maximum tends to occur from about 2 p.m. to

4 p.m. about half of the time, and most values occur between about 12 p.m to 6 p.m at higher

values of the daily maximum 1-h O3 concentration. Although values at Houston can occur

earlier, these are most likely due to episodic releases from the petrochemical industries. 

For small values of the 1-h daily maximum, most of the daily maxima still occur in the

afternoon, but maxima can also occur at any time of the day or night. In the Los Angeles area,

as shown in Figure AX3-45d high values of daily 1-h O3 maxima can occur at any time during

the day or night but with most values occurring during the afternoon. 
AX3-77

Figures AX3-46a-d show the hours in which the 8-h daily maximum O3 concentration

begins. The mean time is about 10 a.m. at these four cities indicating that the 8-h daily

maximum tends to occur on average from about 10 a.m to 6 p.m. However, there can be

deviations from these times. The same general pattern in which the maxima tend to occur within

a narrower time frame at high values than at low values is found in the four cities shown. 

Figure AX3-45a-d. Time of occurrence of daily maximum 1-h O3 concentration in four

cities, averaged from April to October, 2000 to 2004.

Source: Fitz-Simons et al. (2005).
AX3-78

The patterns of diurnal variability for both 1-h and 8-h averages have remained quite stable

over the 15 year period from 1990 to 2004, with times of occurrence of the daily maxima

varying by no more than an hour from year to year in each of the 12 cities.

Figure AX3-46a-d. Time of occurrence of daily maximum 8-h average O3 concentration

in four cities, averaged from April to October, 2000 to 2004. The

hour refers to the start of the 8-h averaging period. 

Source: Fitz-Simons et al. (2005).
AX3-79

Weekday/Weekend Differences

In addition to varying diurnally, O3 concentrations differ from weekdays to weekends. 

Heuss et al. (2003) described the results of a nationwide analysis of weekday/weekend

differences that demonstrated significant variation in these differences across the United States. 

Weekend 1-h or 8-h maximum O3 concentrations varied from 15% lower to 30% higher than

weekday levels across the U.S. The weekend O3 increases were primarily found in and around

large coastal cities in California and large cities in the Midwest and Northeast Corridor. Many

sites that experienced elevated weekday O3 concentrations also had higher O3 on weekends even

though the traffic and O3 precursor levels were substantially reduced on weekends. The authors

reported that detailed studies of this phenomenon indicated that the primary cause of the 

higher O3 on weekends was the reduction in oxides of nitrogen emissions on weekends in a

volatile organic compound (VOC)-limited (NOx-saturated) chemical regime (cf., Chapter 2). 

Heuss et al. (2003) hypothesized that the lower O3 on weekends in other locations may result

from NOx reductions in a NOx-limited regime (cf., Chapter 2).

Pun et al. (2003) described the day-of-week behavior for O3 in Chicago, Philadelphia, and

Atlanta. In Chicago and Philadelphia, maximum 1-h average O3 increases on weekends. In

Atlanta, O3 builds up from Mondays to Fridays and declines during the weekends. Fujita et al.

(2003) pointed out that since the mid-1970s, O3 levels in portions of California’s South Coast

Air Basin on weekends have been as high as or higher than levels on weekdays, even though

emissions of O3 precursors are lower on weekends. Blanchard and Tanebaum (2003) noted that

despite significantly lower O3 precursor levels on weekends, 20 of 28 South Coast Air Basin

sites showed statistically significant higher mean O3 levels on Sundays than on weekdays. 

Chinkin et al. (2003) noted that ambient O3 levels in California’s South Coast Air Basin can be

as much as 55% higher on weekends than on weekdays under comparable meteorological

conditions.

Figures AX3-47a-h show the contrast in the patterns of hourly averaged O3 in the greater

Philadelphia, Atlanta, Houston and Los Angeles areas from weekdays to weekends from May to

September 2004. Daily maximum concentrations occur basically at the same time on either

weekdays or weekends. Mean O3 concentrations at midday are about the same on weekdays and

weekends in Atlanta, Philadelphia, and Houston, but are higher on weekends in the Los Angeles

area. Figures AX3-48a-h show the weekday/weekend differences for the 8-h averages. As can 
AX3-80

be seen from the figures, the lowest O3 concentration observed during weekend afternoons tend

to be higher than on weekday afternoons. On weekends, traffic volumes are lower and there are

fewer diesel vehicles on the road, resulting in a lower rate of scavenging by NO. The spike in

values for Houston in mid-morning shown in Figure AX3-47, resulted from the release of highly

reactive hydrocarbons from the petrochemical industry (which could occur on any day of the 

Figure AX3-47a-d. Diurnal variations in hourly averaged O3 on weekdays and weekends

in four cities. Values shown represent averages from

May to September of 2004. Boxes define the interquartile range and

the whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-81

week). Otherwise, the maximum O3 concentrations could be seen to occur during the week as

they do in Philadelphia and Atlanta, in contrast to Los Angeles. 

Spatial Variability in Diurnal Patterns

Daily maxima in either the 1-h or 8-h averages do not necessarily occur at the same time of

day at each site in the 12 cities, and the diurnal pattern observed at individual sites can vary from 

Figure AX3-47e-h. Diurnal variations in hourly averaged O3 on weekdays and weekends

in four cities. Values shown represent averages from

May to September of 2004. Boxes define the interquartile range and

the whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-82

the composites shown in Figures AX3-41 and 42. Differences in diurnal patterns between sites

are related to differences in transport times from sources of precursors and chemical reactions, in

particular, titration of O3 by NO from local sources. Figure AX3-49a shows the diurnal pattern

of 1-h average O3 at a site in downtown Detroit, MI (cf., Site J in Figure AX3-30). This site is

affected by nearby traffic emissions. Figure AX3-49b shows the diurnal pattern at a site well 

Figure AX3-48a-d. Diurnal variations in 8-h averaged O3 on weekdays and weekends in

four cities. Values shown represent averages from May to September

of 2004. The hour refers to the start of the 8-h averaging period. 

Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-83

downwind (cf., Site D in Figure AX3-30). The peak 1-h average O3 concentrations tend be

higher at the downwind site than at the site in the urban core. Figure AX3-50a shows the diurnal

patterns at a site in downtown St. Louis (cf., Site P in Figure AX3-31) and Figure AX3-50b

shows the diurnal pattern at a site downwind (Site A in Figure AX3-31). The same general

relations are observed at the two sites in the St. Louis urban area as in the Detroit urban area. 

Figure AX3-51a shows the diurnal pattern observed at a site in San Bernadino, CA. This site is 

Figure AX3-48e-h. Diurnal variations in 8-h averaged O3 on weekdays and weekends in

four cities. Values shown represent averages from May to September

of 2004. The hour refers to the start of the 8-h averaging period. 

Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-84

Figure AX3-49b. Diurnal variations in hourly averaged O3 at a site downwind of

downtown Detroit. Boxes define the interquartile range and the

whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).

Figure AX3-49a. Diurnal variations in hourly averaged O3 at a site in downtown Detroit,

MI. Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-85

Figure AX3-50b. Diurnal variations in hourly averaged O3 at a site downwind of

downtown St. Louis. Boxes define the interquartile range and the

whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).

Figure AX3-50a. Diurnal variations in hourly averaged O3 at a site in downtown

St. Louis, MO. Boxes define the interquartile range and the whiskers,

the minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-86

affected by transport of precursors from Los Angeles County, production from local precursors

and by nearby NO sources, driving O3 to very low levels at night as shown. A relatively high

peak 1-h O3 concentrations is reached at 2 to 3 p.m. Figure AX3-51b shows the diurnal pattern

of O3 at a site about 80 km to the east of the site mentioned above (cf., Site Q in Figure AX3-36)

in a relatively unpopulated area. The diurnal pattern of hourly averaged O3 is much flatter and

the 1-h peak concentration is reached about 5 or 6 p.m., on average. The cause of the rise in

concentrations at 2 a.m. is not clear. 

The diurnal variation in the 8-h averages observed at the two contrasting sites in these three

areas are shown in Figures AX3-52a,b, 53a,b, and 54a,b. As might be expected the patterns are

somewhat flatter than for the 1-h averages. This implies that the difference in 8-h averages can

be substantial (i.e., over a factor of two) during early morning, afternoon, and evening. 

The general pattern that emerges from the site to site variability within the urban areas

examined is that peaks in 1-h average concentrations are higher and tend to occur later at 

Figure AX3-51a. Diurnal variations in hourly averaged O3 at a site in

San Bernadino, CA. Boxes define the interquartile range and the

whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-87

downwind sites than in the urban cores. To the extent that monitoring site are either near to or

remote from sources of precursors in urban/suburban areas, the behavior of O3 will follow these

basic patterns. Similar relations are found for the 8-h average O3 concentrations. 

AX3.4.3 Diurnal Patterns in Nonurban Areas

Composite diurnal patterns of O3 are shown in Figure AX3-55 for hourly averaged O3 and

in Figure AX3-56 for 8 hour average O3 at rural (CASTNET) sites. As can be seen from a

comparison of Figures AX3-55 and AX3-56 with Figures AX3-42 and AX3-43, diurnal patterns

of O3 are smoother and shallower at the rural sites than at the urban sites. Maxima in hourly

averaged O3 concentrations also tend to occur in afternoon. However, highest concentrations

observed during any particular hour at night at the CASTNET sites (~0.130 ppm) are

substantially higher than observed in urban areas (<0.100 ppm) and daily 1-h maxima at

CASTNET sites have exceeded 0.150 ppm. The diurnal variations in 8-h average O3

Figure AX3-51b. Diurnal variations in hourly averaged O3 at a site in Riverside County

well downwind of sources. Boxes define the interquartile range and the

whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-88

Figure AX3-52b. Diurnal variations in 8-h average O3 at a site downwind of downtown

Detroit, MI. Boxes define the interquartile range and the whiskers, the

minima and maxima.

Source: Fitz-Simons et al. (2005).

Figure AX3-52a. Diurnal variations in 8-h average O3 at a site in downtown Detroit, MI. 

Boxes define the interquartile range and the whiskers, the minima

and maxima.

Source: Fitz-Simons et al. (2005).
AX3-89

Figure AX3-53a. Diurnal variations in 8-h average ozone at a site in downtown

St. Louis, MO. Boxes define the interquartile range and the whiskers,

the minima and maxima.

Source: Fitz-Simons et al. (2005).

Figure AX3-53b. Diurnal variations in 8-h average O3 at a site downwind of downtown 

St. Louis, MO. Boxes define the interquartile range and the whiskers,

the minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-90

Figure AX3-54b. Diurnal variations in 8-h average O3 at a site in Riverside County well

downwind of sources. Boxes define the interquartile range and the

whiskers, the minima and maxima.

Source: Fitz-Simons et al. (2005).

Figure AX3-54a. Diurnal variations in 8-h average O3 at a site in San Bernadino, CA. 

Boxes define the interquartile range and the whiskers, the minima and

maxima.

Source: Fitz-Simons et al. (2005).
AX3-91

Figure AX3-55. Composite diurnal variability in hourly O3 concentrations observed at

CASTNET sites. Values shown are averages from April to October 2000

to 2004. Boxes define the interquartile range and the whiskers, the

minima and maxima.

Source: Fitz-Simons et al. (2005).

Figure AX3-56. Composite diurnal variability in 8-h average O3 concentrations observed

at CASTNET sites. Values shown are averages from April to October

2000 to 2004. Boxes define the interquartile range and the whiskers, the

minima and maxima.

Source: Fitz-Simons et al. (2005).
AX3-92

concentrations are also much smaller at the CASTNET sites than at the urban sites. Note also

that the maxima in 8-h average O3 concentrations are higher at the CASTNET sites than at the

urban sites. 

The diurnal variability of O3 in urban/suburban areas or in areas affected by local power

plants and highways is usually much greater than in other more isolated areas. The diurnal

variability of two sites that are characteristic of these two patterns is shown in Figure AX3-57. 

The Jefferson County, KY site is characterized as suburban-residential in the AQS database and

is near Louisville, KY. High levels of O3 and NO can be found there. The Oliver County,

ND site is characterized as rural-agricultural in the AQS database. This site is fairly isolated

from combustion sources of precursors and is not near any large urban area. As can be seen

from Figure AX3-57, the diurnal variability of O3 is much smaller at the North Dakota site than

it is at the Kentucky site. The Kentucky site is influenced strongly by emissions of NO that

scavenge O3 during the night and by photochemical reactions that form O3 during the day. These

sources are lacking in the vicinity of the North Dakota site, and O3 observed there arrives mainly

from transport from distant source regions. 

Logan (1989) described the diurnal variability of O3 at several rural locations, shown in

Figure AX3-58, and noted that on average, daily profiles show a broad maximum from about

noon to about 6 p.m. at all the eastern sites, except for the peak of Mt. Washington. Further

results that document the diurnal behavior of O3 in the United States during the past few decades

can be found in the previous AQCD for O3. Figure AX3-59 shows diurnal patterns for several

national forest sites in the EPA AQS database for 2002. Several of the sites analyzed exhibit

fairly flat average diurnal patterns. Such a pattern is based on average concentrations calculated

over an extended period and caution is urged in drawing conclusions concerning whether some

monitoring sites illustrated in the figure experience higher cumulative O3 exposures than other

sites. Variation in O3 concentration occurs from hour to hour on a daily basis, and, in some

cases, elevated hourly average concentrations are experienced either during daytime or nighttime

periods (Lefohn and Mohnen, 1986; Lefohn and Jones, 1986; Logan, 1989; Lefohn et al., 1990a;

Taylor et al., 1992). Because the diurnal patterns represent averaged concentrations calculated

over an extended period, the smoothing from the averaging tends to mask the elevated hourly

average concentrations.
AX3-93

Lefohn et al. (1990b) characterized O3 concentrations at high-elevation monitoring sites. 

The authors reported that a fairly flat diurnal pattern for the Whiteface Mountain summit site

(WF1) was observed (Figure AX3-60a), with the maximum hourly average concentrations

occurring in the late evening or early morning hours. A similar pattern was observed for the

mid-elevation site at Whiteface Mountain (WF3). In contrast, the site at the base of Whiteface

Mountain (WF4) showed the typical diurnal pattern expected from sites that experience some

degree of O3 scavenging. More variation in the diurnal pattern for the highest Shenandoah

National Park sites occurred than for the higher elevation Whiteface Mountain sites, with the

typical variation for urban-influenced sites in the diurnal pattern at the lower elevation

Shenandoah National Park site (Figure AX3-60b). Aneja and Li (1992), in their analysis of the

five high-elevation Mountain Cloud Chemistry Program (MCCP) sites, noted the presence of the

flat diurnal pattern typical of high-elevation sites that has been described previously in the

literature. Aneja and Li (1992) noted that the peak of the diurnal patterns over the period of May

to October (1986 to 1988) occurred between 1800 and 2400 hours for the five sites, whereas

Figure AX3-57. The comparison of the seasonal diurnal patterns for urban-influenced

(Jefferson County, KY) and a rural-influenced (Oliver County, ND)

monitoring sites using 2002 hourly data for April-October.
AX3-94

Figure AX3-58a-d. Diurnal behavior of O3 at rural sites in the United States in July. 

Sites are identified by the state in which they are located.

(a) Western National Air Pollution Background Network sites

(NAPBN); (b) Whiteface Mountain (WFM) located at 1.5 km above

sea level; (c) eastern NAPBN sites; and (d) sites selected from the

Electric Power Research Institute’s Sulfate Regional Air Quality

Study. IN(R) refers to Rockport. 

Source: Logan (1989).
AX3-95

the minimum was observed between 0900 and 1200 hours. However, it is important to note that,

as indicated by Lefohn et al. (1990b), the flat diurnal pattern was not observed for all

high-elevation sites. As mentioned earlier, nonurban areas only marginally affected by nearby

sources usually have a flatter diurnal profile than sites located in urban areas. Nonurban O3

monitoring sites experience differing types of diurnal patterns, as shown in this section. The

difference in diurnal patterns may influence the potential for O3 exposures to affect vegetation.

AX3.5 SEASONAL VARIATIONS IN OZONE CONCENTRATIONS

AX3.5.1 Seasonal Variations in Urban Areas

Seasonal Variability

Figures AX3-61a-h show maximum 1-h O3 concentrations by month for selected urban

sites for 2002. As can be seen from the figure, maximum 1-h O3 concentrations tend to occur

mainly in July and August, but may also occur in other months. For example, they occurred in

Figure AX3-59. Composite diurnal O3 pattern at selected national forest sites in the

United States using 2002 hourly average concentration data.

Source: U.S. Environmental Protection Agency (2003).
AX3-96

Figure AX3-60a,b. Composite diurnal pattern at (a) Whiteface Mountain, NY and

(b) the Mountain Cloud Chemistry Program Shenandoah National

Park site for May to September 1987.

Source: Lefohn et al. (1990a).
AX3-97

Figure AX3-61a-h. Seasonal variations in O3 concentrations as indicated by the 1-h

maximum in each month at selected sites, 2002.

Source: U.S. Environmental Protection Agency (2003).
AX3-98

June in Washington, DC and Denver, CO. The number of months for which data are shown

depends on local preference for the length of monitoring during the year. Due to a number of

factors, the absolute magnitude and the timing of the maximum hourly average concentrations

varies from year to year. 

It should not be assumed that highest O3 levels are confined to the summer. Highest

average O3 concentrations generally occur at RRMS during the second quarter (i.e., during April

or May) versus the third quarter of the year as for urban sites or for nonurban sites heavily

affected by regional pollution sources. 

The seasonal behavior of O3 varies across the 12 cities and high O3 values are also found at

some of the 12 cities outside of summer (e.g., Houston and Los Angeles). Figures AX3-62a-l

show the diurnal variability of hourly average O3 averaged over November through March for

EPA’s 12 cities. Daily maxima tend to occur between about 1 and 2 p.m. standard time is used

across the U.S. accounting for the one hour shift from the warm season. As expected, maximum

values tend to be lower than during the warmer months. The diurnal patterns are not as clear as

in the warmer season as there is a greater tendency for highest values to occur throughout the

day and not only during early afternoon. In most northern cities, the extreme values of the daily

maximum 8-h average O3 concentration are a little more than half of those during the

warm season and the ratio of the medians are more similar as can be judged by comparison of

Figures AX3-41a-l with Figures AX3-62a-l. Differences are even smaller for the southern cities. 

Indeed, some of the highest values are found in the Houston CSA outside of summer.

Figures AX3-63a-l show the diurnal variability of 8-h average O3 averaged over November

through March for EPA’s 12 cities. 

AX3.5.2 Seasonal Variations in Nonurban Areas

In assessing the effects of O3 on vegetation, it is important to characterize the seasons in

which the highest O3 concentrations would be expected to occur in nonurban areas. It should not

be assumed that highest O3 concentrations occur at all locations during the summer. For

example, places where highest average O3 concentrations are observed during the spring (i.e., the

months of April or May) versus the summer (Evans et al., 1983; Singh et al., 1978; Lefohn et al.,

2001) are found at many national parks in the West. Figure AX3-23 shows the hourly average

concentrations for Yellowstone National Park (WY) for the period of January to December 2001.
AX3-99

Figure AX3-62a-f. Diurnal variability in 1-h average O3 concentrations in EPA’s 12 cities. 

Values shown represent averages from November through March, 2000

to 2004. Boxes define the interquartile range and the whiskers, the

minima and maxima.

Source: Fitz-Simons et al., (2005)
AX3-100

Figure AX3-62g-l. Diurnal variability in 1-h average O3 concentrations in EPA’s 12 cities. 

Values shown represent averages from November through March, 2000

to 2004. Boxes define the interquartile range and the whiskers, the

minima and maxima.

Source: Fitz-Simons et al., (2005)
AX3-101

Figure AX3-63a-f. Diurnal variability in 8-h average O3 concentrations in EPA’s 12 cities. 

Values shown represent averages from November through March,

2000 to 2004. Boxes define the interquartile range and the whiskers,

the minima and maxima. The hour refers to the start of the 8-h

averaging period. 

Source: Fitz-Simons et al. (2005).
AX3-102

Figure AX3-63g-l. Diurnal variability in 8-h average O3 concentrations in EPA’s 12 cities. 

Values shown represent averages from November through March,

2000 to 2004. Boxes define the interquartile range and the whiskers,

the minima and maxima. The hour refers to the start of the 8-h

averaging period. 

Source: Fitz-Simons et al. (2005).
AX3-103

Note that, at the Yellowstone National Park site, the highest hourly average concentrations tend

to occur during April and May. Lefohn et al. (2001) and Monks (2000) noted that this was also

observed for other RRMS in North America and northern Europe. 

During spring and summer, O3 concentrations in rural areas of the eastern United States are

affected differently by anthropogenic and natural emissions of NOx and hydrocarbons. These

differences can affect the timing of occurrence of local peak O3 concentrations (Logan, 1989). 

O3 episodes occur when the weather is particularly conducive to photochemical formation of O3. 

Taylor et al. (1992) reported that the temporal patterns of O3 during quarterly or annual periods

did not exhibit definitive patterns at 10 forest sites in North America. Based on the exposure

index selected, different patterns were reported. Meagher et al. (1987) reported that for 

rural O3 sites in the southeastern United States, the daily maximum 1-h average concentration

was found to peak during the summer months. Taylor and Norby (1985) reported that at

Shenandoah National Park, both the highest frequency of episodes and the highest mean duration

of exposure events are found during the month of July.

Aneja and Li (1992) reported that the maximum monthly O3 levels at several rural sites

occurred in either the spring or the summer (May to August), and the minimum occurred in the

fall (September and October). The timing of the maximum monthly values differed across sites

and years. However, in 1988, an exceptionally high O3 concentration year occurred, and the

highest monthly average concentration occurred in June for almost all of the five sites

investigated. June 1988 was also the month in which the greatest number of O3 episodes

occurred in the eastern United States. 

Lefohn et al. (1990a) characterized the O3 concentrations for several sites in the United

States exhibiting low maximum hourly average concentrations. Of the three western national

forest sites evaluated by Lefohn et al. (1990a), Apache National Forset (AZ), Custer National

Forest (MT), and Ochoco National Forest (OR), only at Apache National Forest (AZ) did

maximum monthly mean concentrations occur in the spring. The Apache National Forest site

was above mean nocturnal inversion height, and no decrease of concentrations occurred during

the evening hours. Highest hourly maximum concentration, as well as the highest

W126 O3 exposures were also found at this site. Most of the maximum monthly mean

concentrations occurred in the summer at the other two sites. Maximum monthly mean O3
AX3-104

concentrations were found at the White River Oil Shale site in Colorado during the spring and

summer months. 

The W126 sigmoidal weighting exposure index was also used to identify the month of

highest exposure of vegetation to O3. A somewhat more variable pattern was observed than

when the maximum monthly average concentration was used. In some cases, the highest W126

exposures occurred earlier in the year than was indicated by the maximum monthly

concentration. For example, in 1979, the Custer National Forest site experienced its highest

W126 exposure in April, although the maximum monthly mean occurred in August. In 1980, the

reverse occurred.

There was no consistent pattern for those sites located in the continental United States. 

Maximum exposures to O3 during the spring and summer at the Theodore Roosevelt NP,

Ochoco, and Custer National Forest sites and the White River Oil Shale site. Likewise, the sites

at which highest exposures to O3 occurred during the period from fall to spring did not always

have the lowest exposures to O3.

AX3.6 TRENDS IN OZONE CONCENTRATIONS

Evidence for Trends in Ozone Concentrations at Rural Sites in the United States

Year-to-year variability in the nationwide May to September, mean daily maximum 8-h O3

concentrations are shown in Figure AX3-64. Data flagged because of quality control issues was

removed with concurrence of the local monitoring agency. Only days for which there was

75% data capture (i.e., 18 of 24 hours) were kept, and a minimum of 115 of 153 days (i.e.,

75% data capture) were required in each year. Data for missing years at individual sites were

filled in using simple linear interpolation, as done in EPA Trends reports. Year-to-year

variability in the corresponding 95th percentile values of the daily maximum 8-h O3

concentrations are shown in Figure AX3-65. Sites considered in this analysis are shown in the

map in Figure AX3-3. Mean O3 concentrations were slightly lower in 2003 and 2004 than in

earlier years, and as was shown in Figures AX3-1 and AX3-2, most sites are located in the East. 

The summer of 2003 was slightly cooler than normal in the East (Levinson and Waple, 2004)

and the summer of 2004 was much cooler than normal in the East (Levinson, 2005) accounting

in part for the dip in O3 during these 2 years. Trends in compliance metrics such as the fourth
AX3-105

highest daily maximum 8-h average O3 concentration can be found in the EPA Trends reports

and so are not repeated here. 

Figures AX3-66a-h show year-to-year variability in mean daily 8-h O3 concentrations

observed at selected national park sites across the United States. Figures AX3-67a-h show yearto-year variability in the 95th percentile value of daily maximum 8-h O3 concentrations at the

same sites shown in Figures AX3-66a-h. The same criteria used for calculating values in

Figures AX3-64 and AX3-65 were used for calculating the May to September seasonal averages

for the national parks shown in Figures AX3-66a-h and 67a-h. Trends at these national parks are

shown in Table AX3-9. However, several monitoring sites were moved during the period from

1990 to 2004. Sites were moved at Acadia NP in 1996, Joshua Tree NP in 1993, Mammoth

Figure AX3-64. Year-to-year variability in nationwide mean daily maximum 8-h O3

concentrations. The whiskers on the box plot represent the 10th and

90th percentile concentrations. The “X”s above and below the whiskers

are the values that fall below and above the 10th and 90th percentile

concentrations. The dots inside the box represent the mean, for the

statistic, at all sites.

Source: Fitz-Simons et al. (2005).
AX3-106

Cave NP in 1996, Voyageurs NP in 1996, and Yellowstone NP in 1996 and offsets in O3

concentrations have resulted. As a result, trends are not shown for these sites. 

As noted in The Ozone Report—Measuring Progress through 2003 (U.S. Environmental

Protection Agency, 2004b), O3 trends in national parks in the South and the East are similar to

nearby urban areas and reflect the regional nature of O3 pollution. For example, O3 trends in

Charleston, SC and Charlotte, NC track those in nearby Cowpens NP and Cape Romaine NP in

South Carolina; O3 in Knoxville and Nashville, TN tracks O3 in Great Smoky NP; O3 in

Philadelphia, PA and Baltimore, MD tracks Brigantine NP in New Jersey; and New York, NY

and Hartford, CT track O3 in Cape Cod NS. The situation is not as clear in the West, where

national parks are affected differently by pollution sources that are located at varying distances

away (e.g., Lassen Volcanic National Park and Yosemite National Park, CA). However, data

Figure AX3-65. Year-to-year variability in nationwide 95th percentile value of the daily

maximum 8-h O3 concentrations. The whiskers on the box plot represent

the 10th and 90th percentile values for the statistic. The “X”s above and

below the whiskers are the values that fall below and above the 10th and

90th percentile values. The dots inside the box represent the mean, for the

statistic, at all sites.

Source: Fitz-Simons et al. (2005).
AX3-107

Figure AX3-66a-h. Year-to-year variability in mean daily maximum 8-h O3 concentrations

at selected national park (NP), national wildlife refuge (NWR), and

national monument (NM) sites.

Source: Fitz-Simons et al. (2005).
AX3-108

Figure AX3-66i-p. Year-to-year variability in mean daily maximum 8-h O3 concentrations

at selected national park (NP), national wildlife refuge (NWR), and

national monument (NM) sites.

Source: Fitz-Simons et al. (2005).
AX3-109

obtained at these sites still provide valuable information about the variability in regional

background concentrations, especially since the West has not been broken down into regions as

has been done by Lehman et al. (2004) and shown in Figure AX3-7. 

Figure AX3-66q-v. Year-to-year variability in mean daily maximum 8-h O3 concentrations

at selected national park (NP), national wildlife refuge (NWR), and

national monument (NM) sites.

Source: Fitz-Simons et al. (2005).
AX3-110

Figure AX3-67a-h. Year-to-year variability in 95th percentile of daily maximum 8-h O3

concentrations at selected national park (NP), national wildlife refuge

(NWR), and national monument (NM) sites.

Source: Fitz-Simons et al. (2005).
AX3-111

Figure AX3-67i-p. Year-to-year variability in 95th percentile of daily maximum 8-h O3

concentrations at selected national park (NP), national wildlife refuge

(NWR), and national monument (NM) sites.

Source: Fitz-Simons et al. (2005).
AX3-112

Caution should be exercised in using trends calculated at national parks to infer

contributions from distant sources either inside or outside of North America, because of the

influence of local and regional pollution. For example, using a 15-year record of O3 from Lassen

Figure AX3-67q-v. Year-to-year variability in 95th percentile of daily maximum 8-h O3

concentrations at selected national park (NP), national wildlife refuge

(NWR), and national monument (NM) sites.

Source: Fitz-Simons et al. (2005).
Table AX3-9. Trends in Warm Season (May to September) Daily Maximum 8-h O3 Concentrations a

in the United States (1990 to 2004). Trends are given as ppb yr!1

.

Mean P 95 

Site trend p–value trend p–value trAcadia NP (ME) 0.0401 0.037 1.01 0.037 !0.2 

Brigantine NWR (NJ) !0.802 0.014 !1.72 0.004 !1.9

Cape Cod NS (MA) 0 0.423 0 0.349 !0.5 

Cape Romain NWR (SC) 0.71 0.046 1.01 0.01 1.0 Chiricahua NM (AZ) 0.221 0.046 0.2 0.084 0.1Cowpens NB (SC) 0 0.423 0.1 0.349 0.4 Denali NP (AK) 0.17 0.12 0.61 0.01 0.6

Glacier NP (MT) 0 0.5 0.1 0.349 0.2Grand Canyon NP (AZ) 0.25 0.07 0 0.5 0.1Great Smoky Mountains NP (NC-TN) 0.29 0.248 0.9 0.19 0.4 Joshua Tree NP (CA)3 — — — — —

Lassen Volcanic NP (CA) 0.25 0.141 0.2 0.19 0 Mammoth Cave NP (KY)3 — — — — —Olympic NP (WA) 0.14 0.141 0.31 0.037 0.2 

Pinnacles NM (CA) !0.1 0.218 !0.5 0.07 !0.5Rocky Mountain NP (CO) 0.911 0.004 1.01 0.014 0.8Saguaro NM (AZ) !0.2 0.279 !0.3 0.19 !0.3Sequoia/Kings Canyon NP (CA) 0.38 0.218 0 0.461 0 Shenandoah NP (VA) 0 0.461 !0.2 0.385 0.3Theodore Roosevelt NP (ND) 0.381 0.023 0.2 0.19 0.2 Voyageurs NP (MN)3 — — — — —

Yellowstone NP (WY)3 — — — — —

1 Upward trend, significant at p = 0.05 level.2 Downward trend, significant at p = 0.05 level.3 Site moved. See text for details.

AX3-113
AX3-114

Volcanic National Park, a rural elevated site in northern California; data from two aircraft

campaigns; and observations spanning 18 years from five U.S. West Coast, marine boundary

layer sites, Jaffe et al. (2003) reported that O3 in air arriving from the eastern Pacific in spring

has increased by approximately 10 ppb from the mid-1980s. They concluded that this positive

trend is due to increases of emissions of O3 precursors in Asia. They found positive trends in O3

in all seasons. They also noted that diurnal variations during summer were about 21 ppb, but

only about 6 ppb during spring. Although Lassen Volcanic National Park site is not close to any

major emission sources or urban centers, the site experiences maximum hourly average O3

concentrations above 0.080 ppm during April to May and above 0.100 ppm during the summer

(U.S. Environmental Protection Agency, 2003), suggesting local photochemical production, at

least during summer. However, local springtime photochemical production cannot be ruled out. 

The authors suggested that the likely cause for the spring increases is transport from Asia,

because emissions of precursors have decreased in California over the monitoring period. The

springtime increases appears to be inconsistent with the summer increases, when there is

evidence for the occurrence of more localized photochemical activity. Although emissions of O3

precursors may have decreased in California as a whole over the monitoring period, there still

may be regional increases in areas that could affect air quality in Lassen. 

AX3.7 RELATIONS BETWEEN OZONE, OTHER OXIDANTS, AND

OXIDATION PRODUCTS

Tables of measurements of PAN and peroxypropionyl nitrate (PPN, CH3CH2C(O)OONO2)

concentrations were given in the 1996 O3 AQCD (U.S. Environmental Protection Agency,

1996a). Measurements were summarized for rural and urban areas in the United States, Canada,

France, Greece, and Brazil. The use of measurements from aboard serve to illustrate or support

certain U.S. results as well as to demonstrate the widespread presence of PANs in the

atmosphere. Additional data for H2O2 were also presented in the 1996 O3 AQCD. Data for these

species are obtained as part of specialized field studies and not as part of routine monitoring

operations and thus are highly limited in their ranges of applicability. As a result, it is difficult

to relate the concentrations of O3, other oxidants, and oxidation products on the basis of rather

sparse data sets. This information is simply not available for a large number of environments. 
AX3-115

Instead, it might be more instructive to examine the relations between O3 and other products of

atmospheric reactions on the basis of current understanding of atmospheric photochemical

processes.

In order to understand co-occurrence between atmospheric species, an important

distinction must be made between primary (directly emitted) species and secondary

(photochemically produced) species. In general, it is more likely that primary species will be

more highly correlated with each other, and that secondary species will be more highly

correlated with each other than will species from mixed classes. By contrast, primary and

secondary species are less likely to be correlated with each other. Secondary reaction products

tend to correlate with each other, but there is considerable variation. Some species (e.g., O3 and

organic nitrates) are closely related photochemically and correlate with each other strongly. 

Others (e.g., O3 and H2O2) show a more complex correlation pattern.

Although NO2 is produced mainly by the reaction of directly emitted NO with O3 with

some contributions from direct emissions, in practice, it behaves like a primary species. The

timescale for conversion of NO to NO2 is fast (5 min or less), so NO and NO2 ambient

concentrations rapidly approach values determined by the photochemical steady state. The sum

NO + NO2 (NOx) behaves like a typical primary species, while NO and NO2 reflect some

additional complexity based on photochemical interconversion. As a primary species, NO2

generally does not correlate with O3 in urban environments. In addition, chemical interactions

among O3, NO and NO2 have the effect of converting O3 to NO2 and vice versa, which can result

in a significant anti-correlation between O3 and NO2. 

Organic nitrates consist of PAN, a number of higher-order species with photochemistry

similar to PAN (e.g., PPN), and species such as alkyl nitrates with somewhat different

photochemistry. These species are produced by a photochemical process very similar to that

of O3. Photochemical production is initiated by the reaction of primary and secondary VOCs

with OH radicals, the resulting organic radicals subsequently react with NO2 (producing PAN

and analogous species) or with NO (producing alkyl nitrates). The same sequence (with organic

radicals reacting with NO) leads to the formation of O3. 

In addition, at warm temperatures, the concentration of PAN forms a photochemical steady

state with its radical precursors on a timescale of roughly 30 minutes. This steady state value

increases with the ambient concentration of O3 (Sillman et al., 1990). Ozone and PAN may
AX3-116

show different seasonal cycles, because they are affected differently by temperature. Ambient

O3 increases with temperature, driven in part by the photochemistry of PAN (see description

above). By contrast, the photochemical lifetime of PAN decreases rapidly with increasing

temperature. The ratio, O3/PAN, should show seasonal changes, with highest ratios in summer,

although there is no evidence from measurements. Measured ambient concentrations

(Figures AX3-68a-d) show a strong nonlinear association between O3 and PAN, and between O3

and other organic nitrates (Pippin et al., 2001; Roberts et al., 1998). Moreover, the uncertainty

in the relationship between O3 and PAN grows as the level of PAN increases.

Individual primary VOCs are generally highly correlated with each other and with NOx

(Figure AX3-69). A summary of the results of a number of field studies of the concentrations of

precursors including NOx and nonmethane organic compounds (NMOCs) are summarized in the

1996 O3 AQCD. 

Formation of H2O2 takes place by self-reaction of photochemically generated HO2 radicals,

so that there is large seasonal variation of H2O2 concentrations and values in excess of 1 ppb are

mainly limited to the summer months (Kleinman, 1991). Although H2O2 is produced from

photochemistry that is closely related to O3, it does not show a consistent pattern of correlation

with O3. Hydrogen peroxide is produced in abundance along with O3 only when O3 is produced

under NOx-limited conditions. When the photochemistry is NOx-saturated much less H2O2 is

produced. In addition, increasing NOx tends to slow the formation of H2O2 under NOx-limited

conditions. 

Measurements of gas phase peroxides in the atmosphere were reviewed by Lee et al.

(2000). Ground level measurements of H2O2 taken during the 1970s indicated values of 180 ppb

in Riverside, CA and 10 to 20 ppb during smog episodes in Claremont and Riverside, with

values approaching 100 ppb in forest fire plumes. However, later surface measurements always

found much lower values. For example, in measurements made in Los Angeles and nearby areas

in the 1980s, peak values were always less than about 2 ppb and in a methods intercomparison

study in Research Triangle Park, NC in June 1986, concentrations were <2.5 ppbv. Higher

values ranging up to 5 ppb were found in a few other studies in Kinterbish, Alabama and

Meadview, Arizona. Several of these studies found strong diurnal variations (typically about a

factor three) with maximum values in the mid-afternoon and minimum values in the early 
AX3-117

Figure AX3-68a-d. Measured O3 (ppbv) versus PAN (pptv) in Tennessee, including

(a) aircraft measurements, and (b, c, and d) suburban sites near

Nashville. 

Source: Roberts et al. (1998).

morning. Mean concentrations of organic hydroperoxides at the surface at Niwot Ridge, CO in

the summer of 1988 and State Park, GA during the summer of 1991 were all less than a few ppb. 

Early aircraft measurements of H2O2 over the eastern United States were reported by

Heikes et al. (1987). More recent aircraft measurements of hydroperoxide (H2O2, CH3OOH and

HOCH2OOH) concentrations were made as part of the Southern Oxidants Study intensive

campaign in Nashville, TN in July 1995 (Weinstein-Lloyd et al., 1998). The median
AX3-118

Figure AX3-69. Relationship between benzene and NOy at a measurement site in Boulder,

CO. Instances with SO2 >10 ppb are identified separately (open circles),

because these may reflect different emission sources. 

Source: Goldan et al. (1995).

concentration of total hydroperoxides in the boundary layer between 1100 and 1400 CDT was

about 5 ppbv, with more than 50% contribution from organic hydroperoxides. Median O3 was

about 70 ppbv at the same time. The concentrations of the hydroperoxides depended strongly on

wind direction. For example, values were about 40% lower when winds originated from the

N/NW as opposed to the S/SW.

Elevated O3 is generally accompanied by elevated HNO3, although the correlation is not as

strong as between O3 and organic nitrates. Ozone often correlates with HNO3, because they have

the same precursor (NOx). However, HNO3 can be produced in significant quantities in winter,

even when O3 is low. The ratio between O3 and HNO3 also shows great variation in air pollution

events, with NOx-saturated environments having much lower ratios of O3 to HNO3 (Ryerson

et al., 2001). Aerosol nitrate is formed primarily by the combination of nitrate (supplied

by HNO3) with ammonia, and may be limited by the availability of either nitrate or ammonia. 
AX3-119

Nitrate is expected to correlate loosely with O3 (see above), whereas ammonia is not expected to

correlate with O3. 

In addition to nitrate, other oxidants are present in airborne cloud droplets, rain drops and

particulate matter. Measurements of hydroperoxides, summarized by Reeves and Penkett

(2003), are available mainly for hydrometeors, but are sparse for ambient particles. 

Venkatachari et al. (2005a) sampled the concentrations of total reactive oxygen species (ROS) in

particles using a cascade impactor in Rubidoux, CA during July 2003. Although the species

constituting ROS were not identified, the results were reported in terms of equivalent H2O2

concentrations. Unlike O3 and gas phase H2O2 which show strong diurnal variability (i.e., about

a factor of three variation between afternoon maximum and early morning minimum), the

diurnal variation of particle phase ROS was found to be much weaker (i.e., less than about 20%)

at least for the time between 8 a.m. and midnight. Because the ROS were measured in the fine

aerosol size fraction, which has a lifetime with respect to deposition of much greater than a day,

little loss is expected but their concentrations might also be expected to increase because of

nighttime chemistry, perhaps involving NO3 radicals. The concentration of ROS, expressed as

equivalent H2O2 (5.2 to 6.1 × 10-7 M/m3

, ranged from 20% to 100% that of O3 (diurnal average: 

30%), with highest values at night. The ratio was likely higher at the early morning minimum

for O3. In a companion study conducted in Queens, NY during January and early February 2004,

Venkatachari et al. (2005b) found much lower concentrations of ROS of about 1 × 10-7 M/m3

. 

However, O3 levels were also substantially lower leading to ROS concentrations about 20%

those of O3. It is of interest to note that gas phase OH concentrations measured at the same time

ranged from about 7.5 × 104

/cm3 to about 1.8 × 106/cm3, implying the presence of significant

photochemical activity even in New York City during winter. 

Peroxyacetylnitrate (PAN) is produced during the photochemical oxidation of a wide range

of VOCs in the presence of NOx. It is removed by thermal decomposition and also by uptake to

vegetation (Sparks et al., 2003; Teklemariam and Sparks, 2004). PAN is the dominant member

of the broader family of peroxyacylnitrates (PANs), which includes as other significant

atmospheric components peroxypropionyl nitrate (PPN) of anthropogenic origin and

peroxymethacrylic nitrate (MPAN) produced from oxidation of isoprene. Measurements and

models show that PAN in the United States includes major contributions from both

anthropogenic and biogenic VOC precursors (Horowitz et al., 1998; Roberts et al., 1998). 
AX3-120

Measurements in Nashville during the 1999 summertime Southern Oxidants Study (SOS)

showed PPN and MPAN amounting to 14% and 25% of PANs, respectively (Roberts et al.,

2002). Measurements during the TexAQS 2000 study in Houston indicated PAN concentrations

of up to 6.5 ppbv (Roberts et al., 2003). PAN measurements in southern California during the

SCOS97-NARSTO study indicated peak concentrations of 5-10 ppbv, which can be contrasted to

values of 60-70 ppbv measured back in 1960 (Grosjean, 2003). Vertical profiles measured from

aircraft over the United States and off the Pacific coasts show PAN concentrations above the

boundary layer of only a few hundred pptv, although there are significant enhancements

associated with long-range transport of pollution plumes from Asia (Kotchenruther et al., 2001a;

Roberts et al., 2004). Decomposition of this anthropogenic PAN as it subsides over North

America can lead to significant O3 production, enhancing the O3 background (Kotchenruther

et al., 2001b; Hudman et al., 2004).

Relations between primary and secondary components discussed above are illustrated by

considering data for O3 and PM2.5. Ozone and PM2.5 concentrations observed at a monitoring site

in Fort Meade, MD are plotted as binned means in Figure AX3-70. These data were collected

between July 1999 and July 2001. As can be seen from the figure, PM2.5, regarded as a function

of O3, increases to the left of the inflection point (at about 30 ppbv O3) and also increases 

with O3 to the right of the inflection point. Data to the left of the minimum in PM2.5 were

collected mainly during the cooler months of the year, while data to the right of the minimum

were collected during the warmer months. This situation arises because PM2.5 contains a large

secondary component during the summer and has a larger primary component during winter. 

During the winter, O3 comes mainly from the free troposphere, above the planetary boundary

layer and, thus, may be considered a tracer for relatively clean air. Unfortunately, data for PM2.5

and O3 are collected concurrently at relatively few sites in the United States throughout an entire

year, so these results, while highly instructive are not readily extrapolated to areas where

appreciable photochemical activity occurs throughout the year. Ito et al. (2005) showed the

relation between PM10 and O3 on a seasonal basis in several urban areas (cf., Figure 7-24). 

Although PM10 contains proportionately more primary material than does PM2.5, relations similar

to those shown in Figure AX3-70 are found, reflecting the dominant contribution from PM2.5

to PM10. 
AX3-121

AX3.8 RELATIONSHIP BETWEEN SURFACE OZONE AND

OTHER POLLUTANTS

AX3.8.1 Introduction

Several attempts have been made to characterize gaseous air pollutant mixtures (Lefohn

and Tingey, 1984; Lefohn et al., 1987). The characterization of co-occurrence patterns under

ambient conditions is important for relating human health and vegetation effects to controlled

chamber studies and to ambient conditions. Lefohn et al. (1987) discussed the various patterns

of pollutant exposures. Pollutant combinations can occur at or above a threshold concentration

either together or temporally separated from one another. Patterns that show air pollutant pairs

appearing at the same hour of the day at concentrations equal to or greater than a minimum

Figure AX3-70. Binned mean PM2.5 concentrations versus binned mean O3 concentrations

observed at Fort Meade, MD from July 1999 to July 2001.

Source: Chen (2002).
AX3-122

hourly mean value were defined as simultaneous-only daily co-occurrences. When pollutant

pairs occurred at or above a minimum concentration during the 24-h period, without occurring

during the same hour, a “sequential-only” co-occurrence was defined. During a 24-h period, if

the pollutant pair occurred at or above the minimum level at the same hour of the day and at

different hours during the period, the co-occurrence pattern was defined as “complexsequential.” 

For characterizing the different types of co-occurrence patterns for O3/NO2, O3/SO2,

and NO2/SO2, Lefohn and Tingey (1984) used a 0.05 ppm threshold to identify the number of

hourly simultaneous-only co-occurrences for the period May through September at a large

number of air quality urban monitoring sites along with rural sites. The selection of a 0.05-ppm

threshold concentration was based on vegetation effects considerations. Data used in the

analysis included hourly averaged (1) Environmental Protection Agency Storage and Retrieval

of Aerometric Data (SAROAD; now AQS) data for 1981, (2) EPRI-SURE and Eastern Regional

Air Quality Study (ERAQS) data for 1978 and 1979, and (3) Tennessee Valley Authority (TVA)

data from 1979 to 1982. Lefohn and Tingey (1984) concluded, for the pollutant combinations,

that (1) the co-occurrence of two-pollutant mixtures lasted only a few hours per episode and (2)

the time interval between episodes was generally large (weeks, sometimes months).

Lefohn et al. (1987), using a 0.03-ppm threshold, grouped air quality data from rural and

RRMS (as characterized in the EPA database) within a 24-h period starting at 0000 hours and

ending at 2359 hours. Data were analyzed for the May to September period. Data used in the

analysis included hourly averaged (1) Environmental Protection Agency AQS (SAROAD) data

from 1978 to 1982, (2) EPRI-SURE and –ERAQS data for 1978 and 1979, and (3) TVA data

from 1979 to 1982. Patterns that showed air pollutant pairs appearing at the same hour of the

day at concentrations equal to or greater than a minimum hourly mean value were defined as

simultaneous-only daily co-occurrences. When pollutant pairs occurred at or above a minimum

concentration during the 24-h period, without occurring during the same hour, a “sequentialonly” co-occurrence was defined. During a 24-h period, if the pollutant pair occurred at or

above the minimum level at the same hour of the day and at different hours during the period,

the co-occurrence pattern was defined as “complex-sequential.” A co-occurrence was not

indicated if one pollutant exceeded the minimum concentration just before midnight and the

other pollutant exceeded the minimum concentration just after midnight. As will be discussed
AX3-123

below, studies of the joint occurrence of gaseous NO2/O3 and SO2/O3 reached two conclusions: 

(1) hourly simultaneous and daily simultaneous-only co-occurrences are fairly rare and (2) when

co-occurrences are present, complex-sequential and sequential-only co-occurrence patterns

predominate. The authors reported that year-to-year variability was found to be insignificant;

most of the monitoring sites experienced co-occurrences of any type less than 12% of the

153 days.

Since 1999, monitoring stations across the United States have been routinely measuring the

24-h average concentrations of PM2.5. Because of the availability of the PM2.5 data, daily

co-occurrence of PM2.5 and O3 over a 24-h period was characterized. Because PM2.5 data are

mostly summarized as 24-h average concentrations in the AQS data base, a daily co-occurrence

of O3 and PM2.5 was subjectively defined as when an hourly average O3 concentration $0.05 ppm

and a PM2.5 24-h concentration $40 μg/m3 occurred over the same 24-h period.

For exploring the co-occurrence of O3 and other pollutants (e.g., acid precipitation and

acidic cloudwater), limited data are available. In most cases, routine monitoring data are not

available from which to draw general conclusions. However, published results are reviewed and

summarized for the purpose of assessing an estimate of the possible importance of co-occurrence

patterns of exposure. 

AX3.8.2 Co-Occurrence of Ozone with Nitrogen Oxides

Ozone occurs frequently at concentrations equal to or greater than 0.05 ppm at many rural

and remote monitoring sites in the United States (U.S. Environmental Protection Agency,

1996a). Therefore, for many rural locations in the United States, the co-occurrence patterns

observed by Lefohn and Tingey (1984) for O3 and NO2 were defined by the presence or absence

of NO2. Lefohn and Tingey (1984) reported that most of the sites analyzed experienced fewer

than 10 co-occurrences (when both pollutants were present at an hourly average concentration

$0.05 ppm). Figure AX3-71 summarizes the simultaneous co-occurrence patterns reported by

Lefohn and Tingey (1984). The authors noted that several urban monitoring sites in the South

Coast Air Basin experienced more than 450 co-occurrences. For more moderate areas of the

country, Lefohn et al. (1987) reported that even with a threshold of 0.03 ppm O3, the number of

co-occurrences with NO2 was small. 
AX3-124

Figure AX3-71. The co-occurrence pattern for O3 and NO2.

Source: Lefohn and Tingey (1984).

Using 2001 data from the U.S. EPA AQS database, patterns that showed air pollutant pairs

of O3/NO2 appearing at the same hour of the day at concentrations $0.05 ppm were

characterized. The data were not segregated by location settings categories (i.e., rural, suburban,

and urban and center city) or land use types (i.e., agricultural, commercial, desert, forest,

industrial, mobile, or residential). Data capture was not a consideration in the analysis. The data

were characterized over the EPA-defined O3 season (Table AX3-1). In 2001, there were

341 monitoring sites that co-monitored O3 and NO2. Because of possible missing hourly average

concentration data during periods when co-monitoring may have occurred, no attempt was made

to characterize the number of co-occurrences in the 0 category. Thus, co-occurrence patterns

were identified for those monitoring sites that experienced one or more co-occurrences. 

Figure AX3-72 illustrates the results of the analysis. Similar to the analysis summarized

by Lefohn and Tingey (1984), most of the collocated monitoring sites analyzed, using the 2001

data, experienced fewer than 10 co-occurrences (when both pollutants were present at an hourly

average concentration $0.05 ppm).
AX3-125

Figure AX3-72. The co-occurrence pattern for O3 and NO2 using 2001 data from

the AQS.

AX3.8.3 Co-Occurrence of Ozone with Sulfur Dioxide

Because elevated SO2 concentrations are mostly associated with industrial activities (U.S.

Environmental Protection Agency, 1992), co-occurrence observations are usually associated

with monitors located near these types of sources. Lefohn and Tingey (1984) reported that,

for the rural and nonrural monitoring sites investigated, most sites experienced fewer than

10 co-occurrences of SO2 and O3. Lefohn et al. (1987) reported that even with a threshold of

0.03 ppm O3, the number of co-occurrences with SO2 was small. Figure AX3-73 illustrates the

simultaneous co-occurrence results reported by Lefohn and Tingey (1984). 

Meagher et al. (1987) reported that several documented O3 episodes at specific rural

locations appeared to be associated with elevated SO2 levels. The investigators defined the

co-occurrence of O3 and SO2 to be when hourly mean concentrations were $0.10 and 0.01 ppm,

respectively.

The above discussion was based on the co-occurrence patterns associated with the presence

or absence of hourly average concentrations of pollutant pairs. Taylor et al. (1992) have

discussed the joint occurrence of O3, nitrogen, and sulfur in forested areas using cumulative

exposures of O3 with data on dry deposition of sulfur and nitrogen. The authors concluded in
AX3-126

Figure AX3-73. The co-occurrence pattern for O3 and SO2.

Source: Lefohn and Tingey (1984).

their study that the forest landscapes with the highest loadings of sulfur and nitrogen via dry

deposition tended to be the same forests with the highest average O3 concentrations and largest

cumulative exposure. Although the authors concluded that the joint occurrences of multiple

pollutants in forest landscapes were important, nothing was mentioned about the hourly

co-occurrences of O3 and SO2 or of O3 and NO2. 

Using 2001 data from the EPA AQS database, patterns that showed air pollutant pairs

of O3/SO2 appearing at the same hour of the day at concentrations $0.05 ppm were characterized. 

The data were not segregated by location settings categories (i.e., rural, suburban, and urban and

center city) or land use types (i.e., agricultural, commercial, desert, forest, industrial, mobile,

or residential). Data capture was not a consideration in the analysis. In 2001, there were

246 monitoring sites that co-monitored O3 and SO2. Because of possible missing hourly average

concentration data during periods when co-monitoring may have occurred, no attempt was made

to characterize the number of co-occurrences in the 0 category. Thus, co-occurrence patterns
AX3-127

Figure AX3-74. The co-occurrence pattern for O3 and SO2 using 2001 data from AQS.

were identified for those monitoring sites that experienced one or more co-occurrences. 

Figure AX3-74 shows the results from this analysis for the simultaneous co-occurrence of O3

and SO2. Similar to the analysis summarized by Lefohn and Tingey (1984), most of the

collocated monitoring sites analyzed, using the 2001 data, experienced fewer than 10 cooccurrences (when both pollutants were present at an hourly average concentration $0.05 ppm). 

AX3.8.4 Co-Occurrence of Ozone and Daily PM2.5

Using 2001 data from the EPA AQS, the daily co-occurrence of PM2.5 and O3 over a 24-h

period was characterized. There were 362 sites where PM2.5 and O3 monitors were collocated. 

As described in the introduction selection of this annex, a daily co-occurrence of O3 and PM2.5 is

subjectively defined as an hourly average O3 concentration $0.05 ppm and a PM2.5 24-h

concentration $40 μg/m3 occurring over the same 24-h period. Figure AX3-75 illustrates the

daily co-occurrence patterns observed. Using 2001 data from the AQS, the daily co-occurrence

of PM2.5 and O3 was infrequent. 
AX3-128

Figure AX3-75. The co-occurrence pattern for O3 and PM2.5 using 2001 data from AQS.

AX3.8.5 Co-Occurrence of Ozone with Acid Precipitation

Concern has been expressed about the possible effects on vegetation from co-occurring

exposures of O3 and acid precipitation (Prinz et al., 1985; National Acid Precipitation

Assessment Program, 1987; Prinz and Krause, 1989). Little information has been published

concerning the co-occurrence patterns associated with the joint distribution of O3 and acidic

deposition (i.e., H+). Lefohn and Benedict (1983) reviewed the EPA SAROAD monitoring data

for 1977 through 1980 and, using National Atmospheric Deposition Program (NADP) and EPRI

wet deposition data, evaluated the frequency distribution of pH events for 34 NADP and 8 EPRI

chemistry monitoring sites located across the United States. Unfortunately, there were few sites

where O3 and acidic deposition were co-monitored.

As a result, Lefohn and Benedict (1983) focused their attention on O3 and acidic deposition

monitoring sites that were closest to one another. In some cases, the sites were as far apart as

144 km. Using hourly O3 monitoring data and weekly and event acidic deposition data from the

NADP and EPRI databases, the authors identified specific locations where the hourly mean O3

concentrations were $0.1 ppm and 20% of the wetfall daily or weekly samples were below pH

4.0. Elevated levels of O3 were defined as hourly mean concentrations equal to or greater than

0.1 ppm. Although for many cases, experimental research results of acidic deposition on
AX3-129

agricultural crops show few effects at pH levels >3.5 (National Acid Precipitation Assessment

Program, 1987), it was decided to use a pH threshold of 4.0 to take into consideration the

possibility of synergistic effects between O3 and acidic deposition.

Based on their analysis, Lefohn and Benedict (1983) identified five sites with the potential

for agricultural crops to experience additive, less than additive, or synergistic (i.e., greater than

additive) effects from elevated O3 and H+ concentrations. The authors stated that they believed,

based on the available data, the greatest potential for interaction between acid rain and O3

concentrations in the United States, with possible effects on crop yields, may be in the most

industrialized areas (e.g., Ohio and Pennsylvania). However, they cautioned that, because no

documented evidence existed to show that pollutant interaction had occurred under field growth

conditions and ambient exposures, their conclusions should only be used as a guide for further

research.

In their analysis, Lefohn and Benedict (1983) found no collocated sites. The authors

rationalized that data from non-co-monitoring sites (i.e., O3 and acidic deposition) could be used

because O3 exposures are regional in nature. However, work by Lefohn et al. (1988) has shown

that hourly mean O3 concentrations vary from location to location within a region, and that

cumulative indices, such as the percent of hourly mean concentrations $0.07 ppm, do not form a

uniform pattern over a region. Thus, extrapolating hourly mean O3 concentrations from known

locations to other areas within a region may provide only qualitative indications of actual O3

exposure patterns.

In the late 1970s and the 1980s, both the private sector and the government funded research

efforts to better characterize gaseous air pollutant concentrations and wet deposition. The eventoriented wet deposition network, EPRI/Utility Acid Precipitation Study Program, and the weekly

oriented sampling network, NADP, provided information that can be compared with hourly

mean O3 concentrations collected at several co-monitored locations. No attempt was made to

include H+

 cloud deposition information. In some cases, for mountaintop locations (e.g.,

Clingman’s Peak, Shenandoah, Whiteface Mountain, and Whitetop Mountain), the H+ cloud

water deposition is greater than the H+

 deposition in precipitation (Mohnen, 1989), and the

co-occurrence patterns associated with O3 and cloud deposition will be different from those

patterns associated with O3 and deposition by precipitation. 
AX3-130

Smith and Lefohn (1991) explored the relationship between O3 and H+

 in precipitation,

using data from sites that monitored both O3 and wet deposition simultaneously and within

one-minute latitude and longitude of each other. The authors reported that individual sites

experienced years in which both H+

 deposition and total O3 exposure were at least moderately

high (i.e., annual H+

 deposition $0.5 kg ha!1 and an annual O3 cumulative, sigmoidally weighted

exposure (W126) value $50 ppm-h). With data compiled from all sites, it was found that

relatively acidic precipitation (pH #4.31 on a weekly basis or pH #4.23 on a daily basis)

occurred together with relatively high O3 levels (i.e., W126 values $0.66 ppm-h for the same

week or W126 values $0.18 ppm-h immediately before or after a rainfall event) approximately

20% of the time, and highly acidic precipitation (i.e, pH #4.10 on a weekly basis or pH #4.01 on

a daily basis) occurred together with a high O3 level (i.e., W126 values $1.46 ppm-h for the

same week or W126 values $0.90 ppm-h immediately before or after a rainfall event)

approximately 6% of the time. Whether during the same week or before, during, or after a

precipitation event, correlations between O3 level and pH (or H+ deposition) were weak to

nonexistent. Sites most subject to relatively high levels of both H+ and O3 were located in the

eastern United States, often in mountainous areas.

AX3.8.6 Co-Occurrence of Ozone with Acid Cloudwater

In addition to the co-occurrence of O3 and acid precipitation, results have been reported on

the co-occurrence of O3 and acidic cloudwater in high-elevation forests. Vong and Guttorp

(1991) characterized the frequent O3-only and pH-only, single-pollutant episodes, as well as the

simultaneous and sequential co-occurrences of O3 and acidic cloudwater. The authors reported

that both simultaneous and sequential co-occurrences were observed a few times each month

above the cloud base. Episodes were classified by considering hourly O3 average concentrations

$0.07 ppm and cloudwater events with pH #3.2. The authors reported that simultaneous

occurrences of O3 and pH episodes occurred two to three times per month at two southern sites

(Mitchell, NC and Whitetop, VA) and the two northern sites (Whiteface Mountain, NY and

Moosilauke, NH) averaged one episode per month. No co-occurrences were observed at the

central Appalachian site (Shenandoah, VA), due to a much lower cloud frequency. Vong and

Guttorp (1991) reported that the simultaneous occurrences were usually of short duration 
AX3-131

(mean = 1.5 h/episode) and were followed by an O3-only episode. As would be expected,

O3-only episodes were longer than co-occurrences and pH episodes, averaging an 8-h duration.

AX3.9 THE METHODOLOGY FOR DETERMINING POLICY

RELEVANT BACKGROUND OZONE CONCENTRATIONS

AX3.9.1 Introduction

Background O3 concentrations used for NAAQS-setting purposes are referred to as Policy

Relevant Background (PRB) O3 concentrations. Policy Relevant Background concentrations are

those concentrations that would result in the United States in the absence of anthropogenic

emissions in continental North America (the United Sates, Canada and Mexico). Policy

Relevant Background concentrations include contributions from natural sources everywhere in

the world and from anthropogenic sources outside these three countries. For the purposes of

informing decisions about O3 NAAQS, EPA assesses risks to human health and environmental

effects to O3 levels in excess of PRB concentrations. Issues concerning the methodology for

estimating PRB O3 concentrations are described in detail in Annex AX3, Section AX3.9. 

Contributions to PRB O3 include: photochemical interactions involving natural emissions

of VOCs, NOx, and CO; the long-range transport of O3 and its precursors from outside North

America; and stratospheric-tropospheric exchange (STE). Processes involved in STE are

described in detail in Annex AX2.3. Natural sources of O3 precursors include biogenic

emissions, wildfires, and lightning. Biogenic emissions from agricultural activities are not

considered in the formation of PRB O3. 

Most of the issues concerning the calculation of PRB O3 center on the origin of springtime

maxima in surface O3 concentrations observed at monitoring sites in relatively unpolluted areas

of the United States and on the capability of the current generation of global-scale, threedimensional chemistry transport models to correctly simulate their causes. These issues are

related to the causes of the occurrence of high O3 values, especially those averaged over 1-h to

8-h observed at O3 monitoring sites during late winter through spring (i.e., February to June). 

The issues raised do not affect interpretations of the causes of summertime O3 episodes as

strongly. Summertime O3 episodes are mainly associated with slow-moving high-pressure
AX3-132

systems characterized by limited mixing between the planetary boundary layer and the free

troposphere (Section AX2.3). 

Springtime maxima are observed at national parks mainly in the western United States that

are relatively clean (Section AX3.2.2; Figures AX3-76a,b) and at a number of other relatively

unpolluted monitoring sites throughout the Northern Hemisphere. Spring maxima in

tropospheric O3 were originally attributed to transport from the stratosphere by Regener (1941)

as cited by Junge (1963). Junge (1963) also cited measurements of springtime maxima in O3

concentrations at Mauna Loa (elevation 3400 m) and at Arkosa, Germany (an alpine location,

elevation 1860 m). Measurements of radioactive debris transported downward from the

stratosphere as the result of nuclear testing during the 1960s also show springtime maxima

(Ludwig et al., 1977). However, more recent studies (Lelieveld and Dentener, 2000; Browell

et al., 2003) attribute the springtime maximum in tropospheric O3 concentrations to tropospheric

production rather than transport from the stratosphere. It should be noted here that O3 in the free

troposphere is subject to chemical loss on time scales much shorter than for decay of most

radio-isotopes produced by nuclear testing that were used as tracers of stratospheric air such

as 14C, 137Cs and 90Sr. 

Springtime O3 maxima were observed in low-lying surface measurements during the late

19th century. However, these measurements are quantitatively highly uncertain, and extreme

caution should be exercised in their use. Concentrations of approximately 0.036 ppm for the

daytime average and of 0.030 ppm for the nighttime averages were reported for Zagreb, Croatia

using the Schonbein method during the 1890s (Lisac and Grubišiƒ, 1991). Of the numerous

measurements of tropospheric O3 made in the 19th century, only the iodine catalyzed oxidation

of arsenite has been verified with modern laboratory methods. Kley et al. (1988) reconstructed

the apparatus used between 1876 and 1910 in Montsouris, outside Paris, and evaluated it for

accuracy and specificity. They concluded that O3 mixing ratios ranged from 5 to 16 ppb with

uncertainty of ±2 ppb. Interferences from SO2 were avoided as the Montsouris data were

selected to exclude air from Paris, the only source of high concentrations of SO2 at that time. 

Uncertainties in the humidity correction to the Schonbein reading will lead to considerable

inaccuracies in the seasonal cycle established by this method (Pavelin et al., 1999). Because of

the uncertainties in the earlier methods, it is difficult to quantify the differences between 
AX3-133

Figure AX3-76a. Monthly maximum hourly average O3 concentrations at Yellowstone

National Park, Wyoming in 1998, 1999, 2000, and 2001.

Figure AX3-76b. Hourly average O3 concentrations at Yellowstone National Park,

Wyoming for the period January to December 2001.

Source: U.S. Environmental Protection Agency (2003).
AX3-134

surface O3 concentrations measured in the last half of the 19th century at certain locations in

either Europe or North America with those currently monitored at remote locations in the world. 

Observations of O3 profiles at a large number of sites indicate a positive gradient in O3

mixing ratios with increasing altitude in the troposphere and a springtime maximum in O3

concentrations in the upper troposphere (Logan, 1999). As discussed in Section AX2.3.1, STE

affects the middle and upper troposphere more than the lower troposphere. It is, therefore,

reasonable to suppose that the main cause of this positive gradient is STE. However, deep

convection transports pollutants upward and can result in an increase in the pollutant mixing

ratio with altitude downwind of surface source regions as shown in Figure AX3-77. This effect

can be seen in differences in ozonesonde profiles as one moves eastward across the United States

(Newchurch et al., 2003). In addition, O3 formed by lightning-generated NOx also contributes to

the vertical O3 gradient (Lelieveld and Dentener, 2000). This O3 could be either background or

not, depending on the sources of radical precursors. Another contributing factor is the increase

of O3 lifetime with altitude (Wang et al., 1998). Free-tropospheric O3 is not predominantly of

stratospheric origin, nor is it all natural; it is mostly controlled by production within the

troposphere and includes a major anthropogenic enhancement (e.g., Berntsen et al., 1997;

Roelofs et al., 1997; Wild and Akimoto, 2001). 

Stohl (2001), Wernli and Borqui (2002), Seo and Bowman (2002), James et al. (2003a,b),

Sprenger and Wernli (2003), and Sprenger et al. (2003) addressed the spatial and temporal

variability in stratosphere to troposphere transport. Both Stohl (2001) and Sprenger et al. (2003)

produced 1-year climatologies of tropopause folds based on a 1° by 1° gridded meteorological

model data set. They each found that the probability of deep folds (penetrating to the 800 hPa

level) was maximum during winter (December through February) with the highest frequency of

folding extending from Labrador down the east coast of North America. However, these deep

folds occurred in <1% of the 6-h intervals for which meteorological data was assimilated for grid

points in the continental United States, with a higher frequency in Canada. They observed a

higher frequency of more shallow folds (penetrating to the upper troposphere) and medium folds

(penetrating to levels between 500 and 600 hPa) of about 10% and 1 to 2%, respectively. These

events occur preferentially across the subtropics and the southern United States. At higher

latitudes, other mechanisms such as the erosion of cut-off lows and the breakup of stratospheric 
AX3-135

Figure AX3-77. (a) Contour plot of CO mixing ratios (ppbv) observed in and near the

June 15, 1985, mesoscale convective complex in eastern Oklahoma. 

Heavy line shows the outline of the cumulonimbus cloud. Dark shading

indicates high CO and light shading indicates low CO. Dashed contour

lines are plotted according to climatology since no direct measurements

were made in that area. (b) Same as (a) but for O3 (ppbv). 

Source: Dickerson et al. (1987).
AX3-136

streamers are likely to play an important role in STE. A 15-year model climatology by Sprenger

and Wernli (2003) showed the consistent pattern of STE occurring over the primary storm tracks

along the Asian and North American coasts. This climatology, and the one of James et al.

(2003a,b) both found that recent stratospheric air associated with deep intrusions are relatively

infrequent occurrences in these models. Thus, stratospheric intrusions are most likely to directly

affect the middle and upper troposphere, not the planetary boundary layer. However, this O3 can

still exchange with the planetary boundary layer through convection or through large-scale

subsidence as described later in this subsection and in Sections AX2.3.2, AX2.3.3, and AX2.3.4. 

These results are in accord with the observations of Ludwig et al. (1977) over the western United

States. It should also be remembered that stratospheric O3 injected into the upper troposphere is

subject to chemical destruction as it is transported downward toward the surface.

Ozone concentrations measured at RRMS in the Northern Hemisphere have been compiled

by Vingarzan (2004) and are reproduced here in Tables AX3-10, AX3-11, and AX3-12. Data

for annual mean/median concentrations show a broad range, as do annual maximum 1-h

concentrations. Generally, concentrations increase with elevation and the highest concentrations

are found during spring. The overall average of the annual median O3 concentrations at all sites

in the continental United States is about 30 ppb and excluding higher elevation sites it is about

24 ppb. Maximum concentrations may be related to stratospheric intrusions, wildfires, and

intercontinental or regional transport of pollution. However, it should be noted that all of these

sites are affected by anthropogenic emissions to some extent making an interpretation based on

these data alone problematic. 

Daily 1-h maximum O3 concentrations exceeding 50 or 60 ppb are observed during late

winter and spring in southern Canada and at sites in national parks as shown in

Tables AX3-13, AX3-14, and Figure AX3-78. That these high values can occur during late

winter when there are low sun angles and cold temperatures may imply a negligible role for

photochemistry and a major role for stratospheric intrusions. However, active photochemistry

occurs even at high latitudes during late winter. Rapid O3 loss, apparently due to multiphase

chemistry involving bromine atoms (see Section 2.2.10) occurs in the Arctic marine boundary

layer. The Arctic throughout much of winter is characterized by low light levels, temperatures,

and precipitation, and can act as a reservoir for O3 precursors such as PAN and alkyl nitrates, 
AX3-137

Table AX3-10. Range of Annual (January-December) Hourly Ozone Concentrations

(ppb) at Background Sites Around the World (CMDL, 2004)

Location Elevation (m) Period of Record Range of Annual Means

Pt. Barrow, Alaska 11 1992-2001 23-29

Ny Alesund, Svalbard, Spitsbergena 475 1989-1993 28-33b

Mauna Loa, Hawaiic 3397 1992-2001 37-46d

a

University of Stockholm Meteorological Institute.

b

Annual medians

c

10:00 - 18:00 UTC.

d

High elevation site.

Source: Vingarzan (2004).

Table AX3-11. Range of Annual (January-December) Hourly Median and Maximum

Ozone Concentrations (ppb) at Background Stations in Protected Areas of the

United States (CASTNet, 2004)

Location

Elevation

(m)

Period of

Record

Range of Annual

Medians

Range of Annual

Maxima

Denali NP, Alaska 640 1998-2001 29-34 49-68

Glacier NP, Montana 976 1989-2001 19-27 57-77

Voyageurs NP, Minnesota 429 1997-2001 28-35 74-83

Theodore Roosevelt NP,

North Dakota

850 1983-2001 29-43 61-82

Yellowstone NP, Wyoming 2469 1996-2001 37-45a 68-79a

Rocky Mountain NP, Colorado 2743 1994-2001 40-47a 68-102a

Olympic NP, Washington 125 1998-2001 19-22 50-63

North Cascades NP, Washington 109 1996-2001 14-18 48-69

Mount Rainier NP, Washington 421 1995-2001 38371 54-98

Lassen NP, California 1756 1995-2001 38-43a 81-109a

Virgin Islands NP, 

U.S. Virgin Islands

80 1998-2001 19-24 50-64

a

High elevation site.

Source: Vingarzan (2004).
AX3-138

Table AX3-12. Range of Annual (January-December) Hourly Median and Maximum

Ozone Concentrations (ppb) at Canadian Background Stations (CAPMoNa, 2003)

Location

Elevation

(m)

Period of

Record

Range of Annual

Medians

Range of Annual

Maxima

Kejimkujik, Nova Scotiab 127 1989-2001 25-34 76-116

Montmorency, Quebec 640 1989-1996 28-32 73-99

Algoma, Ontarioa 411 1988-2001 27-33 76-108

Chalk River, Ontario 184 1988-1996 25-31 79-107

Egbert, Ontarioa 253 1989-2001 27-32 90-113

E.L.A., Ontario 369 1989-2001 28-33 64-87

Bratt’s Lake, Saskatchewan 588 1999-2001 26-29 63-68

Esther, Alberta 707 1995-2001 26-31 63-78

Saturna Island, British Columbia 178 1992-2001 23-27 65-82

a

Canadian Air and Precipitation Monitoring Network.

b

Stations affected by long-range transport of anthropogenic emissions.

Source: Vingarzan (2004).

which build up and can then photolyze when sun angles are high enough during late winter and

early spring. Long-range transport of total odd nitrogen species (NOy) (defined in AX2.2.2) and

VOCs to Arctic regions can occur from midlatitude-source regions. In addition, O3 can be

transported from tropical areas in the upper troposphere followed by its subsidence at mid and

high latitudes (Wang et al., 1998). 

Penkett (1983), and later Penkett and Brice (1986), first observed a spring peak in PAN at

high northern latitudes and hypothesized that winter emissions transported into the Arctic would

be mixed throughout a large region of the free troposphere and transformed into O3 as solar

radiation returned to the Arctic in the spring. Subsequent observations (Dickerson, 1985)

confirmed the presence of strata of high concentrations of reactive nitrogen compounds at high

latitudes in early spring. Bottenheim et al. (1990, 1993) observed a positive correlation

between O3 and NO2 in the Arctic spring. Jaffe et al. (1991) found NOy concentrations

approaching 1 ppb in Barrow, Alaska, in the spring and attributed them to long-range transport. 
AX3-139

Table AX3-13. Number of Hours $0.05 ppm for Selected Rural O3 Monitoring in the United 

by Month for the Period 1988 to 2001

Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Denali National Park, Alaska February 0 0 0 0 0 0 0 0 0 0 Denali National Park, Alaska March 0 0 0 0 0 0 0 0 52 0 122 Denali National Park, Alaska April 217 0 2 0 64 10 31 21 12 51 236 Denali National Park, Alaska May 26 1 0 24 10 17 1 54 97 35 79 Denali National Park, Alaska June 0 0 0 0 0 0 0 0 27 0 0 Yellowstone National Park,Wyoming

February 0 0 11 3 0 21 6 0 1 5 

Yellowstone National Park,Wyoming

March 194 2 4 95 26 285 14 7 98 150 

Yellowstone National Park,Wyoming

April 228 17 16 217 62 311 185 65 163 385 

Yellowstone National Park,Wyoming

May 225 2 10 196 47 180 193 212 216 289 

Yellowstone National Park,Wyoming

June 58 67 139 33 28 116 81 94 149 78 
AX3-140

Table AX3-13 (cont’d). Number of Hours $0.05 ppm for Selected Rural O3 Monitoring in the United 

for the Period 1988 to 2001

Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Glacier National Park,Montana

February 0 0 0 0 0 8 0 0 0 

Glacier National Park,Montana

March 49 9 24 10 23 40 35 9 6 

Glacier National Park,Montana

April 31 64 29 5 45 16 46 52 49 

Glacier National Park,Montana

May 20 81 67 41 66 51 51 4 122 

Glacier National Park,Montana

June 24 37 31 5 29 13 119 0 3 

Voyageurs National Park,Minnesota

February 3 0 0 0 0 43 22 0 0 23 0 

Voyageurs National Park,Minnesota

March 6 2 0 0 1 94 10 39 49 220 40 

Voyageurs National Park,Minnesota

April 48 0 31 22 27 56 65 30 64 128 254 

Voyageurs National Park,Minnesota

May 183 33 14 10 174 78 96 107 111 146 191 

Voyageurs National Park,Minnesota

June 92 2 0 55 50 66 190 37 221 25 
AX3-141

Table AX3-14. Number of Hours $0.06 ppm for Selected Rural O3 Monitoring Sites in the United S

for the Period of 1988 to 2001

Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Denali National Park,Alaska

February 0 0 0 0 0 0 0 0 0 0 

Denali National Park,Alaska

March 0 0 0 0 0 0 0 0 0 0 0 

Denali National Park,Alaska

April 0 0 0 0 0 0 0 0 0 0 0 

Denali National Park,Alaska

May 0 0 0 0 0 0 0 0 2 0 0 

Denali National Park,Alaska

June 0 0 0 0 0 0 0 0 0 0 0 

Yellowstone NationalPark, Wyoming

February 0 0 0 0 0 0 0 0 0 0 

Yellowstone NationalPark, Wyoming

March 37 0 0 0 0 0 0 0 1 0 

Yellowstone NationalPark, Wyoming

April 59 0 0 29 0 20 4 0 0 64 

Yellowstone NationalPark, Wyoming

May 20 0 0 61 3 42 24 38 26 54 

Yellowstone NationalPark, Wyoming

June 8 7 18 2 1 13 0 0 22 4 

Glacier National Park,Montana

February 0 0 0 0 0 0 0 0 0 

Glacier National Park,Montana

March 1 0 0 0 0 0 0 0 0 
AX3-142

Table AX3-14 (cont'd). Number of Hours $0.06 ppm for Selected Rural O3 Monitoring Sites in the Unit

for the Period of 1988 of 2001

Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Glacier National Park,Montana

April 0 0 1 0 0 0 0 0 2 

Glacier National Park,Montana

May 2 7 13 0 0 4 5 0 16 

Glacier National Park,Montana

June 0 3 1 0 1 0 16 0 0 

Voyageurs NationalPark, Minnesota

February 1 0 0 0 0 1 8 0 0 0 0 

Voyageurs NationalPark, Minnesota

March 0 0 0 0 0 34 0 5 2 15 0 

Voyageurs NationalPark, Minnesota

April 9 0 1 0 0 5 8 0 17 2 57 

Voyageurs NationalPark, Minnesota

May 77 6 0 0 40 9 40 2 27 46 53 

Voyageurs NationalPark, Minnesota

June 30 0 0 28 17 5 113 12 115 0 
AX3-143

Figure AX3-78. Maximum hourly average O3 concentrations at rural monitoring sites in

Canada and the United States in February from 1980 to 1998. 

Source: Lefohn et al. (2001).

Beine et al. (1997) and Honrath et al. (1996) measured O3, PAN, and NOx in Alaska and

Svalbard, Norway and concluded that PAN decomposition can lead to photochemical O3

production. At Poker Flat, Alaska, O3 production was directly observable. Herring et al. (1997)

tracked springtime O3 maxima in Denali National Park, Alaska, an area one might presume to be

pristine. They measured NOx and hydrocarbons and concluded that, in the spring, O3 was

produced predominantly by photochemistry at a calculated rate of 1 to 4 ppb/day, implying that

the O3 observed could be produced on timescales ranging from about a week to a month. 

Solberg et al. (1997) tracked the major components of NOy in remote Spitsbergen, Norway for

the first half of the year 1994. They observed high concentrations of PAN (800 ppt) peaking

simultaneously with O3 (45 to 50 ppb) and attributed this to the long-range transport of pollution
AX3-144

and to photochemical smog chemistry. These investigators concluded, in general, that large

regions of the Arctic store high concentrations of O3 precursors in the winter and substantial

quantities of O3 are produced by photochemical reactions in the spring. Although reactions with 

high-activation-energy barriers may be ineffective, reactions with low- or no activation-energy

barriers (such as radical-radical reactions) or negative temperature dependencies will still

proceed. Indeed, active photochemistry is observed in the coldest regions of the stratosphere and

mesosphere. While it is expected that photochemical production rates of O3 will increase with

decreasing solar zenith angle as one moves southward from the locations noted above, it should

not be assumed that photochemical production of O3 does not occur during late winter and spring

at mid- and high-latitudes. 

Perhaps the most thorough set of studies investigating causes of springtime maxima in

surface O3 has been performed as part of the AEROCE and NARE studies (cf., Sections

AX2.3.4a,b) and TOPSE (Browell et al., 2003). These first two studies found that elevated or

surface O3 > 40 ppb at Bermuda, at least, arises from two distinct sources: the polluted North

American continent and the stratosphere. It was also found that these sources mix in the upper

troposphere before descending as shown in Figure AX3-79. (In general, air descending behind

cold fronts contains contributions from intercontinental transport and the stratosphere.) These

studies also concluded that it is impossible to determine sources of O3 without ancillary data that

could be used either as tracers of sources or to calculate photochemical production and loss rates.

In addition, subsiding back trajectories do not necessarily imply a free-tropospheric or

stratospheric origin for O3 observed at the surface, since the subsiding conditions are also

associated with strong inversions and clear skies that promote O3 production within the boundary

layer. Thus, it would be highly problematic to use observations alone as estimates of PRB O3

concentrations, especially for sites at or near sea level. 

The IPCC Third Assessment Report (TAR) (2001) gave a large range of values for terms in

the tropospheric O3 budget. Estimates of O3 STE of O3 ranged over a factor of three from 391 to

1440 Tg/year in the twelve models included in the intercomparison; many of the models

included in that assessment overestimated O3 STE. However, the overestimates likely reflected

errors in assimilated winds in the upper troposphere (Douglass et al., 2003; Schoeberl et al.,

2003; Tan et al., 2004; van Noije et al., 2004). The budgets of tropospheric O3 calculated since 

the IPCC TAR are shown in Table AX3-15. Simulation of stratospheric intrusions is
AX3-145

Figure AX3-79. Schematic diagram of a meteorological mechanism involved in high

concentrations of O3 found in spring in the lower troposphere off

the American East Coast. Subsidence behind the first cold front meets

convection ahead of a second cold front such that polluted air and O3

from the upper troposphere/ lower stratosphere are transported in close

proximity (or mixed) and advected over the North Atlantic Ocean. The

vertical scale is about 10 km; the horizontal scale about 1500 km. (Note

that not all cold fronts are associated with squall lines and that mixing

occurs even in their absence.)

Source: Prados (2000).

notoriously difficult in global models, and O3 STE is generally parameterized in these models. 

However, as can be seen from inspection of Table AX3-15, improvements in assimilation

techniques have improved and narrowed estimates of STE. A model intercomparison looking at

actual STE events found significant variations in model results that depended significantly on the

type and horizontal resolution of the model (Meloen et al., 2003; Cristofanelli et al., 2003). 

In particular, it was found that the Lagrangian perspective (as opposed to the Eulerian

perspective used in most global scale CTMs) was necessary to characterize the depths and

residence times of individual events (Sprenger and Wernli, 2003; James et al., 2003a,b). A few

studies of the magnitude of the O3 STE have been made based on chemical observations in the

lower stratosphere or combined chemistry and dynamics (e.g., 450 Tg/year net global [Murphy

and Fahey, 1994]; 510 Tg/year net global extratropics only [Gettelman et al., 1997]; and

550 ± 140 Tg/year [Olsen et al., 2002]). 
Table AX3-15. Global Budgets of Tropospheric Ozone (Tg year!1) for the Present-day Atmo

Reference Model

StratosphereTroposphere

Exchange

(STE)

Chemical

Production 2

Chemical

Loss 2

Dry

Deposition

Burd

(Tg

TAR 4 11 models 770 ± 400 3420 ± 770 3470 ± 520 770 ± 180 300 ± 

Lelieveld andDentener (2000)

570 3310 3170 710 350 

Bey et al. (2001a) 5 GEOS-CHEM 470 4900 4300 1070 320 Horowitz et al.(2003)

MOZART-2 340 5260 4750 860 360 

Von Kuhlmann et al. (2003)

MATCH-MPIC 540 4560 4290 820 290 

Shindell et al. (2003) GISS 417 NR 6 NR 1470 349 

Park et al. (2004) UMD-CTM 480 NR NR 1290 340 Rotman et al. (2004) IMPACT 660 NR NR 830 NR Wong et al. (2004) SUNYA/UiO GCCM 600 NR NR 1100 376 

1 From global CTM simulations describing the atmosphere of the last decade of the 20th century.2 Chemical production and loss rates are calculated for the odd oxygen family, usually defined as Ox = O3 + O + NO2 + 2NO3 + 3N2O5 

 peroxyacylnitrates (and sometimes HNO3), to avoid accounting for rapid cycling of O3 with short-lived species that have little implic

 Chemical production is mainly contributed by reactions of NO with peroxy radicals, while chemical loss is mainly contributed by the 

 and by the reactions of O3 with HO2

C

, COH, and alkenes. Several models in this table do not report production and loss separately (“N

 reporting instead net production. However, net production is not a useful quantity for budget purposes, because (1) it represents a sm

 large production and loss, (2) it represents the balance between STE and dry deposition, both of which are usually parameterized as a 

 condition. 

3 Calculated as the ratio of the burden to the sum of chemical and deposition losses4 Means and standard deviations from an ensemble of 11 CTM budgets reported in the IPCC TAR. The mean budget does not balance 

 only 9 CTMs reported chemical production and loss statistics. 

5 The Martin et al. (2003) more recent version of GEOS-CHEM gives identical rates and burdens.6 Not reported.

AX3-146
AX3-147

Even if the magnitude of cross-tropopause O3 fluxes in global CTMs are calculated

correctly in an annual mean sense, it should be noted that stratospheric intrusions occur

episodically following the passage of cold fronts at midlatitudes. Of major concern is the ability

of global-scale CTMs to simulate individual intrusions and the effects on surface O3

concentrations that may result during these events. As noted in Section AX2.3.1, these

intrusions occur in “ribbons” ~ 200 to 1000 km long, 100 to 300 km wide, and 1 to 4 km thick. 

An example of a stratospheric intrusion occurred in Boulder, CO (EPA AQS Site 080130011;

formally AIRS) on May 6, 1999 (Lefohn et al., 2001). At 1700 UTC (1000 hours LST)

an hourly average concentration of 0.060 ppm was recorded and by 2100 UTC (1400 hours

LST), the maximum hourly average O3 concentration of 0.076 ppm was measured. At 0200

UTC on May 7, 1999 (1900 hours LST on May 6), the hourly average concentration declined to

0.059 ppm. Figure AX3-80 shows the O3 vertical profile that was recorded at Boulder, CO on

May 6, 1999, at 1802 UTC (1102 hours LST). The ragged vertical profile of O3 at > 4 km

reflects stratospheric air that has spiraled downward around an upper-level low and mixed with

tropospheric air along the way. Thus, stratospheric air which is normally extremely cold and dry

and rich in O3, loses its characteristics as it mixes downward. This process was described in

Section AX2.3.1 and illustrated in Figures AX2-7a, b, and c. 

The dimensions given above imply that individual intrusions are not resolved properly in

the current generation of global-scale CTMs (Figure AX3-80). However, as noted in Section

AX2.3.1, penetration of stratospheric air directly to the planetary boundary layer rarely occurs in

the continental United States. Rather, intrusions are more likely to affect the middle and upper

troposphere, providing a reservoir for O3 that can exchange with the planetary boundary layer. 

In this regard, it is important that CTMs be able to spatially and temporally resolve the exchange

between the planetary boundary layer and the lower free troposphere properly. 

AX3.9.2 Capability of Global Models to Simulate Tropospheric Ozone

The current generation of global CTMs includes detailed representation of tropospheric

O3-NOx-VOC chemistry. Meteorological information is generally provided by global data

assimilation centers. The horizontal resolution is typically a few hundred km, the vertical

resolution is 0.1 to 1 km, and the effective temporal resolution is a few hours. These models can

simulate most of the observed variability in O3 and related species, although the coarse 
AX3-148

Figure AX3-80. Ozone vertical profile at Boulder, Colorado on May 6, 1999 at 1802 UTC

(1102 LST).

Source: Lefohn et al. (2001).

resolution precludes simulation of fine-scale structures or localized extreme events. On the

synoptic scale, at least, all evidence indicates that global models are adequate tools to investigate

the factors controlling tropospheric O3. Stratosphere-troposphere exchange of O3 in global

models is generally parameterized. The parameterizations are typically constrained to match the

global mean O3 cross-tropopause flux, which is in turn constrained by a number of observational

proxies (550 ± 140 Tg O3 year!1

 [Olsen et al., 2002]). The model simulations are routinely

compared to ozonesonde observations in the middle and upper troposphere to test the simulation

of stratospheric influence on tropospheric O3 (Logan, 1999). Such evaluations show that the

parameterized cross-tropopause O3 flux in global models results in a good simulation of

tropospheric O3, at least in a mean sense; and that the current generation of models can 
AX3-149

reproduce the tropospheric ozonesonde climatology to within 5 to 10 ppbv, even at mid- and

high-northern latitudes in winter, with the correct seasonal cycle. 

Fiore et al. (2003a) used the GEOS-CHEM global tropospheric chemistry model to

quantify PRB O3 concentrations across the United States. A net global O3 flux of 490 Tg O3

year!1 from the stratosphere to the troposphere is imposed in the GEOS-CHEM model,

consistent with the range constrained by observations (Olsen et al., 2002). Previous applications

of the model have demonstrated that it simulates the tropospheric ozonesonde climatology

(Logan, 1999) generally to within 5 to 10 ppbv, including at mid- and high-latitudes (Bey et al.,

2001a) over Bermuda in spring (Li et al., 2002) and at sites along the Asian Pacific rim (Liu

et al., 2002). The phase of the seasonal cycle is reproduced to within 1 to 2 months (Bey et al.,

2001a; Li et al., 2002; Liu et al., 2002). An analysis of the 210Pb-7

Be-O3 relationships observed

in three aircraft missions over the western Pacific indicates that the model does not

underestimate the stratospheric source of O3 (Liu et al., 2004). These studies and others (Li

et al., 2001; Bey et al., 2001b; Fusco and Logan, 2003) demonstrate that the model provides an

adequate simulation of O3 in the free troposphere at northern midlatitudes, including the mean

influence from the stratosphere. However, it cannot capture the structure and enhancements

associated with stratospheric intrusions, leading to mean O3 under-prediction in regions of

preferred stratospheric downwelling. 

Fiore et al. (2002a, 2003b) presented a detailed evaluation of the model simulation for O3

and related species in surface air over the United States for the summer of 1995. They showed

that the model reproduces important features of observations including the high tail of O3

frequency distributions at sites in the eastern United States (although sub-grid-scale local peaks

are underestimated), the O3 to (NOy - NOx) relationships, and that the highest O3 values exhibit

the largest response to decreases in U.S. fossil fuel emissions from 1980 to 1995 (Lefohn et al.,

1998). Empirical orthogonal functions (EOFs) for the observed regional variability of O3 over

the eastern United States are also well reproduced, indicating that GEOS-CHEM captures the

synoptic-scale transport processes modulating surface O3 concentrations (Fiore et al., 2003b). 

One model shortcoming relevant for the discussion below is that excessive convective mixing

over the Gulf of Mexico and the Caribbean leads to an overestimate of O3 concentrations in

southerly flow over the southeastern United States. Comparison of GEOS-CHEM with the

Multiscale Air Quality Simulation Platform (MAQSIP) regional air quality modeling system
AX3-150

(Odman and Ingram, 1996) at 36 km2

 horizontal resolution showed that the models exhibit

similar skill at capturing the observed variance in O3 concentrations with comparable model

biases (Fiore et al., 2003b). 

Simulations to Quantify Background Ozone Over the United States

The sources contributing to the O3 background over the United States were quantified by

Fiore et al. (2003a) with three simulations summarized in Table AX3-16: (1) a standard

simulation, (2) a background simulation in which North American anthropogenic NOx,

NMVOC, and CO emissions are set to zero, and (3) a natural O3 simulation in which global

anthropogenic NOx, NMVOC and CO emissions are set to zero and the CH4 concentration is set

to its 700 ppbv pre-industrial value. Anthropogenic emissions of NOx, nonmethane volatile

organic compounds (NMVOCs), and CO include contributions from fuel use, industry, and

fertilizer application. The difference between the standard and background simulations

represents regional pollution, i.e., the O3 enhancement from North American anthropogenic

emissions. The difference between the background and natural simulations represents

hemispheric pollution, i.e., the O3 enhancement from anthropogenic emissions outside North

America. Methane and NOx contribute most to hemispheric pollution (Fiore et al., 2002b). 

A tagged O3 tracer simulation (Fiore et al., 2002a) was used to isolate the stratospheric

contribution to the background and yielded results that were quantitatively consistent with those

from a simulation in which O3 transport from the stratosphere to the troposphere was suppressed

(Fusco and Logan, 2003). All simulations were initialized in June 2000; results are reported for

March through October 2001. 

The standard and background simulations were conducted at 2° × 2.5° horizontal

resolution, but the natural simulation was conducted at 4° × 5° resolution to save on

computational time. There was no significant bias between 4° × 5° and 2° × 2.5° simulations

(Fiore et al., 2002a), particularly for a natural O3 simulation where surface concentrations were

controlled by large-scale processes. 

AX3.9.3 Mean Background Concentrations: Spatial and Seasonal Variation

The analysis of Fiore et al. (2003a) focused on the 2001 observations from the Clean Air

Status and Trends Network (CASTNet) of rural and remote U.S. sites (Lavery et al., 2002) 
AX3-151

Table AX3-16. Description of Simulations Used for Source Attribution

(Fiore et al., 2003a)

Simulation Description Horizontal Resolution

Standard Present-day emissions as described in the text 2/ × 2.5/

Background North American anthropogenic NOx, NMVOC, and CO emissions

set to zero

2/ × 2.5/

Natural Global anthropogenic NOx, NMVOC, and CO emissions set to zero

and CH4 concentration set to its 700 ppbv preindustrial value

4/ × 5/

Stratospheric Tagged O3 tracer originating from the stratosphere in standard

simulation

2/ × 2.5/

(Figure AX3-81). Figure AX3-82 shows the mean seasonal cycle in afternoon (1300 to

1700 hours LT) O3 concentrations averaged over the CASTNet stations in each U.S. quadrant. 

Measured O3 concentrations (asterisks) are highest in April to May, except in the Northeast

where they peak in June. Model results (triangles) are within 3 ppbv and 5 ppbv of the

observations for all months in the Northwest and Southwest, respectively. Model results for the

Northeast are too high by 5 to 8 ppbv when sampled at the CASTNet sites; the model is lower

when the ensemble of grid squares in the region are sampled (squares). The model is 8 to

12 ppbv too high over the Southeast in summer for reasons discussed in Section AX3.9.2. 

Results from the background simulation (no anthropogenic emissions in North America; see

Table AX3-16) are shown as diamonds in Figure AX3-82. Mean afternoon background O3

ranges from 20 ppbv in the Northeast in summer to 35 ppbv in the Northwest in spring. It is

higher in the West than in the East because of higher elevation, deeper mixed layers, and

longer O3 lifetimes due to the arid climate (Fiore et al., 2002a). It is also higher in spring than in

summer, in part because of the seasonal maximum of stratospheric influence (Figure AX3-82)

and in part because of the longer lifetime of O3 (Wang et al., 1998). 

Results from the natural O3 simulation (no anthropogenic emissions anywhere;

Table AX3-16) are shown as crosses in Figure AX3-82. Natural O3 concentrations are also

highest in the West and in spring when the influence of stratospheric O3 on the troposphere

peaks (e.g., Holton et al., 1995). Monthly mean natural O3 concentration ranges are 18 to 23,

18 to 27, 13 to 20, and 15 to 21 ppbv in the Northwest, Southwest, Northeast, and Southeast,
AX3-152

respectively. The stratospheric contribution (X’s) ranges from 7 ppbv in spring to 2 ppbv in

summer. 

The difference between the background and natural simulations in Figure AX3-82

represents the increases in monthly mean hemispheric pollution. This increase ranges from 5 to

12 ppbv depending on region and season. It peaks in spring due to a longer O3 lifetime (Wang

et al., 1998) and to e efficient ventilation of pollution from the Asian continent (Liu et al., 2003). 

In contrast to hemispheric pollution, the regional pollution influence (O3 produced from North

American anthropogenic emissions, shown as the difference between the squares and diamonds)

peaks in summer and is highest in the East. For the data in Figure AX3-82, it ranges from

8 ppbv in the northern quadrants in March to over 30 ppbv in the eastern quadrants in summer. 

Monthly mean observed O3 concentrations are influenced by both regional and hemispheric

pollution in all U.S. regions from March through October. 

Figure AX3-81. CASTNet stations in the continental United States for 2001. Sites

discussed in Section AX3.9.4 are labeled: VOY = Voyageurs NP, MI;

COW = Coweeta, NC; YEL = Yellowstone NP, WY; CAD = Caddo

Valley, AR; CVL = Coffeeville, MS; GAS = Georgia Station, GA;

GB = Great Basin, NV; GRC = Grand Canyon, AZ; CAN = Canyonlands,

UT; MEV = Mesa Verde, CO. Crosses denote sites > .5 km altitude. 

Source: Fiore et al. (2003a).
AX3-153

AX3.9.4 Frequency of High-Ozone Occurrences at Remote Sites

Lefohn et al. (2001) pointed out the frequent occurrence of high-O3 events (>50 and

60 ppbv) at remote northern U.S. sites in spring. Fiore et al. (2003a) replicated the analysis of

Lefohn et al. (2001) at the four CASTNet sites that they examined: Denali National Park

(Alaska), Voyageurs National Park (Minnesota), Glacier National Park (Montana), and

Yellowstone National Park (Wyoming). The number of times that the hourly O3 observations at 

Figure AX3-82. Monthly mean afternoon (1300 to 1700 hours LT) concentrations (ppbv)

in surface air averaged over the CASTNet stations (Figure AX3-81) in

each U.S. quadrant for March to October 2001. Observations (asterisks)

are compared with model values from the standard simulation sampled

at the CASTNet sites (triangles) and sampled for the entire quadrant

(squares). The vertical lines show the standard deviation in the observed

and simulated values. Monthly mean model results for the background

(diamonds), natural (crosses), and stratospheric (X’s) contributions

(Table AX3-16) to surface O3 are shown. The U.S. quadrants are

centered at 98.75B

 W and 37B N.

Source: Fiore et al. (2003a).
AX3-154

the sites are >50 and 60 ppbv for each month from March to October 2001 were then calculated

(see results in Table AX3-17) and compared with the same statistics for March to June

1988 to 1998 from Lefohn et al. (2001), to place the 2001 statistics in the context of other years. 

More incidences of O3 above both thresholds occur at Denali National Park and Yellowstone

National Park in 2001 than in nearly all of the years analyzed by Lefohn et al. (2001). The

statistics at Glacier National Park, Montana indicate that 2001 had fewer than average incidences

of high-O3 events. At Voyageurs National Park in Minnesota, March and April 2001 had

lower-than-average frequencies of high-O3 events, but May and June were more typical. 

Overall, 2001 was considered to be a suitable year for analysis of high-O3 events. Ozone

concentrations >70 and 80 ppbv occurred most often in May through August in 2001 and were

found to be associated with regional pollution by Fiore et al. (2003a). 

Fiore et al. (2003a) focused their analysis on mean O3 concentrations during the afternoon

hours (1300 to 1700 LT), as the comparison of model results with surface observations is most

appropriate in the afternoon when the observations are representative of a relatively deep mixed

layer (Fiore et al., 2002a). In addition, the GEOS-CHEM model does not provide independent

information on an hour-to-hour basis, because it is driven by meteorological fields that are

updated every 6-h and then interpolated. Fiore et al. (2003a) tested whether an analysis

restricted to these mean 1300 to 1700 LT surface concentrations captures the same frequency

of O3 >50 and 60 ppbv that emerges from an analysis of the individual hourly concentrations

over 24 hours. Results are reproduced here in Table AX3-17, which shows that the percentage

of individual afternoon (1300 to 1700 LT) hours when O3 >50 and 60 ppbv at the CASTNet sites

is always greater than the percentage of all hourly occurrences above these thresholds, indicating

that elevated O3 concentrations preferentially occur in the afternoon. Furthermore,

Table AX3-17 shows that the frequency of observation of high-O3 events is not diminished when

4-h average (1300 to 1700 LT) concentrations are considered, reflecting persistence in the

duration of these events. Model frequencies of high-O3 events from 1300 to 1700 LT at the

CASTNet sites are similar to observations in spring, as shown in Table AX3-17, and about 10% 

higher in the summer, largely because of the positive model bias in the Southeast discussed in

Section AX3.9.2. 
AX3-155

Table AX3-17. Number of Hours with Ozone Above 50 or 60 ppbv 

at U.S. CASTNet Sites in 2001

Site Mar Apr May Jun Jul Aug Sep Oct

Observations $ 50 ppbv

Denali NP, Alaska 

(64/ N, 149/ W, 0.6 km) 24 302 98 6 0 0 0 0

Voyageurs NP, Minnesota

(48/ N, 93/ W, 0.4 km) 0 0 62 95 14 17 33 0

Glacier NP, Montana

(49/ N, 114/ W, 1.0 km) 4 0 23 0 6 12 0 0

Yellowstone NP, Wyoming

(45/ N, 110/ W, 2.5 km) 307 461 350 172 140 261 173 77

All CASTNet sites (71) 5468

(11%)

15814

(32%)

17704

(36%)

16150

(33%)

14489

(29%)

15989

(32%)

9874

(20%)

5642

(11%)

All sites, 1300-1700 LT

only (hourly data)

1817

(21%)

4684

(56%)

5174

(61%)

4624

(56%)

4613

(54%)

5075

(60%)

3343

(40%)

1945

(23%)

All sites, 1300-1700 LT

mean (4-hour average)

435

(20%)

1153

(55%)

1295

(61%)

1147

(55%)

1161

(54%)

1283

(60%)

841

(40%)

478

(22%)

All sites, model 

1300-1700 LT mean

254

(12%)

1249

(59%)

1527

(69%)

1505

(71%)

1475

(67%)

1500

(68%)

1080

(51%)

591

(27%)

Observations $ 60 ppbv

Denali NP 0 0 9 2 0 0 0 0

Voyageurs NP 0 0 6 32 0 0 15 0

Glacier NP 0 0 0 0 0 0 0 0

Yellowstone NP 4 77 139 18 6 26 1 2

All sites 519

(1%)

4729

(10%)

8181

(16%)

8199

(17%)

5705

(11%)

7407

(15%)

3492

(7%)

2073

(4%)

All sites, 1300-1700 LT

only

235

(3%)

1798

(22%)

2808

(33%)

2721

(33%)

2235

(26%)

2758

(33%)

1416

(17%)

878

(10%)

All sites, 

1300-1700 LT mean 

56

(3%)

428

(20%)

697

(33%)

671

(32%)

550

(26%)

677

(32%)

358

(17%)

214

(10%)

All sites, model 

1300-1700 LT mean

13

(1%)

377

(18%)

834

(38%)

964

(45%)

910

(41%)

834

(38%)

502

(24%)

204

(9%)

Data from 71 U.S. CASTNet sites are included in this analysis: those in Figure AX3-105 plus Denali NP. 

Percentages of total occurrences are shown in parentheses.

NP = National Park; LT = Local Time. 

Reproduced from Fiore et al. (2003a).
AX3-156

NATURAL VERSUS ANTHROPOGENIC CONTRIBUTIONS TO

HIGH-OZONE OCCURRENCES

Figure AX3-83, reproduced from Fiore et al. (2003a), shows probability distributions of

daily mean afternoon (1300 to 1700 LT) O3 concentrations in surface air at the CASTNet sites

for March through October 2001. Model distributions for background, natural, and stratospheric

O3 (Table AX3-16) are also shown. The background (long-dashed line) ranges from 10 to

50 ppbv with most values in the 20 to 35 ppbv range. The full 10 to 50 ppbv range of

background predicted here encompasses the previous 25 to 45 ppbv estimates shown in

Table 3-8. However, background estimates from observations tend to be at the higher end of the

range (25 to 45 ppbv), while these results, as well as those from prior modeling studies

(Table 3-8) indicate that background O3 concentrations in surface air are usually below 40 ppbv. 

The background O3 concentrations derived from observations may be overestimated if

observations at remote and rural sites contain some influence from regional pollution (as shown

below to occur in the model), or if the O3 versus NOy - NOx correlation is affected by different

relative removal rates of O3 and NOy (Trainer et al., 1993). Natural O3 concentrations

(short-dashed line) are generally in the 10 to 25 ppbv range and never exceed 40 ppbv. The

range of the hemispheric pollution enhancement (the difference between the background and

natural O3 concentrations) is typically 4 to 12 ppbv and only rarely exceeds 20 ppbv (< 1% total

incidences). The stratospheric contribution (dotted line) is always less than 20 ppbv and usually

below 10 ppbv. Time series for specific sites are presented below. 

CASE STUDIES: INFLUENCE OF THE BACKGROUND ON ELEVATED OZONE

EVENTS IN SPRING

High-O3 events were previously attributed to natural processes by Lefohn et al. (2001) at: 

Voyageurs National Park, Minnesota in June and Yellowstone National Park, Wyoming in

March through May. Fiore et al. (2003a) used observations from CASTNet stations in

conjunction with GEOS-CHEM model simulations to deconstruct the observed concentrations

into anthropogenic and natural contributions. 

At Voyageurs National Park in 2001, O3 concentrations >60 ppbv occurred frequently in

June but rarely later in summer (Table AX3-17). A similar pattern was observed in 1995 and

1997 and was used to argue that photochemical activity was probably not responsible for these

events (Lefohn et al. 2001). Figure AX3-84 from Fiore et al. (2003a) shows that GEOS-CHEM 
AX3-157

Figure AX3-83. Probability distributions of daily mean afternoon (1300 to 1700 LT) O3

concentrations in surface air for March through October 2001 at U.S.

CASTNet sites (Figure AX3-83): observations (thick solid line) are

compared with model results (thin solid line). Additional probability

distributions are shown for the simulated background (long-dashed line),

natural (short-dashed line), and stratospheric (dotted line) contributions

to surface O3 (Table AX3-23).

Source: Fiore et al. (2003a).

Figure AX3-84. Daily mean afternoon (13 to 17 LT) O3 concentrations in surface air at

Voyageurs National Park (NP), Minnesota in mid-May through June of

2001. Observations (asterisks) are compared with model values from the

standard simulation (triangles). The simulated contributions from

background (diamonds), natural (crosses), and stratospheric (X’s) O3

are also shown.

Source: Fiore et al. (2003a).
AX3-158

Figure AX3-84 shows that regional pollution drives most of the simulated day-to-day variability

and explains all events above 50 captures much of the day-to-day variability in observed

concentrations from mid-May through June, including the occurrence and magnitude of high-O3

events. The simulated background contribution (diamonds) ranges from 15 to 36 ppbv with a 25

ppbv mean. The natural O3 level (crosses) is 15 ppbv on average and varies from 9 to 23 ppbv. 

The stratospheric contribution (X’s) is always < 7 ppbv. The dominant contribution to the

high-O3 events on June 26 and 29 is from regional pollution (44 and 50 ppbv on June 26 and 29,

respectively, calculated as the difference between the triangles and diamonds in Figure AX3-84). 

The background contribution (diamonds) is < 30 ppbv on both days, and is composed of a

20 ppbv natural contribution (which includes 2 ppbv of stratospheric origin) and a 5 ppbv

enhancement from hemispheric pollution (the difference between the diamonds and crosses). 

Beyond these two high-O3 events, ppbv. In 2001, monthly mean observed and simulated O3

concentrations are lower in July (37 and 42 ppbv, respectively) and August (35 and 36 ppbv)

than in June (44 and 45 ppbv). Fiore et al. (2003a) hypothesized that the lower mean O3 and the

lack of O3 >60 ppbv in July and August reflects a stronger Bermuda high-pressure system

sweeping pollution from southern regions eastward before it could reach Voyageurs National

Park. 

Frequently observed concentrations of O3 between 60 to 80 ppbv at Yellowstone NP in

spring (Figures AX3-76a,b) have been attributed by Lefohn et al. (2001) to natural sources,

because they occur before local park traffic starts and back-trajectories do not suggest influence

from long-range transport of anthropogenic sources. More hours with O3 >60 ppbv occur in

April and May of 2001 (Table AX3-17) than in the years analyzed by Lefohn et al. (2001). Fiore

et al. (2003a) used GEOS-CHEM to interpret these events; results are shown in Figure AX3-85. 

The mean background, natural, and stratospheric O3 contributions in March to May are higher

at Yellowstone (38, 22, and 8 ppbv, respectively) as compared to 27, 18, and 5 ppbv at the two

eastern sites previously discussed. The larger stratospheric contribution at Yellowstone reflects

the high elevation of the site (2.5 km). Fiore et al. (2003a) argued that the background at

Yellowstone National Park should be considered an upper limit for U.S. PRB O3 concentrations,

because of its high elevation. While Yellowstone receives a higher background concentration

than the eastern sites, the model shows that regional pollution from North American

anthropogenic emissions (difference between the triangles and diamonds) contributes an 
AX3-159

additional 10 to 20 ppbv to the highest observed concentrations in April and May. One should

not assume that regional photochemistry is inactive in spring. 

Higher-altitude western sites are more frequent recipients of subsidence events that

transport high concentrations of O3 from the free troposphere to the surface. Cooper and Moody

(2000) cautioned that observations from elevated sites are not generally representative of

lower-altitude sites. At Yellowstone, the background O3 rarely exceeds 40 ppbv, but it is even

lower in the East. This point is illustrated in Figure AX3-86, from Fiore et al. (2003a), with time

series at representative western and southeastern CASTNet sites for the month of March, when

the relative contribution of the background should be high. At the western sites, the background

is often near 40 ppbv but total surface O3 concentrations are rarely above 60 ppbv. While

variations in the background play a role in governing the observed total O3 variability at these

sites, regional pollution also contributes. Background concentrations are lower (often <30 ppbv)

in the southeastern states where regional photochemical production drives much of the observed

variability. Cooper and Moody (2000) have previously shown that the high O3 concentrations at

an elevated, regionally representative site in the eastern United States in spring coincide with 

Figure AX3-85. Same as Figure AX3-84 but for Yellowstone National Park, Wyoming in

March to May 2001. Observations (asterisks) are compared with model

values from the standard simulation (triangles). The simulated

contributions from background (diamonds), natural (crosses), and

stratospheric (X’s) O3 are also shown.

Source: Fiore et al. (2003a).
AX3-160

Figure AX3-86. Same as Figure AX3-84 but for March of 2001 at selected western

(left column) and southeastern (right column) sites. Observations

(asterisks) are compared with model values from the standard simulation

(triangles). The simulated contributions from background (diamonds),

natural (crosses), and stratospheric (X’s) O3 are also shown.

Source: Fiore et al. (2003a).
AX3-161

high temperatures and anticyclonic circulation, conditions conducive to photochemical O3

production. Peak O3 concentrations in this region, mainly at lower elevations, are associated

with lower background concentrations because chemical and depositional loss during stagnant

meteorological conditions suppress mixing between the boundary layer and the free troposphere

(Fiore et al., 2002a). Surface O3 concentrations >80 ppbv could conceivably occur when

stratospheric intrusions reach the surface. However, based on information given in

Section AX2.3.2, these events are rare. 

AX3.10 OZONE EXPOSURE IN VARIOUS MICROENVIRONMENTS

AX3.10.1 Introduction

There are many definitions of exposure. Human exposure to O3 and related photochemical

oxidants are based on the measured O3 concentrations in the individual’s breathing zone as the

individual moves through time and space. Epidemiological studies generally use the ambient

concentrations as surrogates for exposure. Therefore, human exposure data and models provide

the best link between ambient concentrations (from measurements at monitoring sites or

estimated with atmospheric transport models), lung deposition and clearance, and estimates of

air concentration-exposure-dose relationships. 

This section discusses the current information on the available human exposure data and

exposure model development. This includes information on (a) the relationships between O3

measured at ambient monitoring sites and personal exposures and (b) factors that affect these

relationships. The information presented in this section is intended to provide critical links

between ambient monitoring data and O3 dosimetry as well as between the toxicological and

epidemiologic studies presented in Annexes AX4, AX5, AX6, and AX7 of this document. 

AX3.10.2 Summary of the Information Presented in the Exposure

Discussion in the 1996 Ozone Criteria Document

The 1996 O3 AQCD (U.S. Environmental Protection Agency, 1996a), based on then

currently available information, indicated that less emphasis should be placed on O3

concentrations measured at ambient monitoring stations. Fixed monitoring stations are generally

used for monitoring associated with air quality standards and do not provide a realistic
AX3-162

representation of individual exposures. Indoor/outdoor O3 ratios reported in the literature were

summarized for residences, hospitals, offices, art galleries, and museums. The differences in

residential I/O were found to be a function of ventilation conditions. The I/O ratios were less

than unity. In most cases, indoor and in-transit concentrations of O3 were significantly different

from ambient O3 concentrations. Ambient O3 varied from O3 concentrations measured at fixedsite monitors. Very limited personal exposure measurements were available at the time the

1996 O3 AQCD was published, so estimates of O3 exposure or evaluated models were not

provided. The two available personal exposure studies indicated that only 40% of the variability

in personal exposures was explained by the exposure models using time-weighted indoor and

outdoor concentrations. The discussion addressing O3 exposure modeling primarily addressed

work reported by McCurdy (1994) on population-based models (PBMs). Literature published

since publication of the 1996 O3 AQCD has also focused on PBMs. A discussion of individualbased models (IBMs) will be included in the description of exposure modeling in this document

to improve our mechanistic understanding of O3 source-to-exposure events and to evaluate their

usefulness in providing population-based estimates.

AX3.10.3 Concepts of Human Exposure

Human exposure to O3 and related photochemical oxidants occurs when individuals come

in contact with the pollutant through “(a) the visible exterior of the person (skin and openings

into the body such as mouth and nostrils) or (b) the so-called exchange boundaries where

absorption takes place (skin, mouth, nostrils, lung, gastrointestinal tract)” (Federal Register,

1986). Consequently, exposure to a chemical, in this case O3, is the contact of that chemical

with the exchange boundary (U.S. Environmental Protection Agency, 1992). Therefore,

inhalation exposure to O3 is based on measurements of the O3 concentration near the individual’s

breathing zone that is not affected by exhaled air.

AX3.10.4 Quantification of Exposure

Quantification of inhalation exposure to any air pollutant starts with the concept of the

variation in the concentration of the air pollutant in the breathing zone, unperturbed by exhaled

breath, as measured by a personal exposure monitor as a person moves through time and space.

Since the concentrations of O3 and related photochemical oxidants vary with time and location
AX3-163

and since people move among locations and activities, the exposure and dose received changes

during the day. Furthermore, the amount of pollutant delivered to the lung is dependent upon the

person’s minute ventilation rate. Thus, the level of exertion is an important consideration in

determining the potential exposure and dose. Inhalation exposure has been defined as the

integral of the concentration as a function of time over the time period of interest for each

individual (Ott, 1982, 1985; Lioy, 1990):

(AX3-2)

where E is inhalation exposure, c(t) is the breathing zone concentration as a function of time and

t1 and t2 the starting and ending time of the exposure, respectively. 

AX3.10.5 Methods to Estimate Personal Exposure

There are two approaches for measuring personal exposure; direct and indirect methods

(Ott, 1982, 1985; Navidi et al., 1999). Direct approaches measure the contact of the person with

the chemical concentration in the exposure media over an identified period of time. For the

direct measurement method, a personal exposure monitor (PEM) is worn near the breathing zone

for a specified time to either continually collect for subsequent analysis or directly measure the

concentrations of the pollutant and the exposure levels. The indirect approach models

concentrations of a pollutant in specific microenvironments. Both methods are subject to

measurement error.

AX3.10.5.1 Direct Measurement Method

The passive monitors commonly used in the direct method provides integrated personal

exposure information. The monitor’s sensitivity to wind velocity, badge placement, and

interference with other copollutants may result in measurement error.

Modified passive samplers have been developed for use in determining O3 exposure. The

difficulty in developing a passive O3 monitor is in identifying a chemical or trapping reagent that

can react with O3. Zhou and Smith (1997) evaluated the effectiveness of sodium nitrite,

3-methyl-2-benzothiazolinone acetone azine (MBTH), p-acetamidophenol (p-ATP), and indigo
AX3-164

carmine as O3-trapping reagents. Only sodium nitrite and MBTH gave sensitive, linear

responses at environmentally relevant concentrations. However, MBTH overestimated the O3

concentrations significantly, suggesting an interference effect. Sodium nitrite was found to be a

valid reagent when an effective diffusion barrier was used. Scheeren and Adema (1996) used an

indigo carmine-coated glass-fiber filter to collect spectrophotometrically measured O3. The

detection limit was 23 ppb for a 1-h exposure, with no interfering oxidants identified. The

reagent was valid for a relative humidity range of 20 to 80%. The uptake rate was wind velocity

dependent. However, wind velocity dependencies was compensated for by using a small

battery-operated fan that continuously blew air across the face of the monitor at a speed of

1.3 m/s. The overall accuracy of the sampler, after correcting for samples collected under lowwind conditions, was 11 ± 9% in comparison to a continuous UV-photometric monitor. Sample

stability was > 25 days in a freezer. Bernard et al. (1999) employed a passive sampler consisting

of a glass-fiber filter coated with a 1,2-di(4-pyridyl)ethylene solution. The sample was analyzed

spectrophotometrically after color development by the addition of 3-methyl-2-benzothiazolinone

hydrazone hydrochloride. The sampler was used at 48 sites in Montpellier, France. The

correlation coefficient was r = 0.9, p < 0.0001. Detection limits were 17 ppb for 12-h and 8 ppb

for 24-h samples with an overall variation coefficient of 5% for field-tested paired samples. The

imprecision was estimated to be 1.0 ppb. 

A series of studies have been conducted using a passive sampler developed by Koutrakis

et al. (1993) at the Harvard School of Public Health. The sampler used sodium nitrate as the

trapping reagent and included a small fan to assure sufficient movement of air across the face of

the badge when sampling was done indoors. The passive sampler has been evaluated against the

standard UV absorption technique used in studies in southern California (Avol et al., 1998a;

Geyh et al., 1999, 2000; Delfino et al., 1996), Baltimore, MD (Sarnat et al., 2000), and Canada

(Brauer and Brook, 1997).

In a study discussed later in this chapter, Avol et al. (1998a) used nitrite-coated passive

samplers to measure O3 air concentrations indoors and outdoors of 126 homes between February

and December 1994 in the Los Angeles metropolitan area. The detection limit of the method

was near 5 ppb. The inconsistent sampler response due to changes in wind pattern and changes

in personal activity made the sampler unacceptable for widespread use. 
AX3-165

Geyh et al. (1997, 1999) compared passive and active personal O3 air samplers based on

nitrite-coated glass-fiber filters. The active sampler was more sensitive allowing for the

collection of short-term, 2.6-h samples. Comparison between the two samplers and UV

photometric O3 monitors demonstrated generally good agreement (bias for active personal

sampler of ~6%). The personal sampler also had high precision (4% for duplicate analyses) and

good compliance when used by children attending summer day camp in Riverside, CA.

AX3.10.5.2 Indirect Measurement Method

The indirect method determines and measures the concentrations in all of the locations or

“microenvironments” a person encounters or determines the exposure levels through the use of

models or biomarkers. The concept of microenvironments is critical for understanding human

exposure and aids in the development of procedures for exposure modeling using data from

stationary monitors (indoor and outdoor). Microenvironments were initially defined as

individual or aggregate locations (and sometimes even as activities taking place within a

location) where a homogeneous concentration of the pollutant is encountered for a specified

period of time. Thus, a microenvironment has often been identified with an “ideal” (i.e.,

perfectly mixed) compartment of classical compartmental modeling. More recent and general

definitions view the microenvironment as a “control volume,” indoors or outdoors, that can be

fully characterized by a set of either mechanistic or phenomenological governing equations,

when properly parameterized, given appropriate initial and boundary conditions. The boundary

conditions typically reflect interactions with the ambient air and with other microenvironments. 

The parameterizations of the governing equations generally include the information on attributes

of sources and sinks within each microenvironment. This type of general definition allows for

the concentration within a microenvironment to be nonhomogeneous, provided its spatial profile

and mixing properties can be fully predicted or characterized. By adopting this definition, the

number of microenvironments used in a study is kept manageable, while existing variabilities in

concentrations are still taken into account. The “control volume” variation could result in a

series of microenvironments in the same location. If there are large spatial gradients within a

location for the same time period, the space should be divided into the number of

microenvironments needed to yield constant pollutant concentrations; the alternative offered by

the control volume approach is to provide concentration as a function of location within it,
AX3-166

(AX3-3)

so that the appropriate value is selected for calculating exposure. Thus, exposure to a person in a

microenvironment is calculated using a formula analogous to equation AX3-3, but as the sum of

the discrete products of measured or modeled concentrations (specific to the receptor and/or

activity of concern) in each microenvironment by the time spent there. The equation is

expressed as:

where i specifies microenvironments from 1 to n, ci

 is the concentration in the ith

microenvironment, and ) ti

 is the duration spent in the ith microenvironment. The total exposure

for any time interval for an individual is the sum of the exposures in all microenvironments

encountered within that time interval. The concentration and time component in this approach

can contribute to measurement error. However, this method should provide an accurate

determination of exposure provided that all microenvironments that contribute significantly to

the total exposures are included and the concentration assigned to the microenvironment is

appropriate for the time period spent in those environments. Results from the error analysis

models developed by Navidi et al. (1999) suggested that neither the microenvironmental nor

personal sampling approach would give reliable health effect estimates when measurement

errors were uncorrected. Using their error analysis models, nondifferential measurement error

biased the effect estimates toward zero under the model assumptions. When the measurement

error is correlated with the health response, a bias away from the null could result. These

researchers proposed the use of bidirectional crossover and multi-level analytic statistical

methods for estimating acute effects of environmental exposures.

Microenvironments typically used to determine O3 exposures include indoor residences,

other indoor locations, outdoors near roadways, other outdoor locations, and in-vehicles. 

Outdoor locations near roadways are segregated from other outdoor locations because N2O

emissions from automobiles alter O3 and related photochemical oxidant concentrations compared

to concurrent typical ambient levels. Indoor residences are typically separated from other indoor

locations, because of the time spent there and potential differences between the residential

environment and the work/public environment. A special concern for O3 and related
AX3-167

photochemical oxidants is their diurnal weekly (weekday-weekend) and seasonal variability. 

Few indoor O3 sources exist, but include electronic equipment, O3 generators, and copying

machines. Some secondary reactions of O3 take place indoors that produce related

photochemical oxidants that could extend the exposures to those species above the estimates

obtained from O3 alone. (See discussion on O3 chemistry and indoor sources and concentrations

later in this Annex.) 

AX3.10.6 Ozone Exposure Models

Measurement efforts to assess population exposures or exposures of large numbers of

individuals over long time periods is labor intensive and costly, so exposure modeling is often

done for large populations evaluated over time. Predicting (or reconstructing) human exposure

to O3 through mechanistic models is complicated by the fact that O3 (and associated 

photochemical oxidants) is formed in the atmosphere through a series of chemical reactions that

are nonlinear and have a wide range of characteristic reaction timescales. Furthermore, these

reactions require the precursors VOCs and NOx that are emitted by a wide variety of both

anthropogenic and natural (biogenic) emission sources. This makes O3 a secondary pollutant

with complex nonlinear and multiscale dynamics in time and space. Concentration levels

experienced by individuals and populations exposed to O3 are therefore affected by (1) emission

levels and spatiotemporal patterns of the gaseous precursors: VOCs and NOx, that can be due to

sources as diverse as a power plant in a different state, automobiles on a highway five miles

away, and the gas stove in one’s own kitchen; (2) ambient atmospheric as well as indoor

microenvironmental transport, removal and mixing processes (convective, advective, dispersive

and molecular/diffusional); and (3) chemical transformations that take place over a multitude of

spatial scales, ranging from regional/sub-continental (100 to 1000 km), to urban (10 to 100 km),

to local (1 to 10 km), to neighborhood (< 1 km), and to microenvironmental/personal. These

transformations depend on the presence of co-occurring pollutants in gas and aerosol phases,

both primary and secondary, and on the nature of surfaces interacting with the pollutants.

Further, the strong temporal variability of O3, both diurnal and seasonal, makes it critical

that definitions of integrated or time-averaged exposure employ appropriate averaging times in

order to produce scientifically defensible analyses for either causes of O3 production or health

effects that result from O3 exposure. An understanding of the effect of temporal profiles of
AX3-168

concentrations and contacts with human receptors is essential. Short-term integrated metrics,

such as hourly averages, 8-h running averages, etc., are needed to understand the relationship

between O3 exposure and observed health and other effects. 

Health effects associated with O3 have mostly been considered effects of acute exposures. 

Peak O3 and related photochemical oxidants concentrations typically occur towards later in the

day during the summer months. Elevated concentrations can last for several hours. 

Furthermore, O3 participates in multiphase (gas/aerosol) chemical reactions in various

microenvironments. Several recent studies show that O3 reacts indoors with VOCs and NOx in

an analogous fashion to that occurring in the ambient atmosphere (Lee and Hogsett, 1999;

Wainman et al., 2000; Weschler and Shields, 1997). These reactions produce secondary

oxidants and other air toxics that could play a significant role in cumulative human exposure and

health-related effects within the microenvironment.

Terminology

Models of human exposure to O3 can be characterized and differentiated based upon a

variety of attributes. For example, exposure models can be classified as (1) potential exposure

models, typically maximum outdoor concentration versus “actual” exposure, including locally

modified microenvironmental outdoor and indoor exposures; (2) population versus “specific

individual”-based exposure models; (3) deterministic versus probabilistic models; and

(4) observation versus mechanistic air quality model-driven estimates of spatial and temporal

correlations. 

Some points should be made regarding terminology and the directions of exposure

modeling research (as related specifically to O3 exposure assessments) before proceeding to

discuss specific recent activities and developments. First, it must be understood that significant

variation exists in the definitions for much of the terminology used in the published literature. 

The science of exposure modeling is an evolving field and the development of a “standard” and

commonly accepted terminology is a process in evolution. Second, very often procedures/efforts

listed in the scientific literature as “exposure models/exposure estimates,” may in fact address

only a subset of the steps or components required for a complete exposure assessment. For

example, some efforts focus solely on refining the subregional or local spatiotemporal dynamics

of local O3 concentrations starting from “raw” data representing monitor observations or regional
AX3-169

grid-based model estimates. It is recognized that ambient air concentrations are used as

surrogates for exposure in some epidemiological studies. Nevertheless, such efforts are included

in the discussion of the next subsection, as they can provide essential components of a complete

exposure assessment. On the other hand, formulations that are identified as exposure models,

but focus only on ambient air quality predictions, are not included in the discussion that follows,

as they do not provide true exposure estimates. These models are reviewed in an earlier section

of this annex. Third, O3-exposure modeling is very often identified explicitly with populationbased modeling, while models describing the specific mechanisms affecting the exposure of an

individual to O3, and possibly some of the co-occurring gas and/or aerosol phase pollutants, are

usually associated with studies focusing on indoor chemistry modeling. Finally, in recent years,

the focus of either individual- or population-based exposure modeling research has shifted from

O3 to other pollutants, mostly airborne toxics and particulate matter. However, many of the

modeling components that have been developed in these efforts are directly applicable to O3

exposure modeling and are, therefore, mentioned in the following discussion. 

A General Framework for Assessing Exposure to Ozone

First, the individual and relevant activity locations for Individual Based Modeling, or the

population and associated spatial (geographical) domain for Population Based Modeling are

defined. The temporal framework of the analysis (period, resolution) and the comprehensive

modeling of individual/population exposure to O3 (and related pollutants) generally require

several steps (or components, as some of them do not have to be performed in sequence). The

steps represent a “composite” outline based on frameworks described in the literature over the

last 20 years (Ott, 1982, 1985; Lioy, 1990; Georgopoulos and Lioy, 1994; U.S. Environmental

Protection Agency, 1992, 1997) as well as on the structure of various existing inhalation

exposure models (McCurdy, 1994; Johnson et al., 1992; Nagda et al., 1987; U.S. Environmental

Protection Agency, 1996c; ICF Consulting, 2003; Burke et al., 2001; McCurdy et al., 2000;

Georgopoulos et al., 2002a,b; Freijer et al., 1998; Clench-Aas et al., 1999; Künzli et al., 1997). 

The conceptional frameworks of the models are similar. Figures AX3-87a,b provides a

conceptual overview of an exposure model. The steps involved in defining exposure models

include (1) estimation of the background or ambient levels of O3 through space-time analysis of

fixed monitor data, or emissions-based, photochemical, air quality modeling; (2) estimation of 
AX3-170

Figure AX3-87a. Detailed diagram illustrating components of an exposure model.Source: ICF Consulting and ManTech Environmental Technology, Inc. (2003)
AX3-171

Figure AX3-87b. Detailed diagram illustrating components of an exposure model.Source: ICF Consulting and ManTech Environmental Technology, Inc. (2003)
AX3-172

levels and temporal profiles of O3 in various outdoor and indoor microenvironments such as

street canyons, residences, offices, restaurants, vehicles, etc. through linear regression of

available observational data sets, simple mass balance models, detailed (nonlinear) gas or

gas/aerosol chemistry models, or detailed combined chemistry and computational fluid dynamics

models; (3) characterization of relevant attributes of individuals or populations under study (age,

gender, weight, occupation, etc.); (4) development of activity event (or exposure event)

sequences for each member of the sample population or for each cohort for the exposure period;

(5) calculation of appropriate inhalation (in general intake) rates for the individuals of concern,

or the members of the sample population, reflecting/combining the physiological attributes of the

study subjects and the activities pursued during the individual exposure events; (6) combination

of intake rates and microenvironmental concentrations for each activity event to assess dose;

(7) calculation of event-specific exposure and intake dose distributions for selected time periods

(1-h and 8-h daily maximum, O3 season averages, etc.); and (8) use of PBM to extrapolate

population sample (or cohort) exposures and doses to the entire populations of interest. This

process should aim to quantify, to the maximum extent feasible, variability and uncertainty in

the various components, assessing their effects on the estimates of exposure. 

Implementation of the above components of comprehensive exposure modeling has

benefitted significantly from recent advances and expanded availability of computational

technologies such as Relational Database Management Systems (RDBMS) and Geographic

Information Systems (Purushothaman and Georgopoulos, 1997, 1999a,b).

AX3.10.6.1 Population Exposure Models

Existing comprehensive inhalation exposure models treat human activity patterns as

sequences of exposure events in which each event is defined by a geographic location and

microenvironment. The U.S. EPA has supported the most comprehensive efforts in this area,

leading to the development of the National Ambient Air Quality Standard Exposure Model and

Probabilistic National Ambient Air Quality Standard Exposure Model (NEM and pNEM)

(Johnson, 2003) and the Modeling Environment for Total Risk Studies/Simulation of Human

Exposure and Dose System (MENTOR/SHEDS) (McCurdy et al., 2000). The Total Risk

Integrated Methodology Inhalation Exposure (TRIM.Expo) model, also referred to as the Air

Pollutants Exposure (APEX) model, was developed by the U.S. EPA as a tool for estimating
AX3-173

human population exposure to criteria and air toxic pollutants. APEX serves as the human

inhalation exposure model within the Total Risk Integrated Methodology (TRIM) framework

(ICF Consulting and ManTech Environmental Technology, Inc. [2003]). APEX, a PC-based

model derived from the probabilistic NAAQS Exposure Model (pNEM), was used in the last O3

NAAQS review (Johnson et al., 1996a, 1996b). Over the past five years, APEX has undergone

several significant improvements in the science reflected in the model and in the databases input

to the model. 

Recent European efforts have produced some formulations that have similar general

attributes as the above models but generally involve major simplifications in some of their

components. Examples of recent European models addressing O3 exposures include the AirPEx

(Air Pollution Exposure) model (Freijer et al., 1998), which basically replicates the pNEM

approach, and the AirQUIS (Air Quality Information System) model (Clench-Aas et al., 1999). 

The NEM/pNEM, APEX, and MENTOR/SHEDS families of models provide exposure

estimates, defined by concentration and minute ventilation rate for each individual exposure

event, and provide distributions of exposure and O3 dose over any averaging period of concern

from 1 h to an entire O3 season. The above families of models also simulate certain aspects of

the variability and uncertainty in the principal factors affecting exposure. pNEM divides the

population of interest into representative cohorts based on the combinations of demographic

characteristics (age, gender, employment), home/work district, residential cooking fuel, and then

assigns activity diary records (Glen et al., 1997) to each cohort according to demographic

characteristic, season, day-type (weekday/weekend), and temperature. APEX and

MENTOR/SHEDS generates a population demographic file containing a user-defined number of

person-records for each census tract of the population based on proportions of characteristic

variables (age, gender, employment, housing) obtained for the population of interest, and then

assigns the matching activity information based on the characteristic variables. A discussion of

databases on time-activity data, and their influence on estimates of long-term ambient O3

exposure, can be found in Künzli et al. (1997), McCurdy (2000), and McCurdy et al. (2000). 

More recent exposure models are designed (or have been redesigned) to obtain such

information from CHAD (Consolidated Human Activities Database; www.epa.gov/chadnet1;

see Table AX3-18). There are now about 22,600 person-days of sequential daily activity pattern

data in CHAD. All ages of both genders are represented in CHAD. The data for each subject
AX3-174

Table AX3-18. Activity Pattern Studies Included in the Consolidated Human Activity Databas

Study Name

Calendar Time

Period

of the Study Age1 Days2

Diary

Rate5

Documentation or

Type Reference 

3 Time4

Baltimore Jan-Feb 1997

Jul-Aug 1998

65+ 391 Diary; 15-min

blocks

24-h Standard No Williams et al. (2000a,b) Mul

part 

CARB: Adolescents and Adults Oct 1987-Sept 1988 12-94 1762 Retrospective 24-h Standard No Robinson et al. (1991)

Wiley et al. (1991a)

CARB: Children Apr 1989-Feb 1990 0-11 1200 Retrospective 24-h Standard No Wiley et al. (1991b)Cincinnati (EPRI) Mar-Apr and Aug

1985

0-86 2614 Diary 24 h; nominal

 7 pm-7 am

Yes Johnson (1989) 3 co

rem

Denver (EPA) Nov 1982-Feb 1983 18-70 805 Diary 24 h; nominal

 7 pm-7 am

No Akland et al. (1985)

Johnson (1984)

Part 

days

Los Angeles: Elem. SchoolChildren

Oct 1989 10-12 51 Diary 24-h Standard Yes Spier et al. (1992) 7 P-

Los Angeles: High SchoolAdoles.

Sept-Oct 1990 13-17 43 Diary 24-h Standard Yes Spier et al. (1992) 23 P

National: NHAPS-A8 Sept 1992-Oct 1994 0-93 4723 Retrospective 24-h Standard No9 Klepeis et al. (1995)

Tsang and Klepeis (1996)

A nsurv

National: NHAPS-B8 As above 0-93 4663 Retrospective 24-h Standard No9 As above As a

University of Michigan: Children

Feb-Dec 1997 0-13 5616 Retrospective 24-h Standard No Institute for Social

Research (1997)

2 daday

Valdez, AK Nov 1990-Oct 1991 11-71 401 Retrospective Varying 24-h

period

No Goldstein et al. (1992) 4 P-

Washington, DC (EPA) Nov 1982-Feb 1983 18-98 699 Diary 24 h; nominal

 7 pm-7 am

No Akland et al. (1985)

Hartwell et al. (1984)

Part 

rem

1 All studies included both genders. The age range depicted is for the subjects actually included; in most cases, there was not an upper limit for the adult studies. Ages 

 babies < 1 year old.

2 The actual number of person-days of data in CHAD after the “flagging” and removal of questionable data. See the text for a discussion of these procedures.3 Retrospective: a “what did you do yesterday” type of survey; also known as an ex post survey. Diary: a “real-time” paper diary that a subject carried as he or she we4 Standard = midnight to midnight.5 Was activity-specific breathing rate data collected?6 PEM = a personal monitoring study. In addition to the diary, a subject carried a small CO or PM2.5 monitor throughout the sampling period. 7 P-D removed = The number of person-days of activity pattern data removed from consolidated CHAD because of missing activity and location information; complete

 the text.

8 National Human Activity Pattern Study; A = the air version; B = the water version. The activity data obtained on the two versions are identical.9 A question was asked regarding which activities (within each 6-h time block in the day) involved “heavy breathing,” lifting heavy objects, and running hard. 

Source: U.S. Environmental Protection Agency (2004a)
AX3-175

consist of one or more days of sequential activities, in which each activity is defined by

start time, duration, activity type (140 categories), and microenvironment classification

(110 categories). Activities vary from 1 min to 1 h in duration. Activities longer than 1 h are

subdivided into clock-hour durations to facilitate exposure modeling. A distribution of values

for the ratio of oxygen uptake rate to body mass (referred to as metabolic equivalents or METs)

is provided for each activity type listed. The forms and parameters of these distributions were

determined through an extensive review of the exercise and nutrition literature. The primary

source of distributional data was Ainsworth et al. (1993), a compendium developed specifically

to “facilitate the coding of physical activities and to promote comparability across studies.” 

Other information on activity patterns has been reported by Klepeis et al. (1996, 2001); Avol

et al. (1998b); Adams (1993); Shamoo et al. (1994); Linn et al. (1996); Künzli et al. (1997). 

Use of the information in CHAD provides a rational way for incorporating realistic intakes into

exposure models by linking inhalation rates to activity information. As mentioned earlier, an

exposure event sequence derived from activity-diary data is assigned to each population unit

(cohort for pNEM- or REHEX-type models, or individual for APEX or MENTOR/SHEDS-type

models). Each exposure event is typically defined by a start and duration time, a geographic

location and microenvironment, and activity level. The most recent pNEM, APEX, and

MENTOR/SHEDS models have defined activity levels using the activity classification coding

scheme incorporated into CHAD. A probabilistic module within the APEX and

MENTOR/SHEDS-type models converts the activity classification code of each exposure event

to an energy expenditure rate, which in turn is converted into an estimate of oxygen uptake rate. 

The oxygen uptake rate is then converted into an estimate of ventilation rate ( ), expressed in VE ⋅

L/min. Johnson (2001) reviewed the physiological principles incorporated into the algorithms

used in pNEM and APEX to convert each activity classification code to an oxygen uptake rate

and describes the additional steps required to convert oxygen uptake to . VE ⋅

McCurdy (1997a,b, 2000) recommended that ventilation rate be estimated as a function of

energy expenditure rate. The energy expended by an individual during a particular activity can

be expressed as: 

(AX3-4)
AX3-176

where EE is the average energy expenditure rate (kcal/min) during the activity, MET (metabolic

equivalent of work) is a ratio specific to the activity and is dimensionless, and RMR is the

resting metabolic rate of the individual expressed in terms of number of energy units expended

per unit of time (kcal/min). If RMR is specified for an individual, then the above equation

requires only an activity-specific estimate of MET to produce an estimate of the energy

expenditure rate for a given activity. McCurdy et al. (2000) developed MET distributions for the

activity classifications appearing in the CHAD database. 

An important source of uncertainty in existing exposure modeling involves the creation of

multiday, seasonal, or year long exposure activity sequences based on 1- to 3-day activity data

for any given individual from CHAD. Currently, appropriate longitudinal data are not available

and the existing models use various rules to derive longer-term activity sequences using 24-h

activity data from CHAD.

The pNEM family of models used by the EPA has evolved considerably since the

introduction of the first NEM model in the 1980s (Biller et al., 1981). The first such

implementations of pNEM/O3 in the 1980s used a reduced form of a mass balance equation to

estimate indoor O3 concentrations from outdoor concentrations. The second generation of

pNEM/O3 was developed in 1992 and used a simple mass balance model to estimate indoor O3

concentrations. Subsequent enhancements to pNEM/O3 and its input databases included

revisions to the methods used to estimate equivalent ventilation rates (ventilation rate divided by

body surface), to determine commuting patterns, and to adjust ambient O3 levels to simulate

attainment of proposed NAAQS. During the mid-1990s, the EPA applied updated versions of

pNEM/O3 to three different population groups in nine selected urban areas (Chicago, Denver,

Houston, Los Angeles, Miami, New York, Philadelphia, St. Louis, and Washington): (1) the

general population of urban residents, (2) outdoor workers, and (3) children who tended to spend

more time outdoors than the average child. Reports by Johnson et al. (1996a,b,c) describe these

versions of pNEM/O3 and summarize the results of the application of the model to the nine urban

areas. These versions of pNEM/O3 used a revised probabilistic mass balance model to determine

O3 concentrations over 1-h periods in indoor and in-vehicle microenvironments (Johnson, 2003). 

The model assumed that there are no indoor sources of O3, that the outdoor O3 concentration and

AER during the clock hour is constant at a specified value, and that O3 decays at a rate

proportional to the outdoor O3 concentration and the indoor O3 concentration.
AX3-177

The new pNEM-derived model, APEX, differs from earlier pNEM models in that the

probabilistic features of the model are incorporated into a Monte Carlo framework. Instead of

dividing the population of interest into a set of cohorts, APEX generates individuals as if they

were being randomly sampled from the population. APEX provides each generated individual

with a demographic profile that specifies values for all parameters required by the model. The

values are selected from distributions and databases that are specific to the age, gender, and other

specifications stated in the demographic profile. The APEX model has not been evaluated,

however, the pCNEM, a Canadian conceptional version of the NEM model, has been evaluated

for estimation of PM10. Since pCNEM is similar to the pNEM/NEM, the APEX model should

work as well as pCNEM. (See discussion on pCNEM later is this section.) The EPA plans to

develop future versions of APEX applicable to O3 and other criteria pollutants. 

The latest version of APEX allows for finer geographical units such as census tracts and

automatically assigns population to the nearest monitor within a cutoff distance. Exposure

district-specific temperatures can be specified and the user can select the variables that affect

each parameter (e.g., the AER parameter in certain indoor microenvironments may depend on air

conditioning status or window position). The mass balance algorithms have been enhanced to

allow window position or vehicle speed to also be considered in determining AERs. 

The APEX model simulates individual movement through time and space to provide an

estimate of exposure to a given pollutant in the indoor, outdoor, and in-vehicle

microenvironments. The model is highly versatile, allowing input data for specific applications. 

APEX provides a good balance in terms of precision and resource expenditure compare with the

more narrowly focused site-specific model and the broadly applicable national screening-level

models.

A key strength of APEX is its ability to estimate hourly exposures and doses for all

simulated individuals in the sampled population. APEX is capable of estimating exposures of

workers in the geographic area where they work, in addition to the geographic area where they

live. APEX is able to represent much of the variability in the exposure estimates resulting from

the variability of the factors affecting human exposure by incorporating stochastic processes

representing the natural variability of personal profile characteristics, activity patterns, and

microenvironment parameters.
AX3-178

A limitation of APEX is that uncertainty in the predicted distributions has not been

addressed. Certain aspects of the personal profiles are held constant (e.g., age) which could be

an issue for simulations with long timeframes. The combined data set for activity patterns

(CHAD) are from a number of different studies and may not constitute a representative sample. 

However, the largest portion of CHAD (about 40 percent) is from a study of national scope and

research has shown that activity patterns are generally similar once you take into account age,

gender, day of week, and season/temperature. The commuting data addresses only home-towork travel and may not accurately reflect current commuting patterns. The population not

employed outside the home is assumed to always remain in the residential census tract. 

Although several of the APEX microenvironments account for time spent in travel, the travel is

assumed to always occur in basically a composite of the home and work tract. Seasonal or year

long sequences for a simulated individual are created by sampling human activity data from

more than one subject, possibly causing an underestimation of the variability from person to

person and an overestimation of the day to day variability for any given individual. The model

does not capture certain correlations among human activities that can impact

microenvironmental concentrations (e.g., cigarette smoking leading to an individual opening a

window, which in turn affects the amount of outdoor air penetrating the residence).

MENTOR/SHEDS estimates the population distribution of pollutant exposure by randomly

sampling from various input distributions. MENTOR/SHEDS is capable of simulating

individuals exposures in eight microenvironments (outdoors, residence, office, school, store,

restaurant, bar, and vehicles) using spatial concentration data for each census tract for outdoor

pollutant concentrations. The indoor and in-vehicle pollutant concentrations are calculated using

specific equations for the microenvironment and ambient pollutant concentration relationship. 

Model simulations use demographic data at the census tract level. Randomly selected

characteristics for a fixed number of individual are selected to match demographics within the

census tract for age, gender, employment status, and housing type. Smoking prevalence

statistics by gender and age is randomly selected for each individual in the simulation. Diaries

for activity patterns are matched for the simulated individual by demographic characteristics. 

The essential attributes of some of the O3 exposure models and approaches are summarized in

Table AX3-19. 
Table AX3-19. Personal and Population Exposure Models for Ozone

Model Name Model Type Microenvironments or Predictors Notes pNEM Probabilistic General population, outdoor workers,

outdoor children

Provides estimates of exposure within a definedpopulation for a specified period of time. Uses activity records from CHAD and CADS

APEX PC-based Outdoors, indoor residence,

in-vehicle

Simulates movement through time and space. Estimates hourly exposures and doses. Uncertainties in predicted distributions have notbeen addressed.

Mentor/SHEDS Probabilistic General population, outdoors, indoors,

in-vehicle

Employees detailed person oriented exposureapproach that includes personal activity data,physiology, and microenvironmental conditions. Allows calculation of exposure and dose foreach activity event.

REHEX General population Provides estimates of exposure for 1-day to

3 yrs. Can represent variability in activities ofthe population to capture extremes in exposuredistributions.

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AX3-180

Zidek et al. (2000, 2005) described a methodology for predicting human exposure to

environmental pollutants. The methodology builds on earlier models such as SHEDS and

pNEM/NEM and provides a WWW platform for developing a wide variety of models. pCNEM,

a platform model developed from this methodology, is a Canadian PC version of NEM. pCNEM

was used to estimate a conditional predictive exposure distribution for PM10 in London. An

important feature of pCNEM is its ability to estimate the effects of reductions in ambient levels

of pollutants.

Rifai et al. (2000) compared applications of an updated version of REHEX, REHEX-II. 

The applications used NHAPS data for the southern states and the 48-state NHAPS or the

Houston-specific time-activity pattern data. The results indicated a sensitivity to the specificity

of the activity data: using Houston-specific data resulted in higher estimates of human exposure

in some of the scenarios. For example, using NHAPS data lead to an estimated 275 thousandexposure-hours between 120 to 130 ppb, while use of the Houston-specific activity data lead to

an estimated 297 thousand-exposure-hours between 120 and 130 ppb (8% higher). Using the

Houston-specific activity data in the model resulted in about 2,400 person-exposure-hours above

190 to 200 ppb O3 while no exposure above this threshold was estimated when the NHAPS

activity were used in the model. 

Of the above families of models only NEM/pNEM implementations have been

extensively applied to O3 studies. However, it is anticipated that APEX will be useful as an

exposure modeling tool for assessing both criteria and hazardous air pollutants in the future. The

1996 O3 AQCD (U.S. Environmental Protection Agency, 1996a) focused on the pNEM/O3

family of models, referring to the review by McCurdy (1994) for the fundamental principles

underlying its formulation and listing, in addition to the “standard” version, three pNEM/O3-

derived models (the Systems Applications International NEM [SAI/NEM]; the Regional Human

Exposure Model [REHEX]; and the Event Probability Exposure Model [EPEM]). 

AX3.10.6.2 Ambient Concentrations Models

As mentioned earlier, background and regional outdoor concentrations of pollutants over a

study domain may be calculated either through emissions-based mechanistic modeling or

through ambient-data-based modeling. Emissions-based models calculate the spatiotemporal

fields of the pollutant concentrations using precursor emissions and meteorological conditions as
AX3-181

inputs. The ambient-data-based models typically calculate spatial or spatiotemporal

distributions of the pollutant through the use of interpolation schemes, based on either

deterministic or stochastic models for allocating monitor station observations to the nodes of a

virtual regular grid covering the region of interest. (See later discussion on population exposure

models). Kriging, a geostatistical technique, provides standard procedures for generating an

interpolated O3 spatial distribution for a given time period, using data from a set of observation

points. The kriging approach, with parameters calculated specifically for each hour of the period

of concern, was compared to the Urban Airshed Model (UAM-IV), a comprehensive

photochemical grid-based model for deriving concentration fields. The concentration fields

were then linked with corresponding population data to calculate potential outdoor population

exposure. Higher exposure estimates were obtained with the photochemical grid-based model

when O3 concentrations were <120 ppb, however, the situation was reversed when O3

concentrations exceeded 120 ppb. The authors concluded that kriging O3 values at the locations

studied can reconstruct aspects of population exposure distributions (Georgopoulos et al.,

1997a,b).

Carroll et al. (1997a,b) developed a spatial-temporal model, with a deterministic trend

component, to model hourly O3 levels with the capacity to predict O3 concentrations at any

location in Harris County, Texas during the time period between 1980 and 1993. A fast modelfitting method was developed to handle the large amount of available data and the substantial

amount of missing data. Ozone concentration data used consisted of hourly measurements from

9 to 12 monitoring stations for the years 1980 to 1993. Using information from the census tract,

the authors estimated that exposure of young children to O3 declined by approximately 20% over

the analysis period. The authors also suggested that the O3 monitors are not sited in locations to

adequately measure population exposures. Several researchers have questioned the suitability of

the model for addressing spatial variations in O3 (Guttorp et al., 1997; Cressie, 1997; Stein and

Fang, 1997). 

Spatiotemporal distributions of O3 concentrations have alternatively been obtained using

methods of the “Spatio-Temporal Random Field” (STRF) theory (Christakos and Vyas,

1998a,b). The STRF approach interpolates monitoring data in both space and time

simultaneously. This method can analyze information on “temporal trends,” which cannot be

incorporated directly in purely spatial interpolation methods such as standard kriging. Further,
AX3-182

the STRF method can optimize the use of data that are not uniformly sampled in either space or

time. The STRF theory was further extended in the Bayesian Maximum Entropy (BME)

framework and applied to O3 interpolation studies (Christakos and Hristopulos, 1998; Christakos

and Kolovos, 1999; Christakos, 2000). The BME framework can use prior information in the

form of “hard data” (measurements), probability law descriptors (type of distribution, mean and

variance), interval estimation (maximum and minimum values) and even constraint from

physical laws. According to these researchers, both STRF and BME were found to successfully

reproduce O3 fields when adequate monitor data are available.

Zidek et al. (1998, 2002), Sun et al. (1998, 2000), Le et al. (1997), and Li et al. (1999,

2001) used a hierarchical Bayesian approach to predict average hourly concentrations of ambient

O3 and PM10 when monitoring data was not available. A trend model and the Gaussian

stochastic residual was used at the primary level to model the logarithmic field. Space-time

modeling occurs at the second level of the hierarchical prior model so that uncertainty about the

model parameters is expressed at the first level. A special feature of this method is that it does

not require all sites to monitor the same set of pollutants. Also, the model can be updated as new

data become available.

AX3.10.6.3 Microenvironmental Concentration Models

Once specific ambient/local spatiotemporal O3 concentration patterns have been derived,

microenvironments that can represent either outdoor or indoor settings must be characterized. 

This process can involve modeling of various local sources and sinks as well as

interrelationships between ambient/local and microenvironmental concentration levels. Three

approaches have been used in the past to model microenvironmental concentrations: empirical,

mass balance, and detailed computational fluid dynamics (CFD).

The empirical fitting approach has been used to summarize the findings of recent field

studies (Liu et al., 1995, 1997; Avol et al., 1998a). These empirical relationships could provide

the basis for future, “prognostic” population exposure models. 

Mass balance modeling has ranged from very simple formulations, assuming ideal

(homogeneous) mixing and only linear physicochemical transformations with sources and sinks,

to models that take into account complex multiphase chemical and physical interactions and

nonidealities in mixing. Mass balance modeling is the most common approach used to model
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pollutant concentrations in enclosed microenvironments. As discussed earlier, the simplest

microenvironmental setting is a homogeneously mixed compartment in contact with possibly

both outdoor/local environments as well as with other microenvironments. The air quality of

this idealized microenvironment is affected primarily by transport processes (including

infiltration of outdoor air into indoor air compartments, advection between microenvironments,

and convective transport); sources and sinks (local outdoor emissions, indoor emissions, surface

deposition); and local outdoor and indoor gas and aerosol phase chemistry transformation

processes (such as the formation of secondary organic and inorganic aerosols). 

Numerous indoor air quality modeling studies have been reported in the literature;

however, depending on the modeling scenario, only a limited number address physical and

chemical processes that affect O3 concentrations indoors (Nazaroff and Cass, 1986; Hayes, 1989,

1991). An example of a mass balance indoor air model for O3 and benzene can be found in the

work of Freijer and Bloemen (2000). They used outdoor O3 measurements to parameterize a

simplified linearized formulation of transport, transformation, and sources and sinks in the

indoor microenvironment.

The pNEM/O3 model includes a sophisticated mass balance model for enclosed (indoor and

vehicle) microenvironments. The general form of this mass balance model is a differential

equation that accounts for outdoor concentration, AER, penetration rate, decay rate, and indoor

sources. To address uncertainty, each of these parameters is represented by a probability

distribution or by a dynamic relationship to other parameters that may change according to time

of day, temperature, air conditioning status, window status, or other factors (Johnson, 2003). 

The simplest form of the model is represented by the following differential equation for a

perfectly mixed microenvironment without an air cleaner:

where dCIN is the indoor pollutant concentration (mass/volume), t is time in hours, v is the air

exchange rate, COUT is the outdoor pollutant concentration (mass/volume), V is the volume of the

microenvironment, and S is the indoor source emission rate. 

(AX3-5)
AX3-184

Nazaroff and Cass (1986) extended the mass balance model to include multiple

compartments and interactions between different compounds. The extended model takes into

account the effects of ventilation, filtration, heterogeneous removal, direct emission, and

photolytic and thermal and chemical reactions. A more in-depth discussion of the mass balance

model may be found in Shair and Heitner (1974) and in Nazaroff and Cass (1986).

Freijer and Bloemen (2000) used the one-compartment mass balance model to examine the

relationship between O3 I/O ratios as influenced by time patterns in outdoor concentrations,

ventilation rate, and indoor emissions. The microenvironment was 250 m3. Three different

ventilation patterns with the same long-term average AER (0.64 h!1

) were used. A source

pattern (direct emissions) of zero was used, because O3 sources are not common. The time series

for outdoor O3 concentrations consisted of 100-day periods during the summer, with hourly

measured concentrations. The following assumptions were made: (1) O3 concentration in the air

that enters the microenvironment is equal to the concentration of the outside air minus the

fraction removed by filtration, (2) the O3 concentration that leaves the microenvironment equals

the O3 concentration in the microenvironment, (3) the decay processes in the microenvironment

are proportional to the mass of the pollutant, and (4) addition or removal of O3 in the

microenvironment also may occur through independent sources and sinks. 

Figure AX3-88 represents the measured outdoor O3 concentrations and modeled indoor O3

concentrations. The indoor modeled O3 concentrations were found to equal approximately 33%

of the outdoor monitored concentrations. 

Few indoor air models have considered detailed nonlinear chemistry, which, however, can

have a significant effect on the indoor air quality, especially in the presence of strong indoor

sources. Indeed, the need for more comprehensive models that can take into account the

complex, multiphase processes that affect indoor concentrations of interacting gas phase

pollutants and particulate matter has been recognized and a number of formulations have

appeared in recent years. For example, the Exposure and Dose Modeling and Analysis System

(EDMAS) (Georgopoulos et al., 1997a) included an indoor model with detailed gas-phase

atmospheric chemistry. This indoor model accounts for interactions of O3 with indoor sinks and

sources (surfaces, gas releases) and with entrained gas. The indoor model was dynamically

coupled with the outdoor photochemical air quality models, UAM-IV and UAM-V (Urban

Airshed Models), which provided the gas-phase composition of entrained air, and with a 
AX3-185

physiologically based O3 uptake and dosimetry model. Subsequent work (Isukapalli et al., 1999)

expanded the framework and features of the EDMAS model to incorporate alternative

representations of gas-phase chemistry as well as multiphase O3 chemistry and gas/aerosol

interactions. The new model is a component of the integrated Modeling Environment for Total

Risk studies (MENTOR). 

Sarwar et al. (2001, 2002) modeled estimates of indoor hydroxyl radical concentrations

using a new indoor air quality model, Indoor Chemistry and Exposure Model (ICEM). The

ICEM uses a modified SAPRC-99 atmospheric chemistry mechanism to simulate indoor

hydroxyl radical production and consumption from reactions of alkenes with O3. It also allows

for the simulation of transport processes between indoor and outdoor environments, indoor

emissions, chemical reactions, and deposition. Indoor hydroxyl radicals, produced from O3 that

penetrates indoors, can adversely impact indoor air quality through dark chemistry to produce

photochemical oxidants.

Sørensen and Weschler (2002) used CFD modeling to examine the production of a

hypothetical product from an O3-terpene reaction under two different ventilation scenarios. The

computational grid used in the model was nonuniform. There were significant variations in the

concentrations of reactants between locations in the room, resulting in varying reaction rates. 

Figure AX3-88. Measured outdoor O3 concentrations (thin line) and modeled indoor

concentrations (bold line).

Source: Adapted from Freijer and Bloemen (2000).
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Because the “age of the air” differed at different locations in the room, the time available for

reactions to occur also differed between locations. 

Very few studies have focused on mechanistic modeling of outdoor microenvironments. 

Fraigneau et al. (1995) developed a simple model to account for fast NO-O3 reaction/dispersion

in the vicinity of a motorway. Proyou et al. (1998) applied a simple three-layer photochemical

box model to an Athens street canyon. However, the adjustments of O3 levels for sources, sinks,

and mixing in outdoor microenvironments are done in a phenomenological manner in existing

exposure models, driven by limited available observations. Ongoing research is evaluating

approaches for quantifying local effects on outdoor O3 chemistry in specific settings. 

Finally, one issue that should be mentioned is that of evaluating comprehensive prognostic

exposure modeling studies, for either individuals or populations, with field data. Attempts had

been made to evaluate pNEM/O3-type models using personal exposure measurements (Johnson

et al., 1990). Although databases that would be adequate for performing a comprehensive

evaluation are not expected to be available any time soon, a number of studies are building the

necessary information base, as discussed previously. Some of these studies report field

observations of personal, indoor, and outdoor O3 concentrations and describe simple

semiempirical personal exposure models that are parameterized using observational data and

regression techniques.

AX3.10.7 Measured Exposures and Monitored Concentrations

AX3.10.7.1 Personal Exposure Measurements

Passive O3 monitors have been used in several field studies to determine average daily O3

exposure as well as in scripted studies to evaluate O3 exposures over one to several-hour time

periods. Table AX3-20 lists the results of O3 exposure studies. Delfino et al. (1996) measured

12-h personal daytime O3 exposures in asthmatic patients in San Diego from September through

October 1993. They found that the mean personal exposures were 27% of the mean outdoor

concentrations. Individual exposure levels among the 12 asthmatic subjects aged 9 to 16 years

varied greatly. Mean personal O3 exposure levels were lower on Friday, Saturday, and Sunday

than on other days of the week (10 versus 13 ppb), while the ambient air concentrations were

higher Friday through Sunday. The authors suggested that the differences were due to higher

weekday NO emissions from local traffic which titrated the ambient O3 levels. The lower 
AX3-187

Table AX3-20. Personal Exposure Measurements

Location, Population, Sample Duration n

Personal Exposure Meana

(range) (ppb) Reference

San Diego, CA, Asthmatics ages 9-18 years,

12 hour

12 12 ± 12 (0-84)

10 weekend

12 weekday

Delfino et al. (1996)

Vancouver, Canada, Adult Workers, Daily

High indoor time

Moderate indoor time

Only outdoor

585

(ND-9)

(ND-12)

(2-44)

Brauer and Brook

(1997)

Southern California, Subjects 10-38 years

Spring

Fall

24

13.6 ± 2.5 (- to 80)

10.5 ± 2.5 (- to 50)

Liu et al. (1997)

Montpellier, France, Adults, Hourly

Winter

Summer

16 34.3 ± 17.6 (6.5-88)

15.4 ± 7.7 (6.5-40)

44.1 ± 18.2(11-88)

Bernard et al. (1999)

Souther California, Children 6-12 years, 

$ 6 days

Upland - winter

- summer

Mountain - winter

- summer

169

6.2 ± 4.7 (0.5-41)

19 ± 18 (0.5-63)

5.7 ± 4.2 (0.5-31)

25 ± 24 (0.5-72)

Geyh et al. (2000)

Baltimore, MD, Technician, Hourlyb

Winter

Summer

1

3.5 ± 7.5 (ND-49)

15 ± 18 (ND-76)

Chang et al. (2000)

Baltimore, MD, Adults 75 ± 7 years, Daily

Winter

Summer

20

3.5 ± 3.0 (ND-9.9)

0. ± 1.8 (ND-2.8)

Sarnat et al. (2000)

a

ND = not detected.

b

Measurements made following scripted activities for 15 days.

personal exposure levels on Friday, Saturday, and Sunday may have been an artifact of greater

noncompliance, with the badges remaining indoors and, therefore, being exposed to lower O3

concentrations. The overall correlation between the personal exposure concentrations between

any two individuals and with the outdoor stationary site was only moderate (r = 0.45; range: 

0.36 to 0.69). The O3 concentrations at the stationary site exceeded the personal levels by an

average of 31 ppb. Avol et al. (1998b) observed a poor correlation between personal exposure

and fixed-site monitoring concentrations (r = 0.28, n = 1336 pairs) for a cohort of children 
AX3-188

(healthy, wheezy, and asthmatic). Personal exposure measurements were generally lower than

integrated hourly data. Sarnat et al. (2000) measured personal O3 exposures during a 12-day

longitudinal study of 20 older adults (>64 years) in Baltimore, MD. The subjects spent >94% of

the time indoors. Ten subjects participated in the summer and winter exposures and the

remaining 10 participated in either the summer or winter exposure. No statistically significant

overall correlations were identified between the personal and the ambient O3 concentrations

during either the winter or summer. Only a single individual (n = 14 summer and 13 winter) had

a significant correlation with outdoor concentrations. Geyh et al. (2000) measured indoor and

outdoor concentration and personal O3 exposures in 169 elementary school children from

116 homes during a year-long sampling protocol in 2 communities in southern California

(Upland and Mountain communities). Samples were collected for 1 week per month. Boys had

higher O3 exposure than girls, probably reflecting the greater amount of time boys spent

outdoors compared to girls (3.8 versus 3.2 h for the spring/summer and 2.9 versus 2.2 h for the

fall/winter). The average personal O3 exposures were lower than the levels measured at the

nearest monitor stations retrieved from the AQS. There was no significant difference in the O3

exposure for both groups during the non-O3 season (6.2 and 5.7 ppb for Upland and the

mountain communities, respectively), however, children in the mountainous region were

exposed to 35% more O3 than children in Upland during the O3 season (18.8 and 25.4 ppb for

Upland and the mountain communities) (two-tailed t-test, p < 0.01). During the O3 season,

differences were found in indoor concentrations and personal O3 exposures between the two

communities participating in the study based on ambient air concentrations and differences in air

exchange rates in the homes. 

Brauer and Brook (1997) conducted personal exposure evaluations in three groups in Frazer

Valley, Vancouver, Canada. The groups were divided by the amount of time spent outdoors: 

(1) the majority of the workday was spent indoors or commuting (25 medical clinic workers), (2)

an intermediate amount of time was spent outdoors (25 overnight camp staff members), and (3)

the entire exposure monitoring period was outdoors (15 adult farm workers). Time-activity data

were collected for the first two groups to assess the proportion of time spent outdoors. 

For groups 1 and 2, the lowest quartile of participants based on the fraction of time spent

outdoors (0 to 25% and 7.5 to 45%, respectively) had significantly lower O3 exposure (mean

personal exposure to outdoor concentration ratio = 0.18 and 0.35, respectively) compared to
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those in the upper quartile (mean ratio = 0.51 and 0.58, respectively; p < 0.05; Bonferroni

multiple range test). The mean ratio was 0.96 with values ranging from near 0 to 2 for group 3,

the group that spent the entire exposure-monitoring period outdoors. The authors attributed the

extreme low ratios to random measurement error at low O3 air concentrations (estimated at

35%), local variability in O3 concentrations, and to differences between ground-level

concentrations (where the personal samples were collected) 3-m above ground level (where the

continuous monitors were located). The highest ratios may be due to either locale variability in

O3 concentrations or to an interference affecting the personal O3 samplers, particularly at the

lower concentration range, leading to a small positive error. Temporal plots of O3 for the mean

daily personal exposures and ambient concentrations showed the same general trend with

general agreement between the personal exposures and ambient air concentrations for group 3. 

However, for groups 1 and 2, the day-to-day variability of the personal exposures and ambient

O3 concentrations had consistent patterns, suggesting that the ambient air was the primary source

for O3 exposure. The day-to-day variability in personal and continuous measurements was 0.60,

0.42, and 0.64 for groups 1 through 3, respectively. The actual O3 concentrations measured in

the personal air space were always considerably lower than the ambient concentrations. Bernard

et al. (1999) assessed O3 personal exposure and in the home and outdoor O concentration for up

to 110 subjects. Measurements were conducted over 5-day periods between June 1995 and

October 1996. As anticipated, O3 concentrations were higher during the warmer months. Mean

O3 concentrations for 70 subjects were 22, 35, 17.4, 40.5, and 18 ppb for personal, outdoor

home, indoor home, outdoor work, and indoor work, respectively for measurements made during

the warmer months. 

In a study by Liard et al. (1999), 55 mild to moderate asthmatic adults (18 to 65 y old) and

39 children (7 to 15 y old) were monitored for O3 exposure. Subjects were monitored during

three periods, 4 days per monitoring period and asked to keep a diary of time spent outdoors and 

in a car. Many of the study subjects O3 exposures were often below the level of detection for the

method used. Ozone exposure levels correlated with the hours spent outdoors. Ozone personal

exposure correlated poorly with the ambient monitoring measurements, however, the mean

values for all subjects correlated with those measurements from the ambient monitoring site

(r = 0.83, p < 0.05). Linn et al. (1996) estimated short-term O3 exposures in 269 children from

three communities in the Los Angeles Basin by monitoring air at head level in school class
AX3-190

rooms, on the roof of one level school buildings, and in personal microenvironments of selected

individuals. Monitoring was carried out for six weeks in the fall, winter, and spring, two

successive weeks per season at each of three schools. Each subject was monitored for one week

in each season over a two year period. According to the authors there were meaningful

associations between personal exposures and central monitoring site O3 measurements (r = 0.61). 

Based on information reported in the questionnaires, outdoor activity increased slightly in

communities/seasons with higher pollution.

Lee et al. (2004) found that personal O3 exposure was positively correlated with time spent

outdoors (r = 0.19, p < 0.01) and negatively correlated with time spent indoors (r = !0.17,

p <0.01) in elementary school children. Thirty-three elementary school children from two

Nashville, TN area school districts participated in a six week long O3 monitoring study during

the summer vacation. The study participants maintained a dairy of daily activities during the

study period. An additional 62 children from the same school completed a telephone interview

on time/activity at least eight times during the study period. Study participants wore a passive

sampler during their non-sleep time and the sampler was placed near their bed at night. 

A passive monitor also was placed outside and inside of the home. Personal exposure correlated

with the amount of time spent outdoors. Exposures ranged from 0.0013 to 0.0064 ppm for

indoor concentrations compared to ambient concentrations of 0.011 to 0.042 ppm O3. 

AX3.10.7.2 Monitored Ambient Concentrations

Ozone has been measured more extensively than the other photochemical oxidants. 

Ambient monitors have been established in most areas of the country, with extensive monitoring

in regions that have been in noncompliance with the previous 1-h daily NAAQS. Monitoring

station-measured hourly concentrations also have been used as surrogates of exposure in

epidemiological studies and in evaluating exposure-related health effects. According to the

Guideline on Ozone Monitoring Site Selection (U.S. Environmental Protection Agency, 1998),

when designing an O3 monitoring network, consideration should be given to (1) proximity to

combustion emission sources, (2) distance from primary emission sources, and (3) the general

wind direction and speed to determine the primary transport pathways of O3 and its precursors. 

Finally, the 1-h daily maximum and 8-h average O3 concentrations can have different spatial

patterns with elevated daily 8-h O3 concentrations typically being over a wider spatial area. 
AX3-191

Therefore, O3 monitoring networks should determine the highest concentrations expected to

occur in the area, representative concentrations for high population density areas, the impact of

sources or source categories on air pollution levels, and general background concentration levels

(U.S. Environmental Protection Agency, 1998). 

The guideline also states that the monitor’s O3 inlet probe should be placed at a height and

location that best approximates where people are usually found. However, complicating factors

(e.g., security considerations, availability) sometimes result in the probe placement being

elevated 3 to 15 m above ground level, a different location than the breathing zone (1 to 2 m) of

the populace. Although there are some commonalities in the considerations for the sampling

design for monitoring and for determining population exposures, differences also exist. These

differences between the location and height of the monitor compared to the locations and

breathing zone heights of people can result in different O3 concentrations between what is

measured at the monitor and exposure and, therefore, should be considered when using ambient

air monitoring data as a surrogate for exposure in epidemiological studies and risk assessments. 

Further, since most people spend the majority of their time indoors, where O3 levels tend to be

much lower than outdoor ambient levels, the use of ambient monitoring data to determine

exposure generally overestimates true personal O3 exposure, resulting in exposure estimates

biased towards the null. Information on monitored ambient concentrations of O3 and other

photochemical oxidants appears earlier in this chapter.

AX3.10.7.3 Ozone Concentrations in Microenvironments

The 1996 O3 AQCD for Ozone (U.S. Environmental Protection Agency, 1996a) reported

O3 I/O ratios for a variety of indoor environments including homes, office/laboratories, a

hospital, museums, a school room, and automobiles and other vehicles. Ozone I/O ratios ranged

from 0.09 to 1.0 for residences, 0.19 to 0.8 for offices/laboratories, hospital and school rooms,

and 0.03 to 0.87 for museums and art galleries. The higher O3 ratios were generally noted in

indoor environments with high AERs or 100% outside air intake. Studies published since

completion of the 1996 O3 AQCD are discussed in this section. The findings of the more recent

studies on O3 I/O ratios are included in Table AX3-21.

Northeast States for Coordinated Air Use Management (NESCAUM, 2002) monitored

levels of O3 inside and outside of nine schools located in the New England states. The schools 
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Table AX3-21. Indoor/Outdoor Ozone Ratios

Location and VentilationConditions

Indoor/Outdoor RatioMean (range) Comments 

Toronto, Canada, Homes

Winter – weekly (68)Summer – weekly (38)Summer – 12 h/day (128)

– 12 h/night (36)

0.07 ± 0.10 (ND - 0.63)0.40 ± 0.29 (ND - 1.15)0.30 ± 0.32 (ND - 1.42)0.43 ± 0.54 (ND - 2.89)

Electrostatic air cleaners were present in about 50% of the homAir conditioners were present in about 80% of the homes, most central units that used recycled air. Air conditioners used in onthe 40 homes on a daily basis. Measurements were made both and outside of the homes for 5 consecutive 24-h periods. Homelectrostatic air cleaners had higher I/O ratios during the winter The mean average weekly AER for all homes during the winter was 0.69 ± 0.88 h!1 with 50% of the homes with an AER of les

0.41 h!1. For the summer months, the mean average AER was 

1.28 h!1 with 50% of the homes with an AER of less than 0.52 

Boston, MA, Homes (26)

Winter – continuously 24 hSummer – continuously 24 h

0.30 ± 0.42 (ND - 1.31)0.22 ± 0.25 (ND - 0.88)

Study examined the potential for O3 to react with VOCs to form 

aerosols. Carbonyls were formed. No clear trend of O3 with A

The average AER was 0.9 h!1 during the winter and 2.6 h!1 dur

summer. Four residences in winter and nine in summer with 24 average concentrations. Air concentrations varied from 0-34.2 indoors and 4.4-40.5 ppb outdoors.

Mexico City, School

Windows/Doors Open (27)Windows/Doors Closed,cleaner off (41)Windows/Doors Closed,cleaner on (47)

0.73 ± 0.040.17 ± 0.020.15 ± 0.02

Study conducted over 4-day period during winter months. Twoaveraged measurements were taken both inside and outside of tschool every 30 min from 10 a.m. to 4 p.m. Estimated air exchwere 1.1, 2.1, and 2.5 h!1 for low, medium, and high flow rates

concentrations decreased with increasing relative humidity.

Los Angeles, CA

Homes (95)Other locations (57)

0.280.18

Study conducted in September. Monitored O3 concentrations c

of twenty-one 24-h periods beginning at 7 p.m. and ending at 7 the following day. Ozone concentrations were higher at the fixmonitoring sites during the afternoon. The weather was sunny temperature was high. I/O ratio was lower when windows werThe effect of air conditioning on the I/O was varied. 
AX3-193

Table AX3-21 (cont’d). Indoor/Outdoor Ozone Ratios

Location and VentilationConditions

Indoor/Outdoor RatioMean (range) Comments 

Mexico City

Homes (237)Schools (59)

0.20 ± 0.18 (0.04 - 0.99)0.1 - 0.30.3 - 0.4

Ozone monitoring occurred between September and July. Studincluded 3 schools and 145 homes. Most of the homes were ladid not have air conditioning. Ninety-two percent of the homecarpeting, 13% used air filters, and 84% used humidifiers. Thipercent opened windows frequently, 43% sometimes, and 22% between 10 a.m. and 4 p.m. Ozone was monitored at the schoofrom 8 a.m. to 1 p.m. daily for 14 consecutive days. Homeswere monitored for continuous 24-h periods for 14 consecutive I/O based on 1-h average concentrations.

Los Angeles, Homes (239)

SummerWinter

0.37 ± 0.25 (0.06 - 1.5)0.43 ± 0.290.32 ± 0.21

Four hundred and eighty-one samples collected inside and immoutside of home from February to December. Ratios based on average O3 concentrations indoors and outdoors. Low outdoor

concentrations resulted in low indoor concentrations. Howeveroutdoor concentrations resulted in a range of indoor concentratand ratios. I/O ratios were highest during the summer months.

California

Homes no AC, window opened (20)  AC, windows closed (3)

0.68 (n = 20)0.09 (n = 3)

I/O ratio was determined for 20 homes. Only 3 of the homes othe air conditioning. I/O ratios based on 24-h continuous ambiconcentrations and 0.5-1 h average indoor concentrations.

Munich Germany

OfficeGymnasium ClassroomResidence Bedroom LivingroomHotel roomCar

0.4 - 0.90.49 - 0.920.54 - 0.770.47 - 1.00.74 - 1.00.020.4 - 0.6

Indoor concentrations were dependent on the type of ventilatio

La Rochelle, France 0 - 0.45 I/O ratio determined for 8 schools. Monitoring conducted for a 

period. Schools located in various areas with different ambient 

concentrations, types of ventilation systems, and the presumedair-tightness of building envelop. Building air-tightness and amconcentration influenced indoor O3 I/O.
AX3-194

Table AX3-21 (cont’d). Indoor/Outdoor Ozone Ratios

Location and VentilationConditions

Indoor/Outdoor RatioMean (range) Comments 

Montpellier, France, Homes (110) 0.41 Ozone measurements were made over 5-day periods in and out

homes during the summer and winter months. The winter I/O r0.31 compared to 0.46 during the summer months.

Southern CA, HomesUpland Mountains

0.68 ± 0.18 (windows open)0.07 - 0.11(AC used)

Ozone measurements were taken at 119 homes (57 in Upland atowns located in the mountains) during April and May. I/O ratbased on average monthly outdoor concentrations and average indoor concentrations. I/O ratio was associated with the home number of bedrooms, and the presence of an air conditioner. I/based on subset of the homes.

Krakow, Poland

Museums (5)

0.13 - 0.42 Ozone continuously monitored at five museums and cultural ce

Monitoring conducted during the summer months for 21-46 h odays at each of the sites. The I/O was found to be dependent oventilation rate, i.e., when the ventilation rate was high, the I/O approached unity, while in rooms sequestered from the outdoor where air was predominantly recycled through charcoal filters, 

levels indoors were greatly reduced resulting in low I/O ratios.

Buildings, Greece

ThessalonikiAthens

0.24 ± 0.18 (0.01 to 0.75) There was no heating/air conditioning system in the building at

Thessaloniki. Windows were kept closed during the entire monperiod. Complete air exchange took place every 3 h. I/O ratio from 0.5-0.90, due to low deposition velocity on indoor surfaceconditioning system in continuous use at the Athens site recircuthe air. Complete air exchange was estimated to be 1 h. Monitlasted for 30 days at each site, but only the 7 most representativwere used for calculation of the I/O ratio.

Southern California, Museum 0.19 ± 0.05 Measurements made over a 2-wk period (24-h avg). Ratio for

concentrations at the buffer zone with the roll-up door closed.

ND = not detectable.
AX3-195

represented a variety of environmental conditions in terms of ambient O3 concentration, sources,

geographic location, population density, traffic patterns, and building types. Schools were

monitored during the summer months to establish baseline O3 concentrations and again during

the fall after classes started. A monitor was placed directly outside of the school entrance and

50 feet away from the entrance in the hall. Where available, monitors were placed at locations

identified as “problem” classrooms, classrooms with carpeting, or in rooms close to outdoor

sources of O3. As expected, outdoor concentrations of O3 were higher than those found indoors.

Averaged O3 concentrations were low during the early morning hours (7:30 a.m.) but peaked to

approximately 25 and 40 ppb around 1:30 p.m. indoors and outdoors, respectively. 

Gold et al. (1996) compared indoor and outdoor O3 concentrations in classrooms in Mexico

City under three different ventilation conditions: windows/doors open, air cleaner off;

windows/doors closed, air cleaner off; and windows/doors closed, air cleaner on. Two-minute

averaged outdoor O3 levels varied between 64 and 361 ppb, while indoor O3 concentrations

ranged from 0 to 247 ppb. The highest indoor O3 concentrations were noted when the

windows/doors were open. The AERs were estimated to be 1.1, 2.1, and 2.5 h!1 for low,

medium, and high air flow rates, respectively. The authors indicated that the indoor levels, and

therefore O3 exposure to students in schools, can be reduced to < 80 ppb by closing windows and

doors even when ambient O3 levels reach 300 ppb. 

In a second Mexico City study, Romieu et al. (1998) measured O3 concentrations inside

and outside of 145 homes and three schools. Measurements were made between November and

June. Most of the homes were large and did not have air conditioning. Ninety-five percent of

the homes had carpeting, 13% used air filters, and 84% used humidifiers. Thirty-five percent of

the homeowners reported that they opened windows frequently between the hours of 10 a.m. and

4 p.m., while 43% opened windows sometimes and 22% reported that they never opened

windows during that time period. Homes were monitored for continuous 24-h periods for

14 consecutive days. Schools were monitored from 8 a.m. to 1 p.m. or continuously for 24 h.

During the school monitoring periods the windows were frequently left open and the doors were

constantly being opened and closed. The mean indoor and outdoor O3 concentrations during 5-h

measurements at the schools were 22 ppb and 56 to 73 ppb, respectively. The mean indoor and

outdoor O3 concentrations for measurements made over a 7- and 14-day period at the test homes

were 5 and 27 ppb and 7 and 37 ppb, respectively. Ozone concentrations inside of homes were
AX3-196

dependent on the presence of carpeting, the use of air filters, and whether the windows were

open or closed. Air exchange rates were not reported.

Reiss et al. (1995) compared indoor and outdoor O3 concentrations for residences in the

Boston, MA area. Four residences were monitored during the winter months and nine residences

during the summer months. Outside monitors were placed ~1 m away from the house. 

Monitoring was conducted over a continuous 24-h period. There were no indoor sources of O3. 

Indoor O3 concentrations were higher during the summer months, with concentrations reaching

34.2 ppb. Indoor O3 concentrations reached as high as 3.3 ppb during the winter monitoring

period. In one instance, O3 concentrations were higher indoors than outdoors. The authors

attributed that finding to analytical difficulties. Outdoor O3 concentrations were generally higher

during the summer monitoring period, with concentrations reaching 51.8 ppb. Indoor

concentrations were dependent on the outdoor O3 concentrations and AER. Indoor and

outdoor O3 concentrations, including the AERs at the times of the monitoring are included in

Table AX3-22. 

Avol et al. (1998a) monitored 126 home in the Los Angeles metropolitan area during

February and December. Uniformly low ambient O3 concentrations were present during the

non-O3 seasons. Indoor O3 concentrations were always below outdoor O3 concentrations. The

mean indoor and outdoor O3 concentrations over the sampling period were 13 ± 12 ppb and 37 ±

19 ppb, respectively. There was a correlation between indoor O3 concentration and ambient

temperatures. The effect was magnified when the windows were open. When a central

refrigerant recirculating air conditioner was used, indoor O3 concentrations declined. The

authors were able to predict indoor O3 levels with nearly the same accuracy using measurements

made at regional stations coupled with window conditions as with measurements made directly

outside the homes coupled with window conditions, suggesting that monitoring station data may

be useful in helping to reduce errors associated with exposure misclassification. The authors

cautioned that varying results may occur at different locations with different housing stock or at

different times of the year.

Lee et al. (2002) reported indoor and outdoor O3 concentrations in 119 homes of school

children in two communities in southern California: Upland and San Bernadino county. 

Measurements were made over one year. Outdoor and indoor O3 concentrations were based on 
AX3-197

Table AX3-22. Indoor and Outdoor O3 Concentrations in Boston, MA

Residence

Indoor

Ozone

(ppb)

Outdoor

Ozone

(ppb)

AER

(h!1

)

Indoor Data Outdoor Data

Relative

Humidity

(%) Temp. (°F)

Relative

Humidity

(%) Temp. (°F)

Winter

1 - Day 1 3.3 11.2 1 25-45 67-75 88 25

1 - Day 2 0 15 0.8 22-40 65-76 62 27

2 - Day 1 2.6 24.4 1 3-19 67-71 44 17

2 - Day 2 1.7 4.4 1 3-8 55-70 40 17

3 - Day 1 20.4 15.6 1 8-24 62-69 33 36

3 - Day 2 3.1 24.5 0.9 13-19 64-70 51 38

4 - Day 1 2.2 11.4 0.7 26-37 60-72 57 39

4 - Day 2 0.3 20.7 0.7 29-38 61-70 77 36

Summer

1 - Day 1 5.6 32.4 3 28-44 71-74 44 65

1 - Day 2 0.6 13.4 2.3 37-44 70-74 59 60

2 - Day 1 0.8 14.3 2.4 48-54 73-79 54 70

2 - Day 2 5 24.1 2.1 46-60 72-78 64 73

3 - Day 1 34.2 38.9 4.6 48-63 64-80 52 71

3 - Day 2 6.9 14 3.1 45-53 65-69 52 62

4 - Day 1 4.3 30 1.4 37-60 66-75 51 67

4 - Day 2 4.9 40.5 1.8 38-68 67-79 64 67

5 - Day 1 1.4 17.5 5.1 30-50 69-74 54 58

5 - Day 2 1.9 19 3.5 39-63 N/A 40 64

6 - Day 1 0.8 8.2 0.5 59-73 74-77 76 72

6 - Day 2 1.7 18.6 0.7 43-66 76-78 47 76

7 - Day 1 3.9 40.1 1.1 57-70 70-77 51 75

7 - Day 2 0 33.9 1.1 58-73 72-75 64 72

8 - Day 1 22.9 51.8 3.2 66-81 71-77 75 75

8 - Day 2 23.5 31.6 6.3 43-67 66-79 48 72

9 - Day 1 1.6 20.9 2.1 N/A N/A 37 70

9 - Day 2 1.2 25 1.7 33-52 75-79 70 66

N/A = not available

Adapted from: Reiss et al. (1995)
AX3-198

cautioned that varying results may occur at different locations with different housing stock or at

different times of the year.

Lee et al. (2002) reported indoor and outdoor O3 concentrations in 119 homes of school

children in two communities in southern California: Upland and San Bernadino county. 

Measurements were made over one year. Outdoor and indoor O3 concentrations were based on

monthly and weekly averages, respectively. Housing characteristics were not found to affect

indoor O3 concentrations. Indoor O3 concentrations were significantly lower than outdoor O3

concentrations. Average indoor and outdoor O3 concentrations were 14.9 and 56.5 ppb. Homes

with air conditioning had lower O3 concentrations, suggesting decreased ventilation or greater

O3 removal. 

Chao (2001) evaluated the relationship between indoor and outdoor levels of various air

pollutants, including O3, in 10 apartments in Hong Kong during May to June. Air monitoring

was conducted over a 48-h period. All participants had the habit of closing the windows during

the evenings and using the air conditioner during the sleep hours. Windows were partially open

during the morning. The air conditioners were off during the working hours. Indoor O3

concentrations were low in all of the monitored apartments, ranging from 0 to 4.9 ppb with an

average of 2.65 ppb. Outdoor O3 concentrations ranged from 1.96 to 15.68 ppb. Table AX3-23

provides information on the indoor and outdoor O3 concentrations and the apartment

characteristics.

Drakou et al. (1995) demonstrated the complexity of the indoor environment. 

Measurements of several pollutants, including O3, were made inside and outside of two

nonresidential buildings in Thessaloniki and Athens, Greece. The building in Thessaloniki was a

58-m3

 metal structure. The ceiling and walls were covered with colored corrugated plastic

sheeting, and the flooring was plastic tile. There was no heating/air conditioning system and the

building was closed during the monitoring period. The AER ranged from 0.3 to 0.35 h!1. The

building in Athens was a 51-m3

 concrete structure. The air conditioning system (recirculated air)

worked continuously during the monitoring period. A window was opened slightly to

accommodate the monitors’ sampling lines. The AER was approximately 1 h!1

. Monitoring

lasted for 30 days at both locations, however, only data from the 7 most representative days were

reported. Indoor O3 concentrations closely followed the outdoor concentrations at the

Thessaloniki building. The averaged 7-day indoor and outdoor O3 concentrations were 9.39 and 
AX3-199

Table AX3-23. Indoor and Outdoor O3 Concentrations in Hong Kong 

Apartment

No.

Floor

Area

Floor

No.

Window Opening

Frequency AER (h!1

)

Indoor

O3 Conc.

Outdoor

O3 Conc.

1 40 14 Seldom 1.44 0 1.96

2 47 13 Sometimes 1.97 4.96* 6.01*

3 140 2 Sometimes 0.83 1.0* 6.96*

4 67 5 Seldom 5.27 4.96* 8.76*

5 86 11 Sometimes 1.64 3.0* 7.80*

6 43 32 Sometimes 15.83 4.01* 8.76*

7 47 9 Always 15.91 0 3.0*

8 30 6 Seldom 3.25 2.05* 3.0*

9 26 35 Sometimes 2.1 4.9 15.68

10 20 15 Seldom 5.5 4.01* 4.96*

*Estimated Concentration.

Adapted from Chao (2001).

15.48 ppb, respectively. The indoor O3 concentrations at the Athens location were highly

variable compared to the outdoor concentration. The authors suggested that a high hydrocarbon

intrusion may be the reason for the variability in O3 concentrations noted at this site. The

averaged 7-day indoor and outdoor O3 concentrations were 8.14 and 21.66 ppb, respectively. 

Weschler et al. (1994) reported that indoor O3 concentrations closely tracked outdoor O3

concentrations at a telephone switching station in Burbank, CA. The switching building was

flat-roofed, two-story (first floor and basement), uncarpeted, with unpainted brick walls. Each

floor was 930 m2

 with a volume of 5095 m3. Indoor O3 concentrations were measured on the

first floor using a perfluorocarbon tracer or an UV photometric analyzer. The AER were

obtained by dividing the volumetric flow to the first floor by the volume of the first floor space

or by perfluorocarbon tracer techniques. The AER ranged from 1.0 to 1.9 h!1

.

The major source of O3 at the switching station was transport from outdoors. Indoor O3

concentrations closely tracked outdoor concentrations, measuring from 30 to 70% of the outdoor

concentrations. Indoor O3 concentrations frequently exceed 50 ppb during the summer months,
AX3-200

but seldom exceeded 25 ppb during the winter. During the early spring through late fall, indoor

O3 concentrations peaked during the early afternoon and approach zero after sunset. Ozone sinks

included a surface removal rate between 0.8 and 1.0 h!1 and reactions with NOx. 

Figures AX3-89 and AX3-90 compare the outdoor and indoor O3 concentrations, including the

AER, for two 1-week periods during the study.

The relationships between indoor and outdoor O3 concentrations in five museums and

cultural centers (Wawel Castle, Matejko Museum, National Museum, Collegium Maius, and

Cloth Hall) in Krakow, Poland were reported by Salmon et al. (2000). Measurements were

made for up to 46 h and up to 33 days. Air exchange measurements were only made for the

Matejko Museum and Wawel Castle. Both were naturally ventilated. However, the summertime

AER for the Matejko Museum was more than twice that of the Wawel Castle site, 1.26 to

1.44 h!1

 compared to 0.56 to 0.66 h!1. The highest indoor O3 concentrations were noted at the

Figure AX3-89. Air exchange rates and outdoor and indoor O3 concentrations during the

summer at a telephone switching station in Burbank, CA.

Source: Weschler et al. (1994).
AX3-201

Matejko Museum during the summer. The findings are included in Table AX3-24 for those

locations with reported AERs. 

Figure AX3-91 shows O3 and PAN concentrations in a private residence in Germany. 

All measurements were made in naturally ventilated rooms. 

Johnson (1997) conducted a scripted study using four trained technicians to measure

hourly average O3 concentrations between 07:00 and 19:00 h in Los Angeles, CA during

September and October 1995. The ratio of the microenvironmental concentrations to the fixed

site monitor on days when the O3 levels $20 ppb were as follows: indoor residence, 0.28; other

locations indoors, 0.18; outdoor near roadways, 0.58; other locations outdoors, 0.59; and

in-vehicle, 0.21. The concentrations indoors and within vehicles varied depending on whether

the windows were opened (higher) or closed (lower) and the use of air conditioning. The lower

outdoor concentrations, particularly near roadways, probably reflect the reaction of O3 with NO

emitted by automobiles. 

Figure AX3-90. Air exchange rates and outdoor and indoor O3 concentrations during the

fall at a telephone switching station in Burbank, CA.

Source: Weschler et al. (1994). 
AX3-202

Table AX3-24. Indoor and Outdoor Ozone Concentrations

Location

Duration

(hours) AER Average O3 (ppb)

Matejko Museum 26 1988-2000

Outdoors (Town Hall Tower) 20

Indoors (third floor, west) 1.26 8.5

Wawel Castle 43

Outdoors (Loggia) 14.7

Indoors (Senator’s Hall) 0.63 2.5

Wawel Castle, outdoors 31.8 42a

Wawel Castle, Room 15 31 8

Wawel Castle, Senator’s Hall 31.8 7

Matejko Museum, outdoors 26.9 21b

Matejko Museum, Indoor Gallery 26.9 9

a

On Loggia of Piano Nobile Level, high above the street.

b

At street level.

Adapted from Salmon et al. (2000).

A study of the effect of elevation on O3 concentrations found that concentrations increased

with increasing elevation. The ratio of O3 concentrations at street level (3 m) compared to the

rooftop (25 m) was between 0.12 and 0.16, though the actual concentrations were highly

correlated (r = 0.63) (Väkevä et al., 1999). Differential O3 exposures may, therefore, exist in

apartments that are on different floors. Differences in elevation between the monitoring sites in

Los Angeles and street level samples may have contributed to the lower levels measured by

Johnson (1997). Furthermore, since O3 monitors are frequently located on rooftops in urban

settings, the concentrations measured there may overestimate the exposure to individuals

outdoors in streets and parks, locations where people exercise and maximum O3 exposure is

likely to occur. 

Chang et al. (2000) conducted a scripted exposure study in Baltimore during the summer of

1998 and winter of 1999, during which 1-h O3 samples were collected by a technician who also

changed his or her activity every hour. The activities chosen were selected to simulate older 
AX3-203

(> 65 years) adults, based on those activities reported in the National Human Activity Pattern

Survey (NHAPS). The scripted activities took place in five different microenvironments: 

indoor residential (apartment in 24-h air conditioned high rise building), indoor other (restaurant,

post office, hospital, shopping mall, and bingo parlor), outdoor near roadway, outdoor away

from roadway, and inside motor vehicle. Personal O3 exposures were significantly lower in

indoor than the outdoor microenvironments, because more time was spent indoors. Mean

summer concentrations were 15.0 ± 18.3 ppb, with a maximum of 76.3 ppb. Significant

correlation was noted for the indoor nonresidential microenvironments and ambient O3 (r = 0.34

in summer, r = 0.46 in winter), however, the authors indicated that this finding was unclear due

to the low personal/ambient ratios. The personal O3 exposure levels within the outdoor and invehicle microenvironments were significantly correlated with ambient concentration, although

the ratio of personal exposure to ambient levels was less than one, with only the top 5% of the

ratios exceeding one, indicating that the ambient measurements lead to the maximum

concentrations and exposures. The indoor concentrations did not correlate with outdoor

Figure AX3-91. Diurnal variation of indoor and outdoor O3 and PAN concentrations

measured in a private residence, Freising, Germany, August 11-12, 1995.

Source: Jaboki and Fabian (1997).
AX3-204

measurements (r = 0.09 and r = 0.05 for summer and winter, respectively). The correlation for

outdoor near roadway and outdoor away from roadway was moderate to high (0.68 #r #0.91).

The scripted exposure studies show that the O3 concentrations in the various

microenvironments were typically lower than the ambient air concentrations measured at

monitoring stations. Exposure models are useful for accounting for the reduced concentrations

usually encountered in various microenvironments compared to ambient monitoring station

concentrations (see discussion on exposure models earlier in this annex). 

Riediker et al. (2003) measured mobile source pollutants inside highway patrol vehicles in

Wake County, NC. Measurements were made during the 3 p.m. to midnight shift between

August 13 and October 11, 2001 in two patrol cars each day for a total of 50 shifts. All areas of

rural and urban Wake County were patrolled. The prominent areas patrolled were major

highways and interstates. Ozone concentrations inside the cars were compared with the O3

measurements at the fixed station in northern Raleigh. The average O3 concentration inside the

cars was 11.7 ppb, approximately one-third of the ambient air concentration. Jakobi and Fabian

(1997) found that O3 concentrations in a moving car were independent of the type of ventilation

(windows closed and ventilator operation/ventilator off and windows open). Ozone

concentrations inside the car were found to closely follow the outdoor concentrations. When the

car was parked, O3 concentrations outdoors greatly exceeded concentrations inside the car (see

Figure AX3-92). 

Few studies have been conducted in indoor environments containing O3 sources. Black

et al. (2000) measured O3 concentrations in a photocopy room at the University of California

during one business day. The room volume was 40 m3

. Ozone concentrations were generally

below 20 ppb, but increased proportionately with increasing photocopier use. Ozone

concentrations reached 40 ppb when the hourly average number of copies reached 45. Helaleh

et al. (2002) reported daily average O3 concentrations from 0.8 to 1.3 ppb and 0.9 to 1.0 ppb in a

laboratory and photocopy room at a university in Japan. Outdoor O3 concentrations ranged from

6 to 11 ppb. Because only limited information was available on the sampling system used in the

study, the adequacy of the sampling system cannot be determined. Jakobi and Fabian (1997)

measured O3 concentrations in an office associated with the use of a photocopier and a laser

printer. They noted a 3.0 ppb increase in O3 from the use of a 3-year old printer run for 20 min 
AX3-205

at a copy rate of 8 pages/min. There was no detectable change in O3 concentrations from the use

of the laser printer. 

The U.S. Environmental Protection Agency (Steiber, 1995) measured O3 concentrations

from the use of three home/office O3 generators. The O3 generators were placed in a 27 m3 room

with doors and windows closed and the heating, ventilating and air conditioning system off; the

AER was 0.3 h!1. The units were operated for 90 min. Ozone concentrations at the low output

setting ranged from nondetectable to 14 ppb (averaged output). At the high output setting,

averaged output O3 concentrations exceeded 200 ppb in several cases and had spike

concentrations as high as 480 ppb. 

Figure AX3-93 includes PAN indoor/outdoor ratios for 10 museums. Four of the museums

were equipped with HVAC and chemical infiltration systems. 

AX3.10.7.4 Factors Affecting Ozone Concentrations Indoors

In the absence of an indoor source, O3 concentrations in indoor environments will depend

on the outdoor concentration, the air exchange rate (AER) or outdoor infiltration, indoor

circulation rate, removal by indoor surfaces, reactions with other indoor pollutants, and 

Figure AX3-92. Indoor and outdoor O3 concentration in moving cars.

Source: Jaboki and Fabian (1997).
AX3-206

temperature and humidity. Indoor concentrations generally closely track outdoor O3

concentrations. Limited information on PAN concentrations indoors also indicate that indoor

PAN concentrations track outdoor concentrations (Jakobi and Fabian, 1997; Hisham and

Grosjean, 1991). Since outdoor concentrations of photochemical oxidants are generally higher

during the warmer months, indoor concentrations will also be highest during that time period. 

(See discussion on ambient concentrations of O3 earlier in this chapter.) 

Figure AX3-93. Indoor/outdoor concentration ratios for PAN at 10 southern California

museums. Code to locations: 1 El Pueblo Historical Park, Los Angeles;

2 Olivas Adobe House, Ventura; 3 Southwest Museum, Los Angeles;

4 Page Museum, Los Angeles; 5 Museum of Natural History,

Los Angeles; 6 Research Library, University of California, Los Angeles;

7 Scott Gallery, Huntington Museum, Pasadena; 8 The J. Paul Getty

Museum, Malibu; 9 Los Angeles County Museum of Art, Los Angeles;

10 Gene Autry Western Heritage Museum, Los Angeles (buffer zone);

11 Gene Autry Museum (Conservation Room).

Source: Hisham and Grosjean (1991).
AX3-207

Air Exchange Rates

Indoor O3 increases with increasing air exchange rate (Gold et al., 1996; Lee et al., 1999;

Jakobi and Fabian, 1997). The AER is the balance of the flow of air in and out of a

microenvironment. Infiltration through unintentional openings in the building envelope is the

dominant mechanism for residential air exchange. Duct systems account for 30% of the total

leakage area of a house. Natural ventilation, airflow through opened windows and doors, also

influences air exchange in residential buildings. Forced or mechanical ventilation is the

dominant mechanism for air exchange in nonresidential buildings. 

Air exchange rates vary depending on the temperature differences, wind effects,

geographical region, type of heating/mechanical ventilation system, and building type (U.S.

Environmental Protection Agency, 1997; Weschler and Shields, 2000; Colome et al., 1994;

Johnson et al., 2004). Air exchange rates are generally higher during the summer and lower

during the winter months (Wilson et al., 1996; Murray and Burmaster, 1995; Colome et al.,

1994; Research Triangle Institute, 1990). The Gas Research Institute, Pacific Gas and Electric

Company, San Diego Gas and Electric Company, and Southern California Gas Company

measured the air exchange rates in a subset of 293 randomly selected homes in California as part

of an air pollution monitoring study. The average AER varied by type of heating system (wall

furnaces >forced-air > electric) and building type (multifamily units > single-family units)

(Billick et al., 1984, 1996; Colome et al., 1994).

Howard-Reed et al. (2002) determined that opening a window or exterior door causes the

greatest increase in AERs with differences between the indoor and outdoor temperature being

important when the windows were closed. Johnson and Long (2004) conducted a pilot study to

evaluate the frequency that windows were left open in a community. They found that a visual

2-h survey could be used to estimate the frequency that windows are left open. The occupancy,

season, housing density, absence of air conditioning, and wind speed were factors in whether the

windows were open.

Johnson et al. (2004) conducted a study using scripted ventilation conditions to identify

those factors that affected air exchange inside a test house in Columbus, OH. The test house was

a wood-framed, split-level structure with aluminum siding covering the wood outer walls. The

house had one exterior door located in the front and another at the rear of the house, single-pane

glazed windows, central gas heat, a window air-conditioning unit, and ceiling fans in three
AX3-208

rooms. Eighteen scenarios with unique air flow conditions were evaluated to determine the

effect on the AER. The elements of the scenarios included: exteriors doors open/closed, interior

doors open/closed, heater on/off, air conditioner on/off, a ceiling fans on/off. The lower level

was sealed off during the study. The various scenarios were evaluated during the winter season. 

The average AER for all scenarios ranged from 0.36 to 15.8 h!1. When all windows and doors

were closed, the AER ranged from 0.36 to 2.29 h!1 (0.77 h!1 geometric mean). When at least one

exterior door or window was open the AER ranged from 0.5 to 15.8 h!1 (1.98 h!1 geometric

mean). 

Williams et al. (2003a, 2003b) reported air exchange rates ranging from 0.001 h!1

 to

4.87 h!1

 (overall arithmetic mean of 0.72 h!1 ) in houses in the Research Triangle Park area in

North Carolina. Air exchange measurements were made in 37 homes as part of a year long study

PM panel study.

Air exchange rates for homes in Houston, TX, Los Angeles County, CA, and Elizabeth, NJ

were reported by Meng et al. (2005) as part of the Relationship of Indoor, Outdoor and Personal

Air (RIOPA) study. The RIOPA study was designed to determine indoor (residual), outdoor,

and personal exposure to several classes of pollutants. Approximately 100 homes from each of

the areas were sampled across all four seasons. The mean air exchange rate for the Los Angeles

County homes was 1.22 h!1

, similar to the air exchange rate (1.51 h!1) homes in Los Angeles

previously reported by Wilson et al. (1996). The mean air exchange rate for Houston and

Elizabeth was 0.71 h!1 and 1.22 h!1, respectively. Air exchange rates for New Jersey were

higher than other reported values in the northeast region. The authors attributed these

differences to differences in the age of housing stock in the various areas.

Chan et al. (2005) compared air leakage measurements for more than 70,000 houses across

the United States, classified as low-income households, energy program houses, and convention

houses, to the building size, construction date and various construction characteristics, and

geographical location. The construction date and building size were the two most significant

predictors of leakage areas. Older and smaller houses had higher normalized leakage areas than

the newer and larger houses. Based on their evaluation of new and older residential

constructions, Sherman and Matson (1997) found that existing home stock (pre-1980) was quite

leaky with an AER of approximately 20.0 h-1. Newer constructions were considerably more

airtight.
AX3-209

Murray and Burmaster (1995) conducted an analysis of data compiled by Brookhaven

National Laboratories on AERs for 2,844 residential structures in four climatic regions based on

heating degree days. (Region 1: IN, MN, MT, NH, NY1, VT, WI; Region 2: CO, CT, IL, NJ,

NY2, OH, PA, WA; Region 3: CA3, MD, OR, WA; Region 4: AZ, CA4, FL, TX). Data were

also separated by seasons (winter, spring, summer, and fall). The highest overall AERs occurred

during the spring and fall season. However, air exchange rates were variable within and between

seasons and between regions. Data from the warmest region during the summer months should

be reviewed with caution because many of the measurements were made in southern California

where windows were more likely to be open than in other areas of the country where airconditioning is used. 

Air exchange rates for 49 nonresidential buildings (14 schools, 22 offices, and 13 retail

establishments) in California were reported by Lagus Applied Technology, Inc. (1995). Average

mean (median) AERs were 2.45 (2.24), 1.35 (1.09), and 2.22 (1.79) h!1

 for schools, offices, and

retail establishments, respectively. Air infiltration rates for 40 of the 49 buildings were 0.32,

0.31, and 1.12 h!1 for schools, offices, and retail establishments, respectively. Air exchange

rates for 40 nonresidential buildings in Oregon and Washington (Turk et al., 1989) averaged

1.5 (1.3) h!1 (mean median). The geometric mean of the AERs for six garages was 1.6 h!1 (Marr

et al., 1998). Park et al. (1998) reported AERs for three stationary cars (cars varied by age)

under different ventilation conditions. Air exchange rates ranged from 1.0 to 3.0 h!1 for

windows closed and fan off, 13.3 to 23.5 h!1 for windows opened and fan off, 1.8 to 3.7 h!1 for

windows closed and fan on recirculation (two cars tested), and 36.2 to 47.5 h!1

 for windows

closed and fan on fresh air (one car tested). An average AER of 13.1 h!1

 was reported by Ott

et al. (1992) for a station wagon moving at 20 mph with the windows closed. 

Ozone Removal Processes

The most important removal process for O3 in the indoor environment is deposition on and

reaction with indoor surfaces. The rate of deposition is material specific. The removal rate

indoors will depend on the indoor dimensions, surface coverings, and furnishings. Smaller

rooms generally have larger surface-to-volume ratios (A/V) and remove O3 faster. Fleecy

materials, such as carpets, have larger A/V ratios and remove O3 faster than smooth surfaces

(Weschler, 2000). O3 can react with carpet, decreasing O3 concentrations and increasing
AX3-210

emissions of formaldehyde, acetaldehyde, and other C5–C10 aldehydes. Off-gassing of

4-phenylcyclohexene, 4-vinylcyclohexene, and styrene was reduced (Weschler et al., 1992). The

rate of O3 reaction with carpet diminishes with cumulative O3 exposure (Morrison and Nazaroff,

2000, 2002). Reiss et al. (1995) reported significant quantities of acetic acid and smaller

quantities of formic acid off-gassing from O3 reactions with latex paint. The emission rate also

was relative humidity-dependent, increasing with higher relative humidity. Klenø et al. (2001)

evaluated O3 removal by several aged (1- to 120-month) but not used building materials (nylon

carpet, linoleum, painted gypsum board, hand polished stainless steel, oiled beech parquet,

melamine-coated particle board, and glass plate). Initially, O3 removal was high for all

specimens tested with the exception of the glass plate. Ozone removal for one carpet specimen

and the painted gypsum board remained high throughout the study. For the oiled beech parquet

and melamine-coated particle board, O3 removal leveled off to a moderate rate. Morrison et al.

(1998) reported that small amounts of O3 (~9%) are removed by lined ductwork of ventilation

systems. The removal efficiency decreases with continued exposure to O3. Unlined ductwork is

less efficient in removing O3. Ozone is scavenged by fiberglass insulation (Liu and Nazaroff,

2001). More O3 was scavenged (60 to 90%) by fiberglass that had not been previously exposed. 

Table AX3-25 lists the removal rates for O3 in different indoor environments.

Jaboki and Fabian (1997) found the O3 decays exponentially. PAN decay is dependent on

room temperature and possibly the properties and structure of the materials it comes in contact

with. They examined O3 and PAN decay in several closed rooms and in a car after a period of

intensive ventilation. Figure AX3-94 plots the O3 and PAN decay rates in these environments. 

Several studies have examined factors within homes that may scavenge O3 and lead to

decreased O3 concentrations (Lee et al., 1999; Wainman et al., 2000; Weschler and Shields,

1997). These reactions produce related oxidant species while reducing indoor O3 levels. Lee

et al. (1999) studied 43 homes in Upland, CA in the Los Angeles metropolitan region and

reported that O3 declined faster in homes with more bedrooms, greater amounts of carpeting, and

lower ceilings (all of which alter the A/V ratio) and with the use of air conditioning. Homes

with air conditioning had indoor/outdoor (I/O) ratios of 0.07, 0.09, and 0.11. Homes without air

conditioning had an I/O ratio of 0.68 ± 0.18. Closed windows and doors combined with the use

of an air cleaner resulted in an I/O ratio of 0.15. The O3 I/O ratio was < 0.2 in homes with gas

stoves. 
AX3-211

Table AX3-25. Rate Constants (h–1) for the Removal of Ozone by Surfaces in Different

Indoor Environments

Indoor environment

Surface Removal Rate,

kd (A/V), h–1 Reference

Aluminum Room (11.9 m3)

Stainless Steel Room (14.9 m3

)

Bedroom (40.8 m3

)

Office (55.2 m3

)

Home (no forced air)

Home (forced air)

3.2

1.4

7.2

4.0

2.9

5.4

Mueller et at. (1973)

Sabersky et al. (1973)

Department Store

Office (24.1 m3

)

Office (20.7 m3

)

Office/Lab

4.3

4.0

4.3

4.3

Thompson et al. (1973)

Allen et al. (1978)

Shair and Heitner (1974)

Office/Lab

Office/Lab

13 Buildings, 24 ventilation systems

Museum

Museum

3.2

3.6

3.6a

4.3

4.3

Shair (1981)

Nazaroff and Cass (1986)

Office/Lab

Office/Lab

Office

Lab

Cleanroom

4

3.2

2.5

2.5

7.6

Weschler et al. (1989)

Telephone Office

43 Homes

0.8 ! 1.0b

2.8 ± 1.3

Weschler et at. (1994)b

Lee et al. (1999)

a A/V = assumes surface area to volume ratio = 2.8 m–1

b Large office, small A/V

Source: Weschler (2000).

Ozone Removal Through Chemical Processes

Ozone chemical reactions in the indoor environment are analogous to those reactions

occurring in the ambient air (See Annex AX2). Ozone reactions with unsaturated VOCs in the

indoor environment are dependent on the O3 indoor concentration, the indoor temperature and, in

most cases, the air exchange rate/ventilation rate and mixing factor. The air exchange rate 
AX3-212

determines the amount of time available for chemical reactions to take place. At low air 

exchange rate, the residence time for the pollutants is longer, the reaction time is greater, and the

concentration of the products produced by O3 chemistry is greater (Weschler and Shields, 2000,

2003). Since O3 is primarily an outdoor pollutant, the air exchange rate will influence the

amount of O3 occurring indoors. 

Most unsaturated VOCs in the indoor environment are terpenes or terpene-related

compounds from cleaning products, air fresheners, and wood products. Some of the reaction

products may more negatively impact human health and artifacts in the indoor environment than

their precursors (Wolkoff et al., 1999; Wilkins et al., 2001; Weschler et al., 1992; Weschler and

Shields, 1997; Rohr et al., 2002; Nøjgaard et al., 2005). The reactions products of O3 and

terpenes are Criegee biradicals, nitrate radicals, and peroxyacyl radicals. Secondary reaction of

Figure AX3-94. Ozone decay processes versus time measured for several indoor rooms. 

Room temperature in all cases was ~27 °C and 29 °C in the car.

Adapted from: Jaboki and Fabian (1997).
AX3-213

the pollutants may form hydroxy, alkyl, alkylperoxy, hydroperoxy, and alkoxy radicals. The

reaction of O3 with alkenes can produce aldehydes, ketones, and organic acids (Weschler and

Shields, 2000; Weschler et al., 1992).

The indoor chemistry of O3 is described by the following equations. The initial reaction

produces an ozonide which rapidly decomposes into one of the two possible combinations.

(AX3-6)

(AX3-7)

or

(AX3-8)

The biradical (*) then rearranges or reacts to produce the highly reactive intermediate products

(hydroxy, hydroperoxy, and alkylperoxy radicals) and stable products (aldehydes, ketones and

organic acids).

Hydroxy radicals formed from the reaction of O3 with VOCs are lost to further reaction

with VOCs. For each molecule of O3 consumed, approximately one molecule of the hydroxy

radical is produced. The hydroxy radical also is formed through the reaction of nitric oxide and

hydroperoxy, and other intermediate products formed from the reaction of O3 with unsaturated

VOCs (Sarwar et al., 2002; Orzechowska and Paulson, 2002). The hydroxy radical can react

with various nitrogen compounds, sulfur dioxide, carbon monoxide and other compounds to

produce significantly more toxic compounds. In studies by Fick et al. (2003, 2004), the

formation of norpinonic and pinonic acid in a ventilation system injected with "-pinene in the

presence of O3 was reported to be almost exclusively the result of oxidation by hydroxy radicals. 

Fan et al. (2003) attributed the formation of some secondary organic aerosols from the reaction

of O3 with 23 VOCs (as toluene) to reactions with hydroxy radicals. Van den Bergh et al. (2000)

found that formaldehyde, acetaldehyde, acetone, campholenealdehyde, and pinonaldehyde are

generated from the reaction of "-pinene with hydroxy radicals. A list of the VOCs occurring in
AX3-214

the indoor environment known to react with O3 and OH radicals is found in Weschler (2000) and

Nazaroff and Weschler (2004). 

The reaction between O3 and terpenes has been shown to increase the concentration of

indoor particles (Weschler and Shields, 1999, 2003; Weschler, 2004; Clausen et al., 2001; Fan

et al., 2003; Wainman et al., 2000). Sarwar et al. (2002) suggested that the hydroxy radical

reacts with terpenes to produce products with low vapor pressures that contribute to fine particle

growth. The acidity of particles was found to enhance the yield of secondary organic aerosols

when "-pinene ozonolysis was carried out in the presence of ammonium sulfate and sulfuric

acid. There was almost a 40% increase in organic carbon particles when "-pinene ozonolysis

occurred in the presence of sulfuric acid aerosols compared to ammonium sulfate aerosols

(Iinuma et al., 2004). Rohr et al. (2002, 2003) measured particle formation in a plexiglas

chamber as part of a mouse bioassay study. They found an increase in ultrafine particle numbers

as the result of O3 and "-pinene reactions. When O3 was introduced into the test chamber,

particle concentrations increased to >107

 particles/cm3. Clausen found that the reaction of

limonene vapor with O3 increased the particle concentration to 3 × 105 from a background

concentration of <103

 particles/cm3. Poupard et al. (2005) and Blondeau et al. (2005) found a

negative correlation between O3 and particle concentration in eight school buildings in France. 

The researchers assumed that the increased particle concentration and decreased O3

concentration was likely the result of homogeneous processes involving O3. However, the

assumption could not be verified because the particles were not analyzed for chemical

composition.

Weschler et al. (1992) suggested that the reaction been O3 and NO2 in the indoor

environment may be a significant source of HNO3. When there are elevated concentrations of

both O3 and NO2 in the indoor environment, the following reaction sequence may occur:

(AX3-9)
AX3-215

PAN and PPN are thermally unstable and will decomposed in the indoor environment to

peroxyacetyl radicals and NO2 (See equation AX3-10). Decomposition and formation of PAN in

the indoor environment is influenced by NO2 and NO.

When the concentration ratio of NO/NO2 is greater than 7, less than 10% of the

peroxyaceyl radicals will revert to PAN. Decomposition of PAN is expected to be a relatively

fast process when indoor O3 levels are low and when motor vehicle emissions are large or there

is an indoor source of NOx (Weshcler and Shields, 1997).

Sources and Emissions of Indoor Ozone

Ozone enters the indoor environment primarily through infiltration from outdoors through

cracks and crevices in the building envelope (unintentional and uncontrolled ventilation) and

through building components such as windows and doors and ventilation systems (natural and

controlled ventilation). Natural ventilation is driven by the natural forces of wind and

temperature. Possible indoor sources of O3 are office equipment (photocopiers, facsimile

machines, and laser printers) and air cleaners (electrostatic air filters and precipitators and O3

generators). Generally O3 emissions from photocopiers and laser printers are limited due to

installed filtering systems (Black and Worthan, 1999; Leovic et al., 1996; Aldrich et al., 1995). 

However, emissions increase under improper maintenance conditions (Leovic et al., 1996). 

Well-maintained photocopiers and laser printers usually emit low levels of O3 by catalytically

reducing the O3 to oxygen (Aldrich et al., 1995). Leovic et al. (1996, 1998) measured O3

emissions from four dry-process photocopiers. Ozone emissions ranged from 1300 to

7900 μg/h.

Most electrostatic air filters and precipitators are designed to minimize the production 

of O3. However, if excessive arcing occurs, the units can emit a significant amount of O3 into

the indoor environment (Weschler, 2000). Niu et al. (2001) measured O3 emissions from 27 air

cleaners that used ionization processes to remove particulates. The test were conducted in a

2 × 2 × 1.60 m3

 stainless steel environmental chamber. The tests were terminated after 1.5 h

if no increase in O3 concentration was noted. If an increase in O3 was noted, the test was

(AX3-10)
AX3-216

continued, in some cases, for up to 20 h. Most of the evaluated units emitted no O3 or only

small amounts. Five units were found to emit O3 ranging from 56 to 2757 μg/h. 

There are many brands and models of O3 generators commercially available. The amount

of O3 emitted by each unit depends on the size of the unit. Ozone emission rates have been

reported to range from tens to thousands of micrograms per hour (Weschler, 2000; Steiber,

1995). Ozone emissions supposedly can be regulated using the units control features. However,

available information suggests that O3 output may not be proportional to the control setting. 

Some units are equipped with a sensor that automatically controls O3 output by turning the unit

on and off. The effectiveness of the sensor is unknown (U.S. Environmental Protection

Agency, 2002).

Peroxyacyl nitrates (PAN and PPN) have no known direct emission sources and are

formed in the atmosphere from the reaction of NO2 and hydrocarbons (Grosjean et al., 1996). 

Peroxyacyl nitrates primarily occur in the indoor environment from infiltration through the

building envelop and through openings in the building envelopment. Peroxyacyl nitrates also

may be formed in the indoor environment through radical chemistry. PAN may be formed from

the reaction of the OH@ or NO3 with acetaldehyde to form the acetyl radical, CH3CO. The acetyl

radical then reacts with oxygen to form and acetylperoxy radical which reacts with NO2 to form

PAN.

(AX3-13)

PPN is formed from when the reaction of the OH@ with propionaldehyde (Weschler and

Shields, 1997).

AX3.10.8 Trends in Concentrations within Microenvironments

There have not been sufficient numbers of measurements of personal exposures or indoor

O3 concentrations to directly document trends over time or location. However, since O3

(AX3-11)

(AX3-12)
AX3-217

concentrations in all microenvironments are primarily derived from ambient sources, trends in

ambient air concentrations should reflect trends in personal exposure unless there are differences

in activity patterns over time or locations. Overall, a significant downward trend in ambient O3

concentrations has occurred from 1980 in most locations in the United States, although the trend

in the latter part of the 1990s suggests that continued improvements in air quality may have

leveled off. Greater declines in ambient O3 concentrations appear to have occurred in urban

centers than in rural regions. The decline in daily and weekly average O3 concentrations from

1989 to 1995 in rural regions was 5% and 7%, respectively (Wolff et al., 2001; Lin et al., 2001;

Holland et al., 1999). A detailed discussion of O3 trends appears earlier in this annex.

AX3.10.9 Characterization of Exposure

AX3.10.9.1 Use of Ambient Ozone Concentrations

The use of ambient air monitoring stations is still the most common surrogate for assigning

exposure in epidemiological studies. Since the primary source of O3 exposure is the ambient air,

monitoring concentration data would provide the exposure outdoors while exercising, a potential

important exposure to evaluate in epidemiological studies as well as a relative assignment of

exposure with time if the concentration were uniform across the region; the time-activity pattern

were the same across the population; and the housing characteristics, such as ventilation rates

and the O3 sinks contributing to its indoor decay rates, were constant for the study area. Since

these factors vary by population and location there will be errors in not only the magnitude of the

total exposure, but also in the relative total exposure assignment based solely on ambient

monitoring data. As discussed earlier in this section, spatial differences in O3 concentrations

within a city and between the height of the monitor and the breath zone (1 to 2 m) exist,

increasing uncertainties. The potential exists to obtain more complete exposure assignments for

both individuals and populations by modeling O3 exposure based on ambient air concentration to

account for spatial variations outdoors and for time spent indoors, provided housing

characteristics and activity patterns can be obtained. For cohort studies, measurement of

personal O3 exposures using passive monitors is also possible.

The potential for error in determining pollutant exposure was expressed by Krzyzanowski

(1997), who indicated that while the typical estimate of exposure in epidemiological studies is

“an average concentration of the pollutant calculated from the data routinely collected in the area
AX3-218

of residence of the studied population. This method certainly lacks precision and, in most cases,

the analyses that use it will underestimate the effect of specific concentrations of a pollutant on

health.” It is further stated that when estimating exposure for epidemiological studies it is

important to define: (1) representativeness of exposure or environmental data for the population

at risk, (2) appropriateness of the averaging time for the health outcome being examined, and

(3) the relationship between the exposure surrogate and the true exposure relative to the

exposure-response function used in the risk assessment. Zeger et al. (2000) suggested that the

largest biases will occur because of errors between ambient and average personal exposure

measures. Sheppard et al. (2005a) further indicated that for non-reactive pollutants with nonambient sources, exposure variability will introduce a large exposure error. However, for acute

effects, time series studies using ambient concentration measurements are adequate (Sheppard,

2005b).

Numerous air pollutants can have common ambient air sources resulting in strong

correlations among pollutant ambient air concentrations. As a result, some observed

associations between an air pollutant and health effects may be due to confounding by other air

pollutants. Sarnat et al. (2001) found that while ambient air concentrations of some air

pollutants were correlated, personal PM2.5 and several gaseous air pollutant (O3, SO2, NO2, CO,

and exhaust-related VOCs) exposures were not generally correlated. The findings were based on

the results of a multipollutant exposure study of 56 children and elderly adults in Baltimore, MD

conducted during both the summer and winter months. Ambient pollutant concentrations were

not associated with corresponding personal exposures, except for PM2.5. The gaseous pollutants

were found to be surrogates of PM2.5 and were generally not correlated. The authors concluded

that multipollutant models in epidemiologic studies of PM2.5 may not be suitable, and health

effects attributed to the gaseous pollutants may be the result of PM2.5 exposure. It should be

noted that the 95th percentile O3 concentrations in the study was lower than 60 ppb, an O3

concentration at which respiratory effects are noted. It would be important to examine whether

O3 is a surrogate for personal PM2.5 at high O3 levels when attributing adverse health effects to

O3 or PM2.5.

Künzli et al. (1996) assessed potential lifetime exposure to O3 based on the responses to a

standardized questionnaire completed by 175 college freshmen in California. Questions

addressed lifetime residential history, schools attended, general and outdoor activity patterns,
AX3-219

driving habits and job history. The purpose was to determine what O3 monitoring data to use for

each time period of their lives, the potential correction factor for indoor levels and periods of

high activity to account for differential doses to the lung due to physical activity. The reliability

of the responses was checked by having each respondent complete the questionnaire twice, on

different days, and the results compared. A lifetime O3 exposure history was generated for each

participant and a sensitivity analysis performed to evaluate which uncertainties would cause the

greatest potential misclassification of exposure. Assigned lifetime O3 concentrations from the

nearest monitor yielded highly reliable cumulative values, although the reliability of residential

location decreased with increasing residential locations. Individuals involved in moderate and

heavy exercise could be reliably identified. Such an approach can be used to evaluate health

outcomes associated with chronic exposures to O3.

AX3.10.9.2 Exposure Selection in Controlled Exposure Studies

Ozone exposures in the environment are variable over time due to changes in the ambient

concentrations during the day as the photochemical reactions proceed and also because people

move between microenvironments that have different concentrations (Johnson, 1997). 

Exposures are repeated on sequential days since weather conditions that produce O3 can move

slowly through or become stagnant within a region. For simplicity, most controlled-exposure

experiments are conducted at a single concentration for a fixed time period, with a limited

number of studies being repeated on a single individual. Few studies have been conducted using

multipollutants or photochemical agents other than O3, to better represent “real-world” exposures

with the exception of NO2. Studies by Hazucha et al. (1992), Adams (2003), and Adams and

Ollison (1997) examined the effect of varying O3 exposure concentrations on pulmonary

function. A description of, and findings in, the studies appears in Annex AX5 of this document.

AX3.10.9.3 Exposure to Related Photochemical Agents

Exposures to other related photochemical agents have not been measured using personal

samplers nor are these agents routinely measured at O3 monitoring stations. Photochemical

agents produced in the ambient air can penetrate indoors and react with other pollutants to

produce other potentially irritating compounds. Reiss et al. (1995) reported that organic acids,

aldehydes and ketones were produced indoors by reactions of O3 with VOCs. The produced

compounds included oxidants that can be respiratory irritants. The indoor concentrations were
AX3-220

dependent upon the O3 concentrations indoors and the AER within the building. Weschler and

Shields (1997) summarized indoor air chemical reactions that depend directly or indirectly on

the presence of O3. They indicated that O3 concentrations are lower indoors than outdoors partly

because of gas-phase reactions that produce other oxidants in an analogous fashion to

photochemical smog in ambient air. The production of these species indoors is a function of the

indoor O3 concentration and the presence of the other necessary precursors, VOCs, and NO2,

along with an optimal AER. A variety of the photochemical oxidants related to O3 that are

produced outdoors, such as PAN and PPN, can penetrate indoors. These oxidants are thermally

unstable and can decompose indoors to peroxacetyl radicals and NO2 through thermal decay. 

PAN removal increases with increasing temperature, and at a given temperature, with increasing

NO/NO2 concentration ratio (Grosjean et al., 2001). Other free radicals that can form indoors

include HOC and HO2

C

. These free radicals can produce compounds that are known or suspected

to be irritating. Little is known about exposure to some of these agents, as not all have been

identified and collection and analytical methodologies have not be developed for their routine

determination. Lee et al. (1999) reported that homogeneous (gas phase) and heterogenous (gas

phase/solid surface) reactions occur between O3 and common indoor air pollutants such as NO

and VOCs to produce secondary products whose production rate depends on the AER and

surface area within the home. Wainman et al. (2000) found that O3 reacts indoors with

d-limonene, emitted from air fresheners, to form fine particles in the range of 0.1 to 0.2 μm and

0.2 to 0.3 μm. The indoor process also produces compounds that have been identified in the

ambient atmosphere. These species, plus others that may form indoors from other terpenes or

unsaturated compounds can present an additional exposure to oxidants, other than O3, at higher

concentrations than present in ambient air, even as the O3 concentration is being reduced

indoors. 

The announcement of smog alerts or air quality indices may influence individuals to alter

behaviors (avoidance behavior). Neidell (2004), in his evaluation of the effect of pollution on

childhood asthma, examined the relationship between the issuance of smog alerts or air quality

indices for several counties in California and hospital admissions for asthma in children under

age 18 years (not including newborns). Smog alerts are issued in California on days when O3

concentrations exceed 200 ppb. There was a significant reduction in the number of asthma-
AX3-221

related hospital admissions in children ages 1 to 12 years on smog alert days, indicating that

avoidance behavior might be present on days of high O3 concentrations. 

Ozone exposure modeling has been conducted for the general population and sensitive

subgroups. The pNEM/O3 model takes into consideration the temporal and spatial distribution

of people and O3 throughout the area of consideration, variations in O3 concentrations within

microenvironments, and the effects of exertion/exercise (increased ventilation) on O3 uptake. 

The pNEM/O3 model consists of two principal parts: the cohort exposure program and the

exposure extrapolation program. The methodology incorporated much of the general framework

described earlier in this section on assessing O3 exposure and consists of five steps: (1) define

the study area, population of interest, subdivisions of the study area, and exposure period;

(2) divide population of interest into a set of cohorts; (3) develop exposure event sequence for

each cohort for the exposure period; (4) estimate pollutant concentration and ventilation rate for

each exposure event; and (5) extrapolate cohort exposures to population of interest (U.S.

Environmental Protection Agency, 1996b).

There are three versions of the pNEM/O3 model: general population (Johnson et al.,

1996a), outdoor workers (Johnson et al., 1996b), and outdoor children (Johnson et al., 1996c,

1997). These three versions of the model have been applied to nine urban areas. The model also

has been applied to a single summer camp (Johnson et al., 1996c). The general population

version of the model uses activity data from the Cincinnati Activity Diary Study (CADS;

Johnson, 1989). Time-activity studies (Wiley et al., 1991a; Johnson, 1984; Linn et al., 1993;

Shamoo et al., 1991; Goldstein et al., 1992; Hartwell et al., 1984) were combined with the CADS

data for the outdoor worker version of the model. Additional time-activity data (Goldstein et al.,

1992; Hartwell et al., 1984; Wiley et al., 1991a,b; Linn et al., 1992; Spier et al., 1992) were also

added to CADS for the outdoor children of the model (U.S. Environmental Protection Agency,

1996b). Home-work commuting patterns are based on information gathered by the U.S. Census

Bureau. Ozone ambient air concentration data from monitoring stations were used to estimate

the outdoor exposure concentrations associated with each exposure event. Indoor O3 decay rate

is assumed to be proportional to the indoor O3 concentration. An algorithm assigns the

equivalent ventilation rate (EVR) associated with each exposure event. The outdoor children

model uses an EVR-generator module to generate an EVR value for each exposure event based

on data on heart rate by Spier et al. (1992) and Linn et al. (1992). The models produce exposure
AX3-222

estimates for a range of O3 concentrations at specified exertion levels. The models were used to

estimate exposure for nine air quality scenarios (U.S. Environmental Protection Agency, 1996b). 

Korc (1996) used the REHEX-II model, a general purpose air pollution exposure model

based on a microenvironmental approach modified to account for the influence of physical

activity along and spatial and the temporal variability of outdoor air pollution. Ozone exposure

was estimated by demographic groups across 126 geographic subregions for 1980 to 1982, and

for 142 geographic subregions for 1990 to 1992. Simulation results were determined for

population race, ethnicity, and per capita income and included indoor, in-transit, and outdoor

microenvironments. Exposure modeling was stratified by age because of differences in timeactivity patterns. Exposure distributions by regional activity pattern data were not considered,

rather it was assumed that all individuals within a county had the same exposure distribution by

race, ethnicity, and socioeconomic status. Model results for southern California indicated that

the segment of the population with the highest exposures were children 6 to 11 years old. 

Individuals living in low income districts may have greater per capita hours of exposure to O3

above the NAAQS than those living in higher income districts. The author indicated that O3

exposure differences by race and ethnicity have declined over time. The noninclusion of details

on activity patterns for different populations in the model limit the extrapolations that can be

made from the model results.

Children appear to have higher exposures than adults and the elderly. Asthmatics appear to

ventilate more than healthy individuals, but tend to protect themselves by decreasing their

outdoor exercise (Linn et al., 1992). Additional data are still needed to identify and better define

exposures to potentially susceptible populations and improve exposure models for the general

population and subpopulation of concern. 
AX3-223

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report]. Sacramento, CA: California Environmental Protection Agency, Air Resources Board; contract no.

A033-205.

Adams, W. C. (2003) Comparison of chamber and face mask 6.6-hour exposure to 0.08 ppm ozone via square-wave

and triangular profiles on pulmonary responses. Inhalation Toxicol. 15: 265-281.

Adams, W. C.; Ollison, W. M. (1997) Effects of prolonged simulated ambient ozone dosing patterns on human

pulmonary function and symptomatology. Presented at: 90th annual meeting of the Air & Waste

Management Association; June; Toronto, Ontario, Canada. Pittsburgh, PA: Air & Waste Management

Association; paper no. 97-MP9.02.

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AX4-1

ANNEX AX4. DOSIMETRY OF OZONE IN

THE RESPIRATORY TRACT

AX4.1 INTRODUCTION

This annex serves to provide supporting material for Chapter 4—Dosimetry, Species,

Homology, Sensitivity, and Animal-to-Human Extrapolation. It includes tables that summarize

new literature published since the 1996 Ozone Air Quality Criteria Document or O3 AQCD (U.S.

Environmental Protection Agency, 1996). In addition, it provides descriptions of the new

findings, in many cases, with more detail than is provided in the chapter. 

Dosimetry refers to the measurement or estimation of the quantity of or rate at which a

chemical and/or it reaction products are absorbed and retained at target sites within the

respiratory tract (RT). The compound most directly responsible for toxic effects may be the

inhaled gas, ozone (O3), or one of its chemical reaction products (e.g., aldehydes or peroxides). 

Complete identification of the actual toxic agents and their integration into dosimetry is a

complex issue that has not been fully resolved. Thus, most dosimetry investigations are

concerned with the dose of the primary inhaled chemical. In this context, a further confounding

aspect can be the units of dose (e.g., mass retained per breath, mass retained per breath per body

weight, mass retained per breath per RT surface area). That is, when comparing dose between

species, what is the relevant measure of dose? This question has not been answered; units are

often dictated by the type of experiment or by a choice made by the investigators. There is also

some lack of agreement as to what constitutes “dose.” Dahl’s seminal paper (1990) classified O3

as a reactive gas and discussed the characterization of dose measurement by parameters,

including: (1) inhaled O3 concentration; (2) amount of O3 inhaled as determined by minute

volume, vapor concentration, and exposure duration; (3) uptake or the amount of O3 retained

(i.e., not exhaled); (4) O3 or its active metabolites delivered to target cells or tissues; (5) O3 or its

reactive metabolites delivered to target biomolecules or organelles; and (6) O3 or its metabolites

participating in the ultimate toxic reactions–the effective dose. This characterization goes from
AX4-2

least complex to greatest, culminating in measurement of the fraction of the inhaled O3 that

participates in the effects of cellular perturbation and/or injury. 

Understanding dosimetry as it relates to O3-induced injury is complex due to the fact

that O3 interacts primarily with the epithelial lining fluid (ELF), which contains surfactant and

antioxidants. Ozone reacts with molecules in the ELF to create reactive metabolites, which can

then diffuse within the lung or be transported out of the lung to generate systemic effects. 

Antioxidant defenses can vary between species, region of the RT, and animal age. Section 5.3.1

contains further information on the cellular targets of O3 interactions and antioxidants.

Experimental dosimetry studies in laboratory animals and humans, as well as theoretical

(dosimetry modeling) studies, have been used to obtain information on O3 dose. Since the

1996 O3 AQCD (U.S. Environmental Protection Agency, 1996), most new experiments have

been carried out in humans to obtain direct measurements of absorbed O3 in the RT, the upper

RT (URT) region proximal to the tracheal entrance, and in the tracheobronchial (TB) region. 

Experimentally obtaining dosimetry data is extremely difficult in smaller RT regions or

locations, such as specific airways or the centriacinar region (CAR; junction of conducting

airways and gas exchange region), where lesions caused by O3 occur. Nevertheless,

experimentation is important for determining dose, making dose comparisons between

subpopulations and between different species, assessing hypotheses and concepts, and validating

mathematical models that can be used to predict dose at specific RT sites and under more

general conditions.

Theoretical studies are based on the use of mathematical models developed for the

purposes of simulating the uptake and distribution of absorbed gases in the tissues and fluids of

the RT. Because the factors affecting the transport and absorption of gases are applicable to all

mammals, a model that uses appropriate species or disease-specific anatomical and ventilatory

parameters can be used to describe absorption in the species and in different-sized, aged, or

diseased members of the same species. More importantly, models also may be used to make

interspecies and intraspecies dose comparisons, to compare and reconcile data from different

experiments, to predict dose in conditions not possible or feasible experimentally, and to better

understand the processes involved in toxicity. However, virtually all of these models have

assumed that the reaction rate of O3 in the liquid lining layer and in tissues is quasi first-order
AX4-3

with respect to O3 concentration. There is considerable discrepancy between rate constants used

in models. Both the uptake of O3 at the gas-liquid interface and the fraction of O3 (or its reaction

products) that reach epithelial cells are sensitive to the value of these reaction rate constants. 

A large disparity in rate constants between studies illustrates the limitations in our current state

of knowledge and can potential lead to erroneous interpretation of O3 model predictions. 

A review (Miller, 1995) of the factors influencing RT uptake of O3 stated that structure of

the RT region, ventilation, and gas transport mechanisms were important. Additionally, local

dose is the critical link between exposure and response. A more detailed discussion of

experimental and theoretical dosimetry studies is available in the 1996 O3 AQCD (Volume III,

Chapter 8, U.S. Environmental Protection Agency, 1996). 

AX4.2 EXPERIMENTAL OZONE DOSIMETRY INVESTIGATIONS

There have been some advances in understanding human O3 dosimetry that better enable

quantitative extrapolation from laboratory animal data. The next two sections review the

available new experimental studies on O3 dosimetry, which involve only human subjects and are

all from the same laboratory. Of the studies considered in the following discussion, five

involved the use of the bolus response method as a probe to obtain information about the

mechanism of O3 uptake in the URT and TB regions. Of the remaining two investigations, one

focused on total uptake by the RT and the other on uptake by the nasal cavities. Table AX4-1

provides a summary of the newer human studies.

AX4.2.1 Bolus-Response Studies

The bolus-response method has been used as a probe to explore the effects of physiological

and anatomical differences or changes on the uptake of O3 by human beings.

Asplund et al. (1996) studied the effects of continuous O3 inhalation on O3 bolus uptake,

and Rigas et al. (1997) investigated the potential effects of continuous coexposure to O3,

nitrogen dioxide (NO2), or sulfur dioxide (SO2) on O3 absorption. In both of these studies, 
AX4-4

Table AX4-1. New Experimental Human Studies on Ozone Dosimetry a

Purpose/Objective

SubjectCharacteristics

Region ofInterest

BreathingPatterns/Exposure Results 

Determine the effectof continuous O3

inhalation on O3uptake

8 male,3 female,22-31 years old,166-186 cm,64-93 kg

Centralconductingairways(70-120 mLfrom lips)

2 h of continuous exposure atrest: 0.0, 0.12, and 0.36 ppmO3. Spontaneous breathing. 

Bolus test breaths every30 min using 250 mL/secconstant flow rate.

Averaged over all subjects and the measurement intervals, the absorbe(AF) changed +0.045, !0.005, and 

the 0, 0.12, and 0.36 ppm continuoexposures, respectively. These chaapproximately +6, !1, and !4 % b

average AF value of 0.7 in the rang120 mL.b Both nonzero exposures 

significantly different than the air e

Evaluate theinfluence of VD on

intersubject variationof O3 dose.

10 male, 22-30 years old,163-186 cm, 64-92 kg; 10 female, 22-35 years old, 149-177 cm,48-81 kg

Conductingairways

Bolus-response test (VT = 500

mL at 250 mL/sec constantflow rate). Fowler singlebreath N2 washout method to

determine VD.

On average, for the same VP , wom

larger AF than men; women had a 

than men. However, for the same vVP/VD, AF for men and women we

indistinguishable. Further analysis “that previously reported gender dimay be due to a failure in properly for tissue surface within the conduairways.”

Investigate theeffect of continuousexposure to O3,

nitrogen dioxide andsulfur dioxide on O3

absorption.

6 male, 21-29 yearsold, 165-185 cm,60-92 kg;6 female,19-33 years old,152-173 cm,48-61 kg

Lowerconductingairways(70-120 mLfrom lips)

2 h of continuous exposureat rest: O3 (0, 0.36 ppm),

SO2 (0, 0.36 ppm), or NO2

(0, 0.36, 0.75 ppm).5-min Bolus test every30 min: VT = 500 mL;

250 mL/sec constantflow rate.

Averaging over all subjects or by gexposures except O3 resulted in an 

AF. Based on an AF reference val

change in AF ranged from !3 to +7 

Only the O3 and the NO2 (0.36 ppm

exposures were significantly differthe air exposures.
AX4-5

Table AX4-1 (cont’d). New Experimental Human Studies on Ozone Dosimetry a

Purpose/Objective

SubjectCharacteristics

Region ofInterest

BreathingPatterns/Exposure Results 

Compare theabsorption ofchlorine and O3. 

Determine how thephysical-chemicalproperties of thesecompounds affecttheir uptakedistribution inthe RT.

5 male, 21-26 yearsold, 168-198 cm,64-95 kg; 5 female,18-28 years old,162-178 cm, 55-68 kgc

Conductingairways. Nasal andoral routes

Bolus-response technique;VT = 500 mL; 3 constant flow

rates: 150, 250, and1000 mL/sec.

Ozone dose to the URT was sensitimode of breathing and to the respirWith increased airflow rate, O3 reta

upper airways decreased from 95 to TB region dose ranged from 0 to 3Mass transfer theory indicated that diffusion resistance of the tissue phimportant for O3. The gas phase re

were the same for O3 and Cl2.

To determine O3uptake relative toinhaled O3 dose.

5 male,5 female,18-35 years old,175 ± 13 (SD) cm,72 ± 13 (SD) kg

Respiratorytract; oralbreathing

Breath-by-breath calculationof O3 retention based on data

from fast response analyzersfor O3 and airflow rates. 

Oral breathing: 0.2 or0.4 ppm O3 at VE of

approximately 20 L/minfor 60 min or 40 L/min for30 min.

The FA for all breaths was 0.86. Concentration, minute volume, and small but statistically significant efwhen compared to intersubject varThe investigators concluded: for a subject, constant O3 exposure, a giv

level, and time <2 h, inhaled dose ireasonable surrogate for the actual of O3. However, the actual doses m

considerably among individuals whexposed to similar inhaled doses.
AX4-6

Table AX4-1 (cont’d). New Experimental Human Studies on Ozone Dosimetry a

Purpose/Objective

SubjectCharacteristics

Region ofInterest

BreathingPatterns/Exposure Results 

Study the effect ofgas flow rate and O3

concentration on O3uptake in the nose.

7 male, 3 female,26 ± years, 170 ± 11 (SD) cm,75 ± 20 (SD) kg

Nasalcavities

For a given flow rate andexposure concentration, thesubjects inhaled through onenostril and exhale through theother. For two 1-h sessions,a series of 9-12 measurementsof AF were carried out for10 s each: (1) O3 exposure

concentration = 0.4 ppm; flowrates = 3, 5, 8, and 15 L/min. (2) O3 exposure = 0.1, 0.2,

and 0.4 ppm; flow rate =15 L/min.(3) O3 exposure

= 0.4 ppm, flow rate= 15 L/min; AF was measuredevery 5 min for 1 h.

(1) With the exposure concentratio0.4 ppm O3, AF decreased from 0.8

0.33 when the flow rate was increa3 to 15 L/min. (2) At a flow rate othe AF changed from 0.36 to 0.32 wexposure concentration increased f0.4 ppm O3. (3) Statistical analysis that the AF was not associated with which the measurement was taken.

Evaluate intersubjectvariability in O3

uptake; correlatedifferences inbreathing pattern andlung anatomy with O3uptake

nonsmokers,32 male, 22.9 ± 0.8years old,178±1 cm,80.6 ± 2.5kg;28 female,22.4 ± 0.9 years old,166 ± 1 cm,62.1 ± 2.2 kg

Respiratorytract; oralbreathing

Continuous: 1 h exposure to0.25 ppm, exercising at30L/min.Bolus: breath-by-breathcalculation of O3 retention.

Timing of bolus varied tocreate penetration volumes of10 to 250 mL. Peak inhaledbolus of ~1 ppm.

Continuous: Fractional O3 uptake 

ranged from 0.70 to 0.98 (mean 0.8Inverse correlation between uptake breathing frequency. Direct correlbetween uptake and tidal volume. differences in forced respiratory redue to differences in O3 uptake.

Bolus: The penetration volume at of the bolus was taken up was 90.4 females and 107 mL in males. DisO3 shifts distally as the size of the 

increases.

a See Appendix A for abbreviations and acronyms.b Fig. 4, Hu et al. (1994), for the 250 mL/s curve and penetration volume range of 70 to 120 mL; the average AF is approximately 0.7.c Subject characteristics are from Nodelman and Ultman (1999b).
AX4-7

subjects were exposed “continuously” to a gas for 2 h. Every 30 min, breathing at 250 mL/s,

a series of bolus test breaths was performed targeted at the lower conducting airways.

Differences in bolus-response absorbed fraction from an established baseline indicated the

degree to which the “continuous” gas exposure affected the absorption of O3. Depending on the

gas and concentration, changes in absorbed fraction ranged from !3 to +7 % (see Table AX4-1). 

Continuous O3 exposure lowered the uptake of O3, whereas NO2 and SO2 increased the uptake

of O3. The investigators concluded that in the tested airways, NO2 and SO2 increased the

capacity to absorb O3 because more of the compounds oxidized by O3 were made available. 

On the other hand, they conjectured that continuous O3 exposure depleted these compounds,

thereby reducing O3 uptake. 

Bush et al. (1996a) investigated the effect of lung anatomy and gender on O3 absorption in

the conducting airways during oral breathing using the bolus-response technique. Absorption

was measured using this technique applied to 10 men and 10 women. Anatomy was defined in

terms of forced vital capacity (FVC), total lung capacity (TLC), and dead space (VD). The

absorbed fraction data were analyzed in terms of a function of penetration volume, airflow rate,

and an “intrinsic mass transfer parameter” called the overall mass transfer coefficient (Ka),

which was determined for each subject and found to be highly correlated with VD, but not with

height, weight, age, gender, FVC, or TLC. That is, in all subjects, whether men or women,

dosimetry differences could be explained by differences in VD. Combining their data with those

of Hu et al. (1994), where absorbed fraction was determined for several flow rates, Bush et al.

(1996a) inferred that Ka was proportional to flow rate/VD. The investigators point out that the

applicability of their results may be limited because of their assumptions that Ka was

independent of location in the RT and that there was no mucous resistance. They also suggested

that the dependence of Ka on flow rate and VD be restricted to flow rates #1000 mL/s until

studies at higher rates have been performed.

With flow rates of 150, 250, and 1000 mL/s, Nodelman and Ultman (1999b) used the

bolus-response technique (a) to compare the uptake distributions of O3 and chlorine gas (Cl2) and

(b) to investigate how their uptakes were affected by their physical and chemical properties. 

Ozone dose to the URT was found to be sensitive to the mode of breathing and to the airflow

rate. With increased rate, O3 retained by the upper airways decreased from 95 to 50% and TB
AX4-8

region dose increased from 0 to 35%. At the highest flow rate only 10% of the O3 reached the

pulmonary region. Data were analyzed by expressing the overall diffusion resistance between

the respired gas and the epithelial cells as the sum of individual gas-phase and liquid-phase

resistances. The liquid-phase resistance made an important contribution to the overall resistance,

implying that changes in the reaction rate of O3 in ELF would cause concomitant changes in

the O3 uptake. The gas-phase resistance was inversely related to the volumes of the oral and

nasal cavities during oral and nasal breathing, respectively. 

Ultman et al. (2004) used separate bolus and continuous exposure sessions to test the

hypotheses that differences in O3 uptake in lungs are responsible for variation in O3-induced

changes in lung function parameters and that differences in O3 uptake are due to variations in

breathing patterns and lung anatomy. Thirty-two males and 28 female nonsmokers were

exposed to bolus penetration volumes ranging from 10 to 250 mL, which was determined by the

timing of the bolus injection. The subjects controlled their breathing to generate a target respired

flow of 1000 mL/sec. At this high minute ventilation, there was very little uptake in the upper

airway and most of the O3 reached areas where gas exchange takes place. To quantify

intersubject differences in O3 bolus uptake, they measured the penetration volume at which 50%

of the O3 was taken up. Values for penetration volume ranged from 69 to 134 mL and were

directly correlated with the subjects’ values for anatomic dead space volume. A better

correlation was seen when the volume of the upper airways was subtracted. The penetration

volume at which 50% of the bolus was taken up was 90.4 mL in females and 107 mL in males. 

This significant difference in uptake suggests to the authors that, in females, the smaller airways

and associated larger surface-to-volume ratio enhance local O3 uptake and cause reduced

penetration of O3 into the distal lung. Data from the continuous exposure sessions indicated that

overall O3 uptake was related to breathing pattern but was not correlated with VD. Thus, these

findings indicate that overall O3 uptake is not related to airway size, but that the distribution

of O3 shifts distally as the size of the airway in increased. 

General comment on estimating mass transfer coefficients: Bush et al. (1996b) and Nodelman

and Ultman (1999a) used a simple model to analyze their bolus-response data. This model,

presented by Hu et al. (1992, 1994), assumed steady-state mass transfer by convection (but no
AX4-9

dispersion) and the mass transfer of O3 to the walls of a tube of uniform cross-sectional area. 

These assumptions led to an analytical solution (for the absorbed fraction) which was a function

of an “overall mass transfer coefficient,” penetration volume, and airflow rate. As the

investigators have shown, the model is very useful for statistical analysis and hypothesis testing. 

Given the absorbed fraction data, the model overall mass transfer coefficients were estimated for

each flow rate. In those bolus-response studies that used this method to analyze data, there was

no discussion of the models’ “accuracy” in representing mass transfer in the human RT with

respect to omitting dispersion. In addition, the formulation of the gas phase mass transfer

coefficient does not take into account that it has a theoretical lower limit greater than zero as the

airflow rate goes to zero (Miller et al., 1985; Bush et al., 2001). As a consequence, there is no

way to judge the usefulness of the values of the estimated mass transfer coefficients for

dosimetry simulations that are based on convection-dispersion equations, or whether or not the

simple model’s mass transfer coefficients, as well as other parameters derived using these

coefficients, are the same as actual physiological parameters.

AX4.2.2 General Uptake Studies

Rigas et al. (2000) performed an experiment to determine the ratio of O3 uptake to the

quantity of O3 inhaled (fractional absorption, FA). Five men and five women were exposed

orally to 0.2 or 0.4 ppm O3 while exercising at a minute volume of approximately 20 L/min for

60 min or 40 L/min for 30 min. Ozone retention was calculated from breath-by-breath data

taken from fast response analyzers of O3 and airflow rates. The FA was statistically analyzed in

terms of subject, exposure concentration, minute volume, and exposure time.

Fractional absorption ranged from 0.56 to 0.98, with a mean ± SD of 0.85 ± 0.06 for all

2000 recorded breaths. Intersubject differences had the largest influence on FA, resulting in a

variation of approximately 10%. Statistical analysis indicated that concentration, minute

volume, and exposure time had statistically significant effects on FA. However, relatively large

changes in these variables were estimated to result in relatively small changes in FA. Note: the

quantity of O3 retained by the RT is equal to FA times the quantity of O3 inhaled; thus, relatively

large changes in concentration, minute volume, or exposure time may result in relatively large
AX4-10

changes in the amount of O3 retained by the RT or absorbed locally. Also, according to Overton

et al. (1996), differences in PAR dose due to anatomical variability may be considerably larger

than corresponding small changes in FA would indicate.

Santiago et al. (2001) studied the effects of airflow rate and O3 concentration on O3 uptake

in the nasal cavities of three women and seven men. Air was supplied at a constant flow rate to

one nostril and exited from the other nostril while the subject kept the velopharyngeal aperture

closed by raising the soft palate. Thus, a constant unidirectional flow of air plus O3 was

restricted to the nasal cavities. The fraction of O3 absorbed was calculated using the inlet and

outlet concentrations. Inlet concentration and airflow rate were varied in order to determine their

effect on O3 uptake.

The mean FA decreased from 0.80 to 0.33, with an increase in flow rate from 3 to

15 L/min. The effect of both flow rate and subject on FA was statistically significant. Further

analysis indicated that the overall mass transfer coefficient was highly correlated with the flow

rate and that the gas phase resistance contributed from 6.3% (15 L/min) to 23% (3 L/min) of the

total resistance to O3 transfer to the nasal cavity surface. Concentration had a small, but

statistically significant effect on FA, when the inlet concentration was increased from 0.1 to

0.4 ppm O3, FA decreased from 0.36 to 0.32. The investigators observed that differences in FA

among subjects were important; generally, subject variability accounted for approximately half

of the total variation in FA.

As mentioned above, Ultman et al. (2004) tested hypotheses that differences in O3 uptake

in lungs are responsible for variation in O3-induced changes in lung function parameters and that

differences in O3 uptake are due to variations in breathing patterns and lung anatomy. Thirtytwo males and 28 female nonsmokers were exposed continuously for 1 h to either clean air or

0.25 ppm O3 while exercising at a target minute ventilation of 30 L/min. Ultman et al. first

determined the forced expiratory response to clean air, then evaluated O3 uptake measuring dead

space volume, cross-sectional area of peripheral lung (Ap) for CO2 diffusion, FEV1, FVC,

and FEF25%-75%. The fractional O3 uptake efficiency ranged from 0.70 to 0.98, with a mean of

0.89 ± 0.06. They found an inverse correlation between uptake and breathing frequency and a

direct correlation between uptake and tidal volume. There was a small, but statistically

significant decrease in uptake efficiency during the four sequential 15 min intervals of the 1 h 
AX4-11

exposure (0.906 ± 0.058 vs. 0.873 ± 0.088, first and last interval, respectively), in part due to the

increased breathing frequency and decreasing tidal volume occurring over the same period. 

Ozone uptake rate correlated with individual %Ap, but did not correlate with individual %FEV1. 

Neither of these parameters correlated with the penetration volume determined in the bolus

studies mentioned above. The authors concluded that the intersubject differences in forced

respiratory responses were not due to differences in O3 uptake. However, these data did partially

support the second hypothesis, i.e., that the differences in cross-sectional area available for gas

diffusion induce differences in O3 uptake. 

Plopper et al. (1998) examined the relationship between O3 dose and epithelial injury in

Rhesus monkeys. Using 18O content in lung tissues, the respiratory bronchioles were confirmed

as the site receiving the greatest O3 dose (mass 18O per dry lung weight). Furthermore, the

greatest cellular injury occurred in the vicinity of the respiratory bronchioles and was dependent

on the delivered O3 dose to these tissues. After a 2 h exposure, the antioxidant glutathione

(GSH) was increased in the proximal intrapulmonary bronchus after 0.4 ppm O3 and decreased

in the respiratory bronchiole after 1.0 ppm O3. Perhaps an adaptive response, chronic O3

exposure leads to increased GSH levels in distal bronchioles of both rats and monkeys relative to

GSH levels in FA-exposed animals (Duan et al ., 1996). Differences in the levels of antioxidants

between species and regions of the lung do not appear to be the primary factor determining

susceptibility to O3-induced tissue injury (Duan et al ., 1993, 1996). Plopper et al

. (1998) concluded that, in monkeys, there was a close association between site-specific O3 dose,

the degree of epithelial injury, and reduced-glutathione depletion. Within a species, antioxidant

defenses against O3 can also vary with animal age (Servias et al ., 2005) and exposure history

(Duan et al., 1996). 

AX4.2.3 Dosimetry Modeling

When all of the animal and human in vivo O3 uptake efficiency data are compared, there is

a good degree of consistency across data sets (U.S. Environmental Protection Agency, 1996). 

This agreement raises the level of confidence with which these data sets can be used to support

dosimetric model formulations. 
AX4-12

Schelegle et al. (2001) reported that the terminal bronchioles supplied by short and long

paths had similar epithelial injury in rats exposed to 1 ppm O3 for 8 h. Interestingly, in rats with

a C-fiber conduction block to prevent O3-induced rapid shallow breathing, it was the long path

terminal bronchioles that received the greatest epithelial injury. Overall, O3-induced rapid

shallow breathing appears to protect the large conducting airways while producing a more even

distribution of injury to the terminal bronchioles (Joad et al ., 2000; Schelegle et al ., 2001). 

Postlethwait et al . (2000) have also identified the conducting airways as a primary site of

acute O3-induced cell injury. Such data must be considered when developing models that

attempt to predict site-specific locations of O3-induced injury. The early models computed

relationships between delivered regional dose and response with the assumption that O3 was the

active agent responsible for injury. It is now known that reactive intermediates, e.g., aldehydes

and hydrohydroxyperoxides are important agents mediating the response to O3 (further discussed

in Section 5.3.1). Thus, models must consider O3 reaction/diffusion in the ELF and ELF-derived

reactions products.

Table AX4-2 presents a summary of new theoretical studies on the uptake of O3 by the RTs

(or regions) of humans and laboratory animals that have become available since the 1996 O3

AQCD review. They are discussed below.

Overton and Graham (1995) described the development and simulation results of a

dosimetry model that was applied to a TB region anatomical model that had asymmetrically

branching airways, but which had identical single-path pulmonary units distal to each terminal

bronchiole. The anatomical model of the TB region was based on Raabe et al. (1976), which

reported lung cast data for the TB region of a 330 g rat. In general, the modeled O3 dose to lung

tissues varied among anatomically equivalent ventilatory units as a function of path length from

the trachea, with shorter paths showing greater dose. This conflicts with Schelegle et al . (2001),

who exposed rats to 1 ppm O3 for 8 h and found that the terminal bronchioles supplied by

short and long paths had similar epithelial injury. In rats with a C-fiber conduction block to

prevent O3-induced rapid shallow breathing, it was the long path terminal bronchioles that

received the greatest epithelial injury. 
AX4-13

Table AX4-2. New Ozone Dosimetry Model Investigationsa

Purpose/Objective

Type of mass transportmodel/Anatomical model b

Species/RT region ofinterest/Regionalanatomical models

Ventilation andExposure Results 

To describe an RTdosimetry model thatuses a branching TBregion anatomicalmodel and toillustrate the resultsof its application to arat exposed to O3.

One-dimensional (along axisof airflow), time-dependent,convection-dispersionequation of mass transportapplied to each airway ormodel segment. URT: singlepath; TB: asymmetricbranching airways. PUL: single path anatomical modeldistal to each terminalbronchiole.

Rat/RT/URT: Patra et al. (1987).TB: multiple pathmodel of Raabe et al.(1976). PUL: Mercer et al.(1991).

f = 150 bpm;VT = 1.5, 2.0 ,2.5 mL.One constantconcentration.

(1) For VT = 2.0 mL, f = 150 bpm: The g

of the dose versus generation plot along athe trachea to a sac is independent of paththe tissue dose decreases with increasing index. In the TB region, the coefficient odose ranges from 0 to 34 %, depending oThe maximum ratio of the largest to smalthe same generation is 7; the average ratiIn the first PUL region model segment, thof variation for the dose is 29 %. (2) The to the first PUL region model segment inincreasing VT.

To incorporate intothe CFD model ofKimbell et al. (1993)resistance to masstransfer in the nasallining and toinvestigate theeffects of this liningon O3 uptake.

Three dimensional steadystate Navier-Stokes equationsfor solving air velocity flowfield. Three dimensionalsteady-state convectiondiffusion equation for O3

transport.Three-dimensional CFDmodel of the nasal passagesof a rat.

Rat/nasal passagesNasal passages: Kimbell et al. (1993).

Steady-stateunidirectional(“inhalation”)flow rate= 576 mL1/min. One constantconcentration.

Predictions of overall uptake were within measured uptake. Results suggest that mis important for describing O3 dosimetry 

thickness may play a role for determining of O3-induced lesions in the rat nasal pass

To determine if thesingle-path model isable to simulatebolus inhalation datarecorded during oralbreathing at quietrespiratory flow.

Single-path, one-dimensional(along axis of airflow),time-dependent, convectiondispersion equation of masstransport. Single-pathanatomical model.

Human/RT/URT(oral): Olson et al.(1973).LRT: Weibel (1963).

VT = 500 mL,

f = 15 bpm,constant flowrate = 250 mL/s. Bolus-responsesimulations.(protocol used isdescribed by Huet al., 1992).

Simulations are sensitive to conducting abut are relative insensitive to characteristrespiratory airspace. Although the gas-phto lateral diffusion limits O3 absorption d

breathing, diffusion through mucus may bimportant at the large respiratory flows thnormally associated with exercise. The sconvection-diffusion model was a reason/to simulate the bolus-response data.
AX4-14

Table AX4-2 (cont’d). New Ozone Dosimetry Model Investigations a

Purpose/Objective

Type of mass transportmodel/Anatomical model b

Species/RT region ofinterest/Regionalanatomical models

Ventilation andExposure Results 

To assess age- andgender-specificdifferences inregional andsystemic uptake.

PBPK, at ages 1, 3, 6, monthsand 1, 5, 10, 15, 25, 50, and75 years.

Human/ET/TB Pulmonary

ventilation rangedfrom 34 mL/s(in 1-month-old)to 190 mL/s(in 15-year-old). VT varied with age.

Regional extraction is insensitive to age. unit surface area is 2- to 8-fold higher in compared to adults. PU and ET regions hincrease in unit extraction with increasing postnatal period is time of largest differendue to immaturity of metabolic enzymes.

To examine theimpact on predictionsdue to the value usedfor the TB regionvolume at FRC anddue to TB regionvolume changeduring respiration.

Single-path, one-dimensional(along axis of airflow),time-dependent, convectiondispersion equation of masstransport. Single-pathanatomical model.

Human/RT/URT: Nunn et al.(1959)LRT: Weibel (1963)Rat/RT/URT: Patra et al. (1987)TB: Yeh et al. (1979)PUL: Mercer et al.(1991)

Human: VT = 500,

2250 mL; f = 15,30 bpm.Rat: VT = 1.4,

2.4 mL; f = 96,157 bpm.One constantconcentration.

(1) A better understanding and characterrole of TB region expansion (mainly the rvolume is important for an improved undrespiratory-tract dosimetry modeling of r(2) Extrapolations based on dose in the Psignificantly from those based on exposuconcentration or total uptake.(3) Human subjects who appear similar ohave very different PAR doses and potenresponses to the same exposure.(Uptake bwas not considered.)

To make parametermodifications so thata single-path modelwould simulate AFfrom bolus-responseexperimentsinvolving O3

(and Cl2).

Single-path, one-dimensional(along axis of airflow), timedependent, convectiondispersion equation of masstransport. Single-pathanatomical model.

Human/RT/URT(oral): Olson et al.(1973).URT (nasal): Olson et al. (1973)and Guilmette et al.(1989) LRT: Weibel (1963).

Oral and nasalbreathing. Flow rates = 150,250, 1000 mL/s,VT = 500 mL. Bolus-responsesimulations.

(Simulation results for O3 only) (1) Using 

values from the literature and assuming thwas gas-phase controlled, the simulations 

were realistic at flow rate = 250 mL/s, buat 1000 mL/s. (2) Accurate simulations arequired modification of mass transfer coreported in the literature for the conductin(3) It was necessary to include a diffusion the ELF based on an assumed O3 reaction 

that was much greater than in in vitro est(4) Partial validation of the final paramet(determined at 250 mL/s) was obtained bof bolus-response data at flow rates of 15mL/s. Validation was obtained also by siinternal measurements of O3 in subjects e

quiet breathing.

aSee Appendix A for abbreviations and acronyms.bThe anatomical models used in an investigation generally differ from those described in the references, e.g., dimensions are often scaled to dimensi

 dosimetry investigation; or the original structure may be simplified, keeping or scaling the original dimensions.
AX4-15

Rat effects data (from the PAR) are available that are identified with the lobe and the

generation in the lobe from which tissue samples were obtained (Pinkerton et al., 1995, 1998).

Models, like Overton et al. (1996), can be helpful in understanding the distribution of the

magnitude of such effects as well as suggesting sampling sites for future experiments.

Using computational fluid dynamics (CFD), Cohen-Hubal et al. (1996) explored the effect

of the mucus layer thickness in the nasal passage of a rat. The nasal lining was composed of

mucus and tissue layers in which mass transfer was by molecular diffusion with first order

chemical reaction. Physicochemical parameters for O3 were obtained from the literature. Three

scenarios were considered: 10 μm thick mucus layer, no mucus layer, and two nasal passage

regions each with a different mucus layer thickness. Predictions of overall uptake were within

the range of measured uptake. Predicted regional O3 flux was correlated with measured cell

proliferation for the CFD simulation that incorporated two regions, each with a different mucus

thickness. The reaction rate constant used by Cohen-Hubal and co-workers may be too low. 

Using bolus-response data, Hu et al. (1994) and Bush et al. (2001) estimated a reaction rate

constant that is more than a 1000 times as large as that used by Cohen-Hubal et al. (1996). 

A rate constant this large could result in conclusions different than those based on the smaller

constant.

With an RT dosimetry model, Overton et al. (1996) investigated the sensitivity of

absorbed fraction (AF), proximal alveolar region (PAR) dose, and PAR dose ratio to TB region

volume (VTB) and TB region expansion in human beings and rats. The PAR was defined as the

first generation distal to terminal bronchioles and the PAR dose ratio was defined as the ratio of

a rat’s predicted PAR dose to a human’s predicted PAR dose. This ratio relates human and rat

exposure concentrations so that both species receive the same PAR dose. In rats the PAR is a

region of major damage from O3. For each species, three literature values of VTB were used: 

a mean value and the mean ± twice the SD. The following predictions were obtained: 

(1) The sensitivity of AF and PAR dose to VTB depends on species, ventilation, TB region

overall mass transfer coefficient (kTB), and expansion. For kTB = 0.26 cm/s and quiet breathing,

AF was predicted to vary by less than 3% for the ±2 SD range of VTB. In contrast, the PAR

dose predicted for the smallest VTB is five times larger than the PAR dose predicted with the 
AX4-16

largest VTB. The effect of VTB is much less during heavy exercise: the ratio of maximum to

minimum PAR dose was approximately 1.5. In any case, the simulations predicted that

fractional changes in AF due to different VTB are not, in general, a good predictor of the

fractional changes in PAR doses.

(2) Relative to no expansion in the TB region, expansion decreases both AF and PAR

dose. The largest effect of including expansion in the human simulations was to decrease the AF

by .8%; in rats, the maximum decrease was .45%. The PAR doses decreased relatively more,

25 and 65% in human beings and rat, respectively.

(3) The authors attempted to obtain an understanding as to uncertainty or variability in

estimates of exposure concentrations (that give the same PAR dose in both species) if the

literature mean value of VTB was used. For various values of f, VT, kTB, and expansion, the PAR

dose ratios at upper and lower values of VTB deviated in absolute values from the PAR dose ratio

calculated at the mean values of VTB by as little as 10% to as large as 310%. The smallest

deviation occurred at the largest VT and smallest kTB for both species; whereas, the largest

deviation occurred at the smallest VT and largest kTB for both species.

Bush et al. (2001) modified the single-path model of Bush et al. (1996b) in order to be able

to simulate absorbed fraction data for O3 (and Cl2, which is not considered) for three airflow

rates and for oral and nasal breathing. By adjusting several parameters, reasonable agreement

between predicted and experimental values was obtained. On the other hand, the O3 plots of the

experimental and predicted values of absorbed fraction versus penetration volume (e.g.,

Figures 4 and 5 of Bush et al., 2001) show sequential groups composed of only positive or only

negative residuals, indicating a lack of fit. Possibly adjusting other parameters would eliminate

this. To obtain an independent validation of the model, Bush et al. (2001) simulated

measurements of O3 concentrations made by Gerrity et al. (1995) during both inhalation and

exhalation at four locations between the mouth and the bronchus intermedius of human subjects. 

Simulated and experimental values obtained are in close agreement. Note, however, that Bush

et al. (2001) made no quantitative assessment of how well their simulations agreed with the

experimental data; assessments were made on the basis of visual inspection of experimental and

simulated values plotted on the same figure. Thus, that evaluation of the model was subjective.
AX4-17

Recently, Sarangapani et al. (2003) used physiologically based pharmacokinetic (PBPK)

modeling to characterize age- and gender-specific differences in both regional and systemic

uptake of O3 in humans. This model indicated that regional extraction of O3 is relatively

insensitive to age, but extraction per unit surface area is 2- to 8-fold higher in infants compared

to adults, due to the region-specific mass transfer coefficient not varying with age. The PU and

ET regions have a large increase in unit extraction with increasing age because both regions

increase in surface area. Males and females in this model have similar trends in regional

extraction and regional unit extraction. In early childhood, dose metrics were as much as

12 times higher than adult levels, but these differences leveled out with age, such that inhalation

exposures varied little after age 5. These data suggest that the early postnatal period is the time

of the largest difference in pharmacokinetics observed, and this difference is primarily due to the

immaturity of the metabolic enzymes used to clear O3 from the RT. 

Mudway and Kelly (2004) attempted to model O3 dose-inflammatory response using a

meta-analysis of 23 exposures in published human chamber studies. The O3 concentrations

ranged from 0.08 to 0.6 ppm and the exposure durations ranged from 60 to 396 min. The

analysis showed linear relationships between O3 dose and neutrophilia in bronchoalveolar lavage

fluid (BALF). Linear relationships were also observed between O3 dose and protein leakage

into BALF. 

AX4.3 SPECIES HOMOLOGY, SENSITIVITY AND ANIMAL-TOHUMAN EXTRAPOLATION

Biochemical differences among species are becoming increasingly apparent, and these

differences may factor into a species’ susceptibility to O3 exposure effects. Lee et al. (1998)

compared SD rats and rhesus monkeys to ascertain species differences in the various isoforms of

CYP moonoxygenases in response to O3 exposure (discussed in more detail in Section 5.3.1.2). 

Differences in activities between rat and monkey were 2- to 10-fold, depending on the isoform

and the specific lung region assayed. This study supports the view that differential expression

of CYPs is a key factor in determining the toxicity of O3. As further characterization of

species- and region-specific CYP enzymes occurs, a greater understanding of the differences
AX4-18

in response may allow more accurate extrapolation from animal exposures to human exposures

and toxic effects.

Arsalane et al. (1995) compared guinea pig and human AM recovered in BALF and

subsequently exposed in vitro to 0.1 to 1 ppm for 60 min. Measurement of inflammatory

cytokines showed a peak at 0.4 ppm in both species. Guinea pig AM had an increase in IL-6

and TNF-" while human AM had increases in TNF-", IL-1b, IL-6 and IL-8. This exposure also

caused an increase in mRNA expression for TNF-", IL-1b, IL-6 and IL-8 in human cells. 

At 0.1 ppm exposures, only TNF-" secretion was increased. These data suggest similar cytokine

responses in guinea pigs and humans, both qualitatively and quantitatively.

Dormans et al. (1999) continuously exposed rats, mice, and male guinea pigs to filtered air,

0.2, or 0.4 ppm O3 for 3 to 56 days or for 28 days to follow recovery at 3, 7, and 28 days PE. 

Depending on the endpoint studied, the species varied in sensitivity. Greater sensitivity was

shown in the mouse as determined by biochemical endpoints, persistence of bronchiolar

epithelial hypertrophy, and recovery time. Guinea pigs were more sensitive in terms of the

inflammatory response, though all three species had increases in the inflammatory response after

three days that did not decrease with exposure. In all species the longest exposure to the highest

dose caused increased collagen in ductal septa and large lamellar bodies in Type II cells, but that

response also occurred in rats and guinea pigs at 0.2 ppm. No fibrosis was seen at the shorter

exposure times and the authors question whether fibrosis occurs in healthy humans after

continuous exposure. The authors do not rule out the possibility that some of these differences

may be attributable to differences in total inhaled dose or dose actually reaching a target site. 

Overall, the authors rated mice as most susceptible, followed by guinea pigs and rats.

Comparisons of airway effects in rats, monkeys and ferrets resulting from exposures of

1.0 ppm O3 for 8 h (Sterner-Kock et al. 2000) demonstrated that monkeys and ferrets had a

similar inflammatory responses and epithelial necrosis. The response of these two species was

more severe than that seen in rats. These data suggest that ferrets are a good animal model

for O3-induced airway effects due to the similarities in pulmonary structure between primates

and ferrets.
AX4-19

The rat is a key species used in O3 toxicological studies, but Watkinson and Gordon,

(1993) suggest that, because the rat has both behavioral and physiological mechanisms that can

lower core temperature in response to acute exposures, extrapolation of these exposure data to

humans may be limited. Another laboratory (Iwasaki et al., 1998) has demonstrated both

cardiovascular and thermoregulatory responses to O3 at exposure to 0.1, 0.3, and 0.5 ppm O3

8 h/day for 4 consecutive days. A dose-dependent disruption of HR and Tco were seen on the

first and second days of exposure, which then recovered to control values. Watkinson et al.

(2003) exposed rats to 0.5 ppm O3 and observed this hypothermic response which included

lowered HR, lowered Tco, and increased inflammatory components in BALF. The authors

suggest that the response is an inherent reflexive pattern that can possibly attenuate O3 toxicity in

rodents. They discuss the cascade of effects created by decreases in Tco, which include: 

(1) lowered metabolic rate, (2) altered enzyme kinetics, (3) altered membrane function,

(4) decreased oxygen consumption and demand, (5) reductions in minute ventilation, which

would act to limit the dose of O3 delivered to the lungs. These effects are concurrent with

changes in HR which lead to: (1) decreased CO, (2) lowered BP, (3) decreased tissue perfusion,

all of which may lead to functional deficits. The hypothermic response has not been observed in

humans, except at very high O3 exposures. 
AX4-20

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AX5-1

AX5. ANNEX TO CHAPTER 5 OF OZONE AQCD
Table AX5-1. Cellular Targets of Ozone Interaction

Concentrationppm Duration Species Effects 0.22 4 h with

exercise

Rat, male, SD, 90 daysold, 300-330 g,n = 6/group

Demonstrated the ozonation of PUFA to form nonanal and hexanal in rIncreases in nonanal not accompanied by significant changes in lung fuepithelial permeability, or airway inflammation. Hexanal levels did not significantly. Levels of both aldehydes returned to baseline by 18 h PE

0.5-10 bothwith andwithout 5% CO2

1 h Rat, male, SD, 90 days

old, 300-330 g,n = 6-14/group

O3 plus CO2 increased the VT and the yield of aldehydes with a maxima

aldehyde yield at 2.5 ppm for 1 h. 0.5 ppm O3 with 5% CO2, levels of h

and nonanal increased at 30 min, decreased slightly from that level at 6was maximal at 90 min and then dropped to 60 min levels at 120 min. heptanal did not change appreciably during this time course. Suggests levels of these aldehydes were dependent on a dynamic relationship bettheir production and the disappearance from the ELF. 

0.25-1.0 30-60 min Rat, male, SD,

250-275 g,n = 3-5/group3 modelsystems:isolatedepithelial lining fluid,intact lung, andliposome suspensions

PUFAs directly react with O3. The amount of bioactive lipids produced 

inversely related to AA availability. 

0.3-1.1 Chemical

systems:15-10 min.Cell: 1-2 h

Interfacial films(dipalmitoylglycero-3-phosphocholine(DPPC));Rat, SDBALF; human lungfibroblast cell line

DPPC films: reduced O3 reactive absorption by antioxidants. Human l

fibroblast cell line: AA produced cell injury; high levels of O3 and AA 

needed to induce cell injury; the DPPC films reduced the amount of celSuggests that O3 reactions with ELF substrates cause cell injury; that fi

active, saturated phospholipids reduce the local dose of O3-derived reac

products; and that these interfacial phospholipids modulate the distributinhaled O3 and the extent of site-specific cell injury.

0.4 1 h with

exercise

Human AM Ozone exposure caused apoptosis, an increase in a 32-kDa protein addu

an increase in ferritin and a 72-kDa heat shock protein. Exposure of AM HNE replicated these effects suggesting that creation of protein adducts apoptotic cell death are cellular toxic effects of acute O3 exposure and t

are mediated, at least in part by HNE.

AX5-2
Table AX5-2. Effects of Ozone on Lung Monooxygenases

Concentrationppm Duration Species Effects 1.01.0

8 h90 days

Rat, male, SD,350-600 g,n = 3-6/group

Increases CYP2E1 activity in lobar-bronchi and major daughter airwwith 8 h exposure. Decreased CYP2E1 activities in both major and mdaughter airways with 90-day exposure. O3 does not result in consis

dramatic alterations in CYP2E1 activities.

0.8 8 h/day for

90 days

Rat, male, SD,275-300 g

CYP2B activity increased. Linked to Clara cells in distal lung only—trachea or proximal airway. 

1 2 h Mice, male, 2-3 months

old, Clara Cell SecretoryProtein deficient,WT strain 129n = 3/group

CCSP-/-mice had increases in IL-6 and MT mRNA that preceded dec

in Clara cell CYP2F2 mRNA. WT mice had levels change, but to a degree. 

NA Rat, male, SD, adult

monkey, Rhesus, 0.75 to9.7 years old

Microdissection for regiospecific and species-specific differences inisoforms of CYPs. Rat parenchyma: both CYP1A1 and CYP2Bwere highest. Rat airways: CYP2E1 was highest. Rat airways andparenchyma: P450 reductase activities were high, and conversely, lotrachea. Monkeys: did not exhibit site-selective differences in CYPCYP1A1, or P450 reductase; however, they had high CYP2E1 activiin parenchyma and distal bronchioles. 

 CYP = Cytochrome P450 WT = wild-type MT = metallothionein CCSP = Clara Cell Secretory Protein

AX5-3
Table AX5-3. Antioxidants, Antioxidant Metabolism, and Mitochondrial Oxygen Consum

Concentrationppm Duration Species Effects 1.0 6 h/day,

5 days/weekfor 2 or3 months

Rat, male Fischer F344,30-32 days old, n = 4

Immunohistochemistry and immunogold labeling studies. In epithecells in airways and parenchyma: reduced Cu-Zn SOD labeling witO3-exposure. In the CAR regions, in both AMs and Type II epithel

cells: significantly increased levels of Mn SOD. Mn SOD levels wincreased in Type I epithelial cells, fibroblasts, or Clara cells. Suggthat the increased levels of Mn SOD in Type II cells in the proximaalveolar duct confer tolerance and protection from further O3-induce

injury. 

0.2 6 h Dog, male, mongrel,

~/9 kg, n = 6/group

Blocking antioxidant transport with probenecid caused heterogeneodistributed increases in peripheral airway resistance and reactivity. Probenecid inhibited O3-induced neutrophilic inflammation, which 

evidence of a dissociation between airway function and inflammatioProbenecid caused a 50-60% decrease in plasma urate, a decrease inascorbate, and a decrease in BALF protein. Suggests probenecid haeither a direct or indirect effect on either cytokine or leukotriene tra

0, 0.1, 0.25,0.5, 1.0 or 1.5

30-720 min Model of continually

mixed, interfacial exposure

Modeled the interactions of O3 with three ELF antioxidants, AA, U

GSH. Ranking of reactivity with O3 was UA > AA > GSH. Antiox

caused no changes in sample pH and protein carbonyl formations. Consumption of the antioxidants occurred in a linear fashion with tiand a positive relationship to O3 concentration. Suggests that GSH 

not an important substrate for O3; UA appeared to be the most impo

substrate. 

Cu = CopperZn = ZincMn = ManganeseSOD = Superoxide DismutaseAM = Alveolar MacrophageBALF = Bronchoalveolar Lavage FluidAA = Ascorbic AcidUA = Uric AcidGSH = Reduced Glutathione

AX5-4
Table AX5-4. Lipid Metabolism and Content of the Lung

Concentrationppm Duration Species/Cell Line Effects NA 60 min Cultured human epithelial

cells (BEAS-2B)

Incubation with 10 μM lipid oxidation products caused significantrelease of arachidonic acid. Suggests that lipid oxidation products cactivation of specific lipases, which then trigger the activation of semessenger pathways (e.g., phospholipase A2 or phospholipase C). 

NA Cultured human bronchial

epithelial cells (NHBE)and BEAS-2B cells

Incubation with lipid ozonation product1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PC-Aand 1-hydroxy-1-hydroperoxynonane (HHP-C9). PC-ALF elicitedrelease of (PAF) and prostaglandin E2, but not IL-6. HHP-C9 causrelease of PAF and IL-6 in these cells, but not prostaglandin E2. Suggests that O3-induced production of lipid ozonation products

causes release of proinflammatory mediators that then generate anearly inflammatory response.

0.06, 0.125, and0.25 ppm

2 to 48 h Lung (calf surfactant) Dose- and time-dependent increase in the formation of

1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine(16:0a/9-al-GPCho), an oxidized phospholipid, which possessedbiological activity in three assays. The 16:0a/9-al-GPCho: (1) decreased macrophage viability by necrosis at 6 μM, (2) induceapoptosis in pulmonary epithelial-like A549 cells at 100-200 μM,and (3) elicited release of IL-8 from A549 cells at 50-100 μM.

0.8 30 min Human red blood cell

(RBC) model

Human RBCs intermittently covered by an aqueous film consisting rat BALF or BALF plus added reagents that included AA, UA, GSHTrolox (a vitamin E analog), SOD, catalase, desferrioxamine,deithylenetriaminepentaacectic acid, mannitol or BSA. Oxidation olipids in BALF or on membranes was assayed by measuring TBARaccumulation and loss of acetylcholinesterase activity. AA and GSinduced dose-dependent oxidative damage to the cell membrane proand lipids via secondary oxidant formation. Conclusion: early in O

exposure, ELF antioxidants are high enough to drive reactive absorpof O3 into the ELF and to concurrently quench secondary reaction

products, thus limiting cell injury. With continued exposure, O3 flu

would decrease, cellular injury would increase due to depletedantioxidants levels. They hypothesize that especially in areas wherO3 deposition is high, unreacted O3 and cytotoxic products can diffu

to the cell membranes, causing injury. 

AX5-5
Table AX5-4 (cont’d). Lipid Metabolism and Content of the Lung

Concentrationppm Duration Species/Cell Line Effects 2.00.2, 0.5, or 1.0

4 h1 h

Rat BALF exposed to O3

in vitro.Cultured human bronchialepithelial cells (16-HBE)

The major reaction products identified were5-hydroperoxyB-homo-6-oxa-cholestan-3,7a-diol,5$,6$-epoxycholesterol, and 3$-hydroxy-5oxo-5,6-seco-cholestan-

Extracted lipid reaction products either immediately or 24 h PE. Higher levels of 5$,6$-epoxycholesterol were recovered in the extr

immediately PE. Both 5$,6$-epoxycholesterol and its most abunda

metabolite, cholestan-6-oxo-3$,5

"-diol, were cytotoxic to 16-HBE 

at physiologically relevant concentrations. Both reaction products walso shown to be potent inhibitors of cholesterol synthesis. 

0.5, 1.0, 2.0,or 3.0

3 h Mice, C57BL/6J,

8-12 weeks old female.n = 4

In BALF, lavaged cells, and whole lung homogenate there was adose-dependent increase in formation cholestan-6-oxo-3$,5

"-diol a

exposure levels of 0.5, 1.0 and 2.0 ppm O3, respectively. In BALF

and lavaged cells O3 induced increases in 5$,6$-epoxycholesterol a

exposure levels of 0.5 and 1.0, respectively.

PAF = Platelet-Activating FactorRBC= Red Blood CellAA = Ascorbic AcidGSH = Reduced GlutathioneIL-6 = Interleukin-6IL-8 = Interleukin-8ELF = Epithelial Lining FluidBALF = Bronchoalveolar Lavage FluidBSA = Bovine Serum AlbuminTBARS = thiobarbituric acidUA = Uric Acid

AX5-6
Table AX5-5. Effects of Ozone on Protein Synthesis

Concentrationppm Duration Species Effects 0.4 1,3,7,28, or

56 days

Rat, male, Wistar,200 g,n = 5/group

Centriacinar thickening of septa after 7 days of exposure, whichprogressed at 28 and 56 days of exposure. After 28 days of O3, the

increase in collagen content in ductular septa was apparent and itincreased progressively until the 56-day time point. Collagen contedecreased with PE recovery, the structural fibrotic changes in ductusepta did not return to control levels. Respiratory bronchioles werepresent at an increasing degree, which persisted after an 80-d recovperiod. Suggests that subchronic O3 exposures in rats creates a

progression of structural lung injury that can evolve into a more chrform, which included fibrosis. 

Table AX5-6. Effects of Ozone on Differential Gene Expression

Concentrationppm Duration Species Effects 1 8 h for three

consecutivenights

Mice, C57BL/6,20-25 g,n = 5-6/group

Ozone exposure induced changes in expression of 260 genes ( 80%repressed and 20% induced). Cell cycle genes upregulated: S-adenmethionine decarboxylase 3, ribonucleotide reductase, and clusterinNF-6B-induced genes upregulated: serum amyloid protein, topoiso

II", monocyte chemoattractant protein, platelet-derived growth fact

and inhibitor of apoptosis. Downregulation of transcripts for isoforof myosins and actins. CYP family genes downregulated: 2a4, and and 2f2, as were aryl-hydrocarbon receptor and several glutathionetransferases. Metallothionein 1 and 2 and lactotransferrin upregulatMajor histocompatibility complex genes and lymphocyte specificproteins downregulated.

AX5-7
Table AX5-7. Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Microbiologic Endpoints0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g

No effect on cumulative mortality from subsequent lung infectiowith 4-8 × 106 Listeria monocytogenes, but concentration-related

effects on morbidity onset and persistence. One-week exposed rlisteric burdens trended higher than in controls; 0.3 ppm rats dispcontinual burden increases and no onset of resolution; in situ IL-

TNF-", and IFN-( levels 48 and 96 h post-infection (4 × 106 lev

higher than controls. Three-week exposed rats: no O3-related chin bacterial clearance; IL-1", TNF-", and IFN-( levels higher th

control only at 48 h post-infection (4 × 106) and only with 0.3 pp

0.8 3 h Rat, male, Fischer F344,

8 weeks old,n = 4-10/group

Single exposure to S. zooepidemicus led to differential clearancepatterns in exposed rats maintained on ad libitum or O3-mitigatin

calorie-restricted diets.

Clearance Endpoints (Non-Microbial)0.01 -1.0 10 min Rat, SD Single 10 min exposure of tracheal explants, followed by 1 h inc

with particles, led to dose-related increases in uptake of amositeasbestos and titanium dioxide particles. Effect inhibited by addecatalase or desferoxamine, but not by superoxide dismutase.

0.4 6 h Dog, male, mixed breed,

1-3 years old,n = 7/group

Increased tracheal permeability to 99mTc-DTPA after direct sublo

exposure to O3. Clearance halftimes remained significantly lowe

1-7 days PE, but recovered by 14 days PE. 

Alveolar Macrophage Endpoints (General)0.8 3 h Rat, male, SD,

250-275 g,n = 5-6/group

Increased ex vivo AM adherence to epithelial cultures mitigated cell pretreatment with anti-CD11b or anti-ICAM-1 antibodies.

0.8 3 h Rat, male, SD,

250-300 g,n = 5/group

Increased ex vivo AM adherence to epithelial cell cultures mitigby cell pretreatment with anti-TNF-"/IL-1" antibodies.

1.0 4 h Mice cell line

(WEH1-3)

Increased intracellular calcium resting levels in WEHI-3 cells. Decreased rates of calcium influx due to digitonin.

AX5-8
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Alveolar Macrophage Endpoints (Functional)0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g

Superoxide anion: increased AM production (1 week; 0.1, 0.3 pno intergroup differences noted after IFN-

( stimulation. 

H2O2: reduced production (1 week; 0.1, 0.3 ppm); further reduc

production after treatment with IFN-

( (0.1, 0.3 ppm, 1 and 3 we

0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g

Increased AM superoxide anion production (1 week; 0.1, 0.3 ppmLower H2O2 production (1 week; 0.1, 0.3 ppm). Reduced produ

after treatment with IFN-

( - superoxide (0.3 ppm, 1 week) and H

(0.1 ppm, 1 week) - relative to cells without IFN-

( treatment. 

No effects from 3-week exposures.

0.3 5 h/day,

5 days/week,4 weeks

Rat, male, Fischer F344,200-250 g,n = 10/group

No effect on AM endotoxin-stimulated IL-1

", IL-6, or TNF-

"

production. Decrease in stimulated, but not spontaneous, superoformation; variable effects on H2O2 formation. No effect on AM

spontaneous, endotoxin-, or IFN-

(-stimulated, NO formation.

0.8 3 h Rat, male, SD, 250-

275 g, n = 5-6/group

Increased AM motility in response to chemotaxin; effect mitigatby cell pretreatment with anti-CD11b or anti-ICAM-1 antibodies

0.8 3 h Rat, male, Fischer F344,

8 weeks old,n = 4-10/group

Decrease in AM phagocytic activity. 

0.8 3 h Mice, female,

(B6J129SV)(C57BL/6X 129 NOS-/-),

8-16 weeks old,n = 3-12/group

Increased AM spontaneous and IFN-

( + LPS-induced NOS expr

and NO production and PGE2 release. Initial decrease in ROI

production, with eventual rebound. Knockout (NOS-/-) mice AM

incapable of similar response to O3 – no inducible NO or PGE2

above control levels and consistent decreased ROI production.

1.0 24 h/day,

3 days

Rat, male, Wistar, 8-12 weeks,

BALF from exposed rats subsequently inhibited IFN-

(-induced 

AM NO production. 

AX5-9
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Cytokines, Chemokines: Production, Binding, and Inducible Endpoints0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g,

Superoxide anion: no intergroup differences noted after IFN-

(

stimulation. H2O2: reduced production after treatment with IFN

0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g,n = 3-5/group

Decreased expression of CD3 among lung lymphocytes (0.1 ppm 3 weeks); effect exacerbated by stimulation with IFN-

" (but not 

IL-1

"). Decreased expression of CD25 (IL-2R) on CD3+ lymph

(0.3 ppm only; 3 weeks); effect worsened by treatment with IL-1

(0.1, 0.3 ppm; 3 weeks). No effects on IL-2-inducible lymphoproliferation. Reduced AM production of ROIs after treatment wIFN-

(; superoxide anion (0.3 ppm, 1 week) and H2O2 (0.1 ppm, 

- relative to untreated cells.

0.3 5 h/day,

5 days/week,4 weeks

Rat, male, Fischer F344,200-250 g,n = 10/group

No effect on AM endotoxin-stimulated IL-1

", IL-6, or TNF-

"

production. 

0.31.0 2.5

24 or 96 h 1, 2, or 4 h,or 24 h

Mice, male, C57BL/6J,adult, n = 3/group

0.3 ppm: Increased lung: MIP-2, MCP-1, and eotaxin mRNAexpression.1.0 ppm: After 4 h, increased lung: MIP-2, MCP-1, eotaxin, anIL-6 mRNA expression.2.5 ppm: After 2 h, increased lung: MIP-2, MCP-1, eotaxin, anIL-6 mRNA expression.No exposure-related increases in lung IL-1

", IL-1$, IL-1R

", IL-

IL-12, or IFN-

( mRNA expression. 

1.0 4 h Mice cell line

(WEH1-3)

Decreased binding of IFN-

( by WEHI-3 cells. Decreased super

anion production by IFN-

(-treated cells; no similar effect on H2O

production. Decreased IFN-

(-stimulated phagocytic activity. N

on IFN-

(-inducible Ia (MHC Class II) antigen expression.

1.0 6 h Rat, male, SD,

200-250 g,n = 3-6/group

Increased AM MIP-1

", CINC, TNF-

", and IL-1$ mRNA expres

Induced increase in MIP-1

" and CINC mRNA temporally inhibi

by cell treatment with anti-TNF-

"/IL-1$ antibodies.

AX5-10
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Cytokines, Chemokines: Production, Binding, and Inducible Endpoints (cont’d)1.0 24 h/day,

3 days

Rat, male, Wistar, 8-12 weeks old

BALF from exposed rats subsequently inhibited: ConA-stimulalymphocyte IFN-

( production, but had no effect on IL-2 product

IL-2-induced lymphoproliferation; and, IFN-

(-induced AM NO

production. 

1.0 24 h Mice, male, C57BL/6J,

8 weeks old, n = 3/group

Increased lung: MIP-2 (4 h PE) and MCP-1 (4 and 24 h PE) mRexpression.

1.0 24 h Mice, male, C57BL/6J,

8 weeks old, n = 3/group

Increased lung MIP-2 and MCP-1 mRNA expression (4 and 24 h no effects on mRNA levels of IL-1

", IL-1$, IL-1R

", IL-6, MIF,

MIP-1

", MIP-1$, eotaxin, or RANTES at either time point in re

period. Enhanced expressions of some cytokines/chemokines wmaintained longer than normal by coexposure to endotoxin.

1.0 8 h/day,

3 days

Mice (C57BL/6)(C57BL/6Ai- NOS-/-)

n = 3-10/group

Knockout (NOS-/-) mice have more lavageable MIP-2 after expo

than wild-type; both greater than control.

1.0, 2.5 4 or 24 h Mice, male, C57BL/6J,

adult, n = 3/group

Dose-related increases in cytokine/chemokine induction. Increalung MIP-1

", MIP-2, eotaxin (4 and 24 h), IL-6 (4 h only), and i

mRNA expression. 

0.6, 2.0 3 h Mice, C57BL/6, Rat,

Wistar, 14-16 weeksold, n = 4-6/group

Increased lung MIP-2 (4 h PE) and MCP-1 mRNA expression(24 h PE); PMN and monocyte increased accumulation in lungsconsistent with sequential expression of the chemokines. NF-kB activation also increased 20-24 h PE.

0.8 3 h Rat, male, SD,

250-300 g, n = 5/group

Increased ex vivo AM adherence to epithelial cells mitigated by treatment with anti-TNF-

" or IL-1

" antibodies.

0.8 3 h Mice, female,

B6J129SV,C57BL/6X 129 NOS-/

,

8-16 weeks,n = 3-12/group

Increased AM IFN-

( + LPS-induced NOS expression and NO

production, as well as induced PGE2 release. Knockout (NOS-/-)

mice AM incapable of similar response to O3 - no inducible NO 

PGE2 above control levels.

AX5-11
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Cytokines, Chemokines: Production, Binding, and Inducible Endpoints (cont’d)0.8 3 h Mice, female,

B6J129SV,C57BL/6X 129 NOS-/-,

8-16 weeks,n = 3-4/group

Increased AM IFN-

( + LPS-induced NOS expression and NO

production. 

2.0 3 h Rat, female, SD,

200-225 g,n = 4-6/group

Increased AM spontaneous and IFN-

( + LPS-induced NOS expr

and NO production. AM from exposed rats showed rapidonset/prolonged activation of NF6B.

0.08-0.25 and 1%OVA

4 h,3 times/week,4 weeks

Mice, female, BALB/c,C57BL/6,6-8 weeks old, n = 4-12/group

O3 - dose-dependent increases in IgE, IL-4, IL-5; recruitment of

eosinophils and lymphocytes in BALB/c; O3 + OVA - increased 

antibody titers, leukotrienes, airway responsiveness, immediatecutaneous hypersensitivity reactions in BALB/c. In C57BL/6 onO3 + OVA caused cutaneous hypersensitivity and altered IgG re

Alveolar Macrophage/Lung NO- and iNOS-Related Endpoints0.3 5 h/day,

5days/week,4 weeks

Rat, male, Fischer F344,200-250 g,n = 10/group

No effect on AM spontaneous, endotoxin-, or IFN-

(-stimulated,

NO formation.

0.8 3 h Mice, female,

B6J129SV,C57BL/6X 129 NOS-/-,

8-16 weeks,n = 3-12/group

Increased AM IFN-

( + LPS-induced NOS expression and NO

production and PGE2 release. Knockout (NOS-/-) mice AM incap

similar response to O3 - no inducible NO or PGE2 above control 

0.8 3 h Mice, female,

B6J129SV,C57BL/6X 129 NOS-/-,

8-16 weeks,n = 3-4/group

Increased AM spontaneous and IFN-

( + LPS-induced NOS expr

and NO production. AM from exposed mice showed rapid andprolonged activation of NF6B, STAT-1 (expression, activity),

phosphoinositide 3-kinase, and protein kinase B.

AX5-12
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Alveolar Macrophage/Lung NO- and iNOS-Related Endpoints (cont’d)1.0 8 h/day,

3 days

Mice, C57BL/6,C57BL/6Ai- NOS-/-,

n = 3-10/group

Knockout (NOS-/-) mice have more lavageable PMN, MIP-2,

and protein in lungs after exposure than wild-type.

1.0 24 h/day,

3 days

Rat, male, Wistar, 8-12 weeks, n = 2/group

BALF from exposed rats subsequently inhibited IFN-

(-induced

AM NO production. 

1.0, 2.5 4 or 24 h Mice, male, C57BL/6J,

adult, n = 3/group

Dose-related increase in lung iNOS mRNA expression. 

2.0 3 h Rat, female, SD,

200-250 g,n = 1-3/group

Increased AM spontaneous, IFN-

(, and LPS-induced NO produc

as well as spontaneous and LPS-induced NOS expression. Effecsomewhat ameliorated by pretreatment with bacterial endotoxin.

2.0 3 h Rat, female, SD,

200-225 g,n = 3-6/group

Increased AM spontaneous and IFN-

( + LPS-induced NOS

expression and NO production. AM from exposed rats showedrapid onset/prolonged activation of NF6B.

3.0 6 h Rat, female, Brown

Norway, 250-300 g,n = 4-8/group

Increased lung iNOS mRNA expression. Effect blocked bypretreatment with dexamethasone.

0.12, 0.5, or 2 3 h Mice, female, BALB/c,

5-6 weeks

Dose-dependent increases in nitrate and Penh; increases in nNOS, 

not iNOS or eNOS.

Surface Marker-Related Endpoints0.8 3 h Rat, male, SD,

250-275 g,n = 5-6/group

Increased expression of AM CD11b, but no effect on ICAM-1. 

1.0 4 h Mice cell line

(WEH1-3)

No effect on IFN-

(-inducible Ia (MHC Class II) antigen express

on WEHI-3 cells.

1.0 2 h Rat, female, SD,

170-210 g,n = 8-12/group

Decreased expression of integrins CD18 on AM and CD11b on PNo effect on PMN CD62L selection.

AX5-13
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Surface Marker-Related Endpoints (cont’d)1.0 3 days Rat, male, Wistar and

Fischer F344, 8-10 weeks, n = 3/group

Increased expression of surface markers associated with antigenpresentation: Ia (MHC Class II) antigen, B7.1, B7.2, and CD11bon BAL cells. Effect attributed to influx of monocytes.

0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g

Decreased expression of CD3 among lung lymphocytes (0.1 ppm 3 weeks); effect exacerbated by stimulation of cells with IFN-

" 

with IL-1

"). Decreased expression of CD25 (IL-2R) on CD3+

lymphocytes (0.3 ppm only; 3 weeks); effect worsened by treatmof cells with IL-1

" (0.1 and 0.3 ppm; 3 weeks). 

NK- and Lymphocyte-Related Endpoints0.1, 0.3 4 h/day,

5 days/week,1 or 3 weeks

Rat, male, Fischer F344,200-250 g

Decreased expression of CD3 among lung lymphocytes (0.1 ppm 3 weeks); effect exacerbated by stimulation of cells with IFN-

"

(but not with IL-1

"). Decreased expression of CD25 (IL-2R) on

CD3+ lymphocytes (0.3 ppm only; 3 weeks); effect worsened by

treatment of cells with IL-1

" (0.1 and 0.3 ppm; 3 weeks). 

Lymphoproliferation: no effect on spontaneous or IL-2-induciblforms; 0.1 ppm increased response to ConA mitogen (1 week on0.3 ppm - decreased response to ConA (1 week only).

0.4, 0.8, 1.6 12 h Mice, male, BALB/c, 

6-8 weeks old,n = 5-8/group

Decreased pulmonary delayed-type hypersensitivity reactions to MW agents, likely via activation of TH2-dependent pathways.

1.0 24 h/day,

3 days

Rat, male, Wistar, 8-12 weeks old

Lavage fluid from exposed rats subsequently inhibited ConA-stilymphocyte IFN-

( production, but had no effect on IL-2 product

material also inhibited IL-2-induced lymphoproliferation. 

AX5-14
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Susceptibility Factors0.3 24 to 72 h Mice 

C57BL/6JC3H/HeJC3H/HeOuJ, 6-8 weeksold, n = 4-8/group

Lavageable protein concentration lowered by inhibition of iNOS targeted disruption of Nos2; reduced Nos2 and Tlr4 mRNA leve

O3-resistant C3H/HeJ mice.

1 4 h CHO-K1 cell line SP-A Differences exist biochemically and functionally in SP-A varian

O3 exposure affects the ability of variants to stimulate TNF-

" an

0.3 24-72 h Mice, male, C57BL/6J,

C3H/HeJ, C3H/HeOuJ,6-8 weeks old,n = 5-16/group 

Identified a candidate gene on chromosome 4, Toll-like receptor (Tlr4), a gene implicated in endotoxin susceptibility and innateimmunity. O3-resistant strain C3H/HeJ and C3H/HeOuJ (differi

the O3-resistant strain by a polymorphism in the coding region o

were exposed, greater protein concentrations were demonstrated OuJ strain. Differential expression of Tlr4 mRNA with O3 expo

Suggests quantitative trait locus on chromosome 4 is responsible significant portion of the genetic variance in O3 -induced lung

hyperpermeability; potential interaction between the innate and aimmune system.

0.1 2 h Mice, male, C57BL/6,

6-8 weeks old

Sensitized the mice to OVA by intratracheal instillation of OVAdendritic cells (the principal antigen-presenting cells in airways)Created Th2 lymphocyte-dependent eosinophilic airway inflammGroups of mice exposed to O3 during sensitization by OVA-puls

dendritic cells showed no modification of the allergic sensitizatioprocess, whereas, previously sensitized mice exposed to O3,

demonstrated increases in allergen-induced airway inflammationSuggests that dendritic cells are an important component of O3-ineosinophilic airway inflammation.

AX5-15
Table AX5-7 (cont’d). Effects of Ozone on Lung Host Defenses

Concentrationppm Duration Species Effects Susceptibility Factors (cont’d)0.1, 0.5, and 1.0 2 h Human lymphocytes Subsequent to O3 exposure, when lymphocytes were stimulated

with pokeweed mitogen (PWM, a T-cell-dependent stimulus)or Staphylococcus aureus Cowan 1 strain (SAC, a T-cell-indepestimulus), both B and T cells were found to be affected by O3preexposure. T cells also demonstrated an increase in IL-6 anda decrease in IL-2, suggesting that O3 may have direct effects on

IgG-producing cells and concurrently an effect that is mediatedby altered production of T cell immunoregulatory molecules.

NA Rat BALF;

Murine macrophagecell line (RAW 264.7)

Both SP-A and SP-D directly protected surfactant phospholipidsand macrophages from oxidative damage. Both proteins blockedaccumulation of TBARS and conjugated dienes generated duringoxidation of surfactant lipids or low density lipoprotein particles a mechanism that does not involve metal chelation or oxidativemodification of the proteins. 

 AM = Alveolar macrophage; PE = Postexposure (i.e., time after O3 exposure ceased); MIP = macrophage inflammatory protein;

 PMN = Polymorphonuclear leukocyte; MLN = Mediastinal lymph node; CINC = cytokine-induce neutrophil chemoattractant; BAL = Bronchoalveolar lavage; DTPA = diethylenetriaminepentaacetic acid; ROI = reactive oxygen intermediate/superoxide anion; IFN = Interferon; BALT = Bronchus-associated lymphoid tissue; MCP = monocyte chemoattractant protein; CON A = Concanavalin  OVA = Ovalbumin; SP-A = Surfactant Protein A; SP-D = Surfactant Protein D 

AX5-16
Table AX5-8. Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 0.10.20.5

0.5 h, in vitro Rat, SD, primary alveolar

Type II cells

Decreased transepithelial resistance (Rt) after 0.5 ppm from 2 

PE and at 48 h in monolayers subjected to PMNs. SignificantRt after PMN treatment at 0.2 and 0.5 ppm.

0.10.20.41.0

1 h, in vitro Guinea pig, male and

female, Hartley, and humanalveolar macrophages

Exposure of guinea pig alveolar macrophages to 0.4 ppm for 6produced a significant increase in IL-6 and TNF-

", and an exp

human alveolar macrophages to identical O3 concentration inc

TNF-

", IL-1$, IL-6 and IL-8 protein and mRNA expression.

0.20.40.8

23 h/day for 1 week Guinea pigs, female

(Hartley), 260-330 gn = 4-10/group

Increase in BALF protein and albumin immediately after0.8 ppm exposure, with no effect of ascorbate deficiency in diO3-induced increase in BALF PMN number was only slightly

augmented by ascorbate deficiency.

0.26 8 h/day, 5 days/week

for 1-90 days

Mice, male (mastcell-deficient and-sufficient), 6-8 weeks oldn = 4-8/group

Greater increases in lavageable macrophages, epithelial cells aPMNs in mast cell -sufficient and mast cell-deficient mice repmast cells than in mast cell-deficient mice. O3-induced perme

increase was not different in genotypic groups. 

0.3 48 h and 72 h. 

Exposures repeatedafter 14 days

Mice, male, C57BL/6J andC3H/HeJ, 6-8 weeks old

Greater BALF protein, inflammatory cell and LDH response iC57BL/6J than in C3H/HeJ after initial exposure. Repeated excaused a smaller increase in BALF protein and numberof macrophages, lymphocytes and epithelial cells in both strainbut PMN number was greater in both strains of mice compared initial exposure.

0.10.31.0

60 min Rat basophilic leukemia cell

line (RBL-2H3)

O3 inhibited IgE- and A23187 - indued degranulation. Sponta

release of serotonin and modest generation of PGD2 occurred under conditions that caused cytotoxicity. 

0.32.0

72 h3 h

Mice, male and female,C57BL/6J and C3H/HeJ

Greater PMN response in C57BL/6J than in C3H/HeJ after acusubacute exposures. Responses of recombinant mice were disand suggested two distinct genes controlling acute and subacuresponses. Genes termed Inf-1 and Inf-2.

0.3 48 h Mice, C57BL/6J and

C3H/HeJ, 6-8 weeks old

Susceptibility to O3 is linked to a quantitative trait locus, and T

is identified as a candidate gene. 

AX5-17
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 0.31.02.5

24 or 48 h1, 2 or 4 h2, 4 or 24 h

Mice, male, C57BL/6J,8 weeks oldn = 3/group

0.3 ppm for 24 h caused increase in mRNA for eotaxin, MIP-1MIP-2.1 ppm for 4 h caused increase in mRNA for eotaxin, MIP-1a, Mand IL-6.2.5 ppm for 2 and 4 h caused increase in mRNA for MIP-1a, Mand IL-6 and metallothionein. Greater increases and lethality h.

0.3 72 h Mice, male {HeJ, OuJ,

Nos2 (+/+) [C57BL/6JNos2 (+/+)], and Nos2(!/!) [C57BL/6J-Nos2 

(!/!)]}, 6-8 weeks old 

O3 induced permeability was decreased by pretreatment with a 

oxide synthase inhibitor and in animals with iNOS gene knock

0.4 5 weeks Guinea pigs, male,

(Hartley), 5 weeks old (350-450 g)n = 7-8/group

Ovalbumin instillation in the nose caused an increase in O3-ind

infiltration of eosinophils in nasal epithelium.

0.15, 0.3,or 0.5 

3 h Rat, male, SD 

6-8 weeks old,n = 2-6/group

Time-related increase in permeability and inflammation, with at 8 h PE, after 0.5 ppm. No change following exposure to 0.1ppm.

0.5 4 h, 12-4 PM for

daytime and 7-11PM for nighttimeexposures. Exposuresrepeated 16 h later.

Rat, male, Wistar,60-90 days oldn = 5-15/group

Significantly greater increase in IL-6, but not inflammation, foa nighttime exposure compared to daytime exposure. An initianighttime exposure resulted in lesser inflammation following asubsequent exposure. Pretreatment with IL-6 receptor antibodabolished cellular adaptive response without affecting inflammresponse induced by initial nighttime exposure.

0.51.02.0

Rat, male, Fisher, 90 days oldn = 6-12/group

Increase in BALF protein and albumin occurred immediatelyafter 2 ppm exposure, and at 18 h after 1 ppm. No increase aft0.5 ppm. The movement of water and protein into airspace wecoupled.

AX5-18
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 1.0-2.0 3 h Mice, C57BL/6, 6-8 weeks

old and rats, Wistar,14-16 weeks oldn = 4-6/group

Steady state MCP-1 mRNA increase after 0.6 ppm, with maximincrease after 2 ppm. After 2 ppm, MIP-2 mRNA peaked at 4 and MCP-1 mRNA peaked at 24 h PE. BALF neutrophils andmonocytes peaked at 24 and 72 h PE, respectively. BALF MCactivity induced by O3 was inhibited by an anti-MCP-1 antibo

0.5 24 h following a 3-d (6

h/day) exposure tocigarette smoke

Mice, male, B6C3F1, 25 ± 2 g, 10 weeks old, n = 6/group

BALF protein, neutrophils and lymphocytes were increased in exposed to smoke and then to O3. Macrophages from this grou

responded with greater release of TNF-" upon LPS stimulatio

0.5 8 h during nighttime Rat, male, Wistar, SD and

Fischer F344, 90 days oldn = 3-8/group

Exposure resulted in a significantly greater injury, inflammatioBALF levels of IL-6 in Wistar than in SD or F344 rats.

0.8 2h and 6 h Rats, male, Fisher F344,

Juvenile (2 months;180-250 g),Adult (9 months; 370-420 g),Old (18 months; 375-425 g), Senescent(24 months; 400-450 g)n = 2/group

Comparable effect on the leakage of alveolar protein in ratsof different age groups, but a greater increase occurred in interand N-acetyl-beta-D-glucosaminidase in senescent animals thajuvenile and adult rats.

0.8 3 h Rat, male, SD,

6-8 weeks old,n = 5/group

Increased adhesion of macrophages from exposed animals torat alveolar type II epithelial cells in culture. Treatment withanti-TNF-" + anti-IL-1" antibody decreased adhesion in vitropermeability in vivo.

0.8 3 h Rat, male, SD

6-8 weeks old,n = 5/group

Increase in fibronectin protein in BALF and lung tissue, andfibronectin mRNA in lung tissue. The increase produced by O

amplified in animals pre-treated intra-tracheally with rabbit seinduce inflammation. 

0.8 3 h Rat, male, SD, 

200-225 g, n = 2-9/group

Treatment of animals with IL-10 prior to O3 exposure caused a

reduction in O3 induced BALF protein, albumin and fibronecti

tissue fibronectin mRNA.

AX5-19
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 0.8 8 h Monkey, male, Rhesus,

3 years 8 months-3 years10 months oldn = 2-6/group

Pretreatment of monkeys with a monoclonal anti-CD18 antiboresulted in a significant inhibition of O3-induced neutrophil em

and accumulation of necrotic airway epithelial cells.

0.81.0-2.0

48 h3 h

Rat, male, SD, 6-8 weeks old,200-225 g,n = 3-8/group

Cyclophosphamide treatment ameliorated O3-induced BALF

neutrophils and albumin after short term and 1-day exposure. neutrophil serum reduced lavageable neutrophils but did not apermeability.

0.8 8 h Monkeys, male, Rhesus,

3 years 8 months-3 years10 months old (5.1-7.6 kg)n = 2-6/group

Tracheal epithelium of exposed animals expressed b6 integrinintegrin expression was reduced or undetectable in animals trewith CD-18 antibody.

0.8 3 h Mice, female,

C57BL/6X 129 NOS-/-

knockout and wild-typeB6J129SV F2,8-16 weeks old,n = 3-12/group

Alveolar macrophages from O3 exposed wild-type mice produ

increased amounts of NO, peroxynitrite, superoxide anion, and Nitrogen intermediates were not produced and PGE2 was at colevel in exposed NOSII knockout mice. These mice were alsoprotected from O3-induced inflammation and injury.

1.0 5 min exposure of

airway segmentsfollowingbronchoscopy

Dogs, male, Mongrel,Adult,n = 1-4/group

Mast cells from O3-exposed airways of ascaris sensitive dogs r

significantly less histamine and PGD2 following in vitro challwith ascaris antigen or calcium ionophore.

1.00.20.51.0

8 h, assayed 1 and2 h PEIn vitro at liquid/airinterface

Monkeys (Rhesus)Primary TBE, BEAS-2b Sand HBE1

Increase in steady state IL-8 mRNA in airway epithelium. IncIL-8 protein staining declined at 24 h after exposure.Dose related increase in IL-8 release in the conditioned mediaproduced greater toxicity in cell lines than in primary cultures

1.0 3 h Rat, male, SD,

6-8 weeks old,n = 4-5/group

Time-related increase in BALF protein, fibronectin (Fn), and aphosphatase (AP) activity. Fn mRNA detected in macrophageAP in Type II cells and in BALF PMNs from exposed animals 

AX5-20
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 1 2 h Rats, female, SD,

170-210 gn = 8-12/group

The expression of CD18 on alveolar macrophages and CD11b blood PMNs was lowered by exposure, but CD62L expression blood PMNs was not affected.

1 3 h Rat, male, SD,

6-8 weeks old,n = 5/group

Time-related increase in BALF albumin, PMNs, MIP-2 and ICand increase in MIP-2 mRNA only at early time point in BALmacrophages. MIP-2 mRNA not detected in lung tissue.

1 3 h Rat, male, SD,

250-275 g,n = 6/group

Ozone induced increase in BALF albumin, fibronectin and PMnumber was associated with an increase in expression of TNF-

1", IL-6 and IL-10 mRNA. Pretreatment with anti-TNF-" ant

caused downregulation of gene expression and reduction of BAalbumin and PMN number, but not fibronectin.

1 6 h Rat, male, SD, 

200-250 g,n = 3-6/group

Increase in number of macrophages with mRNA transcripts animmunocytochemical staining of IL-1, TNF-", MIP-2 and cyt

induced neutrophil chemoattractact (CINC). Chemokine activwere reduced by treatment of macrophages with anti-IL-1$ an

TNF-" antibodies.

0.51.02.5

4 h Mice, male

(129 wild-type or Clara CellSecretory Protein-/-),

2-5 months old,n = 3/group

Increases in IL-6 and metallothionein mRNA by 2 h after expo1 ppm. mRNA increases were further enhanced in CCSP-/- mi

1.0 8 h/night for three

nights

Mice, (C57BL/6 wild-typeand iNOS knockout)n = 3-10/group

O3 exposure produced greater injury, as determined by measur

of MIP-2, matrix metalloproteinases, total protein, cell content tyrosine nitration of whole lung protein, in iNOS knockout miin wild-type mice.

1.0 4 h Mice, male (129 strain,

wild-type and Clara CellSecretory Protein-deficient),2-3 months old,n = 3/group

Increases in abundance of mRNAs encoding eotaxin, MIP-1aand MIP-2 in CCSP-/-, but no change in wild-type mice.

AX5-21
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 1.2 6 h Rat, male, Brown Norway,

200-250 g, n = 4/group

Eotaxin mRNA expression in the lungs increased 1.6-fold immafter and 4-fold at 20 h. Number of lavageable eosinophils inc3- and 15-fold respectively at these time points. Alveolarmacrophages and bronchial epithelial cells stained positively feotaxin.

2.0 3 h Mice, male, C57BL/6J,

6-8 weeks old,n = 5-10/group

O3-induced increase in protein and PMNs in BALF, and pulmo

epithelial cell proliferation were significantly reduced in animtreated with UK-74505, a platelet activating factor-receptor an

2.0 3 h Rat, female, SD,

6-8 weeks old

BALF cells from exposed animals released 2 to 3 times greateand TNF-", and greater fibronectin. Immunocytochemistry sh

greater staining of these mediators in lung tissue from exposed 

1.1 8 h Rat, Wistar, -depleted of

neutrophils, 43 days old,n = 9-10/group

Epithelial necrosis in the nasal cavity, bronchi, and distal airwProliferation of terminal bronchiolar epithelial cells also decreby O3 exposure, suggesting a role for neutrophils in the repair 

0.32 48 h

(subacute)3 h(acute)

Mice, male, C57BL/6J,WTTNRF1KOTNRF2KO6-8 weeks old,n = 3-12/group

TNFR1 and TNFR2 KOs less sensitive to subacute O3 exposur

WT. With acute exposures, airway hyperreactivity was diminKO mice compared to WT mice, but lung inflammation andpermeability were increased. 

0.3 24 to 72 h Mice

C57BL/6JC3H/HeJC3H/HeOuJ6-8 weeks old,n = 5-16/group

Differential expression of Tlr4 mRNA. 

2.0 3 h Mice C3H/HeJ, A/J,

C57BL/6J, 129/SvIm,CAST/Ei, BTBR, DBA/2J,FVB/NJ, BALB/cJ,n = 6-24/group

Two strains consistently O3-resistant: C3H/HeJ and A/J. Two 

consistently O3-vulnerable: C57BL/6J and 129/SvIm. Five st

with inconsistent phenotypes with intermediate responses: CABTBR, DBA/2J, FVB/NJ, and BALB/cJ. 

AX5-22
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 11

3 h- examined at 3 h PE 1 h examined 24 h PE

Guinea pigs, male,Dunkin-Hartley,OVA-sensitized 

PMN levels significantly increased, without any change in BAprotein levels, suggesting a lack of correlation between the twendpoints. Increased AHR.Increase in PMN, no increase in BAL protein levels. No increAHR, suggesting a dissociation between PMN levels and AHR

0.4 1 or 5 days/ 12 h/day,

recovery period in freshair of 5, 10, 15, or 20days after the 5-dpreexposure

Rat, Wistar, male, 7 weeks old,n = 5/group

Exposure for 5 days caused lower BALF proteins, fibronectin, and inflammatory cells than animals exposed for 1 day. Postechallenge with single O3 exposures at different time points sho

that a recovery of susceptibility to O3 (as measured by BALF l

albumin, IL-6, and the number of macrophages and neutrophiloccurred at ~15-20 days, but total protein and fibronectin leveremained attenuated even at 20 days post-5-day exposure. Threcovery with regards to BrdU labeling occurred in 5-10 days 5-day exposure.

2 2 h, examined 2, 12,

and 48 h PE

Rat, female, SD, 200-250 gn = 4-7/group

Adherence of neutrophils to pulmonary vascular endothelium maximal within 2 h after exposure and returned to control leveh PE.

1.0 or 2.5 4, 20, or 24 h,

examined immediatelyPE10 min

Mice, C57BL/6J, 36 h and 8weeks old Endotoxin (10 ng)n = 3/group

RPA for IL-12, IL-10, IL-1", IL-1$, IL-1Ra, MIF, IFN-(, MI

MIP-2,IL-6, and Mt. Newborn mice: increased Mt mRNA on8-week-old mice: increased MIP-1", MIP-2, IL-6, and Mt mR

Both age groups had similar cytokine/chemokine profiles withendotoxin exposure, suggesting that the responses to endotoxindoes not cause epithelial injury, and the responses to O3, which 

demonstrate that differences in inflammatory control betweennewborn and adult mice is secondary to epithelial injury. 

0.8 3 days, continuous Rat, male, SD,

30 days old,n = 6/group

General dietary restriction to 20% of the freely-fed diet for60 days caused an extreme reduction in body weight and highesurvivability. Levels of antioxidants and detoxifying enzymesincreased less than in freely fed animals.

AX5-23
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 1.8 0.11

3 h 24 h/day for up to3 days, assaysimmediately or at 16 hPE

Mice, female, C57BL/6JCBA C3H/HeJ AKR/JSJL/J, 6-8 weeks old,n = 4-7/group

 Both exposure levels caused a transient increase in CC16 inserum that correlated with BALF changes in protein, LDH, aninflammatory cells. Inverse relationship between preexposure of CC16 in BALF and epithelial damage based on serum CC1and BALF markers of inflammation. Inverse relationship betwpreexposure levels of albumin in BALF and lung epithelium dSuggests that a major determinant of susceptibility to O3 is bas

epithelial permeability. C57BL/6J mice had lower levels of C(the more acidic form) than C3H/HeJ. Both the strains had simlevels of CC16b. Suggests that basal lung epithelial permeabimajor determinant of susceptibility; greater epithelial permeabobserved in C57BL/6J may be due to difference in the expressCC16a and possibly other antioxidant/inflammatory proteins. 

1 or 3 2-6 h, assayed at 2,

8 and 24 h PE

Rat, female, BrownNorway, 250-300 g,n = 4-8/group

MIP-2 peaked at 2 h and rapidly declined. PMNs in BALF inat 2, 8 and 24 h. No significant increase in AMs, eosinophils,lymphocytes or epithelial cells. MIP expression preceded incrPMN. Both responses suppressed by dexamethasone, which sa mechanism of glucocorticoid regulation of inflammation.

1 or 3 3 h Rat, male, Brown Norway,

200-250 g,n = 3/group

Increase in lung CINC mRNA within 2 h PE exposure. Significant increase in PMNs in BALF 24 h PE. Anti-CINC a(1 mg, i.v.) suppressed neutrophilia but not the increase in AHto acetylcholine. Anti-CINC antibody inhibited BALF neutroinduced at 3 ppm AHR. Results suggest that CINC causes O3-

neutrophil chemoattraction, but is not involved in the inductioozone-induced AHR.

0.1-22

3 h, assayed 6 h PE(exposure-response)3 h, assayed 0, 2, 6, or24 h PE (time-course)

Mice,C57BL/6,n = 2-4/group

O3 $1 ppm increased MIP-2 mRNA and recruitment of neutro

MIP-2 increase was immediate and decreased to control by 24 

AX5-24
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 0.12,0.24,0.5

3 h, NF-6B assayed 0 h

PE, TNF-" assayed 0,

1, 2, 4, 16, 20 or 22 hPE

Cultures of human nasalepithelial (HNE) cells

Electron spin resonance signal suggested free radical productioSmall dose-response activation of NF-6B coincided with O3-in

free radical production. TNF-" increased with exposures to 0

0.5 ppm at 16 h PE. Results suggest that the human airway epplays a role in directing the inflammatory response to inhaled 

free radical-mediated NF-6B.

0.8 3 h Rats, SD, 200-250 g,

n = 5-6/group

AMs from O3-exposed rats exhibited greater motility and grea

adhesion in cultures of epithelial cells (ARL-14). O3-induced 

and adhesion were attenuated with AMs incubated in the preseMabs to leukocyte adhesion molecules, CD11b, or epithelial cadhesion molecules, ICAM-1. Increased surface expression obut no change in ICAM-1 expression in AMs from O3-exposed 

Demonstration of alteration of AM functions following O3 exp

Possible dependence of these functions on the biologic charactrather than the absolute expression, of cell adhesion molecules

2 3 h Mice, male and female,

C57BL/6J, assayedimmediately or 3, 6, 9, or 21h PE

Increase in tissue expression of ICAM-1 3 -9 h PE, remaining h PE. Bronchioles and terminal bronchiole/alveolar duct regioEnhanced ICAM-1-IR 0 - 3 h PE, returning to baseline by 21 arespectively. Lung parenchyma: maximal ICAM-1 expressioPMN influx concurrent 3 h, followed by transepithelial migratPMNs to the airway lumen. Suggests regional variations in aiinflammatory activity; upregulation of ICAM-1 may play a rolocal regulation of PMN influx to the airways after acute expo

2 4 h Rat, SD, male, 225-250 g,

treated with 10 mg/kgebselen every 12 h from 1 hbefore O3 exposure,

n = 4/group

Ebselen significantly decreased pulmonary inflammation (albuPMN in BALF) 18 h PE without altering AM expression of iNEbselen inhibited the nitration reaction of tyrosine residues anenhanced expression of Cu-, Zn-,and Mn SOD. Suggests that scavenges peroxynitrite during O3-induced inflammation and mprotect against acute lung injuries by modulating the oxidant-rinflammatory process. 

AX5-25
Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and Inflammation

Concentrationppm Duration Species Effects 3 2 h Human transformed

bronchial epithelial cells(16-HBE)Guinea pigs, Hartley, male,450-550 g,n = 3-5/group

NO donors increased IL-8 production dose-dependently. TNF

IL-1$ plus INF( increased IL-8 in culture supernatant of epith

cells. NOS inhibitors (aminoguanidine plus NG-nitro-L-arginmethyl ester) attenuated the cytokine-induced IL-8 productionO3 induced AHR to acetylcholine and increased PMN in BAL

Persisting for 5 h. Pretreatment with NOS inhibitors did not aAHR or PMN accumulation 0 h PE, but, inhibited at 5 h PE.Suggests that endogenous NO, through upregulation of IL-8,modulates O3-induced airway inflammation and AHR. 

0.12,0.5,1, or2

3 h Mice, female, BALB/c, 5-6

weeks old

O3 exposure caused dose-dependent increases in nitrate (indicain vivo NO generation). Increases in enhanced pause (Penh) we

dose-dependent. Increases in NOS-1, but not in NOS-3 or iNOisoforms. Suggest that NOS-1 may induce airway responsivenneutrophilic airway inflammation. 

 PMN = Polymorphonuclear leukocyte PE = Postexposure (time after O3 exposure ceased)

 BAL = Bronchoalveolar lavage BALF = Bronchoalveolar lavage fluid

AX5-26
Table AX5-9. Effects of Ozone on Lung Structure: Acute and Subchronic Exposures

Concentrationppm Duration Species Effects 0.10.51.0

8 h/day × 1 day8 h/day × 1 day8 h/day × 1, 10,75, and 90 days

Rat; male, SD,350-600 g,n = 3-6/group

No dose-related response on CYP2E1, one of six P450 enzymes identin respiratory tissue. CYP2E1 activity was elevated (250% and 280%in the lobar bronchi/major daughters airways immediately after 1.0 pp

exposure for 1 day and 10 days, respectively, but not in the trachea or bronchioles; CYPE1 activity was unchanged and decreased after 1.0 pO3 exposure for 75 and 90 days, respectively.

0.20.4

3, 7, 28, and56 days; 3-, 7-,and 28-dayrecovery from28 days ofexposure

Mice, male, NIH, Rat, male, WistarRIV:ToxGuinea pig, male, HartleyCrl:(HA)BR,7 weeks old,n = 3-9/group

Concentration-related centriacinar inflammation, with a maximum aft3 days of exposure; number of alveolar macrophages and pulmonary cdensity increased progressively until 56 days of exposure, with the gupig the most sensitive species. Concentration and exposure-time depehypertrophy of bronchiolar epithelium in mouse only. Exposure to 0.for 3 and 7 days caused significant histological and morphometric chain all 3 species; exposure for 56 days caused alveolar duct fibrosis in rand guinea pigs. Total recovery in rats after 28-d exposure, but not inguinea pigs or mice.

0.20.40.8

23 h/day for7 days

Guinea pig, female,Hartley; ±AH2 diet

Treatment-related lesions were observed after exposure to 0.4 and 0.8 O3; lesions were primarily seen in the terminal bronchioles and consis

of mononuclear cell and neutrophilic infiltrate and thickening of theperibronchiolar interstitium. Effects were only marginally exacerbateby the AH2 (ascorbic acid) deficient diet and lesions were resolved aft

1 week in FA.

0.4 12 h/day;

1- or 7-dayexposure

Rat, WistarRiV:TOX, male and female,1, 3, 9, and 18 monthsof age,n = 5-6/group

Centriacinar inflammation (increased alveolar macrophages and PMNincreased proximal and ductular septal density) was greatest in young (1 month and 3 months for 1-and 7-day exposures, respectively) anddecreased with age. No major gender differences were noted.

AX5-27
Table AX5-9 (cont’d). Effects of Ozone on Lung Structure: Acute and Subchronic Expos

Concentrationppm Duration Species Effects 0.41.0

2 h Monkey;

adult male Rhesus

Reduced glutathione (GSH) increased in the proximal intrapulmonarybronchus after 0.4 ppm O3 and decreased in the respiratory bronchiole 

1.0 ppm O3. Local O3 dose (measured as excess 18O) varied by as mu

factor of three in different airways of monkeys exposed to 1.0 ppm, wrespiratory bronchioles having the highest concentration and the parenthe lowest concentration. After exposure to 0.4 ppm, the O3 dose was 

to 70% less and epithelial injury was minimal, except in the respiratorbronchiole, where cell loss and necrosis occurred, but was 50% less thfound at 1.0 ppm.

0.5 8 h 

+ BrdU to labelepithelial cells

Rat, male, FischerF344, 13 weeks old,n = 6/group

O3 exposure induced a transient influx of neutrophils and a significant 

loss of NTE cells 2-4 h after exposure. Increased epithelial DNA synwas first detected 12 h PE. LI and ULLI indices of epithelial cell DNsynthesis were greatest 20-24 h and still elevated 36 h PE; numeric deof NTE cells returned to control levels 20-24 h PE.

0.5 8 h/day, 

3 or 5 days;+ fluticasonepropionate (FP)intranasally

Rat, male, FischerF344, 203-232 g,n = 6/group

No significant difference of fluticasone propionate on morphometry omaxilloturbinates; O3 exposure caused neutrophilic rhinitis with 3.3- a

1.6-fold more intraepithelial neutrophils (3-day and 5-day exposure,respectively) and marked mucous cell metaplasia (5-day exposure onlwith numerous mucous cells and approximately 60 times moreintraepithelial mucosubstances in the nasal transitional epithelium;FP-treated rats exposed to O3 had minimal nasal inflammation and mu

cell metaplasia.

0.5 8 h/day,

3 days+ endotoxin(100 μg/mL)intranasally

Rat, male, FischerF344/N Hsd, 12weeks old,n = 6/group

Endotoxin-induced neutrophilia in nasal mucosa with NTE; mucous cmetaplasia was not detected in air/endotoxin-exposed rats, was observin O3/saline-exposed rats, and was most severe in O3/endotoxin-expos

rats. 

AX5-28
Table AX5-9 (cont’d). Effects of Ozone on Lung Structure: Acute and Subchronic Expos

Concentrationppm Duration Species Effects 0.5 8 h/day,

1, 2, or 3 days+ BrdU to labelepithelial cells+ antiratneutrophilantiserum 

Rat, male, FischerF344/N, 10-12 weeksold, n = 6-8/group

Acute O3 exposure induced a rapid increase in rMuc-5AC mRNA leve

prior to the onset of mucous cell metaplasia; neutrophilic inflammatiocoincided with epithelial DNA synthesis and upregulation, but wasresolved when mucous cell metaplasia first appeared in the NTE.Maxilloturbinates lined with NTE determined the epithelial labelingindex, numeric densities of neutrophils, total epithelial and mucous secells, amount of stored intraepithelial mucosubstances, and steady-starMUC-5AC mRNA levels. Four days after a 3-d exposure,antiserum-treated, O3-exposed rats had 66% less stored intraepithelial

mucosubstances and 58% fewer mucous cells in their NTE than did coAntiserum treatment had no effects on O3-induced epithelial cell

proliferation or mucin mRNA upregulation.

0.5 8 h/day,

3 days+ endotoxin

Rat, male, FischerF-344, 10-12 weeksold, n = 6/group

Enhanced epithelial lesions in the NTE and respiratory epithelium of tnose and conducting airways by endotoxin and O3 exposures, respecti

synergistic effects of coexposure mediated by neutrophils. Endotoxinincreased rMuc-5AC mRNA levels in the NTE of O3-exposed rats;

neutrophil depletion, however, had no effect on endotoxin-inducedupregulation of mucin gene mRNA levels. Endotoxin enhanced theO3-induced increase in stored mucosubstances (4-fold increase),

but only in neutrophil-sufficient rats.

0.5 8 h/day,

1 and 3 days+ OVA (1%, 50 μL/nasalpassage)

Rat, male, BrownNorway, 10-12 weeksold, n = 6/group

O3 enhanced the appearance of eosinophils in the maxilloturbinates of

OVA-challenged rats but did not increase inflammation in other nasaltissues; O3/OVA coexposures for 3 days increased the number of epith

cells as well as the appearance of mucus-containing cells in the NTE lthe maxilloturbinates.

1 8 h Rat, male, SD,

10 weeks old,Ferret, male, 18months old,Monkey, male,Rhesus, 4 years old,n = 4-8/group

Severe, acute infiltration of neutrophils along with necrotic bronchiolaepithelium in all lung regions, especially in the centriacinar region; neand inflammation was more severe in ferrets and monkeys than in rats

AX5-29
Table AX5-9 (cont’d). Effects of Ozone on Lung Structure: Acute and Subchronic Expos

Concentrationppm Duration Species Effects 0.5 8 h/day for 3 days,

assayed 2 h or4 days PE

Rat, male, FischerF344/N, with orwithout priorexposure to100 μg/dayendotoxin,10-12 weeks old,n = 8/group

2 h PE: Endotoxin/O3 rats had 48 and 3 times more PMNs in the NTE 

did saline/air- and saline/O3-exposed rats, respectively at 2 h PE. O3-o

rats had 35% more NTE cells and 2-fold more mucin mRNA than didsaline/air-exposed rats. 4 days PE: Endotoxin/O3 rats had 5 and 2 times more IM and mucous 

respectively, than did saline/air- and saline/O3- rats.

No mucous cell metaplasia was present in those rats killed at 4 dayspostexposure. Suggests that pre-existing rhinitis augments O3-induced

mucous cell metaplasia.

0.8 8 h/day for

90 days

Rats, SD, male,275-300 g, treatedi.p. with1-nitronaphthalene(0, 50, or 100 mg/kg)

1-nitronaphthalene (a pulmonary toxicant requiring metabolic activatitreated rats exposed to O3 showed greater histopathologic and morpho

effects in the centriacinar region of the lung. Caused denudation of thbasement membrane and necrosis of remaining epithelial cells. Increaseverity of ciliated cell toxicity in O3-exposed rats. No differences in 

intrapulmonary airways or trachea in sensitivity to 1-nitronaphthalenesuggesting a site-selective synergy between O3 and 1-nitronaphthalene

 AM = Alveolar macrophage PE = Postexposure (i.e., time after O3 exposure ceased)

 LM = Light microscopy EM = Electron microscopy

 RB = Respiratory bronchiole TB = Terminal bronchiole IAS = Interalveolar septum PMN = Polymorphonuclear leukocyte

AX5-30
Table AX5-10. Effects of Ozone on Lung Structure: Subchronic and Chronic Exposur

Concentrationppm Duration Species Effects Mexico CityAmbient:

0.018($0.12 for

18 1-hintervals)

23 h/day for7 weeks

Rat, male andfemale, FischerF344,8 weeks old

No inflammatory or epithelial lesions in nasal airways or respiratory tract. 

0.120.51.0

6 h/day,5 days/weekfor 20 months

Rat, male,Fischer F344,6-8 weeks old

LM morphometry of CAR remodeling. Thickened tips of alveolar septalining ADs (alveolar entrance rings) 0.2 mm from TB in rats exposed to 0.12 pand to 0.6 mm in rats exposed to 1.0 ppm. At 0.5 and 1.0 ppm, atrophy of nasturbinates, mucous cell metaplasia in NTE, increased volume of interstitium aepithelium along ADs due to epithelial metaplasia, and bronchiolar epithelialhyperplasia. At 1.0 ppm, increased AMs and mild fibrotic response (increase interstitial matrix and cellular interstitium; the latter due to increase in volume

in interstitial fibroblasts). More effects in PAR than in terminal bronchioles. Effects not influenced by gender or by aging. Effects similar to, or model of,

early fibrotic human disease (e.g., idiopathic pulmonary fibrosis).

0.120.501.0 

6 h/day,5 days/weekfor 24 and30 months

Mice, male andfemale, B6C3F1,6-7 weeks old,n = 50/group

Effects in the nose and centriacinar region of the lung at 0.5 and 1.0 ppm. Nasal lesions were mild: hyaline degeneration, hyperplasia, squamous

metaplasia, fibrosis, suppurative inflammation of transitional and respiratoryepithelium; and atrophy of olfactory epithelium. Lung lesions: alveolar/bronchiolar epithelial metaplasia and histiocytosis in terminalbronchioles, alveolar ducts, and proximal alveoli. Severity was greatest in

mice exposed to 1.0 ppm O3, but there was minimal interstitial fibrosis.

0.121.0

6 h/day,5 days/week,for 2 or3 months

Rat, male,Fischer F344/N,4-5 weeks old,n = 4/group

Morphometric changes (epithelial thickening, bronchiolarization) occurred aft2 or 3 months exposure to 1.0 ppm O3; effects were similar to those found wit

20 months exposure (see Pinkerton et al., 1995)

AX5-31
Table AX5-10 (cont’d). Effects of Ozone on Lung Structure: Subchronic and Chronic Exp

Concentrationppm Duration Species Effects 0.011 6 months Rat, male,

Wistar, 2 months

CO = 1.25 ppm; PM = 35.18 μg/m3; SO2 = 29.05 μg/m3. Induction of secreto

hypertrophy, acidic mucous secretion, and ciliary damage.

0.250.5

8 h/day,7 days/weekfor 13 weeks

Rat, male,Fischer F344/NHSD, 10-14 weeks oldn = 5-6/group

Mucous cell hyperplasia in nasal epithelium after exposure to 0.25 and 0.5 ppO3; still evident after 13 weeks recovery from 0.5 ppm O3 exposure. Mucous 

metaplasia found only after 0.5 ppm O3, but still detectable 13 weeks PE.

0.4 23.5 h/day

for 1, 3, 7, 28,or 56 days

Rat, Wistar,7 weeks old,n = 5/group

Acute inflammatory response (increased PMNs and plasma protein in BALF)reached a maximum at day 1 and resolved within 6 days during exposure;AMs in BALF increased progressively up to day 56, and slowly returned to ncontrol levels with PE recovery. Histological examination and morphometryof the lungs revealed CAR inflammatory responses throughout O3 exposure;

thickening of septa was observed at day 7. Ductular septa thickened progressat day 7, 28, and 56 of exposure; showed increased collagen at day 28, which further enhanced at day 56. Increased RBs with continuous exposure. Collagand bronchiolization remained present after a recovery period. 

0.5 8 h/day for

1, 3, and6 months

Rat, male,Fischer F344/N

Increased Bcl-2, a regulator of apoptosis, after 1 month, decreasing somewhatthereafter, returning to baseline by 13 weeks PE; increased number of metaplamucous cells in NTE after 3 and 6 months.

0.5 8 h/day for

5 days,every 5 daysfor a total of11 episodes

Monkey;Rhesus,30-day-olds,n = 6/group

Increased density and distribution of goblet cells in RB whole mounts stainedwith AB/PAS; extensive remodeling of distal airway with O3 and O3 + HDMA

challenge; increased airways resistance and reactivity, and respiratory motoradaptation also occurred. Authors conclude that periodic cycles of acute injurand repair associated with the episodic nature of environmental patterns of O3

exposure alters postnatal morphogenesis and epithelial differentiation in thedistal lung of infant primates.

AX5-32
Table AX5-10 (cont’d). Effects of Ozone on Lung Structure: Subchronic and Chronic Exp

Concentrationppm Duration Species Effects 0.8 8 h/day for

90 days+ 1-NN(100 mg/kg)

Rat, male, SD,275-301 g

Increased O3-induced centriacinar toxicity (histopathology, TEM, morphomet

of 1-Nitronaphthalene (1-NN), a pulmonary cytotoxicant requiring metabolicactivation, especially to ciliated cells.

0.5 11 episodes of

5 days each,8 h/dayfollowed by9 days ofrecovery

Monkey,Macaca mulatta,30 days old

In small conducting airways O3 caused decrements in density of airway epithe

nerves. Reduction greater with HDMA + O3. O3 or HDMA + O3 caused incrin number of PGP 9.5 (pan-neuronal marker) in airway. CGRP-IR nerves wein close contact with the PGP9.5 positive cells. Appearance of clusters ofPGP9.5+/CGRP! cells. Suggests episodic O3 alters developmental pattern of

neural innervation of epithelial compartment.

0.5 11 episodes of

5 days each,8 h/dayfollowed by9 days ofrecovery

Monkey,Rhesus,30 days old,n = 6/group

Abnormalities in the BMZ included: (1) irregular and thin collagen throughouthe BMZ; (2) perclecan depeleted or severely reduced; (3) FGFR-1immunoreactivity was reduced; (4) FGF-2 immunoreactivity was absent inperlecan-deficient BMZ, but was present in the lateral intercelluar space (LISin basal cells, and in attenuated fibroblasts; (5) syndecan-4 immunoreactivitywas increased in basal cells.

 TB = Terminal bronchiole PE = Postexposure (i.e., time after O3 exposure ceased)

 AM = Alveolar macrophage LM = Light microscopy TEM = Transmission Electron Microscopy

 BMZ = Basement Membrane Zone EM = Electron microscopy RB = Respiratory bronchiole IAS = Interalveolar septum C × T = Product of concentration and time

AX5-33
Table AX5-11. Effects of Ozone on Pulmonary Function

Concentrationppm Duration Species Effects 0.5 6 or 23 h/day

over 5 days

Rats, male,Fischer 344,90 days old,n = 28-36/group,ambient temperature10, 22, or 34 °C

Toxicity increased with decreases in temperature. At 10 °C: decreaseweight, total lung capacity, BALF protein, alkaline phosphatase activi% PMN, and lysozyme. Ozone-induced changes in lung volume wereattenuated during the 5 exposure days and returned to control levels a

7 days recovery. The responses to repeated O3 exposure in rats were

exacerbated by reduced ambient temperature, presumably as a result oincreased metabolic activity.

2 3 h, assayed 1

and 24 h PE

Mice, male,C57BL/6J C3H/HeJ, 53 days old, n = 5-7/groupchallenged by CO2

(5 or 8%)

C57BL/6J mice: CO2-induced changes in VE were attenuated 1 h afte

exposure; VT was reduced 1 h after O3 exposure; the diminished VT 1 

after O3 was coincident with reduced 

f, mean inspiratory flow, and slo

VE-to-%CO2 relationship compared with FA.; VE partially reversed 24 

O3 relative to FA.

C3H/HeJ: VT was reduced 1 h after O3 exposure; increased 

f to sustai

hypercapnic VE response similar to air exposure.Suggests that control of ventilation during response to CO2 is governe

in part, by genetic factors in these two strains of mice, implying differO3 susceptibility.

0.3 48 and 72 h, with

re-exposure after14 days ofrecovery

Mice, C57BL/6J,C3H/HeJ,6-8 weeks old

VE and f were measured before and immediately after exposure. Norm

VE was greater following subacute O3 exposure in C57BL/6J mice tha

C3H/HeJ mice, due to increased 

f and reduced VT, respectively. Vent

responses to both normocapnia and hypercapnia were similar after O3

reexposure in both strains. Suggests that: increased VT in C57BL/6J 

may contribute to the increased susceptibility to lung injury due to a gdose of O3 reaching the lower lung; mechanistic separation of airway

inflammation and ventilation. 

2 2-3 h, assayed

0 h PE

Mice, male,C57BL/6J,C3H/HeJ, 4 or 11-12 weeks old,n = 4-6/group

Using 18O-labeled O3. C3H/HeJ mice had 46% less 18O in lungs and 6

in trachea, than C57BL/6J. C3H/HeJ mice had a greater body temperdecrease following O3 exposure than C57BL/6J mice. Suggests that tdifferences in susceptibility to O3 are due to differences the ability to 

body temperature and, consequently decrease the dose of O3 to the lun

AX5-34
Table AX5-11 (cont’d). Effects of Ozone on Pulmonary Function

Concentrationppm Duration Species Effects 2 3 h, assayed 6 h

after exposure

Mice, male andfemale, AKR/J,C3H/HeJ, CBA/J,129/J, NJ, C57BL/6J,C3HeB/FeJ, SJL/J

Measured tracheal transepithelial potential in the six strains and in proB6 and C3 strain mice. Fl mice and second generation backcrosses wresistant parent were O3 resistant. Ratios of 1:1 (resistant:susceptible) 

obtained with second generation backcrosses with the susceptible paresuggesting simple autosomal recessive inheritance of susceptibility. Susceptible phenotype: 129/J, A/J, B6, C3HeB/FeJ, and SJL/J.Resistant phenotype: AKR/J, C3, and CBA/J.Different pattern of susceptibility than with inflammation, suggesting the responses are controlled by disparate genetic factors.

2 3 h Mice, C3H/HeJ, A/J,

C57BL/6J, 129/SvIm,CAST/Ei, BTBR,DBA/2J, FVB/NJ,BALB/cJ,n = 6-24/group

Used whole body plethysmography and enhanced pause index (Penh)

evaluations.C57BL/6J, BALB/cJ, 129/Svlm, BTBR: were highly sensitive to O3;

exhibited significant increases in Penh to MCh at 6 and 24 h after expoto O3.

DBA/2J, A/J, FVB/NJ, CAST/Ei, C3H/HeJ: increases in sensitivity tat 6 h after exposure, return to near baseline by 24 h after exposure to 

 VE = Minute ventilation

 VT = Tidal volume

f = Frequency of breathing

 FA = Filtered air MCh = Methacholine

AX5-35
Table AX5-12. Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

0.10.3

4 h/day,4 days/weekfor 24 weeks

Guinea pig, male andfemale, Hartley,200-250 g,n = 10-20/group

O3 exposure did not produce airway hyperresponsiveness to ACh in

nonsensitized animals; in OVA-sensitized animals, there was increaresponsiveness to both nonspecific (ACh) and specific (OVA) airwchallenge that persisted for 4 weeks after exposure 0.1 and 0.3 ppm 

Effects were not gender specific and were not associated with BALinflammatory indicators, but were associated with antigen-specificantibodies in blood.

0.150.300.601.2

4 h Guinea pig, male

Hartley,500-600 g,n = 5-8/group

Increased airway responsiveness to Hist, but not ACh, 16-18 h afte1.2 ppm O3 exposure only. Increased responsiveness to SP occurre

exposure to$0.3 ppm O3.

0.3 4 h/day for 1,

3, 6, 12, 24,or 38 days

Guinea pig, maleHartley,500-600 g,n = 6-7/group

Increased airway responsiveness to SP occurred 16-18 h after expoto 0.3 ppm O3 for 1, 3, 6, 12, and 24 days; but not after 48 days. H

significant correlation between airway responsiveness and BALF tocells, AMs, neutrophils, and eosinophils, suggesting that airwayinflammation is involved.

0.5 8 h/day for 5 days,

repeated every14 days for6 months

Rhesus monkey,male, 30 days old,n = 6/group

Increased airway responsiveness to Hist after 10 episodes of exposuO3 + HDMA in sensitized infant monkeys.

1 1 h Guinea pig, male,

Dunkin-Hartley,250-300 g,n = 6-7/group

Increased bronchial responsiveness at 3 h, but not 24 h after O3; OV

no effect on baseline, but enhanced airway responsiveness 24 h afte

1 1 h Mice, male,

C57BL/6,6 weeks old,n = 10-31/group

Ozone caused increased Cdyn and VE, and decreased PaO2 in OVAsensitized mice. 

2 2 h Rat, male, Fischer

F344,14 months old,n = 6/group

Increased airway responsiveness to MCh 2 h PE. 

AX5-36
Table AX5-12 (cont’d). Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

0.3-3.0 3 h Mice, AJ, male and

female,aged 2, 4, 8, or12 weeks,n = 42-50/group

Nose-only exposure plethysmographs. VE decreased with increasin

O3 caused concentration-related decrease in VE at all ages, but with 

response in the 2-weeks old. Younger mice with less decrease inO3-induced VE demonstrated 3- to 4-times greater inhaled dose wh

normalized for body weight. The 2- to 4-weeks mice showed no Aany dose, while the 8- and 12-week old mice demonstrated dose-relincreases in AHR. Older mice demonstrated increased levels of ILMIP-2. Suggests that young mice are less sensitive to O3 for the en

of two cytokine and AHR.

0.3 5 h Mice, BALB/c,

3 weeks old,n = 5/group

Mice OVA-sensitized day 7-14; exposed day 21-23, assayed day 24 25 Decrease in Penh in rats exposed to O3, as a function of MCh

concentration.

2 3 h Mice, C57BL/6J, and

ob/ob,8-12 weeks old,n = 6-7/group

Compared C57BL/6J and ob/ob mice ( strain obese due to defect in coding for satiety hormone leptin). Intravenous MCh challenge indAHR and inflammation in both groups, but was greater in obese miDose per gram of lung tissue was greater in obese mice. Suggests omice get greater dose of O3.

2 Rats, male and

female, SD,2, 4, 6, 8, or 12weeks,n = 4-19/group

Nose-only-exposure plethysmographs exposure. 8,12 week rats: O3-induced 40-50% decreases in VE (primarily due

to decrease in VT).

6 week rats: O3-induced changes in VE were significantly less. 

2, 4 week rats: no O3-induced changes in VE. 

BALF protein and PGE2 were greater than in older rats. Suggests hdelivered dose to younger rats, decreased ventilatory response, andgreater lung injury.

2 2 h Guinea pigs, male,

Hartley, 400-600 g,n = 6/group

AHR to MCh peaked 2 h PE; PMN in BALF increased until 6 h PETazanolast (a mast cell stabilizing drug, doses 30, 100, or 300 mg/kadministered before O3 exposure inhibited O3-induced AHR dosedependently. Suggests that mast cells may play in role in the

development of AHR.

AX5-37
Table AX5-12 (cont’d). Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

1 or 3 4 h, assayed 4 to

72 PE

Mice, normal WBB6F1(1/1) and mast celldeficient WBB6F1-kit W /kit W-v(kit W /kit W-v)8-12 weeks old,n = 3-11/group

Demonstrated O3-induced cutaneous, as well as bronchial, mast cel

degranulation. PMN influx observed at 1 ppm only in normal miceAHR in response to MCh with 1 ppm observed in both. Suggests tmast cells are involved in O3-induced PMN influx but not AHR.

2 2 h Cat, 2-3 kg,

n = 5/group

Cats anesthetized and mechanically ventilated, challenged with ACPretreated with polyethylene glycol-superoxide dismutase (PEG-SOor PEG-catalase (PEG-CAT) 5 min before O3 exposure. PEG-SOD

partially prevented O3-induced AHR, PEG-CAT did not. Suggests

superoxide involvement in O3-induced AHR.

0.75 4 h, MCh challenge

6 h PE

MiceFVB/N, andFVB/N with

$2-AR transgene,

10-14 weeks old,n = 10/group

Targeted expression (using CCSP promoter) of $2-adrenergic recep

($2-AR) to airway epithelium to mimic agonist activation. Heteroz

mice from generations 2 to 4 used. MCh challenge dose needed to Penh was greater in CCSP-$2-AR mice. CCSP-$2-AR mice less resp

to O3. Suggests that $2-ARs regulate airway responsiveness and th

$-agonists induce bronchodilation through activation of receptors o

smooth muscle cells and epithelial cells.

2 2 h, assayed 2 h PE Rat, male, SD,

2.5-3.5 months old,n = 5/group

Neonatal rats treated with capsaicin. Challenged with MCh follow

Capsaicin-treated rats: O3 had no effect on pulmonary conductance

decreased dynamic compliance; increase in AHR. During O3 exposure: 50% decrease in HR and 2.5 °C decrease in c

temperature in both controls and capsaicin rats.Suggests that C-fibers inhibit O3-induced AHR but do not modulate 

or core temperature.

AX5-38
Table AX5-12 (cont’d). Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

1 3 h, assayed 4 h PE Rat, SD, treated

with capsaicinor tachykininantagonists,n = 6/group

Rats treated with CP-99994 (neurokinin-1 receptor antagonist) andSR-48968 (neurokinin-2-receptor antagonist). O3 induced greater

numbers of PMN in BALF of treated rats. The antagonists has noeffects on pulmonary mechanics or airway responsiveness. Suggests that tachykinins are involved in the protective effects of Cagainst O3-induced inflammation.Capsaicin treatment induced increased PMN in BALF. O3 exposur

reduced VE in both vehicle and capsaicin-treated rats, but the capsa

treatment caused a greater, more immediate reduction. Suggests that the increase in BALF PMN is not due to a greater inhdose of O3 reaching the lung.

2 3 h, ACh challenge

0 and 24 h PE

Mice, 8 weeks old,15-25 g.DBA/2J, AKR/J,A/J, C3H/HeJ,C57BL/6J, SJL/H,129/J,n = 6-8/group

Differing susceptibility to O3: Hyperreactive-DBA/2J, AKR/J, A/J

Hyporeactive-C3H/HeJ, C57BL/6J, SJL/H; Intermediate 129/J. ACh challenge 25 or 50 μg/kg.ACh 24 h PE: Airway responses increased in A/J strain at 25 μg/kg in C57BL/6J and SJL/J strains at 50 μg/kg. Ozone did not alter reactivity in other strains. MCh or carbachol chnot affected by O3, suggesting that cholinesterase function is affect

O3. C57BL/6J and A/J mice treated with cyclophosphamide

(an immunosuppressant) or anti-PMN caused decreased O3-induced

PMN levels but did not alter AHR, suggesting that O3-induced ACh

hyperreactivity correlates with susceptibility and that PMN influxis independent of AHR. 

AX5-39
Table AX5-12 (cont’d). Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

0.05 4 h, challenged with

iv 5-HT

Rats, male, LongEvans, SD, Fisher344, Brown-Norway,BDII, BDE, DA,Lewis and Wistar,6-8 weeks old,n = 10/group

AHR: developed in Lewis, BDII and Long-Evans rats 90 min after 

Baseline AHR differed among strains; did not correlate with O3-ind

AHR. PMN influx: did not occur in any strain.LE rats: AHR lasted $12 h PE with no change in BALF PMN, LD

alkaline phosphatase, or protein.Suggests that O3-induced AHR occurs without airway inflammation 

that genetic factors may alter the sensitivity to O3.

0.2 7 h, assayed 3 h PE Rabbits, New

Zealand white, 5 kg, n = 5-7/group

O3-induced decrease in tracheal transepithelial potential difference, 

change in lung resistance. ACh challenge: no change in compartmentalized lung resistance;140% increase in O3-induced lung resistance.

Bilateral vagotomy: no change in compartmentalized lung resistanenhancement of O3-induced peripheral lung reactivity.

Suggests that O3 exposure may affect tracheal epithelial function an

increase central airway reactivity, possibly through vagally-mediatemechanisms.

0.4 4 h, assayed by

ACh, SP, orhistamine challenge0 or 48 h PE

Rabbits, NewZealand white, maleand female, 2.5-3 kg,n = 4-6/group

Used isolated perfused lung model allowing partitioning of the totapressure gradient into arterial, pre- and postcapillary, and venouscomponents. O3-induced inhibition of pulmonary mechanical react

ACh, SP, and histamine. No change in baseline pulmonary resistandynamic compliance. At 48 h PE O3 altered vasoreactivity of the v

bed.. Ozone-induced modification of the vasoreactivity of the vascat 48 h PE and elevation of arterial segmental pressure. Suggests th

can directly induce vascular constriction both immediately and 2 dafollowing exposure and can inhibit ACh-, SP-, and histamine-inducchanges in lung mechanics. 

AX5-40
Table AX5-12 (cont’d). Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

0, 0.12, 0.5, or1.0

6 h/day,5 days/week for20 months

Rat, male andfemale,Fischer 344,6-7 weeks old

Isolated eighth generation airways following O3 exposure. Circumf

tension development was measured in response to bethanechol,acetylcholine, and electrical field stimulation and normalized to smmuscle area. 0.5 ppm caused an increase in smooth muscle area. Maximum responses of the small bronchi of male rats were significreduced after exposure to 0.12 and 0.5 ppm O3. Suggests that O3 -i

increases in airway responsiveness do not persist with near-lifetimeexposure and that chronic exposure alters smooth muscle cell funct

0.5 8 h/day for 7 days Guinea pig, male,

Hartley, 5 weeks old

Repeated exposure increased rapidly adapting receptor activity tosubstance P, methacholine, and hyperinflation; no significant effectbaseline or substance P- and methacholine-induced changes in lungcompliance and resistance. Suggest that because agonist-induced changes in receptor activity plung function changes, the responsiveness of rapidly adapting recepwas enhanced.

0.5 8 h/day for 5 days

followed by 9 daysof FA; for11 episodes

Monkey, Rhesus,30-d old,n = 6/group

Half of the monkeys were sensitized to house dust mite allergen (Hat 14 and 28 days of age before exposure. HDMA and histamine aechallenges administered until Raw doubled. Baseline Raw elevated a

10 exposure episodes in the HDMA + O3 group compared to the FA

HDMA, and O3 exposure groups. Aerosol challenge with HDMA a

end of the 10th episode did not significantly affect Raw, VT, f, or SaO

AHR appeared to develop following episode 6. Aerosol challenge HDMA at the end of the 10th episode did not significantly affect R

or SaO2. HDMA + O3 group: had increases in serum IgG, histamin

eosinophils; greater alteration in airway structure and content suggethat O3 can enhance the structural remodeling and allergic effects o

HDMA sensitization exposure groups. 

AX5-41
Table AX5-12 (cont’d). Effects of Ozone on Airway Responsiveness

Concentrationppm

ExposureDuration

Species, Sex, Strain,and Age Observed Effect(s) 

1 8 h Rat, Wistar,

some treatedwith capsaicin,n = 6-8/group

Vehicle-treated: O3-induced rapid shallow breathing pattern; BrdU 

started at the bifurcation of the main stem bronchi and increased disCapsaicin treated: no O3-induced changes in respiratory frequency

reduced BrdU labeling density in the terminal bronchioles supplied short airway paths. Suggests that O3-induced rapid shallow breathi

is protective of conducting airways and allows distribution of injury more distal regions.

1 2 h Rat, male, Wistar,

100-120 days old,n = 7-10/group

Examined the site-specific deposition of 18O at breathing frequencie

120, 16, or 200 bpm at a VT to produce a constant minute ventilatio

72.8 ml/min/100 g body weight. All frequencies: parenchymal areas had a lower content of 18O than 

and bronchi; right caudal parenchymal levels did not change.80 to 160 bpm: deposition reduced in midlevel trachea and increasboth mainstream bronchi; increased deposition in parenchyma suppshort (cranial) airway paths. 200 bpm: increased deposition in trachea increased; increased depoin right cranial and caudal bronchi regions: decreased content in rigcranial parenchymal. Suggests that the effect of rapid, shallow breathing is to create a moevenly distributed injury pattern with less deposition of O3) in the tr

and a small effect on deposition in the parenchyma.

 MCh = Methylcholine, ACh = Acetylcholine, Hist = Histamine, 5-HT = 5-Hydroxytryptamine, SP = Substance P, FS = Field Stimula

 TX = Thromboxane, KCl = Potassium Chloride, Pt = Platinum; Route: iv = intravenous, inh = inhalation., sc = subcutaneous, ip = int

 OVA = Ovalbumin, BALF = bronchoalveolar lavage fluid, HDMA = House Dust Mite Allergen, Cdyn = Dynamic Lung Compliance, V

 PaO2 = partial pressure of arterial oxygen, AHR = airway hyperreactivity, VT = Tidal Volume, Raw = airway resistance, 

f = frequency o

 SaO2 = oxygen saturation of arterial blood.

AX5-42
Table AX5-13. Effects of Ozone on Genotoxicity/Carcinogenicity

Concentrationppm

ExposureDuration

Species,Sex, Strain,and Age Observed Effect(s) 

1 0, 12, 24, 48,

72, or 96 h

Guinea pigs,Dunkin-Hartley,male, 2 mo-old,n = 4/group

Following O3 exposure, two main bronchi were removed and tracheobronchial cells we

and assayed for DNA strand breaks using fluormetric analysis. Ozone induced an increBALF protein and in DNA strand breaks, but did not change cell yield or viability. Thof DNA in alkali lysates was decreased at 72 h, which suggests an increase in strand brthat time point.

1 or 22

90 min90 min/dayfor 5 days

Mice, female,BALB/c(20.6 g) orMutaTM (26.0 g)

n = 11-21/group

O3-induced increase in strand breaks up to 200 min following exposure. No effects afte

O3 did not affect the level of oxidized amino acids in lung or the level of 8-oxo-deoxygin nuclear DNA. O3-induced induction of IL-6 mRNA following DNA strand breaks, wnot support inflammation causing DNA damage.Mutagenic mice had no O3-induced mutations in cII transgene.

0.12, 0.50,and 1.0

6 h/day,5 days/week forup to 9 months

Mice, female,A/J,n = 29-35/group

At 5 months, no difference in lung tumor multiplicity or incidence. At 9 months, no diin lung tumor multiplicity between control mice and mice exposed to any concentration 

The highest, and only statistically significant lung tumor incidence, was found in the mto 0.5 ppm O3. In the O3-exposed mice allowed to recover in filtered air, only the mice 

0.12 ppm O3 had increases in lung tumor incidence and multiplicity. Authors consider 

to be spurious and of no significance for data interpretation.

0.5 6 h/day,

5 days/week for12 weeks

Mice, male andfemale, B6C3F1,

5-6 weeks old,n = 20 M and 20F

Sporadic differences in mean body weight between O3-exposed mice and air-exposed c

as well as significant differences in the mean absolute and relative weights of liver, splkidney, testes, and ovary. No O3-related increased incidence of neoplasms in lung tissu

Oviductal carcinomas observed upon histopathologic examination in 30% of O3-expose

female mice. 

0, 0.12, 0.5, or1.0

6 hr/day,5 days/week,to ppm 2-yrand lifetime 

Rats, male andfemale, FischerF-344/N, n = 5 M + 5 F(acute)n = 50 m + 50F/group

Cocarcinogenicity study with subcutaneous administration of 0, 0.1, or 1.0 mg/kg body of 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and inhalation of 0 or 0O3 to male rats. 

O3 caused dose-related increase in inflammation in CAR; increased fibrosis; extension bronchiolar epithelium to the proximal alveoli; but no increase in neoplasms.NNK (1.0 mg/kg) alone causes increased bronchiolar/alveolar neoplasms.NNK + O3: no enhancement of neoplasms.

Suggests that O3 is not carcinogenic; does not enhance neoplasms growth; and creates m

site-specific lesions which persist with continued exposure.

AX5-43
Table AX5-14. Systemic Effects of Ozone

Concentrationppm Duration Species Effects NEUROBEHAVIORAL EFFECTS0.10.20.51.0

4 h Rat, male, Wistar,

47-50 days old, n = 25/group

Rats exposed for 4 h to 0.2, 0.5, and 1 ppm O3 showed long-term memory

deterioration and decreased motor activity, which was reversed 24 h laterBrain and pulmonary Cu/Zn SOD levels were increased in animals exposto 0.1, 0.2, and 0.5 ppm O3, but decreased in animals exposed to 1 ppm O

0.10.40.71.11.5

4 h Rat, male, Wistar,

300-350 g,n = 10/group

O3 caused memory impairment at $0.7 ppm (one trial passive avoidance 

decreased motor activity at $1.1 ppm, and increased lipid peroxidation at

$0.4 ppm. Lipid perioxidation levels from the frontal cortex, hippocamp

striatum and cerebellum increased with increasing O3 concentration.

0.30.6

30 days Mice, CD-1

M, F, 28-33 g, n = 6-7/group

O3 exposure slightly but selectively affected neurobehavioral performanc

male mice assessed with a 5-min open-field test on exposure day 4 and 1on day 3 after the end of the exposure. O3 exposure, however, did not gr

affect neurobehavioral development. Reversal learning in the Morris watmaze test was consistently impaired in both prenatally and adult exposedmice. In addition, longer latency to step-through in the first trial of thepassive avoidance test and a decrease in wall rearing in the hot-plate test recorded in O3 prenatally exposed mice. Except for the first open-field te

altered responses were observed only in animals exposed to 0.3 ppm O3.

0.350.751.5

12 h Rat, male, Wistar,

270 g, n = 10/group

O3 exposure decreased paradoxical sleep after 2 h of exposure, and increa

slow wave sleep after 12 h of exposure at all O3 concentrations; 5-HT

concentrations in the pons increased with increasing O3 concentration.

0.7 4 h Rat, male, Wistar,

47-50 days old,n = 6-10/group

Vitamin E administered before or after O3 exposure blocked memory

deterioration (passive avoidance)and increases in lipid peroxidation levelin the striatum, hippocampus and frontal cortex that were associated withoxidative stress.

0.7 4 h Rat, male, Wistar,

27 months old,n = 3-4/group

O3 exposure increased ultrastructural alterations in the hippocampus and

prefrontal cortex in aged rats compared with controls. These areas are reto learning and memory functions, which are the first degenerative agingchanges observed.

AX5-44
Table AX5-14 (cont’d). Systemic Effects of Ozone

Concentrationppm Duration Species Effects NEUROBEHAVIORAL EFFECTS (cont’d)

0.70.8

4 h Rat, male, Wistar,

47, 540, or 900days old,n = 10-30/group

Taurine (43 mg/kg) given before or after O3 exposure improved memory

deterioration in an age-specific manner. Old rats showed peroxidation in control groups and an improvement in memory with taurine. When tauriwas applied before O3, peroxidation levels were high in the frontal cortex

of old rats and the hippocampus of young rats; in the striatum, peroxidaticaused by O3 was blocked when taurine was applied either before or afte

exposure. 

1 12 h/day

during darkperiod

Rat, female, adult,n = 6/group

O3 exposure during pregnancy affects the neural regulation of paradoxica

sleep and circadian rhythm of rat pups 30, 60, and 90 days after birth.

1 4 h Rat, male, Wistar,

n = 24/group

O3 caused alterations in long-term memory and a significant reduction of

dendritic spines. Results provide evidence that deterioration in memory iprobably due to the reduction in spine density in the pyramidal neurons ohippocampus. 

1 3 h Rat, male, Wistar,

275 g,n = 10/group

O3 or its reaction products affect the metabolism of major neurotransmitte

systems as rapidly as after 1 h of exposure. There were significantincreases in dopamine (DA), and its metabolites noradrenaline (NA)and 3,4 dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindolaceticacid (5-HIAA) in the midbrain and the striatum.

1.5 24 h Rat, male, Wistar,

n = 11/group

Adult rats exposed to O3 spend decreased time in wakefulness and

paradoxical sleep and a significant increase in time in slow-wave sleep. Neurochemical changes include increased metabolism of serotonin inthe medulla oblongata, pons, and midbrain.

0.5 20 h/day

for 5 days

Rat, SD,220-240 g,n = 10-20/group

O3 produced marked neural disturbances in structures involved in the

integration of chemosensory inputs, arousal, and motor control. O3 inhibited tyrosine hydroxylase activity in noradrenergic brainstem celgroups, including the locus ceruleus (-62%) and the caudal A2 subset (!5

Catecholamine turnover was decreased by O3 in the cortex (!49%) and

striatum (!18%) but not in the hypothalamus.

AX5-45
Table AX5-14 (cont’d). Systemic Effects of Ozone

Concentrationppm Duration Species Effects NEUROBEHAVIORAL0.4, 0.8, or 1.2 24 h Cat, male, adult,

n = 5/group

Evaluated EEG of sleep-wake organization in cats. 0.4 O3 did not change 

amount of sleep parameters, did decrease paradoxical sleep during first 8 of exposure. At 1.2 ppm paradoxical sleep was reduced during O3 expos

followed by a dose-related increase of slow-wave sleep. Suggests O3-ind

changes in sleep patterns.

0.75, 1.5 and 3.0 4 h Rat, male, Wistar,

250-300 g,n = 15/group

Recorded evoked potential in visual cortex and lateral geniculate nucleusP1, N1 and P2 components delayed in the visual cortex and lateral genicunucleus at 3.0 ppm O3. N1 component in the visual cortex affected at 1.5 

O3. Suggest O3-induced alterations in synaptic excitability and conductio

mechanisms in the visual pathway.

1-1.5 4 h Rat, male, Wistar,

~250 gn = 5/group

O3-induced loss of dendritic spines on primary and secondary dendrites o

granule cells; swelling of Golgi apparatus and mitochondrion; dilation cisof the rough endoplasmic reticulum; vacuolation of neuronal cytoplasm. Suggests O3-induced oxidative stress creates alterations in the granule lay

of the olfactory bulb and possible modifications of function.

NEUROENDOCRINE EFFECTS

0.5 to 3.0 3 h Rat, male, SD,

44-47 days old,n = 4-6/group

Hyperthyroid, T4-treated rats (0.1-1.0 mg/kg/day for 7 days) had increase

pulmonary injury (BALF LDH, albumin, PMNs) at 18 h PE compared tocontrol rats.

1.0 24 h Rat, male, SD,

3-4 months old

Hyperthyroid, T3-treated rats had increased metabolic activity and O3-ind

pulmonary injury, but lipid peroxidation, as assessed by alkane generatiowas not affected. 

AX5-46
Table AX5-14 (cont’d). Systemic Effects of Ozone

Concentrationppm Duration Species Effects CARDIOVASCULAR EFFECTS0.10.30.5

5 h Rat, Wistar

young (4-6months) and old (22-24 months)n = 9-14/group

Transient rapid shallow breathing with slightly increased HR appeared1-2 min after the start of O3 exposure, possibly due to olfactory sensation

persistent rapid shallow breathing with a progressive decrease in HR occuwith a latent period of 1-2 h. The last 90-min averaged values for relativminute ventilation tended to decrease with the increase in the level ofexposure to O3 and these values for young rats were significantly lower th

those for old rats. An exposure of young rats to 0.1 ppm O3 for shorter th

5 h significantly decreased the tidal volume and HR and increased breathfrequency, but no significant changes were observed in old rats. There wno differences between young and old rats in non-observable-adverse-efflevels (NOAELs) for the O3-induced persistent ventilatory and HR respon

when the NOAELs were determined by exposure to 0.3 and 0.5 ppm O3.

0.10.30.5

8 h/dayfor 4 days

Rat, male, Wistar,10 weeks old,n = 9/group

Circadian rhythms of HR and core body temperature were significantlydecreased on the first and second O3 exposure days in a concentration

dependent manner, and returned to control levels on the third and fourth d

0.25 to 2.0 2 h to 5 days Rat, Fischer F344,

Mice, C57BL/6J,C3H/HeJ, Guineapig, Hartley,n = 4-10/group

Robust and consistent decreases in HR and core body temperature; smalldecreases in metabolism, minute ventilation, blood pressure, and cardiacoutput that vary inversely with ambient temperature and body mass.

0.5 6 h/day

23 h/dayfor 5 days

Rat, male, FischerF-344, 100-120 days old,n = 4-6/group

Minimal extrapulmonary effects were observed at a core body temperatur34 °C; O3 exposures at 22 and 10 °C produced significant decreases in he

rate (160 and 210 beats/min, respectively), core body temperature (2.0 an3.5 °C, respectively), and body weight (15 and 40 g, respectively). Decreases in these functional parameters reached their maxima over the f2 exposure days and returned to control levels after the 3rd day of exposu

AX5-47
Table AX5-14 (cont’d). Systemic Effects of Ozone

Concentrationppm Duration Species Effects CARDIOVASCULAR EFFECTS (cont’d)

0.5 8 h Rat, male, Fischer

F-344, 270-330 g,n = 6/group

O3 exposure increased atrial natriuretic peptides in the heart, lung, and

circulation, suggesting they mediate the decreased BP and pulmonaryedema observed with similar O3 exposures.

00.50.50.5

24 h/day6 h/day 23 h/day

Rat, male, FischerF-344 kept at oneof threetemperatures: 10 °C, 22 °C,34 °C at rest,moderate or heavyCO2-stimulated

ventilation, 100-120 days old,n = 4-8/group

0.5 ppm O3 for both 6 h/day and 23 h/day caused decreases in heart rate a

core temperature (termed hypothermic response) and increases in BALFinflammatory markers. Exercise in 0 ppm O3 caused increases in heart ra

and core temperature, 0.5 ppm O3 decreases. CO2 and O3 induced the

greatest deficits. Dose, animal mass, and environmental stress are suggesto modify the hypothermic response. 

REPRODUCTIVE AND DEVELOPMENTAL EFFECTS

0.20.40.6

Continuous upto days 17 ofpregnancy

Mice, male andfemale, CD-1,25-27 g

No significant effects on either reproductive performance, postnatal somaand neurobehavioral development (as assessed by a Fox test battery) or amotor activity (including within-session habituation); some subtle orborderline behavioral deficits were noted, however.

0.30.60.9

Continuous upto postnatal day26

Mice, male andfemale, CD-1,27-30 g,n = 11-15/group

O3 caused subtle CNS effects, but did not affect the animals' capability to

learn a reflexive response (limb withdrawal); females exposed to 0.6 ppmO3 showed a reduced preference for the right paw than both their same-se

controls and 0.6 ppm males. The effect was more robust in the case of anorganized avoidance response (wall-rearing).

AX5-48
Table AX5-14 (cont’d). Systemic Effects of Ozone

Concentrationppm Duration Species Effects REPRODUCTIVE AND DEVELOPMENTAL EFFECTS (cont’d)

0.30.6

Continuousuntil gestationalday 17

Mice, male andfemale, CD-1, 28-30 g,n = 6-9/group

Exposure to O3 did not grossly affect neurobehavioral development,

as assessed by somatic and sensorimotor development (postnatal day(PND) 2-20), homing performance (PND 12), motor activity (PND 21),passive avoidance (PND 22-23), water maze performances (PND 70-74),and response to a nociceptive stimulus (PND 100).

0.40.81.2

Continuousduring gestationday 7-17

Mice, CD-1 No effect of O3 on reproductive performance; no significant somatic

developmental effects in O3-exposed pups except for a delay in eye

opening that was not concentration dependent.

0.6 Continuous

from birth toweaning

Mice, male andfemale, CD-1,25-27 g,n = 13-16/group

Exposure to O3 did not produce any significant impairment of the acquisi

phase during swimming navigation, a sensitive indicator for hippocampaldamage; however, O3 slightly increased the swimming paths during the laday of the reversal phase. Mice exposed to O3 showed a slightly but

significantly higher swimming speed during all the days, which was unreto differences in body weight and to navigational performances. Moreovmice exposed to O3 (with the exception of one animal) had a strong tende

to make turns to the left while the controls, independent of sex, preferredclockwise turns.

1 12 h/day for

entire gestation,assayed atpostnatal day 0,12, and 60

Rat, male andfemale, Wistar,n = 9-10/group

Histological and planimetric analysis using sagittal sections of the anteriocerebellar lobe.PND 0: O3-induced cerebellar necrosis. 

PND 12: diminished molecular layer; pale nucleoli and perinucleolarbodies in Purkinjie cells. PND 60: Purkinjie cells with clumps of chromaround periphery. Suggests that gestational exposure to O3 induces perm

cerebellar damage.

EFFECTS ON LIVER, SPLEEN, THYMUS

1.02.0

3 h Rat, female, SD, 

200-225 g

High O3 exposure stimulates hepatocytes to produce increased amounts

of nitric oxide as well as protein, possibly mediated by cytokines suchas TNF-" produced by alveolar macrophages. When macrophage functio

is blocked, hepatic injury induced by O3 is prevented.

AX5-49
Table AX5-14 (cont’d). Systemic Effects of Ozone

Concentrationppm Duration Species Effects EFFECTS ON LIVER, SPLEEN, THYMUS (cont’d)

2.0 2 h Rat, male, Fischer

F-344,2, 9, or 24 monthsold,n = 2/group

Utilizing electron paramagnetic resonance (EPR) spectroscopy of chlorofextracts of liver homogenates, a significant flux of hydrogen peroxideproduced from the reaction of O3 with lipids of the extracellular lining co

be a source of biologically relevant amounts of hydroxyl radical. EPR sifor carbon-centered alkoxyl and alkyl adducts were detected with C-phenN-tert-butyl nitrone (PBN) in the liver of animals exposed to O3.

EFFECTS ON CUTANEOUS TISSUE

0.5 2 h Mice, hairless

female

" tocopherol levels in the stratum corneum (SC) were not affected by O3exposure (0.5 ppm) alone, but were significantly depleted by combinedexposure to UV and O3.

0.8 6 h Mice, SKH-1

hairless

Increased lipid peroxidation in the skin epidermis and dermis activated stproteins HSP27 and HO-1, and activated a proteolytic enzyme system(MMP-9) related to matrix injury and repair processes.

0.81.010.0

2 h Mice, SKH-1

hairless

High O3 depletes hydrophilic antioxidants in the SC: vit. C decreased to 

GSH decreased to 41%, and uric acid decreased to 44% of control levels exposure to $1.0 ppm O3.

1.05.010.0

2 h Mice High O3 exerts an oxidizing effect on the outermost layer of the skin (SC

depletes low-molecular-weight antioxidants (" tocopherol, vit. C, glutath

uric acid) in a concentration dependent manner; increases malondialdehylevels associated with lipid peroxidation.

0, 0.8, 1, and 10 2 h Mice, SKH-1

hairless

1 ppm O3 depleted SC levels of vitamin C ( 80%), GSH (41%), and UA

(44%). Suggests that hydrophilic antioxidants in the SC modulate the effof O3-induced oxidative stress.

 RER = Rough endoplasmic reticulum NADPH = Reduced nicotinamide adenine dinucleotide phosphate LPS  PE = Postexposure (i.e., time after O3 exposure ceased) NADH = Reduced nicotinamide adenine dinucleotide SRB

 TSH = Thyroid stimulating hormone B[a]P = Benzo[a]pyrene TBA 

 T3 = Triiodothyronine NK = Natural killer IgE 

 T4 = Thyroxine PHA = Phytohemagglutin PHA cyt. = Cytochrome ConA = Concanavalin A

AX5-50
Table AX5-15. Interactions of Ozone With Nitrogen Dioxide

Concentration

ppm

O3 NO2 Duration Species Endpoints Interaction 

MORPHOLOGY

0.8 14.4 6 h/day, 

7 days/weekfor 90 days

Rat, male, SD,10-12 weeksold,n = 4/group

Morphometry of lungparenchyma; DNA probesfor procollagen; in situmRNA hybridization. 

Syngeristic; more peripheral centriacinar lesion, buafter 7, 78, and 90 days of exposure.

0.3 1.2 Continuous

for 3 days

Rat, male, SD,3 months old,n = 4/group

DNA single strand breaks;polyADPR synthetase ofAMs; total cells, protein,and LDH in BALF.

None; effect due to O3. 

BIOCHEMISTRY

0.8 14.4 6 h/day, 

7 days/weekfor 9 weeks

Rat, male, SD,10-12 weeksoldn = 4/group

Lung hydroxyproline,hydrooxypyridinium,DNA, and protein contentof whole lung; morphologyand labeling index.

Synergistic; fibrosis after 7-8 weeks of exposure;50% mortality at ~10 weeks.

0.4 7 90 days Rat, male, SD,

200-225 g

PMN, pulmonary edema,fibrosis, MIP-2.

1-3 days: enhanced MIP-2, IL-1$, TNF-

", thiored

and IL-6 expression; pulmonary edema and PMN iwhich reversed by day 8; activation of NF6B.

15-45 days: no tissue responses observed, suggestadaptation.60 and 90 days: increased lung collagen; increasedexpression of transforming growth factor-13 and T

activation of NF6B.

MnSOD and GPX not altered during exposure.Suggests that cytokines play a role in the early respto combined O3 and NO2 and that pulmonary fibros

more dependent on concentration than on cumulati

AX5-51
Table AX5-15 (cont’d). Interactions of Ozone With Nitrogen Dioxide

Concentration

ppm

O3 NO2 Duration Species Endpoints Interaction 

BIOCHEMISTRY (cont’d)

0.8 14.4 1, 5, and

8 weeks

Rat, male, SD,10-12 weeksold,n = 4/group

Immunohistochemisty andmorphometric analysis ofTNF-

" and MnSOD levels

in alveolar ducts.

Triphasic response. 1-3 weeks: initial inflammatioTNF-

" increased in proximal area.

4-5 weeks: partial resolution.6-8 weeks: rapidly progressive fibrosis; elevated MTNF-

" increased in proximal area.

TNF-

" increased in interstitial cells at all time poin

Suggests O3-induced increases in MnSOD in areas 

injury and in more protected areas; O3-induced incr

in TNF-

" correlate spatiotemporally with injury.

BAL = Bronchoalveolar lavage. SOD = Superoxide dismutase.PG = Prostaglandin. DR = Disulfide reductase.G-6-PD = Glucose-6-phosphate dehydrogenase. NADPH-CR = Reduced nicotinamide adenine dinucleotide phosphate-c

GDT = GSH-disulfide transhydrogenase. GSH = Glutathione.GSHPX = GSH peroxidase. 6-PG-D = 6-phosphogluconate dehydrogenase.

AX5-52
Table AX5-16. Interactions of Ozone with Formaldehyde

O3 HCHO Duration Species Endpoints Interac

0.4 3.6 8 h/day for

3 days

Rat, male,Wistar, n = 20/group

O3 or HCHO: no changes in formaldehyde dehydrogenase,

glutathione S-transferase, glutathione reductase, and glucose-6-phosphate dehydrogenase activities.O3 + HCHO: slightly decreased enzyme activitiesHCHO alone: rhinitis, necrosis, degeneration, hyperplasia andsquamous metaplasia of nasal respiratory epithelium.O3: PMN influx; disarrangement, flattening and slight basal cellhyperplasia of the nonciliated cuboidal epithelium. Proliferatingcell nuclear antigen levels elevated. 

ProliferresponsNo intereffects

0.6 10 3 h, with

exercise at2× restingventilation

Rat, male,SD, 7 weeks

HCHO did not alter O3-induced changes in breathing pattern.

Parenchymal injury attributed to O3 alone. 

Additivin transiepitheliuand trac

0.2-10 0.4-4 30 min Mice,

BALB/c,n = 4

Continuously measured 

f, VT, expiratory flow, Ti, Te, and

respiratory patterns during acute exposures. HCHO: appeared tobe a pure sensory irritant at lower concentrations. O3: induced

non-dose-dependent transient increase in rapid, shallow breathing. No effect level of HCHO was 0.3 ppm, for O3 1.0 ppm. Suggests

that O3 and HCHO have the same respiratory effects in BALB/c

mice and humans, with similar sensitivities.

Not add

AX5-53
Table AX5-17. Interactions of Ozone with Tobacco Smoke

O3 HCHO Duration Species Endpoints Int

1.5 7 ml breaths at

33% challenge

1 h Guinea pig,

male, Hartley,320-460 g,n = 5 to 9

Pulmonary resistance and dynamic lung compliance were comparedpre- and post-O3 exposure. 

Pre-O3: cigarette smoke induced bronchoconstriction after l min. 

Post-O3: cigarette smoke induced bronchoconstriction more quickly

and for a longer period. Selective antagonism of neurokinin 1 and 2 receptors blocked thenenhanced O3-induced bronchoconstriction, suggesting that endogenous

tachykinins modulate O3-induced bronchoconstriction.

Sy

0.5 ADSS

30 mg/m3

6 h/dayfor 3 days24 h

Mice, male,B6C3F1,10 weeks old,n = 11

Aged and diluted side stream cigarette smoke (ADSS) exposurefollowed by O3. 

ADSS + O3: greater increase in BALF cells, %PMN, and proteins

compared to alone; 402% increase in proliferating cells in CAR;LPS-stimulated release of IL-6 decreased; LPS-stimulated releaseof TNF-

" increased.

ADSS alone: no change in number of proliferating cells in CAR;LPS-stimulated release of TNF-

" increased.

O3 alone: 280% increase in proliferating cells in CAR;

LPS-stimulated release of IL-6 decreased.Suggests that O3-induced lung injury is enhanced by prior ADSS

exposure.

Sy

AX5-54
Table AX5-18. Interactions Of Ozone With Particles

 Concentration

Duration Species Endpoints Interaction 

O3

(ppm)

 PM(mg/m3)

SULFURIC ACID

0.10.2

0.02-0.15(0.4-0.8 μm)

23.5 h/day orintermittent 12 h/dayfor up to 90 days

Rat, male, SD,250-275 g,n = 6/group

MorphologyBiochemistry

No interaction 

0.10.30.6

0.50 (0.3 μm)0.125 (0.3 μm)

3 h Rabbit NZW

male, 3.5-4.5 kg,n = 5/group

AM intracellularpH homeostasis andH+ extrusion

Antagonism 

0.10.30.6

0.50 (0.3 μm)0.125 (0.3 μm)

3 h Rabbit NZW

male, 3.5-4.5 kg,n = 5/group

Airway responsiveness(in vitro bronchialrings + ACh)

Antagonism 

0.6 0.5 (0.06 and 

0.3 μm MMD)

4 h/day for 2 days Rat, male, SD,

250-300 g,n = 10/group

Morphology: volumepercentage of totalparenchyma containing injuredalveolar septae;bromodeoxyuridine celllabeling index in the periacinarregion 

Synergism: ultrafine 

not fineSynergism: fine + O

PARTICLE MIXTURES

0.1 Diesel PM (NIST

#2975) reacted withO3 for 48 h

24 h (IT) Rat, male, SD,

250-300 g,n = 4-13

Inflammation Synergism 

0.160.300.59

0.05-0.22 mg/m3

ammonium bisulfate0.03-0.10 mg/m3 C

0.11-0.39 pm NO2

0.02-0.11 mg/m3 HNO3;(0.3 μm MMAD)

4 h/day, 3 days/weekfor 4 weeks

Rat, male,Fischer F344N,11 weeks old,n = 8-30

breathing pattern, morphology,lavagable protein, andclearance

Complex interactionspossible loss of typicattenuation seen with 

exposure, reflectingpersistence of inflam

AX5-55
Table AX5-18 (cont’d). Interactions Of Ozone With Particles

 Concentration

Duration Species Endpoints Interaction 

O3

(ppm)

 PM(mg/m3

)

PARTICLE MIXTURES (cont’d)

0.2 0.07 and 0.14 mg/m3

ammonium bisulfate(0.45 μm MMMD);0.05 and 0.10 mg/m3carbon

4 h/day, 3 days/weekfor 4 weeks

Rat, male,Fischer F344, 22-24 monthsold,n = 5-10

BAL protein and albumin;plasma hydroxylase andfibronectin

Questionable interactNo changes in BALF or prolyl 4-hydroxylablood. Small decease plasma fibronectin wcombined exposure. 

0.2 0.50 mg/m3 ammonium

bisulfate (0.45 μmMMMD) and elementalcarbon)

4 h/day, 3 days/weekfor 4 weeks; nose only

Rat, FischerF344N-NIA,22-24 months old

DNA labeling of dividing lungepithelial and interstitial cellsby 5-bromo-2-deoxyuridine 

Synergism. Increasephagocytosis and respburst. Decreased luncollagen.

0.3 0.063 to 1.57 mg/m3

CAPs (Boston) + ipOVA sensitization

Sensitized at day 7and 14. Challenged atday 21, 22, and 23.5 h O3 exposure

Mice, BALB/c,n = 5-6/group

Airway function Interaction: increase

and airway responsivnormal and OVA-senmice.

0.4 0.20 and 0.50 mg/m3

fine, H2O2-coated

carbon (0.26 μmMMMD)

4 h/day for 1 or 5 days Rat, SD,

300 g,n = 10

Inflammation Synergism for effect 

Greater response at hcontrasts with O3 alon

inflammation was gre0.4 ppm on day 1. 

0.5 Endotoxin (IN)

100 μg 24 h and 48 h after the 3rdO3 exposure

8 h/day for 3 days Rat, Fischer

F344, 10-12 weeks old,n = 6/group

Nasal morphology Synergism: increased

intraepithelial mucosand mucous cell meta

0.5 OVA (IN)

50 μl (1%)

8 h/day for 1 day or3 consecutive days

Rat, Brown,Norway,10-12 weeks old,n = 6/group

Nasal morphology Synergism: increased

intraepithelial mucosand mucous all metap

AX5-56
Table AX5-18 (cont’d). Interactions Of Ozone With Particles

 Concentration

Duration Species Endpoints Interaction 

O3

(ppm)

 PM(mg/m3)\

PARTICLE MIXTURES (cont’d)

0.8 0.5 mg, 1.5 mg, or

5 mg of PM fromOttawa Canada(EHC-93) 

2, 4, and 7 days afterIT instillation

Rat, male,Wistar,200-250 g,n = 5/group

Inflammation Interaction: increas

in BALF.

1 0.11 mg/m3 ultra fine

carbon (25 nm CMD)+ endotoxin (IH)

6 h Rat, male,

Fischer F344,10 weeks and22 months old,n = 3/groupMice, male,TSK,14-17 monthsold, n = 6-7/group

Inflammation Interaction: increas

PMNs and ROS releBALF cells for old rmice primed with endepressed in young 

1 Endotoxin (37.5 EU)

for 10 min

4, 20, or 24 h Mice,

C57BL/6J, 36 hold, 8 weeks old,n = 12/group

Inflammation Synergism: increase

protein and PMNs.

1 Endotoxin (IN) 0, 2,

or 20 μg in 120 μL

8 h, repeated after24 h

Rat, male,Fischer F344,10-12 weeks old, n = 6/group

Lung morphometric analysisand inflammation

Synergism: increaseBALF PMNs and mglycoprotein; increaintraepithelialmucosubstances andmucingene mRNA.

AX5-57
Table AX5-18 (cont’d). Interactions Of Ozone With Particles

 Concentration

Duration Species Endpoints Interaction 

O3

(ppm)

 PM(mg/m3

)

PARTICLE MIXTURES (cont’d)

0.8 EHC-93,5 mg/m3 or

50 mg/m3

4 h exposure, clean airfor 32 h, 3H injection

followed by assay at90 min

Rat, male,Fischer F344,200-250 g, n = 6/group

Control rats: 3H labeling

(indicative of proliferation)low in bronchioles andparenchyma.ECH-93 alone: no inductionof proliferation.O3 alone: increased cell

labeling in bronchioles andparenchyma, suggestive ofreparative cell proliferation.ECH-93 + O3: both doses

of EHC-93 potentiatedproliferation, especiallyin epithelia of terminalbronchioles and alveolarducts, but not distalparenchyma. Suggests thatambient PM can enhanceO3-induced proliferations

and exacerbate injury.

Synergism of prolifer

0.8 (EHC93) at 50 mg/m3 4 h, exposure, clean

air for 32 h, 3

H

injection followed byassay at 90 min

Rat, male,Fischer F344,200-250 g, n = 4/group

O3 + EHC-93: epithelial cell

injury and proliferation(

3H-labeling) higher than

single exposures; higher inperiductal region than inwhole lung counts; greaternumbers of AMs and PMNs inlung tissue compartment thanin single exposures. Suggeststhat exposures to urban PMhave few effects alone, but canpotentiate O3-induced injury.

Synergism 

AX5-58
Table AX5-18 (cont’d). Interactions Of Ozone With Particles

 Concentration

Duration Species Endpoints Interaction 

O3

(ppm)

 PM(mg/m3) 

PARTICLE MIXTURES (cont’d)

0.15 HNO3 50 μg/m3 4 h/day, 3 days/week

for 40 weeks,nose-only exposure

Rat, male,Fischer F344/N, 8weeks old,n = 4-5/group

O3 alone: 28% increase in

lung putrescine.HNO3 alone: 21% decrease in

lung putrescineO3 and O3 + HNO3: 

56% increase in lungputrescinePulmonary spermidine andspermine did not change withany exposure. Suggests role of putrescine inregulation of inflammation.

Synergism 

0.5 Carbon Black (CB),

0.5 or 1.5 mg/rat

Intratracheal CBfollowed by 7 daysor 2 months of O3

Rat, male, Wistar,7 weeks old,n = 7-8/group

Phagocytotic capacity: decreased in CB-exposedgroup, unchanged in O3 group. 

Formation of superoxide anionradicals and numbers ofingested particles increased at2 months in O3 group.

Chemotactic migration: decreased in CB-treated group.Suggests that CB impairsphagocytosis and chemotacticmigration in AMs, whereas O3

stimulates these functions.

Synergism 

AX5-59
Table AX5-18 (cont’d). Interactions Of Ozone With Particles

 Concentration

Duration Species Endpoints Interaction 

O3

(ppm)

 PM(mg/m3

)

PARTICLE MIXTURES (cont’d)

0.018 CH2O 3.3 ppb

TSP 0.068 mg/m3

PM10 0.032 mg/m3PM2.5 0.016 mg/m3

23 h/day for 7 weeks Rat, male and

female, FischerF344,9 weeks old,n = 5/group

Exposure to filtered andunfiltered Mexico City air. Histopathology revealed nonasal lesions in exposed orcontrol rats; tracheal and lungtissue from both groupsshowed similar levels ofminor abnormalities.

 VMD = Volume median diameter

Fg = Geometric standard deviation

 MMAD = Mass median aerodynamic diameter CMD = Count median diameter PM = Particulate Matter OVA= Ovalbumin RL = Total Pulmonary Resistance

 AED = Aerodynamic diameter BAL = Bronchoalveolar lavage AM = Alveolar macrophage IN = Intranasal IT = IntratrachealUnless indicated otherwise, whole-body exposures used

AX5-60
Table AX5-19. Effects of Other Photochemical Oxidants

Concentrationppm Duration Species Effects H2O2 (10, 20, or

100 ppb) and/or(NH4)2S04

(429 or 215 Ág/m3

;

0.3-0.4 gm massmedian diameter)

2 h,assayed 0or 24 h PE

Rat,female, SD,n = 4-18/group

Exposures alone or in combination. H2O2 + (NH4)2S04: no effect on BALF cell number, viability, protein or LDH at 

time point; increased PMNs adhered to vascular epithelium; increased TNF-

" by 

both time points; at 0 h PE, transient increase in superoxide anion by AMs; decrproduction; nitrotyrosine detected; heme oxygenase-1 expression upregulated in H2O2 only: decreased NO production which persisted for 24 h.

Suggests that PM-induced effects are augmented by H2O2 and that PM-induced t

injury may be modulated by cytotoxic mediators produced by AMs. 

PAN0.13,0.66,1.31 0.077,0.192,0.3840, 15, 39, or 78 ppm

3 h1 h1 h

PBL frommice, male,CD-1, 5 weeksold, n = 25Mice, male,B6C3F1,6 weeks old,n = 4

In vitro: Exposed peripheral blood lympocytes (PBL) to PAN; assayed for chromaberrations, sister chromatid exchanges and DNA damage. DNA damage was obat cytotoxic concentrations of PAN. No effects at noncytotoxic exposures.In vivo: Nose-only exposures. No dose-related effects at any exposure level in assay.Suggests that PAN, both in vitro and in vivo, is not a DNA damaging agent or cl

3 ppm PAN 1 month Hamster,

Chinese,n = 4

Measured frequency of thioguanine-resistant lung fibroblasts and frequency ofmicronuclei in either the bone marrow or the lungs.Mutation frequencies not altered from control levels. No chromosome breakage observed in bone marrow or lung. Suggests no mutagenicity in vivo.

~300 ppb78 ppm~80 ppm 3H-PAN

4, 7, 10, or 12 h24 h1 h

SalmonellaTA100Mice, BigBlue®, male,

4 weeks old,n = 15

Gas phase exposure PAN-induced mutants: 59% GC

6 TA; 29% GC

6 AT;

2% GC

6 CG; 10% multiple mutations — primarily GG

6 TT tandem-base

substitutions.Nose-only exposure. Mutagenic at the lacI gene in the lung; no tandem-base muNasal tissue: 3.9% of the radiolabel.Lung: 0.3 % of radiolabel.Suggests that PAN is weakly mutagenic in Salmonella (with a signature GG

6 

transversion) and in mouse lung.

AX5-61
AX5-62

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AX5-70

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AX5-71

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AX6-1

ANNEX AX6. CONTROLLED HUMAN EXPOSURE

STUDIES OF OZONE AND RELATED

PHOTOCHEMICAL OXIDANTS

AX6.1 INTRODUCTION

Results of ozone (O3) studies in laboratory animals and in vitro test systems were presented

in Chapter 5 and Annex 5. The extrapolation of results from animal studies is one mechanism

by which information on potential adverse human health effects from exposure to O3 is obtained. 

More direct evidence of human health effects due to O3 exposure can be obtained through

controlled human exposure studies of volunteer subjects or through field and epidemiologic

studies of populations exposed to ambient O3. Controlled human exposure studies, discussed in

this chapter, typically use fixed concentrations of O3 under carefully regulated environmental

conditions and subject activity levels. 

Most of the scientific information selected for review and evaluation in this chapter comes

from the literature published since 1996 which, in addition to further study of physiological

pulmonary responses and respiratory symptoms, has focused on mechanisms of inflammation

and cellular responses to injury induced by O3 inhalation. Older studies are discussed where

only limited new data are available and where new and old data are conflicting. The reader is

referred to both the 1986 and 1996 Air Quality Criteria documents (U.S. Environmental

Protection Agency, 1986, 1996) for a more extensive discussion of older studies. Summary

tables of the relevant O3 literature are included for each of the major subsections. 

In summarizing the human health effects literature, changes from control are described if

statistically significant at a probability (p) value less than 0.05, otherwise trends are noted

as such. 
AX6-2

AX6.2 PULMONARY FUNCTION EFFECTS OF OZONE EXPOSURE IN

HEALTHY SUBJECTS

AX6.2.1 Introduction

The responses observed in young healthy nonsmoking human adults exposed to ambient O3

concentrations include decreased inspiratory capacity; mild bronchoconstriction; rapid, shallow

breathing pattern during exercise; and symptoms of cough and pain on deep inspiration. 

In addition, O3 has been shown to result in airway hyperresponsiveness as demonstrated by an

increased physiological response to a nonspecific bronchoconstrictor, as well as airway injury

and inflammation assessed via bronchoalveolar lavage and biopsy. Reflex inhibition of

inspiration and consequent decrease in inspiratory capacity results in a decrease in forced vital

capacity (FVC) and total lung capacity (TLC) and, in combination with mild

bronchoconstriction, contributes to a decrease in the forced expiratory volume in 1 s (FEV1). 

Given that both FEV1 and FVC are subject to decrease with O3 exposures, changes in the

ratio (FEV1/FVC) become difficult to interpret and so are not discussed. 

The majority of controlled human studies have investigated the effects of exposure to

variable O3 concentrations in healthy subjects performing continuous exercise (CE) or

intermittent exercise (IE) for variable periods of time. These studies have several important

limitations: (1) the ability to study only short-term, acute effects; (2) the inability to link shortterm effects with long-term consequences; (3) the use of a small number of volunteers that may

not be representative of the general population; and (4) the statistical limitations associated with

the small sample size. Nonetheless, studies reviewed in the 1996 EPA criteria document

(U.S. Environmental Protection Agency, 1996) provided a large body of data describing the

effects and dose-response characteristics of O3 as function of O3 concentration (C), minute

ventilation (V0 E ), and duration or time (T) of exposure. In most of these studies, subjects were

exposed to O3 and to filtered air (FA [reported as 0 ppm O3]) as a control. The most salient

observations from these studies were: (1) healthy subjects exposed to O3 concentrations

$0.08 ppm develop significant reversible, transient decrements in pulmonary function if V0 E or

T are increased sufficiently, (2) there is a large degree of intersubject variability in physiologic

and symptomatic responses to O3 and these responses tend to be reproducible within a given

individual over a several months period, and (3) subjects exposed repeatedly to O3 over several
AX6-3

days develop a tolerance to successive exposures, as demonstrated by an attenuation of

responses, which is lost after about a week without exposure. 

In this section, the effects of single O3 exposures of 1- to 8-h in duration on pulmonary

function in healthy nonsmoking subjects are examined by reviewing studies that investigate: 

(1) the O3 exposure-response relationship; (2) intersubject variability, individual sensitivity, and

the association between responses; and (3) mechanisms of pulmonary function responses and the

relationship between tissue-level events and functional responses. Discussion will largely be

limited to studies published subsequent to the 1996 EPA criteria document (U.S. Environmental

Protection Agency, 1996)

AX6.2.2 Acute Ozone Exposures for Up to 2 Hours

At-Rest Exposures. Exposure studies investigating the effects of O3 exposures on sedentary

subjects were discussed in the 1986 EPA criteria document (U.S. Environmental Protection

Agency, 1986). The lowest O3 concentration at which significant reductions in FVC and FEV1

were reported was 0.5 ppm (Folinsbee et al., 1978; Horvath et al., 1979). Based on the

average O3 responses in these two studies (corrected for FA responses), resting young adults

(n = 23, age = 22) exposed to 0.5 ppm O3 have a ~4% reduction in FVC and a ~7% reduction

FEV1. At lower O3 concentrations of 0.25 to 0.3 ppm, resting exposures did not significantly

affect lung function. 

Exposures with Exercise. Collectively, the studies reviewed in the 1996 EPA criteria

document (U.S. Environmental Protection Agency, 1996) demonstrated that healthy young

adults performing moderate to heavy IE or CE of 1 to 2.5 h duration, exposed to 0.12 to

0.18 ppm O3 experienced statistically significant decrements in pulmonary function and

respiratory symptoms. As an example, 2 hr exposures to 0.12 and 0.18 ppm O3 during heavy IE

(exercise V0 E = 65 L/min) have resulted in FEV1 decrements of 2.0 ± 0.8% (mean ± SE; n = 40)

and 9.5 ± 1.1% (n = 89), respectively (McDonnell and Smith, 1994). Significant decrements in

pulmonary function have been reported in heavily exercising healthy adults exposed for 1 h with

CE at O3 concentrations of 0.12 ppm (Gong et al., 1986), 0.16 ppm (Avol et al., 1984), and

0.2 ppm (Adams and Schelegle, 1983; Folinsbee et al., 1984). 

In an attempt to describe O3 dose-response characteristics, many investigators modeled

acute responses as a function of total inhaled O3 dose (C × T × V0 E ), which was found to be a
AX6-4

better predictor of response than O3 concentration, V0 E, or T of exposure, alone. In an analysis of

6 studies with 1 to 2 h exposures to between 0.12 and 0.18 ppm O3 with exercise, Folinsbee et al.

(1988) reported a good correlation (r = 0.81) between total inhaled O3 dose and FEV1

decrements. For a given exposure duration, total inhaled O3 dose can be increased by increases

in C and/or V0 E . In exposures of fixed duration, results of several studies suggested that O3

concentration was a more important predictor of response or explained more of the variability in

response than V0 E (Adams et al., 1981; Folinsbee et al, 1978; Hazucha, 1987). Based on a review

of previously published studies, Hazucha (1987) noted that relative to the FEV1 decrement

occurring at a given C and V0 E, doubling C (e.g., from 0.1 to 0.2 ppm) would increase the FEV1

decrement by 400%, whereas doubling the V0 E (e.g., from an exercise V0 E of 20 to 40 L/min)

which would only increase the FEV1 decrement by 190%. Thus, C appears to have a greater

affect than V0 E on FEV1 responses even when total inhaled O3 doses are equivalent. 

New studies (i.e., not reviewed in the 1996 EPA criteria document) that provide

spirometric responses for up to 2 h exposures are summarized in Table AX6-1. Most of these

newer studies have investigated mechanisms affecting responses, inflammation, and/or effects in

diseased groups versus healthy adults, accordingly their findings may be summarized differently

in several sections of this chapter. Rather than being interested in responses due to O3 versus FA

exposures, many of the newer studies have tested the effects of a placebo versus treatment in

modulating responses to O3 exposure. Studies appearing in Table 1, but not discussed in this

section, are discussed in other sections of this chapter as indicated within the table. 

McDonnell et al. (1997) pooled the results of eight studies entailing 485 healthy male

subjects exposed for 2 h on one occasion to one of six O3 concentrations (0.0, 0.12, 0.18, 0.24,

0.30, or 0.40 ppm) at rest or one of two levels of IE (V0 E of 25 and 35 L/min/m2

 BSA). FEV1

was measured preexposure, after 1 h of exposure, and immediately postexposure. Decrements

in FEV1 were modeled by sigmoid-shaped curve as a function of subject age, O3 concentration,

V0 E , and T. The modeled decrements reach a plateau with increasing T and dose rate (C × V0 E ). 

That is, for a given O3 concentration, exercise V0 E level, and after a certain length of exposure,

the FEV1 response tends not to increase further with increasing duration of exposure. The

modeled FEV1 responses increased with C × V0 E and T, decreased with subject age, but were only 
AX6-5

Table AX6-1. Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours During E

Ozone

Concentrationb Exposure

Duration and

Activity

Exposure

Conditions

c

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.00.4

0

784

2 h IE4 × 15 minon bicycle,V

.

E = 30 L/min

NA 5 M, 4 F

6 M, 7 F

Healthy adults25 ± 2 years oldMild atopicasthmatics 22 ± 0.7 years old

O3-induced reductions in FVC (12%, 10%) and 

(13%, 11%) for asthmatic and healthy subjects. Significant reductions in mid-flows in both asthhealthy subjects. Indomethacin pretreatment sidecreased FVC and FEV1 responses to O3 in he

asthmatic subjects. See Section AX6.3.2 and Taand AX6-13.

0.00.2

0

392

2 h IE 4 × 15 minat V

.

E = 20

L/min/m2 BSA

20 °C50% RH

8 M, 5 F Healthy NS

median age 23 years

Median O3-induced decrements of 70 mL, 190 m

400 mL/s in FVC, FEV1, and FEF25-75, respectiv

Spirometric responses not predicted of inflammresponses. See Sections AX6.2.5.2, AX6.5.6, anand Table AX6-12.

0.00.2

0

392

2 h IE 4 × 15 minat V

.

E = 20

L/min/m2 BSA

20 °C50% RH

10 M, 12 F Healthy NS

mean age 24 years

Significant O3-induced decrement in FEV1 imm

postexposure but not significantly different from 2 h later. No correlation between Clara cell proand FEV1 decrement. CC16 levels, elevated by 

remained high at 6 h postexposure, but returned by 18 h postexposure. See Table AX6-13.

0.0

0.33

0

647

2 h IE4 × 15 minon bicycleergometer(600 kpm/min)

NA 9 M Healthy NS

26.7 ± 7 years old

O3-induced reductions in FVC (7%). FRC not a

exposure. Post FA, normal gradient in ventilatiincreased from apex to the base of the lung. Po

ventilation shifted away from the lower-lung inand upper-lung regions. The post O3 increase in to mid-lung region was correlated with decrease midmaximal expiratory flow (r = 0.76, p < 0.05

0.0

0.35

0

690

2.2 h IE 2 × 30 minon treadmill(V

.

E . 50 L/min) 

Final 10 min rest

19-23 °C48-55%RH

15 M Healthy NS

25.4 ± 2 years old

Pre- to post-O3, mean FVC and FEV1 decreased 

14%, respectively. Following O3 exposure, the

pronounced slow phase evident in multibreath nwashouts which, on average, represented a 24% in the washout rate relative to pre-O3. 

AX6-5
Table AX6-1 (cont’d). Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours durin

Ozone

Concentrationb Exposure

Duration and

Activity

Exposure

Conditions c

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.0

0.120.180.240.300.40

0

235353471589784

2 h rest or IE(4 × 15 minat V.

E = 25 or 35

L/min/m2 BSA)

22 °C40% RH

485 M (eachsubjectexposed at oneactivity levelto one O3concentration) 

Healthy NS 18 to 36 years oldmean age 24 years

Statistical analysis of 8 experimental chamber sconducted between 1980 and 1993 by the U.S. Chapel Hill, NC. Decrement in FEV1 described 

shaped curve as a function of subject age, O3 coV

.

E, and time. Response decreased with age, wa

affected by body size corrections, and was not msensitive to O3 concentration than V.

E. Also see 

AX6.5.

0.4 784 2 h IE

20 min mild-mod.exercise, 10 min rest

NA 4 M, 5 F Healthy NS

30 ± 3 years old

Subjects previously in Nightingale et al. (2000) Placebo-control: Immediately postexposure dein FVC (9%) and FEV1 (14%) relative to pre-ex

values. FEV1 decrement only 9% at 1 hr postex

By 3 h postexposure, recovery in FVC to 97% a

to 98% of preexposure values. Significant incre8-isoprostane at 4 h postexposure. Budesonide 2 wk prior to exposure did not affect responses. 

0.00.2

392 2 h IE 

4 × 15 minat V.

E = 20

L/min/m2 BSA

20 °C50% RH

6 M, 9 F9 M, 6 F

Healthy adults24 years oldMild asthmatics29 years old

O3-induced FEV1 decrement (8%, healthy adult

3% asthmatics) and PMN increase (20.6%, heal15.2% asthmatics). Primary goal was to investirelationship between antioxidant defenses and O

responses in asthmatics and healthy adults. See Tables AX6-3 and AX6-13.

0.4 784 2 h IE

20 min mild-mod.exercise, 10 min rest

NA 6 M, 9 F Healthy NS

mean age ~31 years

Placebo-control: O3 caused significant decreme

(13.5%) and FVC (10%) immediately following a small increase in MCh-reactivity, and increasmyeloperoxidase in induced sputum at 4 h postFEV1 at 96% and FVC at 97% preexposure valu

postexposure. Budesonide for 2 wk prior to expnot affect spirometric responses. See Section AXTable AX6-13.

AX6-6
Table AX6-1 (cont’d). Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours durin

Ozone

Concentrationb Exposure

Duration and

Activity

Exposure

Conditions c

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.00.4

784 2 h IE 

4 × 15 min at .

VE =18 L/min/m2

BSA2 exposures: 25% subjectsexposed to air-air,75% to O3-O3

21 °C40% RH

Weak

responders

7 M, 13F

Strong

responders

21 M, 21 F

Healthy NS20 to 59 years old

Significant O3-induced decrements in spirometr

function. Young adults (<35 years) were signifresponsive than older individuals (>35 years). a narcotic analgesic, largely abolished symptom and improved FEV1 in strong responders. Nalo

opioid antagonist, did not affect O3 effects in w

responders. See Section AX6.2.5.1.

0.00.4

784 2 h IE 

4 × 15 minat V.

E = 20

L/min/m2 BSA

20 °C40% RH

Placebo group

15 M, 1 F

Antioxidant

group

13 M, 2 F

Healthy NSmean age 27 years

Placebo and antioxidant groups had O3-induced 

in FEV1 (20 and 14%) and FVC (13 and 10%), 

Percent neutrophils and IL-6 levels in BAL flui1 h postexposure were not different in the two tgroups. See Table AX6-13.

0.0

0.25

490 1 h CE

V

.

E = 30 L/min

NAFace maskexposure

32 M, 28 F Healthy NS

22.6 ± 0.6 years old

Mean O3-induced FEV1 decrements of 15.9% in 

9.4% in females (gender differences not signific

decrements ranged from !4 to 56%; decrement20 subjects and >40% in 4 subjects. Uptake of 

males than females, but uptake not correlated wspirometric responses. 

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration. cStudies conducted in exposure chamber unless otherwise indicated. 

AX6-7
AX6-8

Figure AX6-1. FEV1 decrements as a function of O3 concentration following a 2 h

exposure with incremental exercise (15 min intervals) or rest. Points are

experimental data (mean ± SE) and lines are model predictions for each

activity level. Minute ventilation (V0 E ) represent average across intervals

of rest and exercise. 

Source: McDonnell et al. (1997).

minimally affected by body size corrections to V0 E . Fitted and experimental FEV1 decrements

following a 2 h exposure at three nominal levels of V0 E are illustrated in Figure AX6-1 as a

function of O3 concentration. Their analysis indicated that C was marginally, but not

significantly, more important than V0E in predicting FEV1 response. Additionally, the McDonnell

et al. (1997) analysis revealed that some prior analyses of IE protocols may have over estimated

the relative importance of C over V0 E in predicting FEV1 responses by considering only the V0 E

during exercise and ignoring the V0 E during periods of rest. 
AX6-9

Ultman et al. (2004) measured O3 uptake and pulmonary responses in 60 young heathy

nonsmoking adults (32 M, 28 F). A bolus technique was used to quantify the uptake of O3 as a

function of the volume into the lung which the bolus penetrated. From these measurements, the

volumetric depth at which 50% uptake occurred was calculated. This volumetric lung depth was

correlated with conducting airways volume, i.e., a greater fraction of O3 penetrated to deeper into

the lungs of individuals have larger conducting airways volumes. Two weeks after the bolus

measurements, subjects were exposed via a face mask to FA and subsequently two weeks later to

0.25 ppm O3 for 1 h with CE at a target V0 E of 30 L/min. The breath-by-breath uptake of O3 was

measured. There was a small but significant reduction in the breath-by-breath uptake of O3 from

90.6% on average for the first 15 minutes to 87.3% on average for the last 15 minutes of

exposure. The uptake fraction was significantly greater in males (91.4%) than females (87.1%),

which is consistent with the larger fB and smaller VT of the females than males. Uptake was

not correlated with spirometric responses. However, there was tendency for males to have

greater O3-induced FEV1 decrements than females, 15.9% versus 9.4%, respectively. There was

considerable intersubject variability in FEV1 decrements which ranged from !4 to 56% with

20 subjects having decrements of >15% and 4 subjects with >40% decrements (see Section

AX6.4 for additional discussion regarding intersubject variability). 

Few studies have measured the effect of ozone on ventilation distribution within the lung. 

Foster et al. (1993) measured the effect of ozone on the vertical distribution of inspired air in the

lung using planar gamma scintigraphy. Nine healthy nonsmoking males (26.7 ± 7 years old)

were randomly exposed to FA or 0.33 ppm O3 for 2 h with IE. After each exposure session,

subjects inhaled a 2- to 4-ml bolus of xenon-133 while seated in from of a gamma camera. 

Images were acquired at the end of the first inspiration and 5-6 breaths later after the xenon had

equilibrated between lung regions. Using these images, the distribution of ventilation and

volume between upper-, middle-, and lower-lung regions was quantified. Post-O3 relative to

post-FA, there were significant reductions in FVC (FA, 5.23 ± 0.5; O3, 4.88 ± 0.5 liters) and

midmaximal expiratory flow (FA, 3.82 ± 0.8; O3, 3.14 ± 0.9 liter/sec). Neither FRC nor the

distribution of volume (upper, 26.5%; middle, 42.5%; lower, 31%) between lung compartments

were affected by O3 exposure. After the FA exposure, the distribution of ventilation per unit

volume increased with progression from the apex to the base of the lung, i.e., the lower lung

regions received the greatest ventilation. Following O3 exposure, there was a significant
AX6-10

reduction in the ventilation to the lower-lung and significant increases in ventilation to the

upper- and middle-lung regions relative to the FA values in 7 of the 9 subjects. The post-O3

increase in middle-lung ventilation was correlated with the decrease in midmaximal expiratory

flow (r = 0.76, p < 0.05). 

Foster et al. (1997) measured the effect of ozone on ventilation distribution using a

multiple breath nitrogen washout. Fifteen healthy nonsmoking males (25.4 ± 2 years old) were

randomly exposed to FA or 0.35 ppm O3 for 2.2 h with IE. Subjects alternated between 30 min

periods of rest and treadmill exercise (V0 E . 10×FVC . 50 L/min). The final exercise period

was followed by 10 min rest period. Multiple breath nitrogen washout and spirometry were

measured pre- and immediately postexposure. At 24-h post-O3 exposure, 12 of 15 subjects

returned and completed an addition multibreath nitrogen washout maneuver. Pre- to post-O3

exposure, the mean FVC and FEV1 were significantly decreased by 12 and 14%, respectively. 

Exposure to FA did not appreciably affect spirometry or the multibreath nitrogen washout. 

Following O3 exposure, the washout of nitrogen was delayed and resembled a two-compartment

washout, whereas pre-O3 exposure the log-linear clearance of nitrogen as a function of expired

volume resembled a single-compartment washout. The clearance rate of the slow compartment

was approximated as the slope (Ln[N2] per expired volume) of the nitrogen washout between

20% and 9% nitrogen. Post-O3, there was a pronounced slow phase evident in nitrogen washout

which, on average, represented a 24% decrease in the washout rate relative to pre-O3. Data for a

single subject (see Figure 6-1) allowed for the size of the slow compartment to be determined. 

For this subject, the slow compartment represented 23% of the lung. This is fairly consistent

with Foster et al. (1993) where ventilation to the lower-lung (31% of volume) was reduced

post-O3. At 24-h post-O3, 6 of the 12 subjects who completed an additional nitrogen washout

maneuver had a delayed washout relative to the pre-O3 maneuver. This suggests a prolonged O3

effect on the small airways and ventilation distribution in some individuals. 

AX6.2.3 Prolonged Ozone Exposures

Between 1988 and 1994, a number studies were completed that described the responses of

subjects exposed to relatively low (0.08 to 0.16 ppm) O3 concentrations for exposure durations

of 4 to 8 h. These studies were discussed in the 1996 criteria document (U.S. Environmental

Protection Agency, 1996) and only a select few are briefly discussed here. Table AX6-2 details 
Table AX6-2. Pulmonary Function Effects after Prolonged Exposures to Ozonea

Ozone Concentrationb Exposure

Duration

and Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

Studies with 4 hr Exposures 0.18 353 4 h IE

(4 × 50 min)V

.

E = 35 L/min

23 °C50% RH

2 M, 2 F Adults NS, 21

to 33 years old

FVC decreased 19% and FEV1 decreased 29% in thes

pre-screened sensitive subjects.

0.00.20

 0392

4 h IE (4 × 50 min cycleergometry ortreadmill running [ V

.

E = 40 L/min])

20 °C50% RH

FA: 11 M, 3F O3: 9 M, 3 F 

Adult NS, 19 to41 years old

Decrease in FVC, FEV1, VT, and SRaw and increase i

O3 exposure compared with FA; total cell count and L

increased in isolated left main bronchus lavage and incell influx occurred with O3 exposure compared to FA 

0.2 392 4 h IE

(4 × 50 min)V

.

E = 25 L/min/m2

BSA

20 °C50% RH

42 M, 24 F Adults NS,

18 to 50 yearsold

FEV1 decreased by 18.6%; Pre-exposure methacholin

responsiveness was weakly correlated with the functioto O3 exposure. Symptoms were also weakly correlat

FEV1 response (r = -0.31 to !0.37)

0.00.24

 0470

4 h IE (4 × 15 min) .

VE = 20 L/min

24 °C40% RH

10 M9 M

Healthy NS,60 to 69 yearsCOPD59 to 71 years 

Healthy: small, 3.3%, decline in FEV1 (p = 0.03 [not 

paper], paired-t on O3 versus FA pre-post FEV1). CO

decline in FEV1 (p = ns, O3 versus FA). Adjusted for 

ozone effects did not differ significantly between COPand healthy subjects. See Section AX6.5.1. 

Studies with >6 hr Exposures0.00.060.080.04 (mean,peak of 0.05)0.06 (mean,peak of 0.09)0.08 (mean,peak of 0.15)

 0118157 78 118157

6.6 hIE (6 × 50min)V

.

E = 20 L/min/m2

BSA

25 °C40-60% RH

15 M, 15 F Healthy NS 

Males23.5 ± 3.0 yrsFemales22.8 ± 1.2 yrs

FEV1 and symptom responses after 6.6 h exposure to 

0.06 ppm not significantly different from FA. Followto 0.08 ppm, O3-induced FEV1 (!6.1%, square-wave; 

triangular) and symptom responses significantly great0.04 and 0.06 ppm exposures. Triangular exposure to caused peak decrement in FEV1 at 5.6 h of exposure, 

for square-wave exposure occurred at 6.6 h. 

0.00.040.080.12

 0 78157235

6.6 hIE (6 × 50min)V

.

E = 20 L/min/m2

BSA

23 °C50% RH

15 M, 15 F Healthy NS, 

22.4 ± 2.4 yrsold

FEV1 and total symptoms after 6.6 h exposure to 0.04 

significantly different from FA. FEV1 (!6.4%) and to

significant at 6.6 h exposure to 0.08 ppm. FEV1 (!15

not significantly different between chamber and face mexposure to 0.12 ppm. 

AX6-11
Table AX6-2 (cont'd). Pulmonary Function Effects after Prolonged Exposures to Ozon

Ozone Concentrationb Exposure

Duration

and Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.12 235 3 day-6.6h/day

IE (6 × 50 min)V

.

E = 17 L/min/m2

,

20 L/min/m2

BSA, and 23L/min/m2 BSA

23 °C50% RH

15 M, 15 F Healthy NS, 18

to 31 years old

FEV1 at 6.6 h decreased significantly by 9.3%, 11.7%

respectively at three different exercise V.

E rates, but w

significantly different from each other. Total symptomhighest V.

E protocol were significantly greater than for 

V

.

E protocol beginning at 4.6 h. Largest subjects (2.2 

had significantly greater average FEV1 decrement for 

protocols, 18.5% compared to the smallest subjects (1

BSA), 6.5%.

(a) 0.08(b) 0.08(mean) variedfrom 0.03 to0.15

235235(mean)

6.6 h IE (6 × 50 min)V

.

E = 20 L/min/m2

BSA

23 °C50% RH

15 M15 F

Healthy NS,18 to 25 yearsold

(a) FEV1 decreased 6.2% after 6.6 h in square-wave e

Total symptoms significantly increased at 5.6 and 6.6 (b) FEV1 decreased 5.6 to 6.2% after 4.6 to 6.6 h, resp

in varied exposure; total symptoms significantly increafter 4.6 to 6.6 h. No significant difference between fand chamber exposures.

(a) 0.08(b) 0.30

157588

6.6 h IE (6 × 50 min)V

.

E = 20 L/min/m2

BSA2 hIE (4 × 15 min)V

.

E = 35 L/min/m2

BSA

23 °C50% RH

15 M15 F

Healthy NS,18 to 25 yearsold

Significantly greater FEV1 decrement (12.4%) for 2-h

exposure than for 6.6-h, 0.08 ppm exposure (3.6%). 

(a) 0.12(b) 0.12(mean) variedfrom 0.07 to0.16(c) 0.12(mean) variedfrom 0.11 to0.13(d) 0.12

235235

(mean)

235

(mean)

235

6.6 h IE(6 × 50 min)(a,b,c) V.

E = 20

L/min/m2 BSA

(d) V.

E = 12

L/min/m2 BSA

23 °C50% RH

6 M, 6 F Healthy NS,

19 to 25 yearsold

(a) FEV1 decreased 11% at 6.6 h in square-wave expo

Total symptoms significant from 4.6 to 6.6 h.(b) FEV1 decreased 13% at 6.6 h; not significantly dif

square-wave exposure. Total symptoms significant fr6.6 h.(c) FEV1 decreased 10.3% at 6.6 h; not significantly d

square-wave exposure. Total symptoms significant fr6.6 h.(d) FEV1 decreased 3.6% at 6.6 h; significantly less th

20 L/min/m2 BSA protocols.

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration.

AX6-12
1

Based on two-tailed paired t-test of data in Table III of Horvath et al. (1991).

AX6-13

newer studies of healthy subjects undergoing prolonged exposures at O3 concentrations ranging

from 0.06 to 0.20 ppm. In most of these studies, statistically significant changes in pulmonary

function, symptoms, and airway responsiveness have been observed during and after exposures

to O3 concentrations of 0.08 ppm and higher. As with studies conducted at higher O3

concentrations for shorter periods of time, there is considerable intersubject variability in

response (see Section AX6.4).

Folinsbee et al. (1988) first reported the effects of a 6.6 h exposure to 0.12 ppm O3 in ten

young healthy adults (25 ± 4 yr) with quasi continuous exercise that was intended to simulate a

full workday of heavy physical labor. Except for a 35-min lunch break after 3 h, the subjects

exercised at a moderate level (V0 E . 40 L/min) for 50 min of each hour. Ignoring the lunch

break during which lung function did not change appreciably, approximately linear decreases

were observed in FVC, FEV1, and FEV25-75 with duration of O3 exposure. Correcting for FA

responses, decrements of 8.2, 14.9, and 26.8% in FVC, FEV1, and FEV25-75 occurred as a result

of the O3 exposure. Using the same 6.6 h protocol, but a lower O3 concentration of 0.08 ppm,

Horstman et al. (1990) and McDonnell et al. (1991) observed decrements corrected for FA (and

averaged across studies) of 5, 8, and 11% in FVC, FEV1, and FEV25-75, respectively, in 60 young

adults (25 ± 5 years old). Horvath et al. (1991) observed a 4% (p = 0.03)1

 decrement in FEV1

using the forementioned protocol (i.e., 6.6 h and 0.08 ppm O3) in 11 healthy adults (37 ± 4 yr). 

The smaller decrement observed by Horvath et al. (1991) versus Horstman et al. (1990) and

McDonnell et al. (1991) is consistent with response decreasing as subject age increases (see

Section AX6.5.1).

AX6.2.3.1 Effect of Exercise Ventilation Rate on FEV1 Response to 6.6 h Ozone Exposure

It is well known that response to O3 exposure is a function of V0 E in studies of 2 h or less in

duration (See Section AX6.2.2). It is reasonable to expect that response to a prolonged 6.6-h O3

exposure is also function of V0 E , although quantitative analyses are lacking. 

In an attempt to quantify this effect, Adams and Ollison (1997) exposed 12 young adults

to an average O3 concentration of 0.12 ppm for 6.6 h at varied exercise V0 E . They observed a

mean FEV1 decrements of 10 to 11% in two protocols having a mean exercise V0 E of 33 L/min
AX6-14

and a 14% decrement in a protocol with a mean exercise V0 E of 36 L/min. These FEV1

decrements were significantly greater than the average decrement of 3.6% (not significantly

different from FA response) observed at an exercise V0 E of only 20 L/min. In a subsequent study

of 30 healthy adults (Adams, 2000b), the effect of smaller exercise V0 E differences on pulmonary

function and symptoms responses to 6.6 h exposure to 0.12 ppm O3 was examined. FEV1

decrements of 9.3, 11.7, and 13.9% were observed for the exercise V0 E of 30.2, 35.5, and

40.8 L/min, respectively. Along with the tendency for FEV1 responses to increase with V0 E , total

symptoms severity was found to be significantly greater at the end of the highest V0 E protocol

relative to the lowest V0 E protocol. Although the FEV1 responses were not significantly different

from each other, the power of the study to detect differences between the three V0 E levels was not

reported and no analysis was performed using all of the data (e.g., a mixed effects model). Data

from the Adams and Ollison (1997) and Adams (2000b) studies are illustrated in Figure AX6-2

with data from three older studies. There is a paucity of data below an exercise V0 E of 30 L/min. 

Existing data for exposure to 0.12 ppm O3 suggest that FEV1 responses increase with increasing

exerciseV0 E until at least 35 L/min. 

AX6.2.3.2 Exercise Ventilation Rate as a Function of Body/Lung Size on FEV1 Response

to 6.6 h Ozone Exposure

Typically, with the assumption that the total inhaled O3 dose should be proportional to the

lung size of each individual, exercise V0 E in 6.6 h exposures has been set as a multiple of body

surface area (BSA) (McDonnell et al., 1991) or as a product of eight times FVC (Folinsbee et al.,

1988; Frank et al., 2001; Horstman et al., 1990). Utilizing previously published data, McDonnell

et al. (1997) developed a statistical model analyzing the effects of O3 concentration, V0 E, duration

of exposure, age, and body and lung size on FEV1 response. They concluded that any effect of

BSA, height, or baseline FVC on percent decrement in FEV1 in this population of 485 young

adults was small if it exists at all. This is consistent with Messineo and Adams (1990), who

examined pulmonary function responses in young adult women having small (n = 14) or large

(n = 14) lung sizes (mean FVC of 3.74 and 5.11 L, respectively). Subjects were exposed to

0.30 ppm O3 for 1 h with CE (V0 E = 47 L/min). There was no significant difference between the 
AX6-15

Figure AX6-2. Average FEV1 decrements (±SE) for prolonged 6.6 h exposures to 0.12 ppm

O3 as a function of exercise V0 E . Since age affects response to O3 exposure,

selected studies had subjects with mean ages between 22 and 25 years. 

FEV1 decrements were calculated as mean O3 responses minus mean air

responses. The SE bars illustrate variability in FEV1 responses (pre minus

post) on the O3 exposure day in all cases except for Folinsbee et al. (1994),

where post O3 exposure variability is illustrated. In one case, the SE for V0 E

of 33 L/Min (10.3% decrement) was taken as the SE of data from protocol

with V0 E of 33 L/min (11% decrement). All studies used a constant

0.12 ppm O3 exposure except two (%) which used 0.115 ppm O3 for hours

1-2 and 5-6 and 0.13 ppm O3 for hours 3-4 of exposure. 

group FEV1 decrements (22.1 and 25.6% for small and large lung, respectively). In addition,

Messineo and Adams (1990) also did a retrospective analysis of 36 young adult males who each

had completed similar 1 h exposures to 0.30 ppm O3 with CE (V0 E . 70 L/min) and found lung

size was not related to FEV1 response. 

Adams (2000b) studied a group of 30 young adult men and women exposed to

0.12 ppm O3 for 6.6 h on three occasions while exercising 50 min of each hour at one of three

different V0 E levels (viz., 17, 20, and 23 1/min/m2 BSA). Their postexposure FEV1 responses

were regressed as a function of BSA (which was directly related to the absolute amount of V0 E
AX6-16

during exercise and, thus, primarily responsible for individual differences in total inhaled O3

dose). The slope was significantly different from zero (p = 0.01), meaning that the smallest

subjects, who had the lowest exercise V0 E (. 26 L/min), had a lower FEV1 decrement (!5%)

than the largest subjects (!17%), whose exercise V0 E was .44 L/min. This relationship was not

a gender-based difference, as the mean female’s FEV1 decrement was !11.2%, which was not

significantly different from the male’s !12.2% mean value. Similarly, when total symptoms

severity response was regressed against BSA, the slope was significantly different than zero

(p = 0.0001), with lower values for smaller subjects than for larger subjects. Results of this

study suggest that for the O3 concentration and exposure duration used, responses are more

closely related to V0 E than V0 E normalized to BSA. Further, this observation is in agreement with

McDonnell et al. (1997), who observed no evidence that measurements of lung or body size

were significantly related to FEV1 response in 2 h IE exposures. These authors state that the

absence of an observed relationship between FEV1 response and BSA, height, or FVC may be

due to the poor correlation between these variables and airway caliber (Collins et al., 1986;

Martin et al., 1987). Also, the O3 dosimetry study of Bush et al. (1996) indicated that

normalization of the O3 dose would be more appropriately applied as a function of anatomic

dead space.

AX6.2.3.3 Comparison of 6.6 h Ozone Exposure Pulmonary Responses to Those Observed

in 2 h Intermittent Exercise Ozone Exposures

It has been shown that greater O3 concentration (Horstman et al., 1990) and higher V0 E

(Adams, 2000b) each elicit greater FEV1 response in prolonged, 6.6-h exposures, but data on the

relative effect of O3 concentration, V0 E , and T in prolonged exposures are very limited and have

not been systematically compared to data from shorter (<2-h) exposures. In a recent study

(Adams, 2003b), the group mean FEV1 response for a 2-h IE exposure to 0.30 ppm O3 was

!12.4%, while that for a 6.6-h exposure to 0.08 ppm O3 was !3.5%. The total inhaled O3 dose

(as the simple product of C × T × V0 E ) was 1358 ppmAL for the 2-h exposure and 946 ppmAL for

the 6.6-h exposure. Thus, the FEV1 decrement was 3.5 times greater and the total inhaled O3

dose was 1.44 times greater for the 2-h exposure compared to the 6.6-h exposure. This

difference illustrates the limitations of utilizing the concept of total O3 dose for comparisons

between studies of vastly different exposure durations. 
AX6-17

Adams (2003b) also examined whether prolonged 6.6 h exposure to a relatively low O3

concentration (0.08 ppm) and the 2-h IE exposure at a relatively high O3 concentration (0.30

ppm) elicited consistent individual subject effects, i.e, were those most or least affected in one

exposure also similarly affected in the other? Individual subject O3 exposure reproducibility was

first examined via a regression plot of the postexposure FEV1 response to the 6.6-h chamber

exposure as a function of postexposure FEV1 response to the 2-h chamber exposure. The R2 of

0.40, although statistically significant, was substantially less than that observed in a comparison

of individual FEV1 response to two 2-h IE exposures by chamber and face mask, respectively

(R2

 = 0.83). The Spearman rank order correlation for the chamber 6.6-h and chamber 2-h

exposure comparison was also substantially less (0.49) than that obtained for the two 2-h

exposures (0.85). The primary reason for the greater variability in the chamber 6.6-h exposure

FEV1 response as a function of that observed for the two 2-h IE exposures is very likely related

to the increased variability in response upon repeated exposure to O3 concentrations lower than

0.18 ppm (R = 0.57, compared to a mean R of 0.82 at higher concentrations) reported by

McDonnell et al. (1985a). This rationale is supported by the lower R (0.60) observed by

Adams (2003b) for the FEV1 responses found in 6.6 h chamber and face mask exposures to

0.08 ppm O3, compared to an R of 0.91 observed for responses found for the 2 h chamber and

face mask exposures to 0.30 ppm O3. 

AX6.2.4 Triangular Ozone Exposures

To further explore the factors that determine responsiveness to O3, Hazucha et al. (1992)

designed a protocol to examine the effect of varying, rather than constant, O3 concentrations. 

In this study, subjects were exposed to a constant level of 0.12 ppm O3 for 8 h and to an O3 level

that increased linearly from 0 to 0.24 ppm for the first 4 h and then decreased linearly from

0.24 to 0 over the second 4 h of the 8 h exposure (triangular concentration profile). Subjects

performed moderate exercise (V0 E .40 L/min) during the first 30 minutes of each hour. The total

inhaled O3 dose (i.e., C × T × V0 E ) for the constant versus the triangular concentration profile was

almost identical. FEV1 responses are illustrated in Figure AX6-3. With exposure to the constant

0.12 ppm O3, FEV1 declined approximately 5% by the fifth hour of exposure and then remained

at that level. This observation clearly indicates a response plateau as suggested in other 
AX6-18

Figure AX6-3. The forced expiratory volume in 1 s (FEV1) is shown in relation to exposure

duration (hours) under three exposure conditions. Subjects exercised

(minute ventilation . 40 L/min) for 30 min during each hour; FEV1 was

measured at the end of the intervening rest period. Standard error of the

mean for these FEV1 averages (not shown) ranged from 120 to 150 mL.

Source: Hazucha et al. (1992).

prolonged exposure studies (Horstman et al., 1990; McDonnell et al., 1991). However, with the

triangular O3 concentration profile after a minimal initial response over the first 3 h, Hazucha

et al. (1992) observed a substantial change in FEV1 corresponding to the higher average O3

concentration that reached a maximum decrement of 10.3% at 6 h. Despite 2 h of continued

exposure to a lower O3 concentration (0.12 to 0.00 ppm, mean = 0.06 ppm), FEV1 improved and

was only reduced by 6.3% (relative to the preexposure FEV1) at the end of the 8-h exposure. 

The authors concluded that total inhaled O3 dose (C × V0 E × T) was not a sufficient index of O3

exposure and that, as observed by others (Adams et al., 1981; Folinsbee et al., 1978; Hazucha,

1987; Larsen et al., 1991), O3 concentration appears to be more important in determining

exposure effects than is either duration or the volume of air breathed during the exposure. 
AX6-19

However, it should be noted that the mean O3 concentration for Hazucha et al.’s triangular

exposure profile was 0.12 ppm at 4 h, 0.138 ppm at 5 h, 0.14 ppm at 6 h, and 0.133 ppm at 7 h,

before falling to 0.12 ppm at 8 h. The FEV1 responses of the last 4 hours (Figure AX6-3) follow

a pattern similar to the total mean O3 concentration over the same time period. 

It has become apparent that laboratory simulations of air-pollution risk-assessment need to

employ O3 concentration profiles that more accurately mimic those encountered during summer

daylight ambient air pollution episodes (Adams and Ollison, 1997; Lefohn and Foley, 1993;

Rombout et al., 1986). Neither square-wave O3 exposures or the one 8-h study by Hazucha et al.

(1992) that utilized a triangular shaped varied O3 exposure described above closely resembles

the variable diurnal daylight O3 concentration pattern observed in many urban areas experiencing

air-pollution episodes (Lefohn and Foley, 1993). Recently, 6.6 h less abrupt triangular O3

exposure profiles at lower concentrations more typical of outdoor ambient conditions have been

examined (Adams, 2003a, 2006; Adams and Ollison, 1997).

Using a face-mask inhalation system, Adams and Ollison (1997) observed no significant

differences in postexposure pulmonary function responses or symptoms between the 6.6-h,

0.12 ppm O3 square-wave exposure and those observed for a triangular O3 profile in which

concentration was increased steadily from 0.068 ppm to 0.159 ppm at 3.5 h and then decreased

steadily to 0.097 ppm at end exposure. Further, no attenuation in FEV1 response during the last

2 h was observed in either the 6.6 h square-wave or the triangular exposures. 

In a subsequent study (Adams, 2003a), no significant difference was observed in

pulmonary function responses or symptoms between face-mask and chamber exposure systems

either for a 6.6-h, 0.08 ppm O3 square-wave profile or for the triangular O3 exposure beginning

at 0.03 ppm, increasing steadily to 0.15 ppm in the fourth hour, and decreasing steadily to

0.05 ppm at 6.6 h (mean = 0.08 ppm). For the chamber-exposure comparison, postexposure

values for FEV1 and symptoms were not significantly different from the responses for the

square-wave 0.08 ppm O3 exposure. However, analysis showed that FEV1 response for the

square-wave protocol did not become statistically significant until the 6.6-h postexposure value,

while that for the triangular exposure protocol was significant at 4.6 h (when O3 concentration

was 0.15 ppm). Earlier significant FEV1 responses for the triangular protocol were accompanied

by significant increases in symptoms at 4.6 h, which continued on through the fifth and sixth
AX6-20

hours when the mean O3 concentration was 0.065 ppm. Symptoms for the square-wave 0.08

ppm exposure did not become statistically significant until 5.6 h. 

The FEV1 responses during the last two hours of the triangular exposure by Adams (2003a)

did not decrease as dramatically as in the Hazucha et al. (1992) study (Figure AX6-3). The most

probable reason for differences in the triangular O3 profile observations of Hazucha et al. (1992)

and those of Adams (2003a) is that the increase and decrease in Hazucha et al.’s study (i.e., 0 to

0.24 ppm and back to 0) encompassed a much greater range of O3 concentrations than those used

by Adams (2003a), viz., 0.03 ppm to 0.15 ppm from 0 to 3.6 h, then decreasing to 0.05 ppm for

the final hour of exposure. Nonetheless, the greatest FEV1 decrement was observed at 6 h of

Hazucha et al.’s 8 h triangular exposure (Figure AX6-3) corresponding to the time when total

mean O3 concentration was highest (0.14 ppm), with a very similar response at 7 h when total

mean O3 concentration was 0.138 ppm. 

In a recent study, Adams (2006) employed three square-wave and three triangular chamber

exposure profiles. Ozone concentrations for the 6.6-h exposures were 0.00, 0.06, and 0.08 ppm

for square-wave profile and averaged 0.04, 0.06, and 0.08 ppm for the triangular profile. The

pattern and magnitude of hourly changes in FEV1 and symptoms during filtered air (0.0 ppm)

and 0.04 ppm O3 exposure were essentially the same. Similarly, there was no significant

difference in FEV1 and symptomatic response between the square-wave and triangular 0.06 ppm

exposures. While the 6.6-h postexposure responses to the triangular exposure (mean O3

concentration of 0.08 ppm) did not differ significantly from those observed in the square-wave

exposure, FEV1 and symptoms were significantly different from preexposure at 4.6 h (when the

O3 concentration was 0.15 ppm) in the triangular exposure, but not until 6.6 h in the square-wave

exposure. These observations have confirmed and expanded findings of an earlier study

(Adams, 2003a) showing a clear divergence in the peak and hourly responses in FEV1 between

the square-wave and triangular concentration profiles at the 0.08 ppm O3 level. At the lower

0.06 ppm O3 concentration, however, no temporal pattern differences in FEV1 responses could

be discerned between the square-wave and triangular exposure profiles. The author concluded

that the results support previous evidence that O3 concentration has a greater singular effect in

the total inhaled O3 dose than do V0 E and exposure duration. 

Adams (2006) observed that at O3 concentrations of 0.06 ppm and below differences in

prolonged exposure profiles do not induce statistically different hourly responses. 
AX6-21

Decrements in FEV1 during square-wave O3 exposures between 0.08 to 0.12 ppm tend to

increase with time of exposure (i.e., with steadily increasing total inhaled dose), whereas FEV1

decrements during triangular exposures (Hazucha et al., 1992; Adams, 2003a) occurred 1 to 2 h

after the peak O3 concentration and 1 h to 2 h before the maximal total O3 inhaled dose occurred

at the end of exposure. This difference, especially because O3 concentration profiles during

summer daylight air-pollution episodes rarely mimic a square-wave, implies that triangular O3

exposure profiles most frequently observed during summer daylight hours merit further

investigation. These three studies suggest that depending upon the profile of the exposure,

the triangular exposure can potentially lead to higher FEV1 responses than the square wave

exposures at the overall equivalent ozone dose. 

AX6.2.5 Mechanisms of Pulmonary Function Responses

Inhalation of O3 for several hours while physically active elicits both subjective respiratory

tract symptoms and acute pathophysiologic changes. The typical symptomatic response

consistently reported in studies is that of tracheobronchial airway irritation. This is accompanied

by decrements in lung capacities and volumes, bronchoconstriction, airway hyperresponsiveness,

airway inflammation, immune system activation, and epithelial injury. The severity of

symptoms and the magnitude of response depend on inhaled dose, O3 sensitivity of an individual

and the extent of tolerance resulting from previous exposures. The development of effects is

time dependent during both exposure and recovery periods with considerable overlap of evolving

and receding effects.

Exposure to O3 initiates reflex responses manifested as a decline in spirometric lung

function parameters (9FVC, 9FEV1, 9FEF25-75), bronchoconstriction (8SRaw) and altered

breathing pattern (9VT, 8 fB), which becomes more pronounced as exposure progresses and

symptoms of throat irritation, cough, substernal soreness and pain on deep inspiration develop. 

The spirometric lung function decline and the severity of symptoms during a variable (ramp)

exposure profile seem to peak a short time (about 1 to 2 h) following the highest concentration

of O3 (Hazucha et al., 1992; Adams, 2003a). Exposure to a uniform O3 concentration profile

elicits the maximum spirometric response at the end of exposure (Hazucha et al., 1992; Adams,

2003a). Regardless of exposure concentration profile, as the exposure to O3 progresses, airway

inflammation begins to develop and the immune response at both cellular and subcellular level is
AX6-22

activated. Airway hyperreactivity develops slower than pulmonary function effects, while

neutrophilic inflammation of the airways develops even more slowly and reaches the maximum

3 to 6 h postexposure. The cellular responses (e.g., release of immunoregulatory cytokines)

appear to still be active as late as 20 h postexposure (Jörres et al., 2000). Following cessation of

exposure, the recovery in terms of breathing pattern, pulmonary function and airway

hyperreactivity progresses rapidly and is almost complete within 4 to 6 hours in moderately

responsive individuals. Persisting small residual lung function effects are almost completely

resolved within 24 hours. Following a 2 h exposure to 0.4 ppm O3 with IE, Nightingale et al.

(2000) observed a 13.5% decrement in FEV1. By 3 h postexposure, however, only a 2.7% FEV1

decrement persisted. As illustrated in Figure AX6-4, a similar postexposure recovery in FVC

was observed. In hyperresponsive individuals, the recovery takes longer and as much as

48 hours to return to baseline values. More slowly developing inflammatory and cellular

changes persist for up to 48 hours. The time sequence, magnitude and the type of responses of

this complex series of events, both in terms of development and recovery, indicate that several

mechanisms, activated at different times of exposure, must contribute to the overall lung

function response (U.S. Environmental Protection Agency, 1996).

AX6.2.5.1 Pathophysiologic Mechanisms

Breathing pattern changes

Human studies consistently report that inhalation of O3 alters the breathing pattern without

significantly affecting minute ventilation. A progressive decrease in tidal volume and a

“compensatory” increase in frequency of breathing to maintain steady minute ventilation during

exposure suggests a direct modulation of ventilatory control. These changes parallel a response

of many animal species exposed to O3 and other lower airway irritants (Tepper et al., 1990). 

Although alteration of a breathing pattern could be to some degree voluntary, the presence of the

response in animals and the absence of perception of the pattern change by subjects, even before

appearance of the first subjective symptoms of irritation, suggests an involuntary reflex

mechanism. 

Direct recording from single afferent vagal fibers in animals convincingly demonstrated

that bronchial C-fibers and rapidly adapting receptors are the primary vagal afferents responsible

for O3-induced changes in ventilatory rate and depth (Coleridge et al., 1993; Hazucha and 
AX6-23

Sant'Ambrogio, 1993). In spontaneously breathing dogs, an increase in VT/Ti (Ti decreased more

than VT) was attributed to an increased inspiratory drive due to stimulation of rapidly adapting

receptors and bronchial C-fibers by O3 (Schelegle et al., 1993). Folinsbee and Hazucha (2000)

also observed similar changes in VT/Ti

 and other breath-timing parameters in humans exposed

to O3 implying activation of the same mechanisms. They also reported that Pm0.1 (pressure at

Figure AX6-4a,b. Recovery of spirometric responses following a 2 h exposure to 0.4 ppm

O3 with IE. Immediately postexposure, there were significant

decrements (**p < 0.001, ***p < 0.0005) in FVC (10%) and FEV1

(13.5%) compared to preexposure values. At 3 h postexposure, FVC

and FEV1 were at 96 and 97% of preexposure values, respectively. 

Adapted from Nightingale et al. (2000).
AX6-24

mouth at 0.1 sec of inspiration against a transiently occluded mouthpiece which is considered an

index of inspiratory drive) increased during controlled hypercapnia without a change in the slope

of Pm0.1 versus pCO2 relation suggesting that the primary mechanism is an increased inspiratory

drive. Since no significant within-individual differences in ventilatory response to CO2 between

air exposure and O3 exposure were found, the CO2 chemoreceptors did not modulate the

response. Therefore, the principal peripheral mechanism modulating changes in breathing

pattern appears to be direct and indirect stimulation of lung receptors and bronchial C-fibers

by O3 and/or its oxidative products. The activity of these afferents, centrally integrated with

input from other sensory pathways, drives the ventilatory controller, which determines the depth

and the frequency of breathing.

The potential modulation of breathing pattern by activation of sensory afferents located in

extrathoracic airways by O3 has not yet been studied in humans. Laboratory animal studies have

shown that the larynx, pharynx, and nasal mucosa are densely populated by free-ending,

unmyelinated sensory afferents resembling nociceptive C-fibers (Spit et al., 1993; Sekizawa and

Tsubone, 1994). They are almost certainly stimulated by O3 and likely contribute to overall

ventilatory and symptomatic responses. Nasal only exposure of rats produced O3-induced

changes in breathing pattern that are similar to changes found in humans (Kleinman et al., 1999). 

Symptoms and lung function changes

As already discussed, in addition to changes in ventilatory control, O3 inhalation by

humans will also induce a variety of symptoms, reduce vital capacity (VC) and related functional

measures, and increase airway resistance. Hazucha et al. (1989) postulated that a reduction of

VC by O3 is due to a reflex inhibition of inspiration and not due to a voluntary reduction of

inspiratory effort. Recently, Schelegle et al. (2001) convincingly demonstrated that a reduction

of VC due to O3 is indeed reflex in origin and not a result of subjective discomfort and

consequent premature voluntary termination of inspiration. They reported that inhalation of an

aerosolized topical anesthetic tetracaine substantially reduced if not abolished O3-induced

symptoms that are known to be mediated in part by bronchial C-fibers. Yet, such local

anesthesia of the upper airway mucosa had a minor and irregular effect on pulmonary function

decrements and tachypnea, strongly supporting neural mediation, i.e., stimulation of both
AX6-25

bronchial and pulmonary C-fibers, and not voluntary inhibition of inspiration (due to pain) as the

key mechanism. 

The involvement of nociceptive bronchial C-fibers modulated by opioid receptors in

limiting maximal inspiration and eliciting subjective symptoms in humans was studied by

Passannante et al. (1998). The authors hypothesized that highly variable responses among

individuals might reflect the individual's inability or unwillingness to take a full inspiration. 

Moreover, development of symptoms of pain on deep inspiration, cough and substernal soreness

suggested that nociceptive mechanism(s) might be involved in O3-induced inhibition of maximal

inspiration. If this were so, pain suppression or inhibition by opioid receptor agonists should

partially or fully reverse symptoms and lung functional impairment. Subjects for this study were

pre-screened with exposure to 0.42 ppm O3 and classified either as “weak” (FEV1 $95% of

preexposure value), “strong” (FEV1 # 85% of preexposure value), or “moderate” responders. 

Sixty two (28 M, 34 F) healthy volunteers (18 to 59 yrs old), known from the previous screening

to be “weak” (n = 20) or “strong” (n = 42) O3-responders, participated in this double-blind

crossover study. Subjects underwent either two 2 h exposures to air, or two 2 h exposures to

0.42 ppm O3, with 15 min IE at 17.5 l/min/m2 BSA. Immediately following postexposure

spirometry the “weak” responders were given (in random order) either the potent opioid receptor

antagonist naloxone (0.15 mg/kg) or saline, while “strong” responders received (in random

order) either the potent, rapid-acting opioid agonist and analgesic sufentanil (0.2 μg/kg), or

physiologic saline administered through an indwelling catheter. Administration of saline or

naloxone had no significant effect on the relatively small decrements in FEV1 observed in

“weak” responders. However, as hypothesized, sufentanil rapidly reversed both the O3-induced

symptomatic effects and spirometric decrements (FEV1; p < 0.0001) in “strong” responders

(Figure AX6-5). All the same, the reversal was not complete and the average post-sufentanil

FEV1 remained significantly below (!7.3%) the preexposure value suggesting involvement of

non-opioid receptor modulated mechanisms as well. Uneven suppression of symptoms has

implied involvement of both A-* and bronchial C-fibers. The plasma $-endorphin (a potent

pain suppressor) levels, though substantially elevated immediately postexposure and post-drug

administration, were not related to individuals’ O3 responsiveness. These observations have

demonstrated that nociceptive mechanisms play a key role in modulating O3-induced inhibition

of inspiration. Moreover, these findings are consistent with and further support the concept that 
AX6-26

Figure AX6-5. Plot of the mean FEV1 (% baseline) vs. time for ozone exposed cohorts. 

Solid lines represent data for “strong” males (n = 14; solid squares) and

females (n = 15; solid circles) that received sufentanil and dotted lines

represent data for the same cohorts after receiving saline. Dashed lines

represent data for “weak” males (n = 5; open squares) and females (n = 10;

open circles) that received naloxone and dot-dash lines represent data for

the same cohorts after receiving saline. The arrow denotes the time of drug

administration (~2.1 hrs). Vertical bars associated with the symbols are

one-sided SEM.

Source: Adapted from Passannante et al. (1998).

the primary mechanism of O3-induced reduction in inspiratory lung function, is an inhibition of

inspiration elicited by stimulation of the C-fibers. The absence of effect of naloxone in “weak”

responders shows that the weak response is not due to excessive endorphin production in those

individuals. However, other neurogenic mechanisms not modulated by opioid receptors may

have some though limited role in inspiratory inhibition. 
AX6-27

Airway hyperreactivity

In addition to limitation of maximal inspiration and its effects on other spirometric

endpoints, activation of airway sensory afferents also plays a role in receptor-mediated

bronchoconstriction and an increase in airway resistance. Despite this common mechanism,

post-O3 pulmonary function changes and either early or late airway hyperresponsiveness (AHR)

to inhaled aerosolized methacholine or histamine are poorly correlated either in time or

magnitude. Fentanyl and indomethacin, the drugs that have been shown to attenuate O3-induced

lung function decrements in humans, did not prevent induction of AHR when administered to

guinea pigs prior to O3 exposure (Yeadon et al., 1992). Neither does post-O3 AHR seem to be

related to airway baseline reactivity. These findings imply that the mechanisms are either not

related or are activated independently in time. Animal studies (with limited support from human

studies) have suggested that an early post-O3 AHR is, at least in part, vagally mediated (Freed,

1996) and that stimulation of C-fibers can lead to increased responsiveness of bronchial smooth

muscle independently of systemic and inflammatory changes which may be even absent (Joad

et al., 1996). In vitro study of isolated human bronchi have reported that O3-induced airway

sensitization involves changes in smooth muscle excitation-contraction coupling (Marthan,

1996). Characteristic O3-induced inflammatory airway neutrophilia which at one time was

considered a leading AHR mechanism, has been found in a murine model to be only

coincidentally associated with AHR, i.e., there was no cause and effect relationship (Zhang et al.,

1995). However, this observation does not rule out involvement of other cells such as

eosinophils or T-helper cells in AHR modulation. There is some evidence that release of

inflammatory mediators by these cells can sustain AHR and bronchoconstriction. In vitro and

animal studies have also suggested that airway neutral endopeptidase activity can be a strong

modulator of AHR (Marthan et al., 1996; Yeadon et al., 1992). Late AHR observed in some

studies is plausibly due to a sustained damage of airway epithelium and continual release of

inflammatory mediators (Foster et al., 2000). Thus, O3-induced AHR appears to be a product of

many mechanisms acting at different time periods and levels of the bronchial smooth muscle

signaling pathways. [The effects of O3 on AHR are described in Section AX6.8.]
AX6-28

AX6.2.5.2 Mechanisms at a Cellular and Molecular Level

Stimulation of vagal afferents by O3 and reactive products, the primary mechanism of lung

function impairment is enhanced and sustained by what can be considered in this context to be

secondary mechanisms activated at a cellular and molecular level. The complexity of these

mechanisms is beyond the scope of this section and the reader is directed to Section AX6.9 of

this chapter for greater details. A comprehensive review by Mudway and Kelly (2000) discusses

the cellular and molecular mechanisms of O3-induced pulmonary response in great detail.

Neurogenic airway inflammation

Stimulation of bronchial C-fibers by O3 not only inhibits maximal inspiration but, through

local axon reflexes, induces neurogenic inflammation. This pathophysiologic process is

characterized by release of tachykinins and other proinflammatory neuropeptides. Ozone

exposure has been shown to elevate C-fiber-associated tachykinin substance P in human

bronchial lavage fluid (Hazbun et al. 1993) and to deplete neuropeptides synthesized and

released from C-fibers in human airway epithelium rich in substance P-immunoreactive axons. 

Substance P and other transmitters are known to induce granulocyte adhesion and subsequent

transposition into the airways, increase vascular permeability and plasma protein extravasation,

cause bronchoconstriction, and promote mucus secretion (Solway and Leff, 1991). Although the

initial pathways of neurogenic, antigen-induced, and generally immune-mediated inflammation

are not the same, they eventually converge leading to further amplification of airway

inflammatory processes by subsequent release of cytokines, eicosanoids, and other mediators. 

Significantly negative correlations between O3-induced leukotriene (LTC4/D4/E4) production and

spirometric decrements (Hazucha et al., 1996), and an increased level of postexposure PGE2, a

mediator known to stimulate bronchial C-fibers, show that these mediators play an important

role in attenuation of lung function due to O3 exposure (Mohammed et al., 1993; Hazucha et al.,

1996). Moreover, because the density of bronchial C-fibers is much lower in the small than

large airways, the reported post-O3 dysfunction of small airways assessed by decrement

in FEF25-75 (Weinman et al., 1995; Frank et al., 2001) may be due in part to inflammation. 

Also, because of the relative slowness of inflammatory responses as compared to reflex

effects, O3-triggered inflammatory mechanisms are unlikely to initially contribute to progressive

lung function reduction. It is plausible, however, that when fully activated, they sustain and
AX6-29

possibly further aggravate already impaired lung function. Indeed, a prolonged recovery of

residual spirometric decrements following the initial rapid improvement after exposure

termination could be due to slowly resolving airway inflammation. Bronchial biopsies

performed 6 h postexposure have shown that O3 caused a significant decrease in

immunoreactivity to substance P in the submucosa (Krishna et al., 1997a). A strong negative

correlation with FEV1 also suggests that the release of substance P may be a contributing

mechanism to persistent post-O3 bronchoconstriction (Krishna et al., 1997a). Persistent

spirometry changes observed for up to 48 h postexposure could plausibly be sustained by

the inflammatory mediators, many of which have bronchoconstrictive properties (Blomberg

et al., 1999).

AX6.3 PULMONARY FUNCTION EFFECTS OF OZONE EXPOSURE IN

SUBJECTS WITH PREEXISTING DISEASE

This section examines the effects of O3 exposure on pulmonary function in subjects with

preexisting disease by reviewing O3 exposure studies that utilized subjects with (1) chronic

obstructive pulmonary disease (COPD), (2) asthma, (3) allergic rhinitis, and (4) ischemic heart

disease. Studies of subjects with preexisting disease exposed to O3, published subsequent to or

not included in the 1996 Air Quality Criteria Document (U.S. Environmental Protection Agency,

1996), are summarized in Table AX6-3. Studies examining increased airway responsiveness

after O3 exposure are discussed in Section AX6.8. 

AX6.3.1 Subjects with Chronic Obstructive Pulmonary Disease

Five studies of O3-induced responses in COPD patients were available for inclusion in the

1996 criteria document (U.S. Environmental Protection Agency, 1996). The COPD patients in

these studies were exposed during light IE (4 studies) or at rest (1 study) for 1 to 2 hours to O3

concentrations between 0.1 and 0.3 ppm. None of theses studies found significant O3-induced

changes in pulmonary function. Of the four studies examining arterial oxygen saturation, two

reported small but statistically significant O3-induced decreases in the COPD patients. These

limited data suggest COPD patients experience minimal O3-induced effects for 0.3 ppm O3
Table AX6-3. Ozone Exposure in Subjects with Preexisting Diseasea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Condition

Number and

ppm μg/m Gender of Subjects Subject Characteristics Observed Effect(s) 

3

Subjects with Chronic Obstructive Pulmonary or Heart Disease

0.0

0.24

0

472

4 h IE15 min exercise15 min restV

.

E . 20 L/min

24 °C40% RH

9 M10 M

COPD patientsAge-matched healthy NSAll subjects 59-71 years old

No significant changes in FEV1, FVC, or SR

ozone in COPD patients. Equivocal SaO2 de

during 2nd and 3rd hours of ozone exposure in 

patients. Adjusted for exercise, ozone effectdiffer significantly between COPD patients asubjects. 

0.3 589 3 h IE 

V

.

E . 30 L/min

22 °C50% RH

10 M6 M

Hypertension 42-61 years oldHealthy41-49 years old

O3-induced FEV1 decrements of 6.7 and 7.6% 

and hypertensive subjects, respectively. SigO3-induced reductions in alveolar-arterial ox

in both groups. No significant changes in caenzymes or ECG telemetry. 

Subjects with Allergic Rhinitis

0.00.2

0

392

1 h CE at V.

E = 25 L/min/m2

BSA

20 °C50% RH

13 M, 1 F Dust mite sensitized asthmatics

mean age 29 ± 5 years 

FEV1 decrement following O3 of 10% not sig

different from the 4% decrement following Freceived dust mite antigen challenge at 0.5 h 

postexposures and were lavaged 6 h post-chaAmount of allergen producing 15% FEV1 de

decreased by O3 compared to FA in 9 of 14 s

PMN in proximal airway lavage tended to be O3 than FA (p = 0.06). 

0.1250.2500.125

245490245

3h IE(10 min rest, 15 minexercise on bicycle)V

.

E = 30 L/min

3h IE × 4 days

27 °C50 % RH

5 F, 6 M6 F, 16 M

Mild bronchial asthma 20-53 years oldAllergic rhinitis 19-48 years old

Mean early-phase FEV1 response and numbe

reductions in FEV1 were significantly greate

0.25 ppm O3 or 4 × 0.125 ppm O3. Most of t

late-phase FEV1 responses occurred after 4 d

exposure to 0.125 ppm O3, as well as signific

inflammatory effects, as indicated by increaseosinophils (asthma and allergic rhinitis) and sputum lymphocytes, mast cell tryptase, histLDH (asthma only).

0.0

0.25

0

490

3 h IE,V

. 

E = 30 L/min

15 min ex/10 minrest/5 min no O3;

every 30 min.

27 /C

54% RHmouthpieceexposure

13 M, 11 F6 M, 6 F5 M, 5 F

Atopic mild asthmaPositive allergen and IgE testsHealthy NS

O3-induced FEV1 decrements of 12.5, 14.1, a

in asthmatics, allergic rhinitics and healthy srespectively (group differences not significaMethacholine responsiveness increased in asAllergen responsiveness: increased significa

exposure in asthmatics (. 2 dose shift) and a 

is rhinitics. No change in healthy. Neither amethacholine response correlated with lung were not correlated with each.

AX6-30
Table AX6-3 (cont’d). Ozone Exposure in Subjects with Preexisting Diseasea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

ppm μg/m Gender of Subjects Subject Characteristics Observed Effect(s) 

3

Subjects with Asthma

0.4 784 2h IE

(15 min rest, 15 min exerciseon bicycle)V

.

E = 30 L/min

NA 4 F, 5 M

7 F, 6 M

Healthy(25 ± 2 years old)Mild atopic asthma;beta agonists only(22 ± 0.7 years old)

Significant reductions in FVC (12%FEV1 (13%, 11%) for asthmatic and 

subjects, respectively; attenuated by in healthy subjects only. Significant mid-flows which tended to be greatethan healthy subjects. Indomethacin attenuated mid-flow-reductions somin asthmatics than healthy subjects.

0.00.4

0

784

2h IE4 × 15 min on bicycle,V

.

E = 40 L/min

NA 15

9

Healthy adults18-40 years oldMild atopic asthmatics18-40 years old

Sputum collected 24 h before and 4-

exposure. Baseline CD11b expressicorrelated with O3-induced PMN. In

expression of mCD14 on macrophagO3 compared to FA. Asthmatic PMN 

similar to healthy subjects (also see No spirometric data available. 

0.12 236 Rest 22 /C

40% RH

10 M, 5 F atopic asthma No effect of O3 on airway response t

allergen.

0.00.2

0

392

6 h30 min rest/30 min exerciseV

.

E . 25 L/min

22 °C50% RH

5 M5 M

Healthy NSAsthmatics, physician  diagnosed, All 18-45 years 

Similar spirometric responses in asthhealthy. However, preexposure FEVwere both ~0.4 L lower on O3-day th

More PMN’s in asthmatics. IL-8 anin asthmatics exposed to O3. No rel

spirometry and symptoms to inflamm

0.4 784 3h 6x15 min cycle ergometer

V

.

E . 32L/min

5 consecutive days

31 /C

35% RH

8 M , 2 F Asthmatic NS adults

beta-agonist use only19-48 years old ATS criteria for asthma

FEV1 decreased 35% on first exposu

Methacholine reactivity increased abAlso see Table AX6-7 for repeated e

0.0

 0.12

0

235

1 h restair-antigenO3-antigen

NA 9 M, 6 F Mild allergic asthma; 18 to

49 years of age.

No effect of O3 on airway response t

ragweed allergen.

0.4 784 2 h IE

15 min exercise15 min rest V

.

E . 20L/min

Head maskexposure 

.18 /C

60% RH

5 M, 1 F6 M

Healthy adultsAtopic asthmatics

FEV1 responses of healthy and asthm

(. 15% decrease). Maximal FEV1 r

methacholine increased similarly in (12 h postexposure). Larger increas

healthy subjects. Both groups had inPMN’s in sputum no correlation of Pand lung function.

AX6-31
Table AX6-3 (cont’d). Ozone Exposure in Subjects with Preexisting Diseasea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and 

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

Adult Subjects with Asthma (cont’d)

0.0

0.150.250.25

0

294490490

3 h IE15 min rest (V.

E = 7 L/min)

15 min on bicycle  (V.

E = 26 L/min)

27 ± 1 °C56 ± 7 % RH

10M, 11F5M, 10F

Healthy NS28 ± 5 years oldMild Asthmatic 30 ± 8 years old

No significant O3-induced group differences in sy

spirometry. After 0.25 ppm O3, there were signif

decrements in FEV1 and FVC that tended to be gr

asthmatics than controls. Small but significant neincrease in asthmatics following 0.15 ppm O3. Si

neutrophil increases following 0.25 ppm O3 that d

between groups. 

0.0

0.16

0

314

7.6 h25 min treadmill,25 min cycle/10 min restper hour.V

.

E = 27-32 L/min

18 °C40% RH

13 M7 M, 10 F

Healthy NS,age 19-32 years.Moderate Asthmatics,physician diagnosed,beta agonist users, age 19-32 years.

FEV1 decreased 19% in asthmatics and only 10% 

nonasthmatics. High responders had worse baselstatus. More wheeze in asthmatics after O3.

0.0

0.25

0

490

3 h IE,V

. 

E = 30 L/min

15 min ex/10 min rest/5min no O3; every 30 min

27 °C54% RHmouthpieceexposure

13 M, 11 F6 M, 6 F5 M, 5 F

Atopic mild asthmaPositive allergen andIgE testsHealthy NS

O3-induced FEV1 decrements of 12.5, 14.1, and 1

asthmatics, allergic rhinitics and healthy subjects, (group differences not significant). Methacholineresponsiveness increased in asthmatics. Allergen increased after O3 exposure in asthmatics (=2 dos

a smaller shift occurred in rhinitics, no change ochealthy subjects. Neither allergen nor methacholwere correlated with each other or with lung func

0.16 314 7.6 h

25 min treadmill, 25 mincycle/10 min rest perhour.V

.

E = 25 L/min

22 °C40 % RH

4 M, 5 F Mild atopic asthma; 

no meds 12 hpre-exposure20-35 years old

Significant FEV1 decrease of 9.1 % following O3 

marked individual variability with responses rang% to 26 %.

0.250.40

490784

V

.

E = 25-45 L/min NA 8 M, 4 F

8 M, 10 F22 M, 16 F

AsthmaticsAllergic rhiniticsHealthy adultsAll <26 years old

Healthy 12.2% decrease in FEV1, Rhinitics 10.1%

asthmatics 12.4%

0.00.2

0

392

2 h IE 4 × 15 minat V.

E = 20

L/min/m2 BSA

20 °C50% RH

6 M, 9 F9 M, 6 F

Healthy adults24 years oldMild asthmatics29 years old

O3-induced FEV1 decrement (8%, healthy adults; 

and PMN increase (20.6%, healthy adults; 15.2% Primary goal was to investigate relationship betwdefenses and O3 responses in asthmatics and heal

(see Tables AX6-3 andAX6 -13). 

AX6-32
Table AX6-3 (cont’d). Ozone Exposure in Subjects with Preexisting Diseasea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

Adult Subjects with Asthma (cont'd)

0.2 396 2h IE

(15 min rest, 15 minexercise on bicycle)V

.

E = 20 L/min/m2 BSA

22 °C40 % RH

5 F, 4 M Mild atopic asthma; no

meds 8 h pre-exposure21-42 years old

Significant decrease in FEV1 and a trend tow

in mean inspiratory flow, FEF25, and FEF75 a

exposure. No significant differences in FEF

Raw, or sRaw. No correlation between sputat 6 h postexposure and FEV1 immediately a

0.4 784 2 h rest 21 °C

40% RH

11 M , 11 F Asthmatics sensitive

to D Farinae,physician diagnosed,18 to 35 years

Ozone resulted in nasal inflammation (increaand caused augmented response to nasal alle

0.16 314 7.6 h

25 min treadmill,25 min cycle/ everyhour.

18 °C40% RH

8 M Mild asthmatics,

physician diagnosed, reactive to dust miteD. Farinae.

Increased eosinophils and PMN’s after O3 ex

in initial (bronchial) fraction. No correlation and PMN’s, FEV1 & FVC decreased 14% an

respectively.

0.00.2

0

392

4h50 min exercise,10 min rest each hour.V

.

E . 45-50 L/min

21 °C50% RH

12 M, 6 F 18 adult mild

asthmatics mostlybeta agonist users.

FVC, FEV1 decreased 17.6% and 25% respe

Trend for larger increase in SRaw in asthmatincrease in PMN’s and protein in asthmatics more inflammation. No increase in eosinophSpirometry changes in asthmatics similar to subjects (Aris et al., 1995; Balmes et al., 199

aSee Appendix A for abbreviations and acronyms.bGrouped by rest and exercise; within groups listed from lowest to highest O3 concentration.

AX6-33
AX6-34

exposures less than 2 hours in duration. These findings are also consistent decreasing O3 effects

with increasing age (see Section AX6.5.1). 

More recently, Gong et al. (1997a) exposed 9 COPD patients (age range, 59 to 71 years;

mean age 66 ± 4 years) and 10 healthy NS (age range, 60 to 69 years; mean age 65 ± 3 years)

to 0.24 ppm for 4 h with interment light exercise (.20 L/min). COPD patients had decreases

in FEV1 following both clean air (!11%, p = 0.06) and O3 (!19%, p < 0.01) exposures. 

These FEV1 decrements, presumably due to exercise, were primarily attributable to four of

the patients who lost greater than 14% of their FEV1 following both the air and O3 exposures. 

Relative to clean air, O3 caused a statistically insignificant FEV1 decrement of !8% in COPD

patients which was not statistically different from the decrement of !3% in healthy subjects. 

Ozone-induced symptoms, sRaw, SaO2, and postexposure bronchial activity also exhibited little

or no difference between the COPD patients and the healthy subjects. 

AX6.3.2 Subjects with Asthma

Based on studies reviewed in the 1996 criteria document (U.S. Environmental Protection

Agency, 1996) asthmatics appear to be at least as sensitive to acute effects of O3 as healthy

nonasthmatic subjects. At rest, neither adolescent asthmatics nor healthy controls had significant

responses as a result of an hour exposure to 0.12 ppm O3. Exposure of adult asthmatics to

0.25 ppm O3 for 2 h at rest also caused no significant responses. Preexposure to between 0.10

and 0.25 ppm O3 for 1 hr with light IE does not appear to exacerbate exercise-induced asthma

(Fernandes et al., 1994; Weymer et al., 1994). At higher exposures (0.4 ppm O3 with heavy

IE for 2 h), Kreit et al. (1989) and Eschenbacher et al. (1989) demonstrated significantly

greater FEV1 and FEF25-75 decrements in asthmatics than in healthy controls. With longer

duration exposures to lower O3 levels (0.12 ppm with moderate IE for 6.5 h), asthmatics have

also shown a tendency for greater FEV1 decrements than healthy nonasthmatics (Linn et al.,

1994). Newer clinical studies (see Table AX6-3) continue to suggest that asthmatics are at least

as sensitive as healthy controls to O3-induced responses. 

Studies of less than 3 h duration have reported similar or tendencies for increased

O3-induced spirometric responses up to O3 concentrations of 0.4 ppm. Similar group decrements

in FEV1 and FVC were reported by Hiltermann et al. (1995), who exposed 6 asthmatics and

6 healthy subjects to 0.4 ppm O3 for 2 h with light IE. Alexis et al. (2000) exposed 13 mild
AX6-35

atopic asthmatics and 9 healthy subjects for 2 h to 0.4 ppm O3 with IE (V0 E = 30 L/min). Similar

O3-induced group decrements in FEV1 and FVC were also reported by these investigators. 

A tendency, however, for an increased O3-induced reduction in mid-flows (viz., FEF25, FEF50,

FEF60p, FEF75) was reported for the asthmatics relative to the healthy subjects. In a larger study,

Jörres et al. (1996) exposed 24 asthmatics, 12 allergic rhinitis, and 10 healthy subjects to

0.25 ppm O3 for 3 h with IE. Statistically significant O3-induced decreases in FEV1 occurred in

all groups, but tended to be lower in healthy controls (allergic rhinitis, !14.1%; asthmatics,

!12.5%; healthy controls, !10.2%). Holz et al. (1999) exposed 15 asthmatics and 21 healthy

controls to 0.15 and 0.25 ppm O3 for 3-h with light IE. After the 0.25 ppm O3 exposure, there

were significant decrements in FEV1 and FVC that tended to be slightly greater in the asthmatics

than controls. One study reported that asthmatics tended to have less of an FEV1 response to O3

than healthy controls (Mudway et al., 2001). In that study, however, the asthmatics also tended

to be older than the healthy subjects which could partially explain their lesser response. 

Studies between 4 and 8 h duration, with O3 concentrations of 0.2 ppm or less, also suggest

a tendency for increased O3-induced pulmonary function responses in asthmatics relative to

healthy subjects. Scannell et al. (1996) exposed 18 asthmatics to 0.2 ppm O3 for 4 h with

IE (V0 E .25 L/min/m2 BSA). Baseline and hourly pulmonary function measurements of FEV1,

FVC, and sRaw were obtained. Asthmatic responses were compared to 81 healthy subjects who

underwent similar experimental protocols (Aris et al., 1995; Balmes et al., 1996). Asthmatic

subjects experienced a significant O3-induced increase in sRaw, FEV1 and FVC. The O3-induced

increase in sRaw tended to be greater in asthmatics than the healthy subjects, whereas similar

group decrements in FEV1 and FVC were observed. Basha et al. (1994) also reported similar

spirometric responses between 5 asthmatic and 5 healthy subjects exposed to 0.2 ppm O3 for 6 h

with IE. However, the mean preexposure FEV1 in the asthmatics was about 430 mL less (i.e.,

~12% decreased) on the O3-day relative to the air-day. In a longer exposure duration (7.6 h)

study, Horstman et al. (1995) exposed 17 asthmatics and 13 healthy controls to 0.16 ppm O3 or

FA with alternating periods of exercise (50 min, V0 E .30 L/min) and rest (10 min). Both groups

had significant O3-induced decrements in FEV1, FVC, and FEV25-75. The asthmatic and healthy

subjects had similar O3-induced reductions in FVC. The FEV1 decrement experienced by the

asthmatics was significantly greater in the healthy controls (19% versus 10%, respectively). 
AX6-36

There was also tendency for a greater O3-induced decrease in FEF25-75 in asthmatics relative to

the healthy subjects (24% versus 15%, respectively). 

With repeated O3 exposures asthmatics, like healthy subjects (see Section AX6.6)

develop tolerance. Gong et al. (1997b) exposed 10 asthmatics to 0.4 ppm O3, 3 h per day with

IE (V0 E .32 L/min), for 5 consecutive days. Symptom and spirometric responses were greatest

on the first (!35 % FEV1) and second (!34 % FEV1) exposure days, and progressively

diminished toward baseline levels (!6 % FEV1) by the fifth exposure day. Similar to healthy

subjects, asthmatics lose their tolerance to O3 after 4 to 7 days without O3 exposure. 

Other published studies with similar results (e.g., McBride et al., 1994; Basha et al., 1994;

Peden et al., 1995, 1997; Peden, 2001a; Scannell et al., 1996; Hiltermann et al., 1997, 1999;

Michelson et al., 1999; Vagaggini et al., 1999; Newson et al., 2000; Holz et al., 2002) also

reported that asthmatics have a reproducible and somewhat exaggerated inflammatory response

to acute O3 exposure (see Section AX6.9). For instance, Scannell et al. (1996) performed lavages

at 18 h post-O3 exposure to assess inflammatory responses in asthmatics. Asthmatic responses

were compared to healthy subjects who underwent a similar experimental protocol (Balmes

et al., 1996). Ozone-induced increases in BAL neutrophils and total protein were significantly

greater in asthmatics than healthy subjects. There was also a trend for an ozone related increased

IL-8 in the asthmatics relative to healthy subjects. Inflammatory responses do not appear to be

correlated with lung function responses in either asthmatic or healthy subjects (Balmes et al.,

1996, 1997; Holz et al., 1999). This lack of correlations between inflammatory and spirometric

responses may be due to differences in the time kinetics of these responses (Stenfors et al.,

2002). In addition, airway responsiveness to inhaled allergens is increased by O3 exposure in

subjects with allergic asthma for up to 24 h (see Section AX6.8).

One of the difficulties in comparing O3-induced spirometric responses of healthy subjects

versus asthmatics is the variability in responsiveness of asthmatics. Most of the asthma studies

were conducted on subjects with a clinical history of mild disease. However, classification of

asthma severity is not only based on functional assessment (e.g., percent predicted FEV1), but

also on clinical symptoms, signs, and medication use (Table AX6-4). Although “mild atopic

asthmatics” are frequently targeted as an experimental group, the criteria for classification has

varied considerably within and across the available published studies. Although the magnitude

of group mean changes in spirometry may not be significantly different between healthy and
Table AX6-4. Classification of Asthma Severity1

Lung Function2 Medications3

Classification Step

Days withsymptoms

Nights with

symptoms

FEV1 or PEF

% predicted

oral

PEF

variability

(%) Daily 

Severepersistent

4 Continual Frequent #60 >30 High-dose inhaled steroids (ICS)

and long-acting inhaled $2-agonist

If needed, add oral steroids

Sho

$2-

ster

Moderatepersistent

3 Daily >1/week between 

60 and 80

>30 Low-to-medium-dose ICS and

long-acting $2-agonist (preferred)

Or

Medium-dose ICS (another preferredoption for children ages <5 years)

Or

Low-to-medium-dose ICS and eitherleukotriene modifier or theophylline

Sho

$2-

orareq

Mildpersistent

2 >2/week,

but <1time/day

>2/week $80 20-30 Low-dose inhaled steroids (preferred)

Or

Cromolyn leukotriene modifier,or (except for children aged <5 years)nedocromil or sustained releasetheophylline to serum concentrationof 5-15 μg/mL

Sho

$2-

orareq

Mildintermittent

1 #2/week <2/month $80 <20 No daily medicine needed Sho

$2-

orareq

1 Sources: Centers for Disease Control (2003); National Institutes of Health (1997, 2003). 2For adults and children aged >5 years who can use a spirometer or peak flow meter.3The medications listed here are appropriate for treating asthma at different levels of severity. The preferred treatments, dosage, and ty

 recommended vary for adults and children and are detailed in the EPR-Update 2002 stepwise approach to therapy. The stepwise app therapy should be stepped up as necessary and stepped down when possible to identify the least amount of medication required to ac The stepwise approach to care is intended to assist, not replace, the clinical decision-making required to meet individual patient need

AX6-37
AX6-38

asthmatic subjects, many of the studies have reported clinically significant changes in some

individuals. 

Alexis et al. (2000) explored the possibility that the mechanisms of O3-induced spirometric

responses may differ between asthmatics and healthy subjects. Physician-diagnosed mild

atopic asthmatics and healthy subjects were pretreated with 75 mg/day of indomethacin

(a COX inhibitor) or placebo and then exposed for 2 h to 0.4 ppm O3 or to FA during mild

IE (V0 E = 30 L/m). The number and severity of O3-induced symptoms were significantly

increased in both asthmatics and healthy subjects. These symptom responses were similar

between the subject groups and unaffected by indomethacin pretreatment. Asthmatics and

healthy subjects also had similar O3-induced reductions in FVC and FEV1. These restrictivetype responses, occurring due to the combined effects of bronchoconstriction and reflex

inhibition of inspiration (see Section AX6.2.1), were attenuated by indomethacin in the healthy

subjects but not the asthmatics. Thus, in healthy subjects but not asthmatics, COX metabolites

may contribute to O3-induced reductions in FVC and FEV1. As assessed by the magnitude of

reductions in mid-flows (viz. FEF25, FEF50, FEF60p, FEF75), the small airways of the asthmatics

tended to be more affected than the healthy subjects. This suggests asthmatics may be more

sensitive to small airway effects of O3, which is consistent with the observed increases in

inflammation and airway responsiveness. Indomethacin pretreatment attenuated some of

these O3-induced small airways effects (FEF50 in healthy subjects, FEF60p in asthmatics).

AX6.3.3 Subjects with Allergic Rhinitis

Most O3 exposure studies in humans with existing respiratory disease have focused on lung

diseases like COPD and asthma. However, chronic inflammatory disorders of the nasal airway,

especially allergic rhinitis, are very common in the population. People with allergic rhinitis have

genetic risk factors for the development of atopy that predispose them to increased upper airway

responsiveness to specific allergens as well as nonspecific air pollutants like O3. Studies

demonstrating the interaction between air pollutants and allergic processes in the human nasal

airways and rhinoconjunctival tissue have been reviewed by Peden (2001b) and Riediker et al.

(2001), respectively. Ozone exposure of subjects with allergic rhinitis has been shown to induce

nasal inflammation and increase airway responsiveness to nonspecific bronchoconstrictors,

although to a lesser degree than experienced by asthmatics.
AX6-39

McDonnell et al. (1987) exposed nonasthmatic adults with allergic rhinitis to 0.18 ppm O3. 

The allergic rhinitics were no more responsive to O3 than healthy controls, based on symptoms,

spirometry, or airway reactivity to histamine although they had a small but significantly greater

increase in SRaw. The data on subjects with allergic rhinitis and asthmatic subjects suggest that

both of these groups have a greater rise in Raw to O3 with a relative order of airway

responsiveness to O3 being normal < allergic < asthmatic.

Bascom et al. (1990) studied the upper respiratory response to acute O3 inhalation, nasal

challenge with antigen, and the combination of O3 plus antigen in subjects with allergic rhinitis. 

Exposure to O3 caused significant increases in upper and lower airway symptoms, a mixed

inflammatory cell influx with a seven-fold increase in nasal lavage PMNs, a 20-fold increase in

eosinophils, and a 10-fold increase in mononuclear cells, as well as an apparent sloughing of

epithelial cells. McBride et al. (1994) also observed increased nasal PMN’s after O3 exposure in

atopic asthmatics. Peden et al. (1995), who studied allergic asthmatics exposed to O3, found

that O3 causes an increased response to nasal allergen challenge in addition to nasal

inflammatory responses. Their data suggested that allergic subjects have an increased immediate

response to allergen after O3 exposure. In a follow-up study, Michelson et al. (1999) reported

that 0.4 ppm O3 did not promote early-phase-response mediator release or enhance the response

to allergen challenge in the nasal airways of mild, asymptomatic dust mite-sensitive asthmatic

subjects. Ozone did, however, promote an inflammatory cell influx, which helps induce a more

significant late-phase response in this population.

Jörres et al. (1996) found that O3 causes an increased response to bronchial allergen

challenge in subjects with allergic rhinitis. This study also compared responses in subjects

with mild allergic asthma (see Sections AX6.3.2 and AX6.8). The subjects were exposed to

0.25 ppm O3 for 3 h with IE. Airway responsiveness to methacholine was determined 1 h before

and after exposure; responsiveness to allergen was determined 3 h after exposure. Statistically

significant decreases in FEV1 occurred in subjects with allergic rhinitis (13.8%) and allergic

asthma (10.6%), and in healthy controls (7.3%). Methacholine responsiveness was statistically

increased in asthmatics, but not in subjects with allergic rhinitis. Airway responsiveness to an

individual’s historical allergen (either grass and birch pollen, house dust mite, or animal dander)

was significantly increased after O3 exposure when compared to FA exposure. In subjects with

asthma and allergic rhinitis, a maximum percent fall in FEV1 of 27.9 % and 7.8%, respectively,
AX6-40

occurred 3 days after O3 exposure when they were challenged with of the highest common dose

of allergen. The authors concluded that subjects with allergic rhinitis, but without asthma, could

be at risk if a high O3 exposure is followed by a high dose of allergen.

Holz et al. (2002) extended the results of Jörres et al. (1996) by demonstrating that

repeated daily exposure to lower concentrations of O3 (0.125 ppm for 4 days) causes an

increased response to bronchial allergen challenge in subjects with preexisting allergic airway

disease, with or without asthma. There was no major difference in the pattern of bronchial

allergen response between subjects with asthma or rhinitis, except for a 10-fold increase in the

dose of allergen required to elicit a similar response ($20% decrease in FEV1) in the asthmatic

subjects. Early phase responses were more consistent in subjects with rhinitis and late-phase

responses were more pronounced in subjects with asthma. There also was a tendency towards a

greater effect of O3 in subjects with greater baseline response to specific allergens chosen on the

basis of skin prick test and history (viz., grass, rye, birch, or alder pollen, house dust mite, or

animal dander). These data suggest that the presence of allergic bronchial sensitization, but not a

history of asthma, is a key determinant of increased airway allergen responsiveness with O3. 

[A more complete discussion of airway responsiveness is found in Section AX6.8]

AX6.3.4 Subjects with Cardiovascular Disease

Superko et al. (1984) exposed six middle-aged males with angina-symptom-limited

exercise tolerance for 40 min to FA and to 0.2 and 0.3 ppm O3 while they were exercising

continuously according to a protocol simulating their angina-symptom-limited exercise training

prescription (mean V0 E = 35 L/min). No significant pulmonary function impairment or evidence

of cardiovascular strain induced by O3 inhalation was observed. Gong et al. (1998) exposed

hypertensive (n = 10) and healthy (n = 6) adult males, 41 to 78 years of age, to FA and on the

subsequent day to 0.3 ppm O3 for 3 h with IE at 30 L/min. The ECG was monitored by

telemetry, blood pressure by cuff measurement, and a venous catheter was inserted for

measurement of routing blood chemistries and cardiac enzymes. Pulmonary artery and radial

artery catheters were placed percutaneously for additional blood sampling and for measurement

of hemodynamic pressures, cardiac output, and SaO2. Other hemodynamic variables were

calculated, including cardiac index, stroke volume, pulmonary and systemic vascular resistance,

left and right ventricular stroke-work indices, and rate-pressure product. Spirometric volumes
AX6-41

(FVC, FEV1) and symptoms of breathing discomfort were measured before and after the

O3 exposures. There were significant O3-induced FEV1 decrements in both subject groups that

did not defer between groups (hypertensive, 7.6%; healthy, 6.7%). The overall results did not

indicate any major acute cardiovascular effects of O3 in either the hypertensive or normal

subjects. However, statistically significant O3 effects for both groups combined were increases

in HR, rate-pressure product, and the alveolar-to-arterial PO2 gradient, suggesting that impaired

gas exchange was being compensated for by increased myocardial work. These effects might be

more important in some patients with severe cardiovascular disease. [See Section AX6.10 for

discussion of extrapulmonary effects of O3 exposure.]

AX6.4 INTERSUBJECT VARIABILITY AND REPRODUCIBILITY

OF RESPONSE

Analysis of the factors that contribute to intersubject variability is important for the

understanding of individual responses, mechanisms of response, and health risks associated with

acute O3 exposures. Bates et al. (1972) noted that variation between individuals in sensitivity

and response was evident in respiratory symptoms and pulmonary function following O3

exposure. A large degree of intersubject variability in response to O3 has been consistently

reported in the literature (Adams et al., 1981; Aris et al., 1995; Folinsbee et al., 1978; Kulle

et al., 1985; McDonnell et al., 1983). Kulle et al. (1985) noted that the magnitude of variability

between individuals in FEV1 responses increases with O3 concentration. Similarly, McDonnell

et al. (1983) observed FEV1 decrements ranging from 3 to 48% (mean 18%) in 29 young adult

males exposed to 0.40 ppm O3 for 2 h during heavy IE. At a lower O3 concentration of

0.18 ppm, 20 similarly exposed subjects had FEV1 decrements ranging from 0 o 23%

(mean = 6%), while those exposed to FA (n = 20) had decrements ranging from !2% to 6%

(mean = 1%) (McDonnell et al., 1983). All of the subjects in these studies were young adult

males. (Intersubject variability related to age and gender is discussed in Sections AX6.5.1 and

AX6.5.2, respectively.)

More recently, McDonnell (1996) examined the FEV1 response data from three 6.6 h

exposure studies of young adult males conducted at the EPA Health Effects Research Laboratory

in Chapel Hill, NC (Folinsbee et al., 1988; Horstman et al., 1990; McDonnell et al., 1991). 
AX6-42

The response distributions for subjects at each of four O3 concentrations (0.0, 0.08, 0.10, and

0.12 ppm) are illustrated in Figure AX6-6. It is apparent that the FEV1 responses in FA are

small with most tightly grouped around zero. With increasing O3 concentration, the mean

response increases as does the variability about the mean. At higher O3 concentrations, the

distribution of response becomes asymmetric with a few individuals experiencing large FEV1

decrements. The response distribution in Figure AX6-6 allows estimates of the number or

percentage of subjects responding in excess of a certain level. With FA exposure, none of

87 subjects had a FEV1 decrement in excess of 10%; however, 26%, 31%, and 46% exceeded a

10% decrement at 0.08, 0.10, and 0.12 ppm, respectively. FEV1 decrements as large as 30 to

50% were even observed in some individuals. In 6.6-h face mask exposures of young adults

(half women) to 0.08 ppm O3, Adams (2002) found that 6 of 30 subjects (20%) had >10%

decrements in FEV1. The response distributions in Figure AX6-6 underlines the wide range of

response to O3 under prolonged exposure conditions and reinforces the observations by others

consequent to 2 h IE exposures at higher O3 concentrations (Horvath et al.,1981; McDonnell

et al., 1983). 

Figure AX6-6. Frequency distributions of FEV1 decrements following 6.6-h exposures

to O3 or filtered air. During each hour of the exposures, subjects were

engaged in moderate exercise for 50 minutes. With increasing O3

concentration, the distribution of responses becomes asymmetric, with a

few individuals exhibiting large FEV1 decrements. The percentage in each

panel indicates the portion of subjects having a FEV1 decrement in excess

of 10%.

Source: McDonnell (1996).
AX6-43

Some of the intersubject variability in response to O3 inhalation may be due to intrasubject

variability, i.e., how reproducible the measured responses are in an individual between several

O3 exposures. The more reproducible the subject’s response, the more precisely it indicates

his/her intrinsic responsiveness. McDonnell et al. (1985a) examined the reproducibility of

individual responses to O3 in healthy human subjects (n = 32) who underwent repeated

exposures within a period of 21 to 385 days (mean = 88 days; no median reported) at one of

five O3 concentrations ranging from 0.12 to 0.40 ppm. Reproducibility was assessed using the

intraclass correlation coefficient (R). The most reproducible responses studied were FVC

(R = 0.92) and FEV1 (R = 0.91). However, at the lowest concentration, 0.12 ppm, relatively

poor FEV1 reproducibility was observed (R = 0.58) due, in part, to a lack of specific O3 response

or a uniformly small response in the majority of subjects. McDonnell et al. (1985a) concluded

that for 2 h IE O3 exposures equal to or greater than 0.18 ppm, the intersubject differences in

magnitude of change in FVC and FEV1 are quite reproducible over time and likely due to

differences in intrinsic responsiveness of individual subjects. Hazucha et al. (2003) exposed

47 subjects on three occasions for 1.5 h, with moderate intensity IE, to 0.40 to 0.42 ppm O3. 

Reproducibility of FEV1 responses was related to the length of time between re-exposures,

with a Spearman correlation R of 0.54 obtained between responses for exposures 1 and

2 (median = 105 days), and an R of 0.85 between responses for exposures 2 and 3

(median = 7 days). 

Identification of mechanisms of response and health risks associated with acute O3

exposures are complicated by a poor association between various O3-induced responses. 

For example, McDonnell et al. (1983) observed a very low correlation between changes in sRaw

and FVC (r = !0.16) for 135 subjects exposed to O3 concentrations ranging from 0.12 to

0.40 ppm for 2.5 h with IE. In a retrospective study of 485 male subjects (ages 18 to 36 yrs)

exposed for 2 h to one of six O3 concentrations at one of three activity levels, McDonnell et al.

(1999) observed significant, but low, Spearman rank order correlations between FEV1 response

and symptoms of cough (R = 0.39), shortness of breath (R = 0.41), and pain on deep inspiration

(R = 0.30). The authors concluded from their data that the O3-induced responses are related

mechanistically to some degree, but that there is not a single factor which is responsible for the

observed individual differences in O3 responsiveness across the spectrum of symptom and lung

function responses. This conclusion is supported by differences in reproducibility observed by
AX6-44

McDonnell et al., (1985a). Compared to the intraclass correlation coefficient for FEV1

(R = 0.91), relatively low but statistically significant R values for symptoms ranged from 0.37 to

0.77, with that for sRaw being 0.54. The reproducibility correlations for fB (R = !0.20) and VT

(R = !0.03) were not statistically significant.

The effect of this large intersubject variability on the ability to predict individual

responsiveness to O3 was demonstrated by McDonnell et al. (1993). These investigators

analyzed the data of 290 male subjects (18 to 32 years of age) who underwent repeat 2 h IE

exposures to one or more O3 concentrations ranging from 0.12 to 0.40 ppm in order to identify

personal characteristics (i.e., age, height, baseline pulmonary functions, presence of allergies,

and past smoking history) that might predict individual differences in FEV1 response. Only age

contributed significantly to intersubject responsiveness (younger subjects were more

responsive), accounting for just 4% of the observed variance. Interestingly, O3 concentration

accounted for only 31% of the variance, strongly suggesting the importance of as yet undefined

individual characteristics that determine FEV1 responsiveness to O3. A more general form of

this model was developed to investigate the O3 exposure FEV1 response relationship (McDonnell

et al., 1997). These authors used data from 485 male subjects (age = 18 to 36 years) exposed

once for 2 h to one of six O3 concentrations (ranging from 0.0 to 0.40 ppm) at one of 3 activity

levels (rest, n = 78; moderate IE, n = 92; or heavy IE, n = 314). In addition to investigating the

influence of subject’s age, the model focused on determining whether FEV1 response was more

sensitive to changes in C than to changes in V0 E , and whether the magnitude of responses is

independent of differences in lung size. It was found that the unweighted proportion of the

variability in individual responses explained by C, V0 E , T, and age was 41%, with no evidence

that the sensitivity of FEV1 response to V0 E was different than changes in C, and no evidence that

magnitude of response was related to measures of body or lung size. The authors concluded that

much inter-individual variability in FEV1 response to O3 remains unexplained. 
2

Personal communication from authors, correction to Table 2 in Gong et al. (1997a), the %FEV1 change at

the end of the ozone exposure for subject ID 2195 should read 4.9 and not the published value of !4.3, the mean and

standard deviation reported in the table are correct. 

AX6-45

AX6.5 INFLUENCE OF AGE, GENDER, ETHNIC, ENVIRONMENTAL

AND OTHER FACTORS

AX6.5.1 Influence of Age

On the basis of results reported from epidemiologic studies, children and adolescents are

considered to be at increased risk, but not necessarily more responsive, to ambient oxidants than

adults. However, findings of controlled laboratory studies that have examined the acute effects

of O3 on children and adolescents do not completely support this assertion (Table AX6-5). 

Children experience about the same decrements in spirometric endpoints as young adults

exposed to comparable O3 doses (McDonnell et al., 1985b; Avol et al., 1987). In contrast to

young adults, however, they had no symptomatic response, which may put them at an increased

risk for continued exposure. Similarly, young adults (Linn et al., 1986; Avol et al., 1984) have

shown comparable spirometric function response when exposed to low O3 dose under similar

conditions. Among adults, however, it has been repeatedly demonstrated that older individuals

respond to O3 inhalation with less intense lung function changes than younger adults. Thus,

children, adolescents, and young adults appear to be about equally responsive to O3, but more

responsive than middle-aged and older adults when exposed to a comparable dose of O3 (U.S.

Environmental Protection Agency, 1996).

Gong et al. (1997a) studied ten healthy men (60 to 69 years old) and nine COPD patients

(59 to 71 years old) from the Los Angeles area who were exposed to 0.24 ppm O3 while

intermittently exercising every 15 min at a light load (~20 L/min) for 4 h. Healthy subjects

showed a small but significant O3-induced FEV1 decrement of 3.3% (p = 0.03 [not reported in

paper] paired-t on O3 versus FA pre-post FEV1)

2

. Small but statistically nonsignificant changes

were also observed for respiratory symptoms, airway resistance and arterial O2 saturation. In the

COPD patients, there was an 8% FEV1 decrement due to O3 exposure which was not

significantly different from the response in the healthy subjects. The authors have concluded

that typical ambient concentrations of O3 are unlikely to induce “a clinically significant acute

lung dysfunction” in exposed older men. However, they also acknowledged that the “worst

case” scenario of O3 exposure used in their study causes acute spirometric responses. 
Table AX6-5. Age Differences in Pulmonary Function Responses to Ozonea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.400.42

784823

2 h IE (15' ex/15' rest) .

VE . 33-45 L/min

(47 subjects only)1.5 h IE (20' ex/10' rest) .

VE . 33-45 L/min

(All subjects)

.22 °C

40% RHtreadmill

146 M94 F

Healthy NS 18 to 60 years old

Young individuals of both gender (<3significantly more responsive than oldsubjects. Strong responses are less coover the age of 35 years, especially in The variability of an individual’s respto repeated exposures to O3 decreases 

0.00.40

0784

2 h, IE (15' ex/15' rest) .

VE . 18 L/min/m2 BSA

2 exposures: 25% of subj.exposed to air-air, 75% exposed to O3-O3

21 °C40% RHtreadmill

28 M34 F

Healthy NS 18 to 57 years oldHealthy NS 18 to 59 years old

Significant decrements in spirometric function in all groups. Young males a(<35 years) were significantly more rethan older individuals (>35 years).

0.00.24

0470

4 h, IE (15' ex/15' rest) .

VE = 20 L/min

24 °C40% RH

10 M9 M

Healthy NS 60 to 69 years oldCOPD 59 to 71 years old

Healthy: small, 3.3%, decline in FEV1 (p = 

reported in paper], paired-t on O3 versus FA 

FEV1). COPD: 8% decline in FEV1 (p = n

FA). Adjusted for exercise, ozone effects dsignificantly between COPD patients and hsubjects.

0.00.120.180.240.300.40

0235353471589784

2 h rest or IE(4 × 15 minat V.

E = 25 or 35

 L/min/m2 BSA)

22 °C40% RH

485 WM (eachsubjectexposed at oneactivity levelto one O3concentration)

Healthy NS 18 to 36 years oldmean age 24 years

Statistical analysis of 8 experimental cstudies conducted between 1980 and 1U.S. EPA in Chapel Hill, NC. O3-ind

decrement in FEV1 predicted to decrea

age. FEV1 response of a 30 year old p

be 50% the response of a 20 year old. Table 6-1

0.00.120.180.240.300.40

0235353471589784

2.33 h IE(4 × 15 minat V.

E = 25 

 L/min/m2 BSA)

22 °C40% RH

371 (WM,BM, WF, BF;~25% pergroup) eachsubjectexposed to oneO3concentration

Healthy NS 18 to 35 years oldmean age 24 years

Statistical analysis of experimental dacollected between 1983 and 1990 by tEPA in Chapel Hill, NC. O3-induced in FEV1 predicted to decrease with agresponse of a 30 year old predicted to the response of a 20 year old. No effemenstrual cycle phase on FEV1 respon

Inconsistent effect of social economic FEV1 response.

AX6-46
Table AX6-5 (cont’d). Age Differences in Pulmonary Function Responses to Ozonea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.180.240.300.40

353470588784

2.33 hIE.

VE = 20 L/min/m2 BSA

NA 48 WF, 55 BF Healthy NS,

18 to 35 years old,black and white

Older women had smaller changes in 

younger women. No age- related diffSRaw or cough score.

0.45 882 1 h, CE .

VE . 26 L/min 

2 h, IE .

VE . 26 L/min

.23 °C

58% RHcycle/treadmill

7 M5 F

Healthy NS,60 to 79 years old(all in 60s exceptone 79 years old)

Comparison of 1-h CE protocol and 2protocol indicated no difference betwechanges in pulmonary function followtwo protocols.

0.45 882 2 h, IE (20' ex/20' rest)

Male: .

VE = 28.5 L/min

Female: .

VE = 26.1 L/min

23 °C46% RHcycle/treadmill

10 M, 6 F

Healthy NS,60 to 89 years old

Mean decrement in FEV1 = 5.7%; eigh

had a 5% or greater difference betweeresponse to O3 and FA, and the other e

less than a 5% difference between theresponses to FA and 0.45 ppm O3.

0.45 882 2 h, IE (20' ex/20' rest) .

VE . 26 L/min

.24 °C

63% RHcycle

8 M8 F

Healthy NS,51 to 69 years oldHealthy NS,56 to 76 years old

13 subjects had decrements in FEV1 o

separate exposures to 0.45 ppm within their mean response to the three exposother three subjects were not reproducSymptom reports did not correlate wepulmonary function changes.

0.12 235 1 h IE (mouthpiece) .

VE = 4 to 5 × resting

22 °C75% RHtreadmill

5 M, 7 F Healthy NS,

12 to 17 years old

No significant changes in any pulmonfunction in healthy subjects.

0.200.30

392588

1 h (mouthpiece)50' rest/10' ex for first 7males, 20' rest/10' ex forremaining subjectsMale: .

VE . 29 L/min 

Female: .

VE . 23 L/min 

.22 °C$75% RH

treadmill

9 M, 10 F Healthy NS,

55 to 74 years old

No spirometic changes for either grouFemales had 13% increase in RT at 3 a

22 min after 0.30-ppm exposure.

0.113c +

otherambientpollutants

221 1 h CE (bicycle) .

VE . 22 L/min

32.7 °C.43% RH

cycle

33 M, 33 F NS for both groups,

mean age =9.4 years old

No differences in responses of boys anSimilar decrements (<5% on average)following both purified air and ambien

at 0.11 ppm) exposures.

AX6-47
Table AX6-5 (cont’d). Age Differences in Pulmonary Function Responses to Ozonea

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.45 882 2 h, IE (20' ex/20' rest) .

VE . 26 L/min

.23 °C

53% RHcycle

8 M,8 F

Healthy NS,51 to 76 years old

Mean decrement in FEV1 = 5.6 ± 13%

decrements = 0 to 12%.

0.120.18

235353

40 min (mouthpiece)IE, 10 min exercise at .

VE = 32.6 L/min 

40 min (mouthpiece)IE, 10 min exercise at .

VE = 41.3 L/min

NAtreadmill

3 M, 7 F4 M, 6 F

Healthy NS,14 to 19 years old

No significant change in FEV1; increa

with exposure to 0.18 ppm O3. Some 

responded to 5 to 10 mg/mL methacho0.18-ppm O3 exposure, whereas none 

to 25 mg/mL methacholine at baselinebronchochallenge.

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration. cOzone concentration is the mean of a range of ambient concentrations.

AX6-48
AX6-49

Although Gong et al. (1997a) and others (see Table AX6-5) have examined responses to O3

exposure in subjects of various ages, the exposure conditions differ between most studies

so that age effects remain uncertain. Three recent studies, which analyzed large data sets

($240 subjects) of similarly exposed subjects, show clearly discernable changes in FEV1

responses to O3 as a function of age. 

Seal et al. (1996) analyzed O3-induced spirometric responses in 371 young nonsmokers

(18 to 35 years of age). The subject population was approximately 25% white males, 25% white

females, 25% black males, and 25% black females. Each subject was exposed once to 0.0, 0.12,

0.18, 0.24, 0.30, or 0.40 ppm ozone for 2.3 h during IE at a V0 E of 25 L/min/m2

 BSA. A logistic

function was used to model and test the significance of age, socioeconomic status (SES), and

menstrual cycle phase as predictors of FEV1 response to O3 exposure. Menstrual cycle phase

was not a significant. SES was inconsistent with the greatest response observed in the medium

SES and the lowest response in high SES. FEV1 responses decreased with subject age. On

average, regardless of the O3 concentration, the response of 25, 30, and 35 year old individuals

are predicted to be 83, 65, and 48% (respectively) of the response in 20 year olds. For example,

in 20 year old exposed to 0.12 ppm ozone (2.3 h IE, V0 E = 25 L/min/m2 BSA) a 5.4% decrement

in FEV1 is predicted, whereas, a similarly exposed 35 yr old is only predicted to have a 2.6%

decrement. The Seal et al. (1996) model is limited to predicting FEV1 responses immediately

postexposure in individuals exposed for 2.3 h during IE at a V0 E of 25 L/min/m2

 BSA. 

McDonnell et al. (1997) examined FEV1 responses in 485 healthy white males (18 to

36 years of age) exposed once for 2 h to an O3 concentration of 0.0, 0.12, 0.18, 0.24, 0.30, or

0.40 ppm at rest or one of two levels of IE (V0 E of 25 and 35 L/min/m2 BSA). FEV1 was

measured preexposure, after 1 h of exposure, and immediately postexposure. Decrements

in FEV1 were modeled by sigmoid-shaped curve as a function of subject age, O3 concentration,

V0 E , and duration of exposure. Regardless of the O3 concentration or duration of exposure, the

average responses of 25, 30, and 35 year old individuals are predicted to be 69, 48, and 33%

(respectively) of the response in 20 year olds. The McDonnell et al. (1997) model is best suited

to predicting FEV1 responses in while males exposed to O3 for 2 h or less under IE conditions. 

Hazucha et al. (2003) analyzed the distribution of O3 responsiveness in subjects (146 M,

94 F) between 18 and 60 years of age. Subjects were exposed to 0.42 ppm O3 for 1.5 h with IE
AX6-50

Figure AX6-7. Effect of O3 exposure (0.42 ppm for 1.5 h with IE) on FEV1 as a function

of subject age. Left panel data for males (n = 146; 19 to 60 yrs old),

right panel data for females (n = 94; 18 to 59 yrs old). In a 45 yr old

male and 52 yr old female, FEV1 decreased to 37 and 72% of baseline,

respectively. These two outliers, not illustrated above, demonstrate that

some individuals may still experience substantial responses despite

increasing age. 

Source: Adapted from Hazucha et al. (2003).

at V0 E = 20 L/min/m2 BSA. Figure AX6-7 illustrates FEV1 responses to O3 exposure as a

function of subject age. Consistent with the discussion in Section 6.4, a large degree of

intersubject variability is evident in Figure AX6-7. Across all ages, 18% of subjects were weak

responders (#5% FEV1 decrement), 39% were moderate responders, and 43% were strong

responders ($15% FEV1 decrement). Younger subjects (#35 years of age) were predominately

strong responders, whereas, older subjects (>35 years of age) were mainly weak responders. 

In males, the FEV1 responses of 25, 35, and 50 year olds are predicted to be 94, 83, and 50%

(respectively) of the average response in 20 year olds. In females, the FEV1 responses of 25, 35,

and 50 year olds are predicted to be 82, 46, and 18% (respectively) of the average response in

20 year olds. The Hazucha et al. (1996) model is limited to predicting FEV1 responses

immediately postexposure in individuals exposed to 0.42 ppm O3 for 1.5 h during IE at a V0 E of

20 L/min/m2

 BSA. 
AX6-51

The pathophysiologic mechanisms behind the pronounced age-dependent, genderdifferential rate of loss of O3 responsiveness are unclear. Passannante et al. (1998) have

previously demonstrated that O3-induced spirometric decrements (FEV1) in healthy young and

middle-aged adults are principally neural in origin, involving opioid-modulated sensory

bronchial C-fibers. (The methodological details of this study are presented in Section AX6.2.3 of

this chapter.) The peripheral afferents are most likely the primary site of action, which would be

compatible with a reflex action as well as a cortical mechanism. The pattern of progressive

decline, as well as the subsequent rate of recovery of spirometric lung function, suggest

involvement of both direct and indirect (possibly by PGE2") stimulation and/or sensitization of

vagal sensory fibers. (For details, see Section AX6.2.3.1 of this chapter.)

The additional pulmonary function data published since the release of last O3 criteria

document (U.S. Environmental Protection Agency, 1996) and reviewed in this section reinforce

the conclusions reached in that document. Children and adolescents are not more responsive

to O3 than young adults when exposed under controlled laboratory conditions. However, they

are more responsive than middle-aged and older individuals. Young individuals between the age

of 18 and 25 years appear to be the most sensitive to O3. With progressing age, the sensitivity

to O3 declines and at an older age (>60 yrs) appears to be minimal except for some very

responsive individuals. Endpoints other than FEV1 may show a different age-related pattern

of responsiveness.

AX6.5.2 Gender and Hormonal Influences

The few late 1970 and early 1980 studies specifically designed to determine symptomatic

and lung function responses of females to O3 were inconsistent. Some studies have concluded

that females might be more sensitive to O3 than males, while others found no gender differences

(U.S. Environmental Protection Agency, 1996). During the subsequent decade, seven studies

designed to systematically explore gender-based differences in lung function following O3

exposure were completed (Table AX6-6). Protocols included mouthpiece and chamber

exposures, young and old individuals, normalization of ventilation to BSA or FVC, continuous

and intermittent exercise, control for menstrual cycle phase, and the use of equivalent effective

dose of O3 during exposures. These studies have generally reported no statistically significant

differences in pulmonary function between males and females (Adams et al., 1987; Drechsler-
Table AX6-6. Gender and Hormonal Differences in Pulmonary Function Responses to Oz

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditionsc

Number and Gender

of Subjects

Subject

ppm μg/m Characteristics Observed Effect(s

3

0.0

0.25

490 1 h CE

V

.

E = 30 L/min

NAFace maskexposure

32 M, 28 F Healthy NS

22.6 ± 0.6 years old

Mean O3-induced FEV1 decrem

in males and 9.4% in females (gdifferences not significant). FE

ranged from !4 to 56%; decrem

20 subjects and >40% in 4 subjeof O3 greater in males than fema

uptake not correlated with spiroresponses. 

0.400.42

784823

2 h, IE (15' ex/15' rest)V

.

E = 33-45 L/min

1.5 h IE (20' ex/10' rest)V

.

E = 33-45 L/min

22 °C40% RHtreadmill

146 M94 F

Healthy NS,18 to 60 years old

No significant gender difference

among young (<35 years) and oindividuals. Strong responses acommon over the age of 35 yearin women.

0.00.35

0686

1.25 h, IE (30' ex/15' rest/30' ex)V

.

E = 40 L/min

22 °C40% RHtreadmill

19 F O3 responders

22.1 ± 2.7 years old

FVC and FIVC changes about th

!13%, FEV1 !20%. Increased a

responsiveness to methacholineof small effects on both inspired spirometry past 18 h. Chemorecactivated but ventilatory drive waccelerated.

0.00.4

0784

2 h, IE (15' ex/15' rest)V

.

E . 18 L/min/m2 BSA

2 exposures: 25% ofsubj. exposed to air-air,75% exposed to O3-O3

21 °C40% RHtreadmill

28 M34 F

Healthy NS, 20-59 years old Significant decrements in spirom

function. No significant differe

between young females and malfemales and males either in respnonresponders subgroups.

00.120.240.300.40

0235470588784

2.33 h IE (15' ex/15' rest)V

.

E = 20 L/min/m2 BSA

one exposure per subject

22 °C40% RHtreadmill

48 WF, 55 BF Healthy NS,

18 to 35 years old

Significant menstrual cycle phainteraction for FEV1. No signifi

menstrual cycle phase effect whwhites were analyzed separatelyNo significant menstrual phase SRaw or cough score.

AX6-52
Table AX6-6 (cont’d). Gender and Hormonal Differences in Pulmonary Function Responses t

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditionsc

Number and Gender

of Subjects

Subject

ppm μg/m Characteristics Observed Effect(s

3

0.00.35

0686

2.15 h, IE(30' ex/30' rest)

19-24 °C48-55% RHtreadmill

12 M12 F

Healthy NS,5 F follicular and 7 lutealphase exposure,regular menstrual cycles, 18to 35 years old 

Changes in FVC, FEV1, FEF25-75

.

Vmax25% were similar during bot

and luteal phases. No significanbetween males and females.

0.3 588 1 h CE

V

.

E . 50 L/min

NA 9 F Healthy NS, regular

menstrual cycles,20 to 34 years old

FEV1 decreased 13.1% during th

phase and 18.1% during the follDecrement in FEF25-75 was signi

during the follicular phase than phase. Changes in FVC were siboth phases.

00.120.180.240.300.40

0235353470588784

2.33 h (15' ex/15' rest)V

.

E = 25 L/min/m2 BSA

(one exposure/subject)

22 °C40% RHtreadmill

30 to 33 F and 30 to33 M in eachconcentration group;total of372 individualsparticipated

Healthy NS, 18 to 35 yearsold, blacks and whites

Decrements in FEV1, increases i

cough, correlated with O3 conce

There were no significant differthe responses of males and fema

00.180.30

0353588

1 h (mouthpiece), CEV

.

E . 47 L/min

exposures $4 days apart

21 to 25 °C45 to 60% RHcycle

14 F14 F

FVC = 5.11 ± 0.53 L,NS, 20 to 24 years oldFVC = 3.74 ± 0.30 L,NS, 19 to 23 years old

Small lung group, FVC = 3.74 ± Large lung group, FVC = 5.11 ± Significant concentration-responFVC and FEV1; lung size had no 

percentage decrements in FVC o

0.00.45

0882

2 h, IE (20' ex/20' rest)V

.

E = 28.5 L/min for M

V

.

E = 26.1 L/min for F

repeated O3 exposures

23.1 °C46.1% RHcycle/treadmill

10 M6 F

Healthy NS,60 to 89 years oldHealthy NS,64 to 71 years old

Mean decrement in FEV1 = 5.7%

Decrements in FVC and FEV1 w

pulmonary functions significantO3 exposure. No significant dif

between responses of men and w

00.200.30

0392588

1 h (mouthpiece) IE(50' rest/10' ex first 7 M)(20' rest/10' ex all others)

.

V

.

E . 28 L/min for M

VE . 23 L/min for F 

.22 °C$75% RH

treadmill

9 M, 10 F Healthy NS,

55 to 74 years old

No change in any spirometic meeither group. Females had 13% 

after 0.30-ppm exposure. Gendnot evaluated.

AX6-53
Table AX6-6 (cont’d). Gender and Hormonal Differences in Pulmonary Function Responses t

Ozone

Concentrationb

Exposure Duration

and Activity

Exposure

Conditionsc

Number and Gender

of Subjects

Subject

ppm μg/m Characteristics Observed Effect(s

3

0.3 588 1 h (mouthpiece), CE

V

.

E . 70 L/min for men

V

.

E . 50 L/min for

women

21 to 25 °C45 to 60% RHcycle

20 M20 F

NS, 18 to 30 years old NS, 19 to 25 years old

Significant decrements in FVC, 

FEF25-75 following O3 exposure. 

No significant differences betwewomen for spirometry or SRaw

0.00.45

0882

2 h, IE (20' rest/ 20' ex)V

.

E . 27.9 L/min for M

V

.

E . 25.4 L/min for F

repeated O3 exposures

24 °C58% RHcycle

8 M8 F

Healthy NS,51 to 69 years oldHealthy NS,56 to 76 years old

Range of responses in FEV1: 

0 to !12% (mean = !5.6%). 

No significant difference in respand women.Tendency for women to have gr

0.48 941 2 h, IE

V

.

E . 25 L/min

21 °C(WBGT) cycle

10 F Healthy NS,

19 to 36 years old

Mean decrement in FEV1 = 22.4

Significant decrements in all spimeasurements. Results not signdifferent from a similar study on (Drechsler-Parks et al., 1984).

a See Appendix A for abbreviations and acronyms.b Listed from lowest to highest O3 concentration.c WBGT = 0.7 Twet bulb + 0.3 Tdry bulb or globe.

AX6-54
AX6-55

Parks et al., 1987a; Messineo and Adams, 1990; Seal et al., 1993; Weinmann et al., 1995)

although in some studies females appeared to experience a slightly greater decline then males

(Drechsler-Parks et al., 1987a; Messineo and Adams, 1990). The comparative evaluations were

based on responses that included spirometry, airway resistance, nonspecific bronchial

responsiveness (NSBR) determinations, and changes in frequency and severity of respiratory

symptoms. However, depending on how the O3 dose was calculated and normalized, the

findings of at least three studies may be interpreted as showing that females are more sensitive

to O3 than males. The findings of the seven studies are presented in detail in Section 7.2.1.3 of

the previous O3 criteria document (U.S. Environmental Protection Agency, 1996). 

Some support for a possible increased sensitivity of females to O3 comes from a study of

uric acid concentration in nasal lavage fluid (NLF). Housley et al. (1996) found that the NLF of

females contains smaller amounts of uric acid than the NLF of males. The primary source of

uric acid is plasma; therefore, lower nasal concentrations would reflect lower plasma

concentrations of this antioxidant. The authors have speculated that in females, both lower

plasma and NLF levels (of uric acid) can plausibly make them more susceptible to oxidant

injury, since local antioxidant protection may not be as effective as with higher levels of uric

acid, and consequently more free O3 can penetrate deeper into the lung. 

Several studies also have suggested that anatomical differences in the lung size and the

airways between males and females, and subsequent differences in O3 distribution and

absorption, may influence O3 sensitivity and potentially differential O3 response. The study of

Messinio and Adams (1990) have, however, convincingly demonstrated that the effective dose to

the lung, and not the lung size, determines the magnitude of (FEV1) response. Furthermore,

the O3 dosimetry experiments of Bush et al. (1996) have shown that despite gender differences in

longitudinal distribution of O3, the absorption distribution in conducting airways was the same

for both sexes when expressed as a ratio of penetration to anatomic dead space volume. This

implies that gender differences, if any, are not due to differences in (normal) lung anatomy. 

The data also have shown that routine adjustment of O3 dose for body size and gender

differences would be more important if normalized to anatomic dead space rather than the usual

FVC or BSA. 

One of the secondary objectives of a study designed to examine the role of neural

mechanisms involved in limiting maximal inspiration following O3 exposure has been to
AX6-56

determine if gender differences occur. A group of healthy males (n = 28) and females (n = 34)

were exposed to 0.42 ppm O3 for 2 h with IE. The methodological details of the study are

presented in Section AX6.2.5.1 of this document. As Figure AX6-4 shows, the differences

between males and females were, at any condition, measurement point, and O3 sensitivity status

only minimal and not significant (Passannante et al., 1998). 

In another investigation, Folinsbee and Hazucha (2000) exposed a group of

19 O3-responsive young females (average age of 22 years, prescreened for O3 responsiveness by

earlier exposure) to air and 0.35 ppm O3. The randomized 75-min exposures included two

30-min exercise periods at a .VE of 40 L/min. In addition to standard pulmonary function tests,

they employed several techniques used for the first time in human air pollution studies

assessment of O3 effects. The average lung function decline from a pre-exposure value was 13%

for FVC, 19.9 % for FEV1 , and 30% for FEF25-75. The infrequently measured forced inspiratory

vital capacity (FIVC) was the same as FVC suggesting that the lung volume limiting

mechanisms are the same. The reduction in peak inspiratory flow (PIF) most likely reflects an

overall reduction in inspiratory effort associated with neurally mediated inhibition of inspiration. 

Persistence of small inspiratory and expiratory spirometric effects, airway resistance, and airway

responsiveness to methacholine for up to 18 h postexposure suggests that recovery of pulmonary

function after O3 exposure involves more than the simple removal of an irritant. Incomplete

repair of damaged epithelium and still unresolved airway inflammation are the likely causes of

the residual effects that in some individuals persisted beyond 24 h postexposure. However, by

42 hours no residual effects were detected. No significant changes were found in ventilatory

response to CO2 between air and O3 exposures, suggesting that chemoreceptors were not affected

by O3. However, O3 inhalation did result in accelerated timing of breathing and a modest

increase in inspiratory drive. These observations are consistent with, and further supportive of,

the primary mechanisms of O3-induced reduction in inspiratory lung function, namely an

inhibition of inspiration elicited by stimulation of the C-fibers and other pulmonary receptors. 

Because the measures of inspiratory and chemical drive to assess O3 effects were not reported in

any previous human study, no comparisons are possible. Because no male subjects were

recruited for the study, it is not possible to compare gender effects. Despite being O3-responsive,

however, the average post-O3 decline in expiratory lung function from preexposure (13% for

FVC; 19.9% for FEV1; 30% for FEF25-75) was similar to that seen in female cohorts studied by
AX6-57

other investigators under similar conditions of exposure. These were the same studies that found

no gender differences in O3 sensitivity (Adams et al., 1987; Messineo and Adams, 1990). 

The study by Hazucha et al. (2003), discussed in the previous section, has in addition to

aging also examined gender differences in O3 responsiveness. The male (n = 146) and female

(n = 94) cohorts were classified into young (19 to 35 year-old) and middle-aged (35 to 60 yearold) groups. This classification was selected in order to facilitate comparison with data reported

previously by other laboratories. Using a linear regression spline model (with a break point at

35 years), the authors reported that the rate of loss of sensitivity is about three times as high in

young females as in young males (p < 0.003). In young females, the average estimated decline

in FEV1 response is 0.71% per year, while in young males it is 0.19% per year. Middle-aged

groups of both genders show about the same rate of decline (0.36 to 0.39%, respectively). 

At 60 years of age, the model estimates about a 5% post-O3 exposure decline in FEV1 for males,

but only a 1.3% decline for females. These observations suggest that young females lose O3

sensitivity faster than young males, but by middle age, the rate is about the same for both

genders. Descriptive statistics show that there were practically no differences in the mean value,

standard error of the mean, and coefficient of variation for % FEV1 decrement between the group

of young males (n = 125; 83.7 ± 1.1%; CV = 13.5%) and young females (n = 73; 83.4 ± 1.25%;

CV = 12.8%). A straight linear regression model of these data was illustrated in Figure AX6-7. 

The slopes, significant in both males (r = 0.242; p = 0.003) and females (r = 0.488; p = 0.001),

represent the decline in responsiveness of 0.29% and 0.55% per year respectively, as assessed

by FEV1. 

Two earlier studies of the effects of the menstrual cycle phase on O3 responsiveness have

reported conflicting results (U.S. Environmental Protection Agency, 1996). Weinmann et al.

(1995) found no significant lung function effects related to menstrual cycle, although during the

luteal phase the effects were slightly more pronounced than during the follicular phase; while

Fox et al., (1993) reported that follicular phase enhanced O3 responsiveness. In a more recent

investigation of possible modulatory effects of hormonal changes during menstrual cycle on O3

response, young women (n = 150) 18 to 35 years old were exposed once to one of multiple O3

concentrations (0.0, 0.12, 0.18, 0.24, 0.30, 0.40 ppm) for 140 min with IE at 35 L/min/m2 BSA. 

The women’s menstrual cycle phase was determined immediately prior to O3 exposure. Post-O3,

no significant differences in % predicted FEV1 changes that could be related to the menstrual
AX6-58

cycle phase were found. Admittedly, a less precise method of determining menstrual cycle

phase used in this study could have weakened the statistical power. Unfortunately, the direction

and magnitude of O3 response as related to the menstrual cycle phases were not reported (Seal

et al., 1996). Considering the inconclusiveness of findings of this study and the inconsistency of

results between the two earlier studies, it is not possible to make any firm conclusions about the

influence of the menstrual cycle on responses to O3 exposure. 

Additional studies presented in this section clarify an open-ended conclusion reached in the

previous O3 criteria document (U.S. Environmental Protection Agency, 1996) regarding the

influence of age on O3 responsiveness. Healthy young males and females are about equally

responsive to O3, although the rate of loss of sensitivity is higher in females than in males. 

Middle-aged men and women are generally much less responsive to O3 than younger individuals. 

Within this range, males appear to be slightly more responsive than females, but the rate of agerelated loss in FEV1 is about the same. The O3 sensitivity may vary during the menstrual cycle;

however, this variability appears to be minimal.

AX6.5.3 Racial, Ethnic, and Socioeconomic Status Factors

In the only laboratory study designed to compare spirometric responses of whites and

blacks exposed to a range of O3 concentrations (0 to 0.4 ppm), Seal et al. (1993) reported

inconsistent and statistically insignificant FEV1 differences between white and black males and

females within various exposure levels. Perhaps, with larger cohorts the tendency for greater

responses of black than white males may become significant. Thus, based on this study it is still

unclear if race is a modifier of O3 sensitivity, although the findings of epidemiologic studies

reported in the previous criteria document “can be considered suggestive of an ethnic difference”

(U.S. Environmental Protection Agency, 1996). However, as Gwynn and Thurston (2001)

pointed out, it appears that it is more the socioeconomic status (SES) and overall quality of

healthcare that drives PM10- and O3-related hospital admissions than an innate or acquired

sensitivity to pollutants. 

This assertion is somewhat supported by the study of Seal et al. (1996) who employed a

family history questionnaire to examine the influence of SES on the O3 responsiveness of

352 healthy, 18- to 35-year-old black and white subjects. Each subject was exposed once under

controlled laboratory conditions to either air or 0.12, 0.18, 0.24, 0.30, 0.40 ppm O3 for 140 min
AX6-59

with 15 min IE at 35 L/min/m2

 BSA. An answer to the “Education of the father” question was

selected as a surrogate variable for SES status. No other qualifying indices of SES were used or

potential bias examined. Of the three SES categories, individuals in the middle SES category

showed greater concentration-dependent decline in % predicted FEV1 (4-5% @ 0.4 ppm O3) than

low and high SES groups. The authors did not have an “immediately clear” explanation for this

finding. The SES to %predicted FEV1 relationship by gender-race group was apparently

examined as well; however, these results were not presented. Perhaps a more comprehensive

and quantitative evaluation of SES status would have identified the key factors and clarified the

interpretation of these findings. With such a paucity of data it is not possible to discern the

influence of racial or other related factors on O3 sensitivity.

AX6.5.4 Influence of Physical Activity

Apart from the importance of increased minute ventilation on the inhaled dose of O3 during

increased physical activity, including work, recreational exercise, and more structured exercise

like sports, no systematic effort has been made to study other potential physical factors that may

modulate O3 response. The typical physiologic response of the body to exercise is to increase

both the rate and depth of breathing, as well as increase other responses such as heart rate, blood

pressure, oxygen uptake, and lung diffusion capacity.

Physical activity increases minute ventilation in proportion to work load. At rest, and

during light exercise, the dominant route of breathing is through the nose. The nose not only

humidifies air, among other physiologic functions, but also absorbs O3 thus decreasing the

overall dose. As the intensity of exercise increases, the minute ventilation increases and the

breathing switches from nasal to oronasal mode. There is considerable individual variation in

the onset of oronasal breathing, which ranges from 24 to 46 L/min (Niinimaa et al., 1980). 

During heavy exercise, ventilation is dominated by oral breathing. Consequently, the residence

time of inhaled air in the nose and the airways is shorter, reducing the uptake of O3 (Kabel et al.,

1994). Moreover, increasing inspiratory flow and tidal volume shifts the longitudinal

distribution of O3 to the peripheral airways, which are more sensitive to injury than the larger,

proximal airways. Ozone uptake studies of human lung showed that at simulated quiet

breathing, 50% of O3 was absorbed in the upper airways, 50% in the conducting airways, and

none reached the small airways (Hu et al. 1994). With ventilation simulating heavy exercise
AX6-60

(60 L/min), the respective O3 uptakes were 10% (upper airways), 65% (conducting airways), and

25% (small airways). These observations imply that equal O3 dose (C × T × V0 E ) will have a

greater effect on pulmonary function and inflammatory responses when inhaled during heavy

physical activity than when inhaled during lighter activity. Although, Ultman et al. (2004)

recently reported that spirometric response are not correlated with O3 uptake. (See Chapter 4 of

this document for more information on the dosimetry of O3.)

Other physiologic factors activated in response to physical activity are unlikely to have as

much impact on O3 responsiveness as does minute ventilation; however, their potential influence

has not been investigated. 

AX6.5.5 Environmental Factors

Since the 1996 O3 criteria document, not a single human laboratory study has examined the

potential influence of environmental factors such as rural versus urban environment, passive

cigarette smoke exposure, and bioactive admixtures such as endotoxin on healthy individual’s

pulmonary function changes due to O3 (U.S. Environmental Protection Agency, 1996). 

Some of the unresolved issues, e.g., health effects of ETS and O3 interaction, which need to

be examined in human studies were explored very recently in laboratory animal studies (see

Chapter 5 for more details). In one study on mice, preexposure of animals to sidestream

cigarette smoke (ETS surrogate), which elicited no immediate effects, resulted in a potentiation

of subsequent O3-induced inflammatory response. This finding suggests that typical adverse

effects of ETS do not necessarily have to elicit an immediate response to ETS, but may in fact

potentiate the effects of a subsequent exposure to another pollutant like O3 (Yu et al., 2002). The

key mechanism by which smoke inhalation may potentiate subsequent oxidant injury appears to

be damage to cell membranes and the resulting increase in epithelial permeability. Disruption of

this protective layer may facilitate as well as accelerate injury to subepithelial structures when

subsequently exposed to other pollutants (Bhalla, 2002). Although this may be a plausible

mechanism in nonsmokers and acute smokers exposed to ETS and other pollutants, studies

involving chronic smokers who most likely already have chronic airway inflammation do not

seems to show exaggerated response with exposure to O3.

More than 25 years ago, Hazucha et al. (1973) reported that the spirometric lung function

of smokers declined significantly less than that of nonsmokers when exposed to 0.37 ppm O3. 
AX6-61

The findings of this study have been confirmed and expanded (Table AX6-7). Frampton et al.

(1997a) found that exposure of current smokers (n = 34) and never smokers (n = 56) to

0.22 ppm O3 for 4 h with IE for 20 min of each 30 min period at 40 to 46 L/min, induced a

substantially smaller decline in FVC, FEV1 and SGaw of smokers than never smokers. Smokers

also demonstrated a much narrower distribution of spirometric endpoints than never smokers. 

Similarly, nonspecific airway responsiveness to methacholine was decreased in smokers. 

However, both groups showed the consistency of response from exposure to exposure. It should

be noted that despite seemingly lesser response, the smokers were more symptomatic post air

exposure than never smokers, but the opposite was true for O3 exposure. This would suggest

that underlying chronic airway inflammation present in smokers has blunted stimulation of

bronchial C-fibers and other pulmonary receptors, the receptors substantially responsible for

post-O3 lung function decrements. In addition to desensitization, the other “protective”

mechanisms active in smokers may be an increase in the mucus layer conferring not only a

mechanical protection, but also acting as an O3 scavenger. Another plausible explanation of a

diminished responsiveness of smokers may be related to elevated levels of reduced glutathione

(GSH), an antioxidant, found in epithelial lining fluid of chronic but not acute smokers (MacNee

et al., 1996).

Despite some differences in a release of proinflammatory cytokines and subsequent

recruitment of inflammatory cells, both smokers and nonsmokers developed airway

inflammation following O3 exposure. This was demonstrated by the Torres et al. (1997) study

that involved exposures of about equal size cohorts of otherwise healthy young smokers,

nonsmoker O3 nonresponders (<5% FEV1 post-O3 decrement) and nonsmoker O3 responders

(>15% FEV1 post-O3 decrement) to air and two 0.22 ppm O3 atmospheres for 4 hours, alternating

20 min of moderate exercise (25 L/min/m2 BSA) with 10 min of rest. Both O3 exposures were

followed by nasal lavage (NL) and bronchoalveolar lavage (BAL) performed immediately post

one of exposures and 18 hr later following the other exposure. Neither O3 responsiveness nor

smoking alters the magnitude or the time course of O3-induced airway inflammation. The

overall cell recovery was lower immediately postexposure but higher, particularly in

nonsmokers, 18 h post-O3 exposure when compared to control (air) in all groups. Recovery of

lymphocytes, PMNs and AMs in both alveolar and bronchial lavage fluid showed the largest

increase in response to O3 in all groups, with nonsmokers showing greater relative increases than
Table AX6-7. Influence of Ethnic, Environmental, and Other Factors

Ozone

Concentration Exposure

Duration

and Activity

Exposure

Conditions

Number

and Gender

of Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.00.4

0780

2 hIE, 15' ex/15' restV

.

E = 20 L/min/m2

BSA

20 °C40% RH

15 M, 1 F13 M, 2 F

Placebo group:healthy NSavg age 27 yrs.Antiox. Suppl. Gr.: Healthy NSavg age 27 yrs.

PF decrements in the supplementatgroup were signif. smaller for FVC(p < 0.046) and near significant for 

(p < 0.055). The inflammatory resp(BAL) showed no significant differbetween the two groups either in threcovery of cellular components or concentrations and types of inflammcytokines. 

0.00.12

0235

0.75 hIE, 15' ex/15' restV

.

E = 40-46 L/min

60% RH 5 M, 12 F Asthmatics

sensitive to SO2

19 to 38 yrs old

No significant differences due to O

between placebo and antioxidantsupplement cohort in eitherspirometric responses or bronchialhyperresponsiveness to 0.1 ppm SO

0.00.220.22

0431431

4 hIE, 20' ex/10' restV

.

E = 40-46 L/min

21 °C37% RH

25 (M/F) Healthy NS

O3 responders and

nonresponders18 to 40 yrs old

Glutathione peroxidase (GPx) activeGPx protein level were significan(p = 0.0001) depleted in ELF for at 18 h postexp. In BAL both endpoiwere elevated (ns). No associationbetween cell injury, PF, or GPx act

0.00.12-0.24a

0235-470a

2.17 hIE, 10' ex/ 10' restV

.

E = 36-39 L/min

22 °C or 30 °C45-55% RH

5 M, 4 F Healthy NS

24 to 32 yrs old

FEV1 decreased (p < 0.5) by ~8% a

22 °C and ~6.5% at 30 °C. 19 h podecline of 2.3% still signif. (p < 0.0SGaw signif. (p < 0.05) declined at but not at 22 °C. The AHR assessepostexp. as PC50 sGaw methacholin

signif. (p < 0.05) higher at bothtemperatures.

AX6-62
Table AX6-7 (cont’d). Influence of Ethnic, Environmental, and Other Factors

OzoneConcentration Exposure

Duration

and Activity

Exposure

Conditions

Number

and Gender

of Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.00.40

0780

2 hIE, 20' ex/ 10' restV

.

E = mild to mod.

6 M, 9 F Healthy NS

avg age 31 yrs.

Corticosteroid pretreatment had no on post-O3 decline in PF, PMN res

and sputum cell count under both thplacebo and treatment conditions. Methacholine PC20 FEV1 was equa

decreased in both cond. 4 h afterexposure. No changes in exhaled Nand CO.

0.00.22

0431

4 hIE20' ex/10' restV

.

E = 40-46 L/min

21 °C37% RH

90 M 56 never smokers

34 currentsmokers18 to 40 yrs. old

Smokers are less responsive to O3 a

assessed by spirometric andplethysmographic variables. Neithgender, nor methacholine responsivwere predictive of O3 response. 

0.00.220.22

0431431

4 hIE, 20' ex/10' restV

.

E = 25 L/min/m2

BSA

21 °C37% RH

10 M, 2 F10 M, 3 F11 M, 2 F

NS, O3 nonresp.,

avg age 25 yrs.;NS, O3 resp., avg age 25 yrs;smokers avgage 28 yrs

Neither O3 responsiveness nor smo

has altered the magnitude and the tcourse of O3-induced airway

inflammation. Inflammation involvall types of cells accessible by BALThe recovery profile of these cells time was very similar for all groupshowing highest values 18 hpostexposure. 

aRamp exposure from 0.12 ppm to 0.24 ppm and back to 0.12 ppm at the end of exposure.

bRelated studies, sharing of some subjects .

AX6-63
AX6-64

smokers. Of the two cytokines, IL-6 and IL-8, IL-6 was substantially and significantly

(p < 0.0002) elevated immediately postexposure but returned back to control 18 h later in all

groups; but only nonsmokers’ effects were significantly higher (p < 0.024). IL-8 showed a

similar pattern of response but the increase in all groups, though still significant (p < 0.0001),

was not as high as for IL-6. Between group differences were not significant. This inflammatory

response involved all types of cells present in BAL fluid and the recovery profile of these cells

over time was very similar for all groups. In contrast to BAL, NL did not prove to be a reliable

marker of airway inflammation. The lack of association between lung function changes

(spirometry) and airway inflammation for all three groups confirms similar observations

reported from other laboratories. This divergence of mechanisms is further enhanced by an

observation that a substantially different spirometric response between O3 responders and

nonresponders, the airway inflammatory response of the two groups was very similar, both in

terms of magnitude and pattern (Torres et al., 1997).

The influence of ambient temperature on pulmonary effects induced by O3 exposure in

humans has been studied infrequently under controlled laboratory conditions. Several

experimental human studies published more than 20 years ago reported additive effects of heat

and O3 exposure (see U.S. Environmental Protection Agency, 1986, 1996). In the study of

Foster et al. (2000) 9 young (mean age 27 years) healthy subjects (4F/5M) were exposed for

130 min (IE 10 min @ 36 to 39 l/min) to filtered air and to ramp profile O3 at 22° and 30 °C,

45-55% RH. The order of exposures was randomized. The O3 exposure started at 0.12 ppm,

reached the peak of 0.24 ppm mid-way through and subsequently declined to 0.12 ppm at the

end of exposure. Ozone inhalation decreased VT and increased fB as compared to baseline at

both temperatures. At the end of exposure FEV1 decreased significantly (p < 0.5) by ~8% at

22 °C and ~6.5% at 30 °C. One day (19 h) later, the decline of 2.3% from baseline was still

significant (p < 0.05). FVC decrements were smaller and significant only at 22 °C immediately

postexposure. SGaw significantly (p < 0.05) declined at 30 °C but not at 22 °C. A day later,

sGaw was elevated above the baseline for all conditions. The nonspecific bronchial

responsiveness (NSBR) to methacloline assessed as PC50 sGaw was significantly (p < 0.05)

higher one day following O3 exposure at both temperatures but more so at 30 °C. Thus, these

findings indicate that elevated temperature has partially attenuated spirometric response but

enhanced airway reactivity. Numerous studies have reported an increase in NSBR immediately
AX6-65

after exposure to O3. Whether the late NSBR reported in this study is a persistent residual effect

of an earlier increase in airway responsiveness, or is a true one day lag effect cannot be

determined from this study. Whatever the origin, however, a delayed increase in airway

responsiveness raises a question of potentially increased susceptibility of an individual to

respiratory impairment, particularly if the suggested mechanism of disrupted epithelial

membrane holds true. 

AX6.5.6 Oxidant-Antioxidant Balance

Oxidant-antioxidant balance has been considered as one of the determinants of O3

responsiveness. Amateur cyclists who took antioxidant supplements (vitamins C, E, and

$-carotene) for three months showed no decrements in spirometric lung function when cycling

on days with high O3 levels. In contrast, matched control group of cyclists not pretreated with

vitamin supplements experienced an almost 2% decline in FVC and FEV1 and >5% reduction in

PEF during the same activity period. Adjustment of data for confounders such as PM10 and NO2

did not change the findings. Apparently, substantially elevated levels of plasma antioxidants

may afford some protection against lung function impairment (Grievink et al.,1998, 1999).

Both laboratory animal and human studies have repeatedly demonstrated that antioxidant

compounds present the first line of defense against the oxidative stress. Thus, upregulation of

both enzymatic and nonenzymatic antioxidant systems is critical to airway epithelial protection

from exposure to oxidants such as O3 and NO2 (see Table AX6-7). As an extension of an earlier

study focused on pulmonary function changes (Frampton et al., 1997a), Avissar et al. (2000)

hypothesized that concentration of glutathione peroxidase (GPx), one of the antioxidants in

epithelial lining fluid (ELF), is related to O3 and NO2 responsiveness. They exposed healthy

young nonsmokers (n = 25), O3-responders, and nonresponders to filtered air and twice to

0.22 ppm O3 for 4 h (IE, 20' ex /10' rest, @ .VE 40 to 46 L/min). In the NO2 part of the study,

subjects were exposed to air and twice to NO2 (0.6 and 1.5 ppm) for 3 h, with IE of 10 min of

each 30 min @ .VE of 40 L/min. Ozone exposure elicited a typical pulmonary function response

with neutrophilic airway inflammation in both responders and nonresponders. The GPx activity

was significantly reduced (p = 0.0001) and eGPx protein significantly depleted (p = 0.0001) in

epithelial lining fluid (ELF) for at least 18 h postexposure. In contrast, both GPx and eGPx were

slightly elevated in bronchoalveolar lavage fluid (BALF). However, neither of the two NO2
AX6-66

exposures had a significant effect on pulmonary function, airway neutrophilia, epithelial

permeability, GPx activity, or eGPx protein level in either ELF or BALF. The lack of a

significant response to NO2 has been attributed to the weak oxidative properties of this gas. 

No association has been observed between cell injury, assessed by ELF albumin, or pulmonary

function and GPx activity for O3 exposure. Thus, it is unclear what role antioxidants may have

in modulation of O3-induced lung function and inflammatory responses. The authors found a

negative association between lower baseline eGPx protein concentration in ELF and post-O3

neutrophilia to be an important predictor of O3-induced inflammation; however, the causal

relationship has not been established.

The effects of dietary antioxidant supplementation on O3-induced pulmonary and

inflammatory response of young healthy individuals has been investigated by Samet et al.

(2001). Under controlled conditions, subjects received ascorbate restricted diet for three weeks. 

After the first week of prescribed diet, subjects were randomly assigned into two groups, and

exposed to air (2 h, IE every 15 min at 20 L/min/m2

 BSA). Thereafter, one group received daily

placebo pills and the other a daily supplement of ascorbate, "-tocopherol and a vegetable juice

for the next two weeks. At the end of a two week period subjects were exposed to 0.4 ppm O3

under otherwise similar conditions as in sham exposures. Serum concentration of antioxidants

determined prior to O3 exposure showed that subjects receiving supplements had substantially

higher concentrations of ascorbate, tocopherol and carotenoid in blood than the control group. 

Plasma levels of glutathione and uric acid (cellular antioxidants) remained essentially the same. 

Ozone exposure reduced spirometric lung function in both groups; however, the average

decrements in the supplementation group were smaller for FVC (p = 0.046) and FEV1

(p = 0.055) when compared to the placebo group. There was no significant correlation between

individual lung function changes and respective plasma levels of antioxidants. Individuals in

both groups experienced typical post-O3 subjective symptoms of equal severity. Similarly, the

inflammatory response as assessed by BALF showed no significant differences between the two

groups either in the recovery of cellular components or the types and concentrations of

inflammatory cytokines. Because of the complexity of protocol, the study was not designed as a

cross-over type. However, it is unlikely that the fixed air-O3 sequence of exposures influenced

the findings in any substantial way. Although the study did not elucidate the protective

mechanisms, it has demonstrated the value of dietary antioxidants in attenuating lung function
AX6-67

effects of O3. This observation may appear to contradict the findings of Avissar’s and colleagues

study (2000) discussed above; however, neither study found association between lung function

changes and glutathione levels. The lack of such association suggests that activation of

antioxidant protective mechanisms is seemingly independent of mechanisms eliciting lungfunction changes and that dietary antioxidants afford protection via a different pathway than

tissue-dependent antioxidant enzymes. Moreover, the findings of this study have provided

additional evidence that symptomatic, functional, inflammatory, and antioxidant responses are

operating through substantially independent mechanisms.

Further evidence that the levels and activity of antioxidant enzymes in ELF may not be

predictive or indicative of O3-induced lung function or inflammatory effects has been provided

by a study of Blomberg et al. (1999). No association was found between the respiratory tract

lining fluid redox potential level, an indicator of antioxidants balance, and either spirometric or

inflammatory changes induced by a moderate exposure of young individuals to O3 (0.2 ppm/2 h,

intermittent exercise at 20 L/min/m2

 BSA). However, O3 exposure caused a partial depletion of

antioxidants (uric acid, GSH, EC-SOD) in nasal ELF and a compensatory increase in plasma uric

acid, affording at least some local protection (Mudway et al. 1999). More recently, Mudway

et al. (2001) investigated the effect of baseline antioxidant levels on response to a 2-h exposure

to 0.2 ppm O3 in 15 asthmatic and 15 healthy subjects. In the BALF of 15 healthy subjects,

significant O3-induced reductions in ascorbate and increases in glutathione disulphide and

EC-SOD were observed, whereas, levels were unaffected by O3 exposure in the asthmatics. 

In both groups, BALF levels of uric acid and "-Tocopherol were unaffected by O3. 

Trenga et al. (2001) studied the potential protective effects of dietary antioxidants (500 mg

vitamin C and 400 IU of vitamin E) on bronchial responsiveness of young to middle-aged

asthmatics. Recruited subjects were prescreened by exposure to 0.5 ppm SO2 for 10 min while

exercising on a treadmill and selected for study participation if they experienced a >8% decease

in FEV1. Prior to the 1st exposure, subjects took either two supplements or two placebo pills at

breakfast time for 4 weeks. They continued taking respective pills for another week when the

2nd exposure took place. The 45-min exposures to air and 0.12 ppm O3 (15 min IE, V0 E . 3×

resting rate) via mouthpiece were randomized. Each exposure was followed by two 10-min

challenges to 0.10 and 0.25 ppm SO2 with exercise to determine bronchial hyperresponsiveness. 

Due to potential variability of baseline lung function between days, and the way the data have
AX6-68

been presented, it is difficult to interpret the results. All spirometric measures (FEV1,

FVC, FEF25-75, and PEF) were significantly decreased from baseline at subsequent time points

following both the FA and O3 exposures. Exposure to O3 caused significant decrements in FEV1

and PEF. The post FA and O3 exposure decrements in lung function were not affected by the

treatment regimen (placebo versus vitamin). Bronchial hyperresponsiveness to 0.1 ppm SO2 was

also unaffected by treatment regimen. Based on the prescreening SO2 challenge, subjects were

ranked by their bronchial responsiveness to SO2 as “less-severe” (8 to 16% FEV1 decrements)

and “more-severe” (27 to 44% FEV1 decrements). The authors concluded O3 exposure increases

bronchial responsiveness to SO2 in asthmatics and that antioxidant supplementation has a

protective effect against this responsiveness, especially in the “more-severe” responders. 

AX6.5.7 Genetic Factors

It has been repeatedly postulated that genetic factors may play an important role in

individual responsiveness to ozone. Recent studies (Bergamaschi et al., 2001; Corradi et al,

2002; Romieu et al, 2004) have indeed found that genetic polymorphisms of antioxidant

enzymes, namely NAD(P)H:quinone oxidoreductase (NQO1) and glutathione-S-transferase M1

(GSTM1), may play an important role in attenuating oxidative stress of airway epithelium. 

Bergamaschi and colleagues (2001) studied young nonsmokers (15 F, 9 M; mean age 28.5 years)

who cycled for two hours on a cycling circuit in a city park on days with the average ozone

concentration ranging from 32 to 103 ppb. There was no control study group nor the intensity of

bicycling has been reported . Since spirometry was done within 30 min post-ride, it is difficult

to gage how much of the statistically significant (p = 0.026) mean decrement of 160 ml in FEV1

of 8/24 individuals with NQO1 wild type (NQO1wt) and GSTM1null (GSTM1null) genotypes

was due to ozone. Individuals with other genotype combinations including GSTM1null had a

mean post-ride decrement of FEV1 of only 40 mL. The post-ride serum level of Clara cell

protein (CC16), a biomarker of airway permeability, has been elevated in both subgroups. Only

a “susceptible” subgroup carrying NQO1wt in combination with GSTM1null genotype, serum

concentration of CC16 showed positive correlation with ambient concentration of ozone and

negative correlation with FEV1 changes. Despite some interesting observations, the study results

should be interpreted cautiously. 
AX6-69

A subsequent study from the same laboratory was conducted in a more controlled

environment (Corradi et al., 2002). Healthy young (mean 30.1 yrs) individuals (12 M, 10 F)

underwent a single exposure to 0.1 ppm O3 for 2 h while intermittently exercising at a moderate

load on a bicycle ergometer. The study design did not incorporate sham exposure, though the

authors have stated that in a separate experiment the effects of exercise on markers of

inflammation in blood and EBC were negligible. The eight subjects with NQO1wt and

GSTM1null genotype, the “susceptible” group, indeed showed an increase in markers of

inflammation (IL-6, IL-8, TBARS, LTB4) and oxidative stress (8-isoprostane, H2O2)

immediately post and 18 hrs postexposure. The fourteen subjects with other combination of

genotypes showed small and inconsistent response in EBC and blood biomarkers, though PMN

activity in both groups was significantly increased by exposure. The DNA adduct 8-hydroxy-2'-

deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was elevated immediately

postexposure in both groups but only in the “susceptible” group the increase became significant. 

The spirometric endpoints (not reported) were not affected by the exposure at any time point,

which contrasts the previous study. The incomplete study design calls for a careful

interpretation of the findings.

It is of interest to note, that human nasal mucosa biopsies of GSTM1 deficient subjects

showed higher antioxidant enzymes activity than biopsies of GSTM1 positive individuals when

incubated for 24 h in 120 ppb O3 environment (Otto-Knapp et al., 2003). 

The influence of functional polymorphism of inflammatory and other genes on O3

susceptibility was studied by Yang et al. (2005). In this study 54 nonsmoking subjects

(11 healthy subjects, 15 mild asthmatics, 25 with rhinitis) were exposed to 250 ppb O3 for 3 h

(44 subjects), 200 ppb for 4 h (4 subjects), and 400 ppb for 2 h (3 subjects). During these

exposures subjects intermittently exercised (~14 L/min/m2

 BSA). The pooled data of the tumor

necrosis factor " (TNF-"), lymphotoxin-" (LTA), Toll-like receptor 4 (TLR4 ), superoxide

dismutase (SOD2) and glutathione peroxidase (GPX1) genes appear to show only TNF-" as a

promising genetic factors of susceptibility. However, as the authors stated “the functional

significance of individual TNF-" polymorphisms remains controversial” (Yang et al., 2005).

More specific genotyping has shown that O3 responsiveness and asthma risk may be related

to the presence of variant Ser allele for NQO1. In a field study of susceptibility to ambient O3 in

Mexico City, 4- 17 yrs old asthmatic children (n = 218) were genotyped, including variant alleles
AX6-70

(David et al., 2003). The risk of asthma was related to the 1-h daily max ambient O3 which

ranged from 12 to 309 ppb. Relative to Pro/Pro genotype the presence of at least one NQO1

Ser allele variant lowered the risk of asthma in these children (RR = 0.8). In children with

GSTM1null genotype combined with at least one NQO1 Ser allele variant the decreased risk of

asthma became statistically significant (RR = 0.4). The presence of Ser allele which renders

NQO1 less active, thus affecting the conjugation of quinones and formation of ROS

subsequently reducing the oxidative stress, may plausibly explain the protective effect of this

genotypic combination.

Another field study of asthmatic children (n = 158) exposed to ambient O3 (12-309 ppb

1-h max during the 12 week study period) has found that in children with genetic deficiency of

GSTM1 the decrements in FEF25-75 were related to the previous day 1-h daily max O3. The

association was more pronounced in moderate to severe asthmatics. Children with GSTM1pos

variant showed no significant decrement in lung function. Randomly administered antioxidant

supplementation (vit. C 250 mg/day and vit. E 50 mg/day) attenuated post-ozone lung function

response in GSTM1null children (Romieu et al., 2004).

These recent studies have shown that individual’s innate susceptibility to ozone may be

linked to genetic background of an individual. Although a number of potential ozone

susceptibility genes have been identified, additional better designed and controlled studies are

needed to ascertain the link between susceptibility and polymorphism. 

AX6.6 REPEATED EXPOSURES TO OZONE

Repeated daily exposure to O3 in the laboratory for 4 or 5 days leads to attenuated changes

in pulmonary function responses and symptoms (Hackney et al., 1977a; U.S. Environmental

Protection Agency, 1986, 1996). A summary of studies investigating FEV1 responses to

repeated daily exposure for up to 5 days is given in Table AX6-8. The FEV1 responses to

repeated O3 exposure typically have shown an increased response on the second exposure day

(Day 2) compared to the initial (Day 1) exposure response. This is readily apparent in repeated

exposures to a range of concentrations from 0.4 to 0.5 ppm O3 accompanied by moderate

exercise (Folinsbee et al., 1980; Horvath et al., 1981; Linn et al., 1982), and at lower

concentrations, 0.20 to 0.35 ppm, when accompanied by heavy exercise (Brookes et al., 1989; 
Table AX6-8. Changes in Forced Expiratory Volume in One Second After Repeated Daily Expo

Ozone

Concentrationb Exposure Duration

and Activityc

Number and Gender

of Subjects

Percent Change in FEV1 on Consecutive

Exposure Days 

ppm μg/m3

First Second Third Fourth Fifth

0.12 235 6.6 h, IE (40) 17 M !12.79 !8.73 !2.54 !0.6 0.2 

0.20 392 2 h, IE (30) 10 M +1.4 +2.7 !1.6 — — 

0.20 392 2 h, IE (18 and 30) 8 M, 13 F !3.0 !4.5 !1.1 — — 0.20 392 2 h, IE (18 and 30) 9 !8.7 !10.1 !3.2 — — 0.20 392 1 h, CE (60) 15 M !5.02 !7.8 — — — 

0.25 490 1 h, CE (63) 4 M, 2 F !20.2 !34.8 — — — 

5 M, 2 F !18.8 — !22.3 — —

0.35 686 2 h, IE (30) 10 M !5.3 !5.0 !2.2 — — 0.35 686 1 h, CE (60) 8 M !31.0 !41.0 !33.0 !25.0 — 

0.35 686 1 h, CE (60) 10 M !16.1 !30.4 — — — 

10 M !14.4 — !20.6 — —

0.35 686 1 h, CE (60) 15 M !15.9 !24.6 — — — 

0.40 784 3 h, IE (4-5 × resting) 13 Mf !9.2 !10.8 !5.3 !0.7 !1.0 

0.40 784 3 h, IE (4-5 × resting) 11 Ff !8.8 !12.9 !4.1 !3.0 !1.6 

0.4 784 2 h, IE (65) 8 M !18.0 !29.9 !21.1 !7.0 !4.4 0.4 784 3 h, IE (32) 8 M, 2 Fh !34.7 !31.1 !18.5 !12.0 !6.2 

0.42 823 2 h, IE (30) 24 M !21.1 !26.4 !18.0 !6.3 !2.3 0.45 882 2 h, IE (27) 1 M, 5 F !13.3 — !22.8 — — 

0.45 882 2 h, IE (27) 10 M, 6 F !5.8 !5.6 !1.9 — — 0.47 921 2 h, IE (3 × resting) 8 M, 2 Fg !11.4 !22.9 !11.9 !4.3 — 

0.5 980 2 h, IE (30) 8 M !8.7 !16.5 !3.5 — — 

0.5 980 2.5 h, IE (2 × resting) 6 !2.7 !4.9 !2.4 !0.7 — 

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration.cExposure duration and intensity of IE or CE were variable; 

.

VE (number in parentheses) given in liters per minute or as a multiple of resting ventilat

dFor a more complete discussion of these studies, see Table AX6-9 and U.S. Environmental Protection Agency (1986).eSubjects were especially sensitive on prior exposure to 0.42 ppm O3 as evidenced by a decrease in FEV1 of more than 20%. These nine subjects are 

21 individuals used in this study.

fBronchial reactivity to a methacholine challenge also was studied.gSeven subjects completed entire experiment.hSubjects had mild asthma.

AX6-71
AX6-72

Folinsbee and Horvath, 1986; Foxcroft and Adams, 1986; Schonfeld et al., 1989). Mechanisms

for enhanced pulmonary function responses on Day 2 have not been established, although

persistence of acute O3-induced damage for greater than 24 h may be important (Folinsbee et al.,

1993). An enhanced Day 2 FEV1 response was less obvious or absent in exposures at lower

concentrations or those that caused relatively small group mean O3-induced decrements. 

For example, Bedi et al. (1988) found no enhancement of the relatively small pulmonary

function responses in older subjects (median age, 65 years) exposed repeatedly to O3. Three

reports (Bedi et al., 1985; Folinsbee and Horvath, 1986; Schonfeld et al., 1989) demonstrated

that enhanced pulmonary function responsiveness was present within 12 h, lasted for at least

24 h and possibly 48 h, but was absent after 72 h. 

After 3 to 5 days of consecutive daily exposures to O3, FEV1 responses are markedly

diminished or absent. One study (Horvath et al., 1981) suggested that the rapidity of this decline

in FEV1 response was related to the magnitude of the subjects’ initial responses to O3 or their

“sensitivity.” A summary of studies examining the effects of repeated exposures to O3 on FEV1

and other pulmonary function, symptoms, and airway inflammation is given in Table AX6-9. 

Studies examining persistence of the attenuation of pulmonary function responses following

4 days of repeated exposure (Horvath et al., 1981; Kulle et al., 1982; Linn et al., 1982) indicate

that attenuation is relatively short-lived, being partially reversed within 3 to 7 days and typically

abolished within 1 to 2 weeks. Repeated exposures separated by 1 week (for up to 6 weeks)

apparently do not induce attenuation of the pulmonary function response (Linn et al., 1982). 

Gong et al. (1997b) studied the effects of repeated exposure to 0.4 ppm O3 in a group of mild

asthmatics and observed a similar pattern of responses as those seen previously in healthy

subjects. The attenuation of pulmonary responses reached after 5 days of consecutive O3

exposure was partially lost at 4 and 7 days postexposure. 

In addition to the significant attenuation or absence of pulmonary function responses after

several consecutive daily O3 exposures, symptoms of cough and chest discomfort usually

associated with O3 exposure generally are substantially reduced or absent (Folinsbee et al., 1980,

1994; Foxcroft and Adams, 1986; Linn et al., 1982). Airway responsiveness to methacholine is

increased with an initial O3 exposure (Holtzman et al., 1979; Folinsbee et al., 1988), may be

further increased with subsequent exposures (Folinsbee et al.,1994), and shows a tendency for

the increased response to diminish with repeated exposure (Dimeo et al., 1981; Kulle et al., 
Table AX6-9. Pulmonary Function Effects with Repeated Exposures to Ozonea

Ozone

Concentrationb Exposure

Duration and

Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.25 490 2 h IE, (30 min

rest, 30 minexercise),V

.

E = 39 L/min

21.4 °C 43.9% RH 4 days consecutiveFA exposure; 4 daysconsecutive O3

exposure

5 M, 3 F Healthy, NS FVC and FEV1 decrements were signific

attenuated on Day 4 of O3 exposure com

1 of O3 exposure. Significant small airw

depression accompanied by significant nin BALF one day following the end of O

0.2 392 4 h IE

(4 × 30 minexercise), V.

E =

14.8 L/min/m2

BSA

1 day FA, 1 day, O3;

4 days consecutiveexposure to O3

15 M, 8 F Healthy, NS 

21 to 35 years old

FEV1 decrement and symptoms significa

reduced on Day 4 of O3 exposure compa

1 of O3 exposure. Airway inflammation 

persisted on Day 4 although some inflammarkers in BALF attenuated significantl

0.2 392 4 h IE

(4 × 30 minexercise), V.

E =

25 L/min/m2

BSA

20 °C 50% RH(1 day, O3; 4 days

consecutive exposureto O3

9 M, 6 F Healthy, NS 

23 to 37 years old

Significant decrease in FVC, FEV1, SRa

symptoms on Day 4 of O3 exposure com

single day of O3 exposure. Number of P

fibronectin, and IL6 in BALF were signidecreased on Day 4 compared to a single 

exposure. 

0.4 784 3h/day for 5

daysIE (15 min rest,15 minexercise)V

.

E = 32 L/min

31 °C35% RH5 consecutive daysplus follow up @ 4 or7 days

8 M, 2 F Mild asthma

adult

FEV1 decreased 35% on day 1 and only 5. Bronchial reactivity increased after dremained elevated. Adaptation of asthmsimilar to healthy subjects but may be slless complete.

0.12 235 6.6 h

50 minexercise/10 minrest, 30 minlunchV

.

E = 38.8

L/min

18 °C40% RHfive consecutivedaily exposures

17 M Healthy NS FEV1 responses were maximal on first d

exposure (!13%), less on second day (!

thereafter. Symptoms only the first 2 daMethacholine airway responsiveness wadoubled on all exposure days, but was hisecond day of O3. Airway responsivene

higher than air control after 5 days of O3 

Trend to lessened response, but it was noafter 5 days.

AX6-73
Table AX6-9 (cont'd). Pulmonary Function Effects with Repeated Exposures to Ozon

Ozone

Concentrationb

Exposure Duration

and Activity Exposure Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.4 784 2 h IE (15 min rest,

15 min exerciseV

.

E . 60 L/min

5 days consecutive O3

exposure

16 M Healthy NS O3-exposure FEV1 decrement wa

day 2, 29.9%, than day 1, 18.0%decreased on day 3, 21.1%, day 4day 5, 4.4%

0.45 882 2 h

IE (3 × 20 minexercise)V

.

E = 27 L/min

23.3 °C63% RHExposed for3 consecutive days,not exposed for 2 days,then exposed to 0.45 ppmagain for 1 day

10 M, 6 F Healthy NS

60 to 89 years oldmedian 65 yearsold; mean FVC =3.99 L; mean FEV1

= 3.01 L;FEV1/FVC range =

61 to 85%

Overall increase in symptoms, busymptom increased significantlydecreased 111 mL and 104 mL oand 2, respectively. FEV1 fell by 

164 mL, and FEV3 fell by 185 an

No significant changes on Days with FA. FEV1 changes were !5

!1.9, and !1.7% on the four O3 d

0.20/0.200.35/0.200.35/0.35

392/392686/392686/686

1 hCE at 60 L/min

21 to 25 °C40 to 60% RH(three 2-day sets of exposures)

15 M Healthy aerobically

trained NS,FVC = 4.24 to6.98 L

Consecutive days of exposure to produced similar FEV1 responses 

(!5.02, !7.80); 0.35/0.20 ppm p

increased response to 0.20 ppm oday (!8.74); 0.35/0.35 ppm causincreased response on Day 2 (!1

Symptoms were worse on the secexposure to 0.35 ppm, but not wiexposure to 0.20 ppm.

0.35 686 60 min CE 

V

.

E = 60 L/min

21 to 25 °C40 to 60% RH(two exposures for eachsubject separated by 24,48, 72, or 120 h)

40 M(4 groupsof 10)

NS; nonallergic,non-Los Angelesresidents for >6 mo;=25 years old

No differences between responseexposures separated by 72 or 120 Enhanced FEV1 response at 24 h 

!30.4%). Possible enhanced res

(!14.4% vs. !20.6%). Similar tr

observed for breathing pattern an

0.45 882 2 h IE 

(3 × 20 minexercise)V

.

E = 26 L/min

23.3 °C62.5% RH(three exposures witha minimum 1-weekinterval)

8 M, 8 F Healthy NS, 61

years old for M and65 years old for F(FVC = 4.97 L forM and 3.11 L for F)

Spirometric changes were not repfrom time to time after O3 exposuR < 0.50). Repeat exposures to aconsistent responses.

AX6-74
Table AX6-9 (cont'd). Pulmonary Function Effects with Repeated Exposures to Ozon

Ozone

Concentrationb

Exposure Duration

and Activity Exposure Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.18 353 2 h

IE (heavy) V

.

E . 60 to 70 L/min

(35 L/min/m2 BSA)

31 °C35% RH(screen exposures in spring 1986;second exposures insummer/fall 1986 andwinter 1987 and spring1987 for responders andnonresponders only)

59 adultLos Angelesresidents12 responsive13nonresponsive

Responders: 19 to 40 years old 6 atopic, 2 asthmatic, 4 normalNonresponders:18 to 39 years old, 13 normal

Responders had 

aFEV1 = !12.4% 

screening; nonresponders had no Responders had nonsignificant relate summer or early winter, but responsive again in early spring 

!385 mL; Autumn 1986, !17 mL

1987, +16 mL; spring 1987, !34

Nonresponders did not change wSuggests that responders responswith ambient exposure, but nonrgenerally remain nonresponsive.

0.45

(+0.30PAN)

882 2 h

IE (20 min rest,20 min exercise)V

.

E = 27 L/min

22 °C60% RH5 days consecutiveexposure to PAN + O3

3 M, 5 F Healthy NS, 

Mean age =24 years

FEV1 decreased .19% with O3 a

on Day 1 of O3 + PAN, .5% on 

+ PAN, .7% 3 days after 5 days 

PAN, .15% after 5 days of O3 + 

Similar to other repeated O3 expo

O3 responses peaked after 2 daysdepressed 3 days later, and resporeturned 7 days later. PAN probeffect on repeated to O3 exposure 

0.35 686 .1 h CE 

(see paperfor details)

22 to 25 °C35 to 50% RH(1 day FA; 1 day O3;4 days consecutiveexposure to O3)

8 M Aerobically trained

healthy NS (somewere known O3

sensitive), 22.4 ± 2.2 years old

Largest FEV1 decrease on second 

O3 exposure (!40% mean decrea

for attenuation of pulmonary funresponse not complete in 4 days. 

decreased with single acute O3 ex

(!6%) but was not significant aft

O3 exposure (!4%). Performanc

less after acute O3 (211 s) exposu

FA (253 s).

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration.

AX6-75
AX6-76

1982). The initially enhanced and then lessened response may be related to changes that occur

during the repair of pulmonary epithelia damaged as a consequence of O3 exposure. 

Inflammatory responses (Koren et al., 1989a), epithelial damage, and changes in permeability

(Kehrl et al., 1987) might explain a portion of these responses. By blocking pulmonary function

responses and symptoms with indomethacin pretreatment, Schonfeld et al. (1989) demonstrated

that in the absence of an initial response, pulmonary function and symptoms effects were not

enhanced on Day 2 by repeated exposure to 0.35 ppm O3. These results suggest that airway

inflammation and the release of cyclooxygenase products of arachidonic acid play a role in the

enhanced pulmonary function responses and symptoms observed upon reexposure to O3 within

48 h.

Response to laboratory O3 exposure as a function of the season of the year in the South

Coast Air Basin of Los Angeles, CA, has been examined in several studies (Avol et al., 1988;

Hackney et al., 1989; Linn et al., 1988). Their primary purpose was to determine whether O3

responsive subjects would remain responsive after regular ambient exposure during the “smog

season”. The subjects were exposed to 0.18 ppm O3 for 2 h with heavy IE on four occasions,

spring, fall, winter, and the following spring. The marked difference in FEV1 response between

responsive and nonresponsive subjects seen initially (!12.4% versus +1%) no longer was present

after the summer smog season (fall test) or 3 to 5 months later (winter test). However, when the

subjects were exposed to O3 during the following spring, the responsive subjects again had

significantly larger changes in FEV1, suggesting a seasonal variation in response.

Brookes et al. (1989) and Gliner et al. (1983) tested whether initial exposure to one O3

concentration could alter response to subsequent exposure to a different O3 concentration. 

Gliner et al. (1983) showed that FEV1 response to 0.40 ppm O3 was not influenced by previously

being exposed to 0.20 ppm O3 for 2 h on 3 consecutive days. Brookes et al. (1989) found

enhanced FEV1 and symptoms upon exposure to 0.20 ppm after previous exposure to

0.35 ppm O3. These observations suggest that, although preexposure to low concentrations of O3

may not influence responses to higher concentrations, preexposure to a high concentration of O3

can significantly increase responses to a lower concentration on the following day.

Foxcroft and Adams (1986) demonstrated that decrements in exercise performance seen

after 1 h of exposure to 0.35 ppm O3 with heavy CE were significantly less after 4 consecutive

days exposure than they were after a single acute exposure. Further, exercise performance,
AX6-77

VO0 2max, V0 Emax and HRmax were not significantly different after 4 days of O3 exposure compared to

those observed in a FA exposure. Despite the change in exercise performance, Foxcroft and

Adams (1986) did not observe a significant attenuation of FEV1 response, although symptoms

were significantly reduced. However, these investigators selected known O3-sensitive subjects

whose FEV1 decrements exceeded 30% on the first 3 days of exposure. The large magnitude of

these responses, the trend for the responses to decrease on the third and fourth day, the decreased

symptoms, and the observations by Horvath et al. (1981) that O3-sensitive subjects adapt slowly,

suggest that attenuation of response would have occurred if the exposure series had been

continued for another 1 or 2 days. These observations support the contention advanced by

Horvath et al. (1981) that the progression of attenuation of response is a function of initial “O3

sensitivity.” 

Drechsler-Parks et al. (1987b) examined the response to repeated exposures to 0.45 ppm O3

plus 0.30 ppm peroxyacetyl nitrate (PAN) in 8 healthy subjects and found similar FEV1

responses to exposures to O3 (!19%) and to O3 plus PAN (!15%). Thus, PAN did not increase

responses to O3. Further, repeated exposure to the PAN plus O3 mixture resulted in similar

changes to those seen with repeated O3 exposure alone. The FEV1 responses fell to less than

!5% after the fifth day, with the attenuation of response persisting 3 days after the repeated

exposures, but being absent after 7 days. These observations suggest that PAN does not

influence the attenuation of response to repeated O3 exposure. If the PAN responses are

considered negligible, this study confirms the observation that the attenuation of O3 responses

with chamber exposures lasts no longer than 1 week. [More discussion on the interaction of O3

with other pollutants can be found in Section AX6.11.]

Folinsbee et al. (1993) exposed a group of 16 healthy males to 0.4 ppm O3 for 2 h/day on

5 consecutive days. Subjects performed heavy IE (V0 E = 60 to 70 L/min). Decrements in FEV1

averaged 18.0, 29.9, 21.1, 7.0, and 4.4% on the 5 exposure days. However, baseline preexposure

FEV1 decreased from the first day’s preexposure measurement and was depressed by an average

of about 5% by the third day. This study illustrates that, with high-concentration and heavyexercise exposures, pulmonary function responses may not be completely recovered within 24 h. 

During this study, BALF also was obtained immediately after the Day 5 exposure, with results

reported by Devlin et al. (1997). These authors found that some inflammation and cellular

responses associated with acute O3 exposure were also attenuated after 5 consecutive days of O3
AX6-78

exposure (compared to historical data for responses after a single-day exposure), although

indicators of epithelial cell damage—not seen immediately after acute exposure—were present

in BALF after the fifth day of exposure. When reexposed again 2 weeks later, changes in BALF

indicated that epithelial cells appeared fully repaired (Devlin et al., 1997).

Frank et al. (2001) exposed 8 healthy young adults to 0.25 ppm O3 for 2 h with moderate

IE (exercise V0 E = 40 L/min) on 4 consecutive days. In addition to standard pulmonary function

measures, isovolumetric FEF25-75, V0 max50 and V0 max75 were grouped into a single value representing

small airway function (SAWgrp). Exercise ventilatory pattern was also monitored each day,

while peripheral airway resistance was measured by bronchoscopy followed by lavage on Day 5. 

The authors observed two patterns of functional response in their subjects— attenuation and

persistent. Values of FVC and FEV1 showed significant attenuation by Day 4 compared to Day

1 values. However, SAWgrp and rapid shallow breathing during exercise persisted on Day 4

compared to Day 1, and were accompanied by significant neutrophilia in BALF 1 day following

the end of O3 exposure. Frank et al. (2001) suggested that both types of functional response (i.e.,

attenuation and persistence) are linked causally to inflammation. They contend that the

attenuation component is attributable at least in part to a reduction in local tissue dose during

repetitive exposure that is likely to result from the biochemical, mechanical, and morphological

changes set in motion by inflammation. They speculated that the persistent component

represents the inefficiencies incurred through inflammation. Whether the persistent small airway

dysfunction is a forerunner of more permanent change in the event that oxidant stress is extended

over lengthy periods of time is unknown.

Early repeated multihour (6 to 8 h) exposures focused on exposures to low concentrations

of O3 between 0.08 and 0.12 ppm (Folinsbee et al., 1994; Horvath et al., 1991; Linn et al., 1994). 

Horvath et al. (1991) exposed subjects for 2 consecutive days to 0.08 ppm using the 6.6-h

prolonged exposure protocol (see Table AX6-2). They observed small pre- to postexposure

changes in FEV1 (!2.5%) on the first day, but no change on the second day. Linn et al. (1994)

observed a 1.7% decrease in FEV1 in healthy subjects after 6.6 h exposure to 0.12 ppm O3. 

A second consecutive day exposure to O3 yielded even smaller (<1%) responses. In a group of

asthmatics exposed under similar conditions (Linn et al., 1994), the FEV1 response on the first

day was !8.6% which was reduced to !6.7% on day 2, both significantly greater than those

observed for the nonasthmatics group. The observations of Horvath et al. (1991) and Linn et al.
AX6-79

(1994) elicited a somewhat different pattern of response (no enhancement of response after the

first exposure) than that seen at higher concentrations in 2 h exposures with heavy exercise

(Tables AX6-8 and AX6-9). However, the subjects studied by Horvath et al. (1991) were

exposed only to 0.08 ppm O3 and were somewhat older (30 to 43 yrs) than the subjects studied

by Folinsbee et al. (1994), mean age of 25 yrs, while the nonasthmatic subjects studied by Linn

et al. (1994) were also older (mean = 32 yrs), had lower exercise V0 E (!20%) and were residents

of Los Angeles who often encountered ambient levels of O3 at or above 0.12 ppm.

Folinsbee et al. (1994) exposed 17 subjects to 0.12 ppm O3 for 6.6 h, with 50 min of

moderately heavy exercise (V0 E = 39 L/min) each hour, on 5 consecutive days. Compared with

FA, the percentage changes in FEV1 over the five days were !12.8%, !8.7%, !2.5%, !0.06%,

and +0.18%. A parallel attenuation of symptoms was observed, but the effect of O3 in enhancing

airway responsiveness (measured by increase in SRaw upon methacholine challenge) over

5 days was not attenuated (3.67, 4.55, 3.99, 3.24, and 3.74, compared to 2.22 in FA control). 

Nasal lavage revealed no increases in neutrophils except on the first O3 exposure day.

Christian et al. (1998) exposed 15 adults (6 females and 9 males; mean age = 29.1 yrs) to

4 consecutive days at 0.20 ppm O3 for 4 h, with 30 mm of IE (exercise V0 E = 25 L/min/m2) each

hour. Measures of FEV1, FVC, and symptoms were all significantly reduced on Day 1, further

decreased on Day 2, and then attenuated to near FA control values on Day 4. The pattern of

SRaw response was similar, being greatest on Day 2 and no different from FA control on Day 4. 

BAL was done on Day 5 and showed that neutrophil recruitment to the respiratory tract was

attenuated with repeated short-term exposures, compared to Day 1 control O3 exposure, while

airway epithelial injury appeared to continue as reflected by no attenuation of IL-6, IL-8, total

protein, and LDH. The authors concluded that such injury might lead to airway remodeling,

which has been observed in several animal studies (Brummer et al., 1977; Schwartz et al., 1976;

Tepper et al., 1989; Van Bree et al., 1989). In a similar study to that of Christian et al. (1998),

Jörres et al. (2000) exposed 23 adults (8 females and 15 males; mean age = 27.9 yrs) on

4 consecutive days to 0.20 ppm O3 for 4 h, with 30 min of IE (exercise V0 E = 26 L/min) each

hour. The authors observed that FEV1 was significantly reduced and symptoms were

significantly increased on Day 1. On Day 2, FEV1 was further decreased, while symptoms

remained unchanged. By Day 4, both FEV1 and symptoms were attenuated to near FA, control

values. Twenty hours after the Day 4 exposure, BAL and bronchial mucosal biopsies were
AX6-80

performed. These authors found via bronchial mucosal biopsies that inflammation of the

bronchial mucosa persisted after repeated O3 exposure, despite attenuation of some inflammatory

markers in BALF and attenuation of lung function responses and symptoms. Further, Jörres

et al. (2000) observed persistent although small decrease in baseline FEV1 measured before

exposure, thereby suggesting that there are different time scales of the functional responses

to O3, which may reflect different mechanisms. The levels of protein remaining elevated after

repeated exposures confirms the findings of others (Christian et al., 1998; Devlin et al., 1997),

and suggests that there is ongoing cellular damage irrespective of the attenuation of cellular

inflammatory responses with the airways. [Further discussion on the inflammatory responses to

O3 can be found in Section AX6.9.]

Based on studies cited here and in the previous O3 criteria documents (U.S. Environmental

Protection Agency, 1986, 1996), several conclusions can be drawn about repeated 1- to 2-h O3

exposures. Repeated exposures to O3 can cause an enhanced (i.e., greater) lung function

response on the second day of exposure. This enhancement appears to be dependent on the

interval between the exposures (24 h is associated with the greatest increase) and is absent with

intervals >3 days. As shown in Figure AX6-8, an enhanced response also appears to depend

on O3 concentration and to some extent on the magnitude of the initial response. Small

responses to the first O3 exposure are less likely to result in an enhanced response on the second

day of O3 exposure. Repeated daily exposure also results in attenuation of pulmonary function

responses, typically after 3 to 5 days of exposure. This attenuated response persists for less than

1 week or as long as 2 weeks. In temporal conjunction with the pulmonary function changes,

symptoms induced by O3, such as cough and chest discomfort, also are attenuated with repeated

exposure. Ozone-induced changes in airway responsiveness attenuate more slowly than

pulmonary function responses and symptoms. Attenuation of the changes in airway

responsiveness appear to persist longer than changes in pulmonary function, although this has

been studied only on a limited basis. In longer-duration (6.6 h), lower-concentration studies that

do not cause an enhanced second-day response, the attenuation of response to O3 appears to

proceed more rapidly. Inflammatory markers from BALF on the day following both 2 h (Devlin

et al., 1997) and 4 h (Christian et al., 1998; Jörres et al., 2000) repeated O3 exposure for 4 days

indicate that there is ongoing cellular damage irrespective of the attenuation of some cellular

inflammatory responses of the airways, lung function responses and symptoms. 
AX6-81

AX6.7 EFFECTS ON EXERCISE PERFORMANCE

AX6.7.1 Introduction

In an early epidemiologic study examining race performances in Los Angeles area high

school cross-country runners, Wayne et al. (1967) observed that endurance exercise performance

was depressed by inhalation of ambient oxidant air pollutants. The authors concluded that the

detrimental effects of oxidant air pollutants on race performance might have been related to the

associated discomfort in breathing, thus limiting the runners’ motivation to perform at high

levels, although physiologic effects limiting O2 availability could not be ruled out. 

Figure AX6-8. Regression curves were fitted to day-by-day postexposure FEV1 values

obtained after repeated daily acute exposures to O3 for 2 to 3 h with

intermittent exercise at a VE of 24 to 43 L/min (adaptation studies). 

Symbols represent the results from individual studies conducted at 0.2 ppm

for 2 h (—), 0.35 ppm for 2 h (#), 0.4 ppm for 2 h ([), 0.5 ppm for 2 h (r),

and 0.54 ppm for 3 h (•). Also shown for comparison are the FEV1 values

obtained after exposure to 0.12 ppm O3 for 10 h (!).

Source: Modified from Hazucha (1993).
AX6-82

Subsequently, the effects of acute O3 inhalation on endurance exercise performance have been

examined in numerous controlled laboratory studies. These studies were discussed in the

previous O3 criteria document (U.S. Environmental Protection Agency, 1996) in two categories: 

(1) those that examined the effects of acute O3 inhalation on maximal oxygen uptake ( VO0 2max)

and (2) those that examined the effects of acute O3 inhalation on the ability to complete

strenuous continuous exercise protocols of up to 1 h in duration. In this section, major

observations in these studies are briefly reviewed with emphasis on reexamining the primary

mechanisms causing decrements in VO0 2max and endurance exercise performance consequent

to O3 inhalation. A summary of major studies of O3 inhalation effects on endurance exercise

performance, together with observed pulmonary function and symptoms of breathing discomfort

responses, is given in Table AX6-10.

AX6.7.2 Effect on Maximal Oxygen Uptake

Three early studies (Folinsbee et al., 1977; Horvath et al., 1979; Savin and Adams, 1979)

examining the effects of acute O3 exposures on VO0 2max were reviewed in an earlier O3 criteria

document (U.S. Environmental Protection Agency, 1986). Briefly, Folinsbee et al. (1977)

observed that VO0 2max was significantly decreased (10.5%) following a 2-h exposure to

0.75 ppm O3 with light (50 Watts) IE. Reduction in VO0 2max was accompanied by a decrease in

maximal ventilation, maximal heart rate, and a large decrease in maximal tidal volume. 

In addition, the 2-h IE O3 exposure resulted in a 22.3% decrease in FEV1 and significant

symptoms of cough and chest discomfort. In contrast, Horvath et al. (1979) did not observe a

change in VO0 2max or other maximal cardiopulmonary endpoints in subjects exposed for 2 h at rest

to either 0.50 or 0.75 ppm, although FVC was significantly decreased 10% following the latter

exposure. Without preliminary exposure to O3, Savin and Adams (1979) examined the effects of

a 30-min exposure to 0.15 and 0.30 ppm O3 while performing a progressively incremented

exercise test to volitional fatigue (mean = 31.5 min in FA). No significant effect on maximal

work time or VO0 2max was observed compared to that observed upon FA exposure. Further, no

significant effect on pulmonary function, maximal heart rate, and maximal tidal volume was

observed, although maximal V0 E was significantly reduced 7% in the 0.30 ppm O3 exposure. 

Results of these early studies suggest that VO0 2max is reduced if the incremented maximal exercise
Table AX6-10. Ozone Effects on Exercise Performancea

Ozone

Concentration b

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Effect(s) 

3

0.06-0.070.12-0.13

120-140245-260

CE(V

.

E = 30 to 120 L/min)

16 to 28 min progressivemaximum exerciseprotocol

23 to 24.5 °C50 to 53% RH

12 M, 12 F Athletic Reduced maximum performance time and increa

of breathing discomfort during O3 exposure.

0.18 353 1 h CE or competitive

simulation at mean V

.

E = 94 L/min

NA # not given;

all males

Well-traineddistance runners

Maximal treadmill run time reduced from 71.7 m66.2 min during O3 exposure with no decease in 

saturation.

0.35 686 50 min CE 

V

.

E = 60 L/min

22 to 25 °C35 to 50% RH

8 M Trained

nonathletes

VT decreased, fB increased with 50-min O3 expos

in FVC, FEV1, FEF25-75, performance time, 

.

VO2

HRmax from FA to 0.35-ppm O3 exposure.

0.120.20

235392

1 h CE V

.

E = 89 L/min

31 °C 15 M, 2 F Highly trained

competitivecyclists

Decrease in 

.

VEmax, 

.

VO2max, VTmax, workload, rid

and FEV1 with 0.20 ppm O3 exposure, but not si

0.12-ppm O3 exposure, as compared to FA expo

0.120.180.24

235353470

1 h competitivesimulation exposures atmean V

.

E = 87 L/min

23 to 26 °C45 to 60% RH

10 M Highly trained

competitivecyclists

Decrease in exercise time of 7.7 min and 10.1 munable to complete the competitive simulation at ppm O3, respectively; decrease in FVC and FEV

0.24-ppm O3 exposure compared with FA expos

0.21 412 1 h CE at 75% V

.

O2max 19 to 21 °C

60 to 70% RH

6 M, 1 F Well-trained

cyclists

Decrease in FVC, FEV1, FEF25-75, and MVV with 

compared with FA exposure.

0.200.35

392686

1 h CE or competitivesimulation at mean V

.

E = 77.5 L/min

23 to 26 °C45 to 60% RH

10 M Well-trained

distance runners

VT decreased and fB increased with continuous 5

exposures; decrease in FVC, FEV1, and FEF25-75 

0.20 ppm and FA to 0.35-ppm O3 exposure in all 

three subjects unable to complete continuous and protocols at 0.35 ppm O3.

0.250.500.75

4909801,470

2 h rest NA 8 M, 5 F FVC decreased with 0.50- and 0.75-ppm O3 exp

compared with FA; 4% nonsignificant decrease 

.

VO2max following 0.75 ppm O3 compared with F

0.150.30

294588 ~30 min, progressively

incremented exercise tovoluntary exhaustion 

23 °C 50% RH

9 M Healthy, NS 

21 to 44 years old

Exposure to 0.15 and 0.30 ppm O3 did not decre

exercise performance or 

.

VO2max compared to FA

No significant pulmonary function or symptom robserved, although a trend (P < .10) was evident

0.75 1,470 2 h IE 

(4 × 15 min light [50 W]bicycle ergometry)

NA 13 M 4 light S,

9 NS

Decrease in FVC, FEV1, ERV, IC, and FEF50% a

0.75-ppm O3 exposure; decrease in V

.

O2max, 

.

VTma

maximal workload, and HRmax following 0.75-p

exposure compared with FA.

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration.

AX6-83
AX6-84

test is preceded by an O3 exposure of sufficient total inhaled dose of O3 to result in significant

pulmonary function decrements and symptoms of breathing discomfort.

Using trained nonathletes, Foxcroft and Adams (1986) observed significant (p < 0.05)

reductions in rapidly incremented VO0 2max exercise performance time (!16.7%), VO0 2max (!6.0%),

maximal V0 E (!15.0%), and maximal heart rate (!5.6%) immediately following an initial 50-min

exposure to 0.35 ppm O3 during heavy CE (V0 E = 60 L/min). These decrements were

accompanied by a significant reduction in FEV1 (!23%) and the occurrence of marked

symptoms of breathing discomfort. Similarly, Gong et al. (1986) found significant reductions in

rapidly incremented VO0 2max exercise performance time (!29.7%), VO0 2max (!16.4%), maximal V0 E

(!18.5%), and maximal workload (!7.8%) in endurance cyclists immediately following a 1-h

exposure to 0.20 ppm O3 with very heavy exercise (V0 E 89 L/min), but not following exposure to

0.12 ppm. Gong et al. (1986) observed only a 5.6% FEV1 decrement and mild symptoms

following exposure to 0.12 ppm, but a large decrement in FEV1 (!21.6%) and substantial

symptoms of breathing discomfort following the 0.20 ppm exposure, which the authors

contended probably limited maximal performance and VO0 2max.

AX6.7.3 Effect on Endurance Exercise Performance

A number of studies of well trained endurance athletes exposed to O3 have consistently

observed an impairment of 1-h continuous heavy exercise performance of some individuals

(Adams and Schelegle, 1983; Avol et al., 1984; Folinsbee et al., 1984; Gong et al., 1986). The

performance impairment is indicated by an inability to complete the prescribed O3 exposures

(even at concentrations as low as 0.16 ppm) that subjects were able to complete in FA (Avol

et al., 1984). Other indications of impaired endurance exercise performance upon exposure to O3

include a !7.7% reduced endurance treadmill running time when exposed to 0.18 ppm O3

(Folinsbee et al., 1986), which was accompanied by significantly decreased FEV1 and

significantly elevated symptoms of breathing discomfort. Another study (Schelegle and Adams,

1986) observed the failure of some trained endurance athletes to complete a 1-h competitive

simulation protocol upon exposure to O3 (30 min warm-up, followed immediately by 30 min at

the maximal workload that each subject could just maintain in FA; mean V0 E = 120 L/min). 

In this study, all subjects (n = 10) completed the FA exposure, whereas one, five, and seven
AX6-85

subjects could not complete the 0.12, 0.18, and 0.24 ppm O3 exposures, respectively. Following

the 0.18 ppm and 0.24 ppm O3 exposures, but not the 0.12 ppm exposure, FEV1 was reduced

significantly and symptoms were significantly increased. Linder et al. (1988) also observed

small decrements in performance time (1 to 2 min) during a progressive maximal exercise test

(mean = 21.8 min) at O3 concentrations of 0.065 and 0.125 ppm. These small effects were

accompanied by a significant increase in subjective perception of overall effort at 0.125 ppm, but

with no significant reduction in FEV1 at either O3 concentration. Collectively, reduced

endurance exercise performance and associated pulmonary responses are clearly related to the

total inhaled dose of O3 (Adams and Schelegle, 1983; Avol et al., 1984; Schelegle and Adams,

1986).

Mechanisms limiting VO0 2max and maximal exercise performance upon O3 exposure have

not been precisely identified. Schelegle and Adams (1986) observed no significant effect of O3

on cardiorespiratory responses, and there was no indirect indication that arterial O2 saturation

was affected. The latter is consistent with the observation that measured arterial O2 saturation at

the end of a maximal endurance treadmill run was not affected by O3 (Folinsbee et al., 1986). 

In studies in which O3 inhalation resulted in a significant decrease in VO0 2max, and/or maximal

exercise performance, significantly decreased FEV1 and marked symptoms of breathing

discomfort were observed (Adams and Schelegle, 1983; Avol et al., 1984; Folinsbee et al., 1977,

1984, 1986; Foxcroft and Adams, 1986; Gong et al., 1986; Schelegle and Adams, 1986). 

However, Gong et al. (1986) observed rather weak correlations between FEV1 impairment and

physiological variable responses during maximal exercise (R = 0.26 to 0.44). Rather, these

authors concluded that substantial symptoms of breathing discomfort consequent to 1 h of

very heavy exercise while exposed to 0.20 ppm O3, probably limited maximal performance

and VO0 2max either voluntarily or involuntarily (Gong et al., 1986). Strong support for this

contention is provided by the observation of significant increases in VO0 2max (4.7%) and maximal

performance time (8.8%) following four consecutive days of 1 h exposure to 0.35 ppm O3 with

heavy exercise (V0 E = 60 L/min) compared to initial O3 exposure (Foxcroft and Adams, 1986). 

These improvements, which were not significantly different from those for FA, were

accompanied by a significant reduction in symptoms of breathing discomfort with no significant

attenuation of FEV1 and other pulmonary function responses. In this regard, Schelegle et al.

(1987) observed a disparate effect of indomethacin pretreatment (an inhibitor of the cyclo-
AX6-86

oxygenation of arachidonic acid to prostaglandins associated with inflammatory responses)

on O3-induced pulmonary function response (significant reduction) and an overall rating of

perceived exertion and symptoms of pain on deep inspiration and shortness of breath (no

significant effect). 

AX6.8 EFFECTS ON AIRWAY RESPONSIVENESS

Increased airway responsiveness, also called airway hyperresponsiveness or bronchial

hyperreactivity, indicates that the airways are more reactive to bronchoconstriction induced by a

variety of stimuli (e.g., specific allergens, exercise, SO2, cold air) than they would be when

normoreactive. In order to determine the level of airway responsiveness, airway function

(usually assessed by spirometry or plethysmography) is measured after the inhalation of small

amounts of an aerosolized specific (e.g., antigen, allergen) or nonspecific (e.g., methacholine,

histamine) bronchoconstrictor agent or measured stimulus (e.g., exercise, cold air). The dose or

concentration of the agent or stimulus is increased from a control, baseline level (placebo) until a

predetermined degree of airway response, such as a 20% drop in FEV1 or a 100% increase

in Raw, has occurred (Cropp et al., 1980; Sterk et al., 1993). The dose or concentration of the

bronchoconstrictor agent that produced the increased responsiveness often is referred to as the

“PD20FEV1” or “PC20FEV1” (i.e., the provocative dose or concentration that produced a 20%

drop in FEV1) or the “PD100SRaw” (i.e., the provocative dose that produced a 100% increase in

SRaw). A high level of bronchial responsiveness is a hallmark of asthma. The range of

nonspecific bronchial responsiveness, as expressed by the PD20 for example, is at least 1,000-

fold from the most sensitive asthmatics to the least sensitive healthy subjects. Unfortunately, it

is difficult to compare the PD20FEV1 or PD100SRaw across studies because of the many different

ways of presenting dose response to bronchoconstrictor drugs, for example, by mg/mL,

units/mL, and molar solution; or by cumulative dose (CIU or CBU) and doubling dose (DD). 

Further confounding comparisons by affecting the site of drug delivery, dose, and ultimately

bronchial responses, the size of aerosolized agents used in challenges can vary between

nebulizers and as a function of supply air pressure in otherwise identical systems. Other typical

bronchial challenge tests with nonspecific bronchoconstrictor stimuli are based on exercise

intensity or temperature of inhaled cold air. 
AX6-87

Increases in nonspecific airway responsiveness were previously reported as an important

consequence of exposure to O3 (e.g., Golden et al., 1978; Table AX6-11). König et al. (1980)

and Holtzman et al. (1979) found the increased airway responsiveness after O3 exposure in

healthy subjects appeared to be resolved after 24 h. Because atopic subjects had similar

increases in responsiveness to histamine after O3 exposure as nonatopic subjects, Holtzman et al.

(1979) concluded that the increased nonspecific bronchial responsiveness after O3 exposure was

not related to atopy. Folinsbee and Hazucha (1989) showed increased airway responsiveness in

18 female subjects 1 and 18 h after exposure to 0.35 ppm O3. Taken together, these studies

suggest that O3-induced increases in airway responsiveness usually resolve 18 to 24 h after

exposure, but may persist in some individuals for longer periods.

Gong et al. (1986) found increased nonspecific airway responsiveness in elite cyclists

exercising at competitive levels with O3 concentrations as low as 0.12 ppm. Folinsbee et al.

(1988) found an approximate doubling of the mean methacholine responsiveness in a group of

healthy volunteers exposed for 6.6 h to 0.12 ppm O3. Horstman et al. (1990) demonstrated

significant decreases in the PD100SRaw in 22 healthy subjects immediately after a 6.6-h exposure

to concentrations of O3 as low as 0.08 ppm. No relationship was found between O3-induced

changes in airway responsiveness and changes in FVC or FEV1 (Folinsbee et al., 1988; Aris

et al., 1995), suggesting that changes in airway responsiveness and spirometric volumes occur by

different mechanisms.

Dimeo et al. (1981) were the first to investigate attenuation of the O3-induced increases in

nonspecific airway responsiveness after repeated O3 exposure. Over 3 days of a 2 h/day

exposure to 0.40 ppm O3, they found progressive attenuation of the increases in airway

responsiveness such that, after the third day of O3 exposure, histamine airway responsiveness

was no longer different from the sham exposure levels. Kulle et al. (1982) found that there was

a significantly enhanced response to methacholine after the first 3 days of exposure, but this

response slowly normalized by the end of the fifth day. Folinsbee et al. (1994) found a more

persistent effect of O3 on airway responsiveness which was only partially attenuated after

5 consecutive days of O3 exposure.

The occurrence and duration of increased nonspecific airway responsiveness following O3

exposure could have important clinical implications for asthmatics. Kreit et al. (1989)

investigated changes in airway responsiveness to methacholine that occur after O3 exposure in 
TABLE AX6-11. Airway Responsiveness Following Ozone Exposuresa

OzoneConcentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of Subjects

Subject

ppm μg/m Characteristics Observed Effect(

3

0.1250.2500.125

245490245

3h IE(10 min rest, 15 minexercise on bicycle)V

.

E = 30 L/min

3h IE × 4 days

27 °C50 % RH

5 F, 6 M20-53 years old6 F, 16 M19-48 years old

Mild bronchialasthmaAllergic rhinitis

Mean early-phase FEV1 respon

of $20% reductions in FEV1 w

significantly greater after 0.25 

4 × 0.125 ppm O3. Most of the 

phase FEV1 responses occurred 

exposure to 4 × 0.125 ppm O3, 

significant inflammatory effectby increased sputum eosinophiallergic rhinitis) and increased lymphocytes, mast cell tryptaseand LDH (asthma only).

0.4 784 2 h IE .

VE = 20 L/min/m2

BSA

NA 6 F

1 M19-26 years old

Stable mild asthma;no meds 8 hpreexposure

Increased bronchial responsivemethacholine 16 h after exposuapocynin treatment significantl

induced airway responsiveness

0.12 235 45 min IE

exercise, rest, exercise .

VE = 3 × resting

60% RH 12 F

5 M19-38 years old

Physician diagnosedasthma; SO2-inducedairwayhyperreactivity

The authors concluded O3 expo

bronchial responsiveness to SO

and that antioxidant supplemenprotective effects against this respecially in the “more-severe” 

0.2 392 4 h IE .

VE = 25 L/min/m2

BSA

20 °C62% RH

4F8M23-47 years old

Healthy nonsmokers Increased sputum total cells, % 

IL-6, and IL-8 at 18 h after expincreased airway responsivenesmethacholine 2 h after postexpreturned to 5% of base-line; no inflammatory effect of azithrom

0.4 784 2 h IE

40 min/h @ 50 W

NA 15 healthy subjects ;

9 F, 6 M; 31.1 ± 2.1years old

Healthy; nonatopic Decreased FEV1 and FVC; incr

bronchial reactivity to methach4 h postexposure; no protection inhaled corticosteroid, budeson

0.16 314 7.6 h IE

50 min/h .

VE –25 l/min

22/C 40% RH

5 F4 M

Mild atopicasthma, HMDsensitive, 20-35 yearsold

Mean 9.1% FEV1 decrease 18 h 

exposure; provocative dose of allergen decreased from 10.3 to units.

AX6-88
TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone Exposuresa

OzoneConcentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of Subjects

Subject

ppm μg/m Characteristics Observed Effect(

3

0.2 392 4 h IE

40 min/h @ 50 W

NA 10 asthmatic

(6 F, 4 M), 26.6 ± 2.3 years old;10 healthy(4 F, 6 M), 27.3 ± 1.4 years old

Mild atopic asthma;nonatopic healthysubjects; no meds8 weeks pre-exposure

Decreased FEV1 in asthmatic (

and healthy (6.7%) subjects; insputum neutrophils in both grono change in methacholine airw24 h postexposure.

0.12Air-antigen

235 1 h rest NA 6 F

9 M

Mild allergic asthma;18 to 49 years if age

No effect of O3 on airway respor ragweed allergen.

0.4 784 2 h IE .

VE= 20 L/min/m2

BSA

NA 5F

1M18-27 years old

Stable mild asthma;no meds 8 hpreexposure

Increased airway responsivenemethacholine 16 h postexposurno effect of proteinase inhibito

0.2 392 4 h IE

50 min/h .

VE = 25 L/min/m2

BSA

20 °C50% RH

6 F12 M18-36 years old

Physician-diagnosedmild asthma; no medsprior to exposure

Decreased FEV1 and FVC, incr

lower respiratory Sx; increased% neutrophils, total protein, LDfibronectin, IL-8, GM-CSF, anin BAL. Correlation between pmethacholine challenge and O3SRaw increase.

0.4 784 3 h/d for 5 days;

alternating 15 min of restand exercise at .

VE = 32 L/min

31 °C35% RH

2 F8 M19-48 years old

Mild asthmarequiring onlyoccasionalbronchodilatortherapy

Significant FEV1 and Sx respon

2nd O3 exposure days, then dim

continued exposure; tolerance p4 and 7 days postexposure; broreactivity to methacholine peak

exposure day, but remained elecontinued exposure.

0.12 236 Rest 22 °C

40% RH

5 F10 M

atopicasthma

No effect of O3 on airway respo

allergen.

0.25 490 3 h IE .

VE = 30 L/min

15 min ex/10 min rest/5 min no O3; every

30 min.

27 °C54% RHmouthpieceexposure

24 mild asthmatics11 F / 13 M12 allergic rhinitics6 M / 6 F10 healthy 5 M/5 F

atopic mild asthmaticNS

Increased allergen responsiven

exposure in subjects with allergdisease, with or without asthma

AX6-89
TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone Exposuresa

OzoneConcentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of Subjects

Subject

ppm μg/m Characteristics Observed Effect(

3

0.2 392 4h IE

50 min/10 minexercise/rest each hour

22 °C50% RH

42 M/24 F 18-50 years

NS healthy

FEV1(!18.6%), FVC (!14.6%)after O3. Baseline PC100 for mewas not related to changes in F

a weak association was seen fo

increased SRaw.

0.12 235 1 h R Ambient T

& RH forexposure;23 °C &50% RH forexercisechallenge

8 F7 M19-45 years old

Mild stable asthma No significant difference in % 

V40p; no increase in bronchial r

to exercise challenge.

0.12 235 6.6 h, IE x 5 days

50 min exercise/10 minrest, 30 min lunch .

VE = 38.8 L/min

18 °C40% RH

17 M25 ± 4 years old 

Healthy nonsmokers FEV1 responses were maximal 

exposure (!13%), less on seconabsent thereafter. Sx responses 2 days. Methacholine airway rwas at least doubled on all expbut was highest on the second d

0.100.250.40

196490785

1 h light IE2 × 15 min on treadmill .

VE = 27 L/min

21 °C40% RH

9 F12 M 19-40 years old

Stable mildasthmatics with FEV1>70% andmethacholineresponsiveness

No significant differences in FE

were observed for 0.10 and 0.2

exposures or postexposure exer12 subjects exposed to 0.40 ppm 

significant reduction in FEV1.

Air-antigen0.12 ppmO3-antigen

1 h at rest NA 4 M, 3 F Asthmatic,

21 to 64 years old

Increased bronchoconstrictor reinhaled ragweed or grass after compared to air.

0.080.100.12

157196235

6.6 hIE at .39 L/min

18 °C40% RH

22 M Healthy NS,

18 to 32 years old

33, 47, and 55% decreases in cof methacholine required to proincrease in SRaw after exposur

0.10, and 0.12 ppm, respective

AX6-90
TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone Exposuresa

OzoneConcentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of Subjects

Subject

ppm μg/m Characteristics Observed Effect(

3

0.12 ppm O3-100 ppb SO20.12 ppmO3-0.12 ppm O3Air-100 ppb SO2

45 min in first atmosphereand 15 min in second IE 

22 °C75% RH

8 M, 5 F Asthmatic, 

12 to 18 years old

Greater declines in FEV1 and 

V

greater increase in respiratory rO3-SO2 than after O3-O3 or air-

0.35 686 70 min with IE at

40 L/min

NA 18 F Healthy NS, 

19 to 28 years old

PD100 decreased from 59 CIU a

exposure to 41 CIU and 45 CIU18 h after O3 exposure, respect

0.40 784 2 h with IE at .

VE = 53 to 55 L/min

22 °C50% RH

8 M, 10 F 9 asthmatics (5 F,

4 M), 9 healthy (5 F, 4 M), 18 to 34 years old

Decreased PC100SRaw from 33 

8.5 mg/mL in healthy subjects PC100SRaw fell from 0.52 mg/m

0.19 mg/mL in asthmatic subjeexposure to O3 and from 0.48 mto 0.27 mg/mL after exposure t

0.12 235 6.6 h with IE at

.25 L/min/m2 BSA

NA 10 M Healthy NS, 

18 to 33 years old

Approximate doubling of meanmethacholine responsiveness aOn an individual basis, no relatbetween O3-induced changes in 

responsiveness and FEV1 or FV

0.120.20

235392

1 h at .

VE = 89 L/min

followed by 3 to 4 minat .150 L/min

31 °C35% RH

15 M, 2 F Elite cyclists, 

19 to 30 years old

Greater than 20% increase in hresponsiveness in one subject aO3 and in nine subjects at 0.20 

0.40 784 3 h/day for 5 days in a

row

13 M, 11 F Healthy NS, 

19 to 46 years old

Enhanced response to methachfirst 3 days, but this response nDay 5.

0.200.400.40

392784784

2 h with IE at 2 × resting2 h with IE at 2 × resting2 h/day for 3 days

22 °C55% RH

12 M, 7 F Healthy NS,

21 to 32 years old

110% increase in 

)SRaw to a 1

histamine (1.6%) aerosol challeexposure to O3 at 0.40 ppm, bu

at 0.20 ppm. Progressive adapeffect over 3-day exposure.

AX6-91
TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone Exposuresa

OzoneConcentrationb

Exposure Duration

and Activity

Exposure

Conditions

Number and

Gender of Subjects

Subject

ppm μg/m Characteristics Observed Effect(

3

0.100.321.00

1966271,960

2 h NA 14 Health NS, 

24 ± 2 years old

Increased airway responsiveneto methacholine immediately aat the two highest concentration

0.60 1,176 2 h with IE at 2 × resting 22 °C

55% RH

11 M, 5 F 9 atopic, 

7 nonatopic, NS, 21 to 35 yearsold

Ten-breath methacholine or hischallenge increased SRaw $15

16 nonasthmatics after O3. On 

atopic subjects had greater respthe nonatopic subjects. The incresponsiveness resolved after 2premedication blocked the O3-i

increase in airway responsiven

0.6 1,176 2 h at rest NA 5 M, 3 F Healthy NS,

22 to 30 years old

300% increase in histamine-ind

5 min after O3 exposure; 84 and 

increases 24 h and 1 week after (p > 0.05), respectively. Two san increased response to histamafter exposure.

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration.

AX6-92
AX6-93

mild asthmatics. They found that the baseline PC100SRaw declined from 0.52 to 0.19 mg/mL

after a 2-h exposure to 0.40 ppm O3, as compared to a decline from 0.48 to 0.27 mg/mL after air

exposure; however, because of the large variability in responses of the asthmatics, the percent

decrease from baseline in mean PC100SRaw was not statistically different between healthy and

asthmatic subjects (74.2 and 63.5%, respectively). 

Two studies examined the effects of preexposure to O3 on exacerbation of exercise-induced

bronchoconstriction (Fernandes et al., 1994; Weymer et al., 1994). Fernandes et al. (1994)

preexposed subjects with stable mild asthma and a history of >15% decline in FEV1 after

exercise to 0.12 ppm O3 for 1 h at rest followed by a 6-min exercise challenge test and found no

significant effect on either the magnitude or time course of exercise-induced

bronchoconstriction. Similarly, Weymer et al. (1994) observed that preexposure to either 0.10 or

0.25 ppm O3 for 60 min while performing light IE did not enhance or produce exercise-induced

bronchoconstriction in otherwise healthy adult subjects with stable mild asthma. Although the

results suggested that preexposure to O3 neither enhances nor produces exercise-induced asthma

in asthmatic subjects, the relatively low total inhaled doses of O3 used in these studies limit the

ability to draw any definitive conclusions.

Gong et al. (1997b) found that subjects with asthma developed tolerance to repeated

O3 exposures in a manner similar to normal subjects; however, there were more persistent effects

of O3 on airway responsiveness, which only partially attenuated when compared to filtered air

controls. Volunteer subjects with mild asthma requiring no more than bronchodilator therapy

were exposed to filtered air or 0.4 ppm O3, 3 h/d for 5 consecutive days, and follow-up

exposures 4 and 7 days later. Symptom and FEV1 responses were large on the 1st and 2nd

exposure days, and diminished progressively toward filtered air responses by the 5th exposure

day. A methacholine challenge was performed when postexposure FEV1 returned to within 10%

of preexposure baseline levels. The first O3 exposure significantly decreased PD20FEV1 by an

order of magnitude and subsequent exposures resulted in smaller decreases, but they were still

significantly different from air control levels. Thus, the effects of consecutive O3 exposures on

bronchial reactivity differ somewhat from the effects on lung function. The same conclusion

was drawn by Folinsbee et al. (1994) after consecutive 5-day O3 exposures in healthy subjects,

despite a much lower bronchial reactivity both before and after O3 exposure.
AX6-94

A larger number of studies examined the effects of O3 on exacerbation of antigen-induced

asthma. Molfino et al. (1991) were the first to report the effects of a 1-h resting exposure to

0.12 ppm O3 on the response of subjects with mild, stable atopic asthma to a ragweed or grass

allergen inhalation challenge. Allergen challenges were performed 24 h after air and

O3 exposure. Their findings suggested that allergen-specific airway responsiveness of mild

asthmatics is increased after O3 exposure. However, Ball et al. (1996) and Hanania et al. (1998)

were unable to confirm the findings of Molfino et al. (1991) in a group of grass-sensitive mild

allergic asthmatics exposed to 0.12 ppm O3 for 1 h. The differences between Hanania et al.

(1998) and Molfino et al. (1991), both conducted in the same laboratory, were due to better, less

variable control of the 1 h 0.12 ppm O3 exposure and better study design by Hanania and

colleagues. In the original, Molfino et al. (1991) study, the control (air) and experimental (O3)

exposures were not randomized after the second subject because of long-lasting (3 months),

O3-induced potentiation of airway reactivity in that subject. For safety reasons, therefore, the air

exposures were performed prior to the O3 exposures for the remaining 5 of 7 subjects being

evaluated. It is possible that the first antigen challenge caused the significant increase in the

second (post-O3) antigen challenge. 

Jörres et al. (1996) later confirmed that higher O3 concentrations cause increased airway

reactivity to specific antigens in subjects with mild allergic asthma, and to a lesser extent in

subjects with allergic rhinitis, after exposure to 0.25 ppm O3 for 3 h. The same laboratory

repeated this study in separate groups of subjects with asthma and rhinitis and found similar

enhancement of allergen responsiveness after O3 exposure (Holz et al., 2002); however, the

effects of a 3-h exposure to 0.25 ppm O3 were more variable, most likely due to performing the

allergen challenges 20 h after exposure, rather than the 3 h used in the first study. 

The timing of allergen challenges in O3-exposed subjects with allergic asthma is important. 

Bronchial provocation with allergen, and subsequent binding with IgE antibodies on mast cells

in the lungs, triggers the release of histamine and leukotrienes and a prompt early-phase

contraction of the smooth muscle cells of the bronchi, causing a narrowing of the lumen of the

bronchi and a decrease in bronchial airflow (i.e., decreased FEV1). In many asthma patients,

however, the release of histamine and leukotrienes from the mast cells also attracts an

accumulation of inflammatory cells, especially eosinophils, followed by the production of mucus

and a late-phase decrease in bronchial airflow for 4 to 8 h. 
AX6-95

A significant finding from the study by Holz et al. (2002) was that clinically relevant

decreases in FEV1 ($20%) occurred during the early-phase allergen response in subjects with

rhinitis after a consecutive 4-day exposure to 0.125 ppm O3. Kehrl et al. (1999) previously

found an increased reactivity to house dust mite antigen in asthmatics 16 to 18 h after exposure

to 0.16 ppm O3 for 7.6 hours. These important observations indicate that O3 not only causes

immediate increases in airway-antigen reactivity, but that this effect may persist for at least 18 to

20 h. Ozone exposure, therefore, may be a clinically important co-factor in the response to

airborne bronchoconstrictor substances in individuals with pre-existing allergic asthma. It is

plausible that this phenomenon could contribute to increased symptom exacerbations and, even,

consequent increased physician or ER visits, and possible hospital admissions (see Chapter 7).

A number of human studies, especially more recent ones, have been undertaken to

determine various aspects of O3-induced increases in nonspecific airway responsiveness, but

most studies have been conducted in laboratory animals (See the toxicology chapter, Section

5.3.4.4.). In humans, increased airway permeability (Kehrl et al., 1987; Molfino et al., 1992)

could play a role in increased airway responsiveness. Inflammatory cells and mediators also

could affect changes in airway responsiveness. The results of a multiphase study (Scannell

et al., 1996; Balmes et al., 1997) showed a correlation between preexposure methacholine

responsiveness in healthy subjects and increased SRaw caused by a 4 h exposure to 0.2 ppm O3,

but not with O3-induced decreases in FEV1 and FVC. The O3-induced increase in SRaw, in turn,

was correlated with O3-induced increases in neutrophils and total protein concentration in BAL

fluid. Subjects with asthma had a significantly greater inflammatory response to the same O3

exposures, but it was not correlated with increased SRaw, and nonspecific airway provocation

was not measured. Therefore, it is difficult to determine from this series of studies if underlying

airway inflammation plays a role in increased airway responsiveness to nonspecific

bronchoconstrictors. The study, however, confirmed an earlier observation (e.g., Balmes et al.,

1996) that O3-induced changes in airway inflammation and lung volume measurements are not

correlated. 

Hiltermann et al. (1998) reported that neutrophil-derived serine proteinases associated

with O3-induced inflammation are not important mediators for O3-induced nonspecific airway

hyperresponsiveness. Subjects with mild asthma, prescreened for O3-induced airway

 responsiveness to methacholine, were administered an aerosol of recombinant antileukoprotease
AX6-96

(rALP) or placebo at hourly intervals two times before and six times after exposure to filtered air

or 0.4 ppm O3 for 2 h. Methacholine challenges were performed 16 h after exposure. Treatment

with rALP had no effect on the O3-induced decrease in FEV1 or PC20FEV1 in response to

methacholine challenge. The authors speculated that proteinase-mediated tissue injury caused

by O3 may not be important in the development of airway hyperresponsiveness of asthmatics

to O3. In a subsequent study using a similar protocol (Peters et al., 2001), subjects with mild

asthma were administered an aerosol of apocynin, an inhibitor of NADPH oxidase present in

inflammatory cells such as eosinophils and neutrophils, or a placebo. In this study, methacholine

challenge performed 16 h after O3 exposure showed treatment-related effects on PC20FEV1,

without an effect on FEV1. The authors concluded that apocynin could prevent O3-induced

bronchial hyperresponsiveness in subjects with asthma, possibly by preventing superoxide

formation by eosinophils and neutrophils in the larger airways.

Nightingale et al. (1999) reported that exposures of healthy subjects and subjects with mild

atopic asthma to a lower O3 concentration (0.2 ppm) for 4 h caused a similar neutrophilic lung

inflammation in both groups but no changes in airway responsiveness to methacholine measured

24 h after O3 exposure in either group. There were, however, significant decreases in FEV1 of

6.7 and 9.3% immediately after O3 exposure in both healthy and asthmatic subjects, respectively. 

In a subsequent study, a significant increase in bronchoresponsiveness to methacholine was

reported 4 h after healthy subjects were exposed to 0.4 ppm O3 for 2 h (Nightingale et al., 2000). 

In the latter study, preexposure treatment with inhaled budesonide (a corticosteroid) did not

protect against O3-induced effects on spirometry, methacholine challenge, or sputum neutrophils. 

These studies also confirm the earlier reported findings that O3-induced increases in airway

responsiveness usually resolve by 24 h after exposure. 

Ozone-induced airway inflammation and hyperresponsiveness were used by Criqui et al.

(2000) to evaluate anti-inflammatory properties of the macrolide antibiotic, azithromycin. In a

double-blind, cross-over study, healthy volunteers were exposed to 0.2 ppm O3 for 4 h after

pretreatment with azithromycin or a placebo. Sputum induction 18 h postexposure resulted in

significantly increased total cells, percent neutrophils, IL-6, and IL-8 in both azithromycin- and

placebo-treated subjects. Significant pre- to postexposure decreases in FEV1 and FVC also were

found in both subject groups. Airway responsiveness to methacholine was not significantly

different between azithromycin-treated and placebo-treated subjects when they were challenged
AX6-97

2 h after postexposure FEV1 decrements returned to within 5 % of baseline. Thus, azithromycin

did not have anti-inflammatory effects in this study.

The effects of dietary antioxidants on O3-induced bronchial responsiveness to SO2

provocation were evaluated in adult asthmatic subjects by Trenga et al. (2001). This study and

potential interpretative problems are discussed in detail in Section AX6.5.6. Briefly, 17 adult

asthmatic subjects sensitive to SO2 provocation took vitamin supplements (400 IU vitamin E and

500 mg vitamin C) or placebo once a day for 5 weeks. After the fourth and fifth weeks of

vitamin or placebo, subjects were randomly exposed to FA and 0.12 ppm O3 for 45 min during

IE (V0 E . 3× resting rate) followed by two sequential 10 min exposures to 0.1 and 0.25 ppm SO2. 

Vitamin treatment was not associated with decreased bronchial responsiveness following the

0.1 ppm SO2 challenge. However, the change in spirometric responses (FEV1, FVC, FEF25-75,

and PEF) between the 0.1 and 0.25 ppm SO2 challenges were more severe for the placebo than

the vitamin treatment regimen (p = 0.009). The authors concluded O3 exposure increases

bronchial responsiveness to SO2 in asthmatics and that antioxidant supplementation has a

protective effect against this responsiveness. 

AX6.9 EFFECTS ON INFLAMMATION AND HOST DEFENSE

AX6.9.1 Introduction

In general, inflammation can be considered as the host response to injury, and the

induction of inflammation can be accepted as evidence that injury has occurred. Several

outcomes are possible: (1) inflammation can resolve entirely; (2) continued acute inflammation

can evolve into a chronic inflammatory state; (3) continued inflammation can alter the structure

or function of other pulmonary tissue, leading to diseases such as fibrosis or emphysema;

(4) inflammation can alter the body’s host defense response to inhaled microorganisms; and

(5) inflammation can alter the lung’s response to other agents such as allergens or toxins. 

At present, it is known that short-term exposure of humans to O3 can cause acute inflammation

and that long-term exposure of laboratory animals results in a chronic inflammatory state (see

Chapter 5). However, the relationship between repetitive bouts of acute inflammation in humans

caused by O3 and the development of chronic respiratory disease is unknown.
AX6-98

Bronchoalveolar lavage (BAL) using fiberoptic bronchoscopy has been utilized to sample

cells and fluids lining the respiratory tract primarily from the alveolar region, although the use of

small volume lavages or balloon catheters permits sampling of the airways. Cells and fluid can

be retrieved from the nasal passages using nasal lavage (NL) and brush or scrape biopsy.

Several studies have analyzed BAL and NL fluid and cells from O3-exposed humans for

markers of inflammation and lung damage (see Tables AX6-12 and AX6-13). The presence of

neutrophils (PMNs) in the lung has long been accepted as a hallmark of inflammation and is an

important indicator that O3 causes inflammation in the lungs. It is apparent, however, that

inflammation within airway tissues may persist beyond the point that inflammatory cells are

found in BAL fluid. Soluble mediators of inflammation such as the cytokines (IL-6, IL-8) and

arachidonic acid metabolites (e.g., PGE2, PGF2", thromboxane, and leukotrienes [LTs] such as

LTB4) have been measured in the BAL fluid of humans exposed to O3. In addition to their role

in inflammation, many of these compounds have bronchoconstrictive properties and may be

involved in increased airway responsiveness following O3 exposure. 

Some recent evidence suggests that changes in small airways function may provide a

sensitive indicator of O3 exposure and effect (see Section AX6.2.5), despite the fact that inherent

variability in their measurement by standard spirometric approaches make their assessment

difficult. Observations of increased functional responsiveness of these areas relative to the more

central airways, and of persistent effects following repeated exposure, may indicate that further

investigation of inflammatory processes in these regions is warranted.

Under normal circumstances, the epithelia lining the large and small airways develop tight

junctions and restrict the penetration of exogenous particles and macromolecules from the

airway lumen into the interstitium and blood, as well as restrict the flow of plasma components

into the airway lumen. O3 disrupts the integrity of the epithelial cell barrier in human airways, as

measured by markers of plasma influx such as albumin, immunoglobulin, and other proteins into

the airways. Markers of epithelial cell damage such as lactate dehydrogenase (LDH) also have

been measured in the BAL fluid of humans exposed to O3. Other soluble factors that have been

studied include those involved with fibrin deposition and degradation (Tissue Factor, Factor VII,

and plasminogen activator), potential markers of fibrogenesis (fibronectin, platelet derived

growth factor), and components of the complement cascade (C3a).
Table AX6-12. Studies of Respiratory Tract Inflammatory Effects from Controlled Human Expo

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Upper Airway Studies

0.4 784 2 h At rest 12 mild,

asymptomatic dustmite-sensitiveasthmatics; 18-35 years of age

Release of early-onset mast cell-derived mediators response to allergen not enhanced following O3 exp

Neutrophil and eosinophil inflammatory mediators increased after O3 exposure or enhanced after allerg

challenge. O3 increased eosinophil influx followin

exposure. 

0.2 392 2 h IE 

(15 min/30 min);(

.

VE) . 20

L/min/m2 BSA

8 M, 5 F healthy NS20-31 years of age

No neutrophilia in NL samples by 1.5 h postexposuDepletion of uric acid in NL fluid by 30% during h exposure with increase in plasma uric acid levels. No depletion of ascorbic acid, reduced glutathione,extracellular superoxide dismutase.

0.4 980 2 h At rest 10 mild NS

asthmatics18-35 years old

Response to allergen increased (NS). PMN andeosinophils increased after O3 plus allergen challen

Ozone alone increased inflammation in the nose.

0.120.24

235470

1.5 h IE 

(20 L/min) at15-min intervals

5 M, 5 F, asthmatic; 4 M, 4 F,nonasthmatic;18 to 41 years old

NL done immediately and 24 h after exposure. Increased number of PMNs at both times in asthmaexposed to 0.24 ppm O3; no change in nonasthmati

No change in lung or nasal function.

0.5 980 4 h Resting 6 M, 6 F,

allergic rhinitics, 31.4 ± 2.0 (SD)years old

NL done immediately after exposure. Increased upand lower respiratory symptoms and increased leveeosinophils, and albumin in NL fluid.

0.4 784 2 h IE 

(70 L/min) at15-min intervals

11 M,18 to 35 years old

NL done immediately before, immediately after, anexposure. Increased numbers of PMNs at both timexposure; increased levels of tryptase, a marker of degranulation, immediately after exposure; increasof albumin 22 h after exposure.

0.5 980 4 h on

2 consecutive days

Resting 41 M

(21 O3-exposed,

20 air-exposed), 18 to 35 years old

NL done immediately before and after each exposuand 22 h after the second exposure. Increased leveat all times after the first exposure, with peak valueimmediately prior to the second exposure.

AX6-99
Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human E

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Lower Airway Studies

0.2 392 2 h IE 

(15 min/30 min);(

.

VE) . 20

L/min/m2 BSA

6M, 6F healthy,nonatopic and 9 M, 6F mildasthmatic subjects,19-48 years of age

Significantly higher baseline expression of IL-4 anbronchial mucosal biopsies from asthmatic vs. heal6 h postexposure. Following O3 exposure, epitheli

expression of IL-5, GM-CSF, ENA-78, and IL-8 insignificantly in asthmatics, as compared to healthy 

0.1 196 2 h mild IE 12 M, 10 F 

healthy subjectsmean age ~30years

Markers of exposure in exhaled breath condensate, increased 8-isoprostane, TBARS and LTB-4, and a ROS-DNA interaction in peripheral blood leukocyt(8-OHdG), were increased in a sub-set of subjects bwild genotype for NAD(P)H:quinone oxidoreductanull genotype for glutathione-S-transferase M1.

0.2 392 2 h IE 

(15 min/30 min);(

.

VE) . 20

L/min/m2 body

surface area

6M, 9F healthysubjects and 9 M, 6F mildasthmatics

No evidence seen for increased responsiveness to tinflammatory effects of O3 in mild asthmatics versu

subjects at 6 h following exposure. Used neutrophrecruitment and exacerbation of pre-existing inflam

0.27 529 2 h IE 

(20 min/ 60 min);(

.

VE) . 25

L/min/m2 BSA 

12 subjects withintermittent-mildasthma exhibiting adual response; 18-37years of age

Exposure to O3 24 h following allergen challenge r

significant decrease in FEV1, FVC and VC and incsymptom scores compared to air exposure. The peeosinophils, but not neutrophils, in induced sputum 6 h after O3 than after air.

0.22 431 4 h IE 

(15 min/30 min);(

.

VE) = 25

L/min/m2 BSA

12 nonsmoker,nonresponders;13 nonsmoker,responders;13 smokers; 18-40 years of age

Recovery of AM was approximately 3-fold higher from smokers versus nonsmokers. Unstimulated Asmokers released ~2-fold greater amounts of superthan from nonsmokers at 30 min and 18 h postexporelease was not further enhanced by stimulation of ROS generation by AM from nonsmokers decreaseexposure at 18 h; markers of epithelial permeability No relationship was found between measures of ROproduction and lung function responsiveness to O3. 

AX6-100
Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human E

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Lower Airway Studies (cont’d)

0.2 392 2 h IE 

(15 min/30 min);(

.

VE) . 20

L/min/m2 BSA

8M, 5F healthynonsmokers;20-31 years of age

Early (1.5 h postexposure) increase in adhesion moexpression, submucosal mast cell numbers and altelining fluid redox status. No clear relationship betwmarkers of response and lung function deficits. 2.5increase in % human leukocyte antigen (HLA)-DRmacrophages in BAL. 

0.4 784 2 h IE

(15 min/30 min);(

.

VE) . 20

L/min/m2 BSA

10M, 6F subjectswith intermittentasthma; 19-35 years of age

In a cross-over study, levels of eosinophil cationic and percentage eosinophils were found to be highly in induced sputum and BAL 16 h following O3 exp

0.4 784 2 h At rest 12 mild,

asymptomatic dustmite-sensitiveasthmatics;18-35 years of age

Release of early-onset mast cell-derived mediators response to allergen not enhanced following O3 exp

Neutrophil and eosinophil inflammatory mediators increased after O3 exposure or enhanced after allerg

challenge. O3 increased eosinophil influx followin

exposure. 

0.4 784 1 h Continuous

exercise; (

.

VE) . 30

L/min/m2 BSA

4 healthy subjects Apoptosis was observed in cells obtained by airway 

6 h following exposure. AM obtained by BAL shopresence of a 4-hydroxynonenal (HNE) protein addstress proteins, 72-kD heat shock protein and ferriteffects were replicated by in vitro exposure of AM 

0.2 392 2 h 15 healthy

nonsmokers 

Increased numbers of CD3+, CD4+, and CD8+ T lsubsets, in addition to neutrophils, in BAL 6 h post

0.4 784 2 h/day for 5 days,

2 h either 10 or20 days later

IE (40 L/min) at15-min intervals

16 M; 18 to 35 yearsof age

BAL done immediately after fifth day of exposure after exposure 10 or 20 days later. Most markers oinflammation (PMNs, IL-6, PGE2, fibronectin) sho

to complete attenuation; markers of damage (LDH, protein, "1-antitrypsin, elastase,) did not. Reversa

attenuation was not complete for some markers, ev20 days. 

AX6-101
Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human E

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Lower Airway Studies (cont’d)

0.22 431 4 h IE 

20 min ex/19 minrest(

.

VE) . 39-45 l/min

31M, 7Fsmokers andnonsmokers

Post-O3 exposure FEV1 in 3 groups: Smokers (!13

nonresponders (!1.4%) and responders (!28.5%). increased immediately and at 18 h in all groups. Eand lymphocytes increased after O3. IL-6 increase

nonsmokers. No relationship of symptoms with inlung function changes not related to inflammation. lavage indicators did not predict bronchial or alveoinflammation.

0.12 235 2 h IE 

(15 min/30 min); (

.

VE) . 20

L/min/m2 BSA

9M, 3F healthynonsmokers; meanage ~28 years

Increase in the percentage of vessels expressing P-bronchial biopsies at 1.5 h postexposure. No chang

FVC, inflammatory cells or markers in BAL, or veexpressing VCAM-1, E-selectin or ICAM-1 in biop

0.16 314 7.6 h IE 

50 min/hr(

.

VE) = 25 L/min

8 asthmatics sensitiveto dust mites

Increased numbers of eosinophils in BAL after O3 

0.2 392 4 h 

T = 20 °CRH = 50%

IE (50 min/60 min);(

.

VE) . 44 L/min

14 M, 6 Fhealthy NS

Ozone increased PMN, protein, IL-8, for all subjecNo relationship of inflammation with spirometric r

0.4 784 2 h

T = 22 °CRH = 50%

15 min rest15 min exercisecycle ergometer(

.

VE) . 55 l/min

11 healthynonsmokers; 18-35 years

Mean FEV1, change = !10%. BAL occurred at 0, 

postexposure. Small n limits statistical inference. PMN’s to be highest at 4 h. LTC4 increased at all t

No change in PGE2 or thromboxane.

0.4 784 2 h

15 min, ex/15 min, rest

(

.

VE) = 66 l/min 8 M

healthy nonsmokers

Comparison of BAL at 1 h postexposure vs. 18 h pAt 1 h, PMN’s, total protein, LDH, "1-antitrypsin, 

PGE2, thromboxane B2, C3a, tissue factor, and clott

VII were increased. IL-6 and PGE2 were higher af

18 h. Fibronectin and tissue plasminogen activator 18 h. No time differences for PMN and protein.

0.2 392 4 h 

T = 20 °CRH = 50%

IE (50 min/60 min);(

.

VE) . 44 L/min

17 M, 6Fmild asthmatics

Increased PMN, protein, IL-8, LDH, in BAL. Inflaresponses were greater than a group of nonasthmat(Balmes et al., 1996)

AX6-102
Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human E

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Lower Airway Studies (cont’d)

0.4 784 2 h mouthpiece

exposure20 °C42% RH

15 min exercise 15 min rest(

.

VE) . 40 l/min

5M, 5F healthy; age . 30

Sputum induction 4 h after O3 exposure 3-fold incrneutrophils and a decrease in macrophages after O3 

IL-6, IL-8, and myeleperoxidase increased after O3

relationship of IL-8 and PMN levels.

0.2 392 4 h IE 

(50 min/60 min); (

.

VE) = 40 L/min

15 M, 13 F, 21 to 39 years old

Bronchial lavage, bronchial biopsies, and BAL donafter exposure. BAL shows changes similar to othAirway lavage shows increased cells, LDH, IL-8. show increased number of PMNs.

0.080.10

157196

6.6 h IE 

(50 min/60 min) +35 min lunch; (

.

VE) = 40 L/min 

18 M, 18 to 35 years of age

BAL fluid 18 h after exposure to 0.1 ppm O3 had si

increases in PMNs, protein, PGE2, fibronectin, IL-6

dehydrogenase, and "-1 antitrypsin compared with 

subjects exposed to FA. Similar but smaller increamediators after exposure to 0.08 ppm O3 except for 

fibronectin. Decreased phagocytosis of yeast by almacrophages was noted at both concentrations.

0.4 784 2 h IE 

(15 min/30 min);(

.

VE) = 70 L/min 

10 M, 18 to 35 years old

BAL fluid 1 h after exposure to 0.4 ppm O3 had sig

increases in PMNs, protein, PGE2, TXB2, IL-6, LD

antitrypsin, and tissue factor compared with the samexposed to FA. Decreased phagocytosis of yeast bmacrophages.

0.3 588 1 h 

(mouth-piece)

CE (60 L/min) 5 M Significantly elevated PMNs in the BAL fluid 1, 6

after exposure, with peak increases at 6 h.

0.40 784 2 h IE 

(15 min/30 min);(

.

VE) = 70 L/min 

11 M, 18 to 35 years old

Macrophages removed 18 h after exposure had charate of synthesis of 123 different proteins as assayecomputerized densitometry of two-dimensional gel profiles.

0.40 784 2 h IE 

(15 min/30 min);(

.

VE) = 70 L/min 

11 M, 18 to 35 years old

BAL fluid 18 h after exposure contained increased coagulation factors, tissue factor, and factor VII. Min the BAL fluid had elevated tissue factor mRNA.

0.4 784 2 h IE 

(15 min/30 min);(

.

VE) = 70 L/min 

11 M, 18 to 35 years old

BAL fluid 18 h after exposure had significant increPMNs, protein, albumin, IgG, PGE2, plasminogen 

elastase, complement C3a, and fibronectin.

AX6-103
Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human E

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Repeated Exposure Studies

0.125

0.25

245490

3 h exposures toboth O3 concs. and

to FA;3 h on fourconsecutive days to0.125; study armsseparated by>4 wks

IE(15 min/30 min)

5M, 6F allergicasthmatic and 16M, 6F allergicrhinitic subjects;19-53 years of age

All subjects underwent 4 exposure arms and were cwith allergen 20 h following the last exposure in eawas induced 6-7 h later. In rhinitics, but not asthmincidence and magnitude of early phase FEV1 decr

Ag were greater after 0.25 and 4x 0.125 ppm O3. Rexposure caused increases in neutrophil and eosinonumbers in both subject groups, as well as increasepercentage and number of lymphocytes in the asthm

0.25 490 2 h on four

consecutive days;O3 and FA exposurestudy armsseparated by$3 wks

IE (30 min/60 min);(

.

VE) . 8 times the

FVC/min

5M, 3F healthysubjects; 25-31 years of age

Maximal mean reductions in FEV1 and FVC were o

day 2, and became negligible by day 4. FEF25-75, VVmax75 were combined into a single value represeairway function (SAWgrp). This variable was the show persistent depression of the 24 h postexposurfrom day 2 to day 5 measurements. Numbers of PMfluid on day 5 were significantly higher in subjects O3, compared to air, exposures.

0.2 392 single, 

4 h exposures to O3

and to FA;4 h on fourconsecutive days toO3; study armsseparated by>4 wks

IE (15 min/30 min); (Mean .

VE) =

14.8 L/min/m2

BSA

15M, 8F healthysubjects;21-35 years of age

All subjects underwent 3 exposure arms with BAL bronchial mucosal biopsies performed 20 h followiexposure in each. After repeated exposure, functioBAL cellular responses were not different from thowhereas total protein, IL-6, IL-8, reduced glutathioortho-tyrosine remained elevated. Also at this timemacroscopic scores of inflammation and tissue neuwere increased in mucosal biopsies. IL-10 was detin BAL fluid following repeated O3 exposure.

0.2 392 single, 4 h

exposure; 4 h exposures onfour consecutivedays; study armsseparated by>4 wks 

IE (30 min/60 min);(Mean .

VE) = 25

L/min/m2 BSA

9M, 6F healthy NS23-37 years of age

Subjects were randomly assigned to each of the expregimens in a crossover design. Compared to singlrepeated exposure resulted in an initial progression an attenuation of decrements in FEV1, FVC and sp

airways resistance by day 4. Bronchial and BAL wshowed decreases in the numbers of PMNs and fibrlevels and IL-6 was decreased in BAL fluid on day 

AX6-104
Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human E

Ozone Concentrationb

ExposureDuration

Activity Level

(

.

VE)

Number and Gender

ppm μg/m of Subjects Observed Effect(s) 

3

Repeated Exposure Studies (cont’d)

0.4 784 2 h/day for 5 days,

2 h either 10 or20 days later

IE (60 L/min) at15-min intervals

16 M; 18 to 35 years of age

BAL done immediately after fifth day of exposure after exposure 10 or 20 days later. Most markers oinflammation (PMNs, IL-6, PGE2, fibronectin) sho

complete attenuation; markers of damage (LDH, IL

"1-antitrypsin, elastase) did not. Reversal of attenu

not complete for some markers, even after 20 days

0.400.60

784 2 h IE

(83 W for women,100 W for men)at 15-min intervals

7M, 3F23 to 41 years of age

BAL fluid 3 h after exposure had significant increain PMNs, PGE2, TXB2, and PGF2" at both O3 conce

a See Appendix A for abbreviations and acronyms.b Listed from lowest to highest O3 concentration.

AX6-105
Table AX6-13. Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro Studies Rel

Human Exposure to Ozonea

Ozone

Concentrationb

Exposure

Duration

Activity Level

( .

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Host Defense

0.2 392 2 h IE (15 min/30

min);(

.

VE) . 20

L/min/m2 BSA

4M, 5Fmild atopicasthmatics;21-42 years of age

A significant decline in FEV1 and VC immediately following 

A 2-fold increase in percent PMNs, with no changes in otherbiomarkers, was observed at 6 h postexposure. By 24 h postePMNs had decreased, but albumin, total protein, myeloperoxeosinophil cationic protein had increased.

0.3 588 6 h/day for 

5 consecutive

days

IE (light treadmill) 24 M 

(12 O3, 12 air)

Subjects inoculated with type 39 rhinovirus prior to exposureperformed on the morning of Days 1 to 5, 8, 15, and 30. No in virus titers in NL fluid of air and O3-exposed subjects at an

tested. No difference in PMNs or interferon gamma in NL flblood lymphocyte proliferative response to viral antigen.

0.2 382 2 h IE 

(15 min/30 min);(

.

VE) . 30 L/min 

10M, 2F healthy NS mean ~28 yearsof age

Subjects were exposed to O3 and FA in a cross-over design an

underwent BAL 6 h postexposure. O3 exposure induced a 3-f

increase in % PMNs and epithelial cells, and increased IL-8, 

and total protein in BAL fluid. % PMNs correlated positively chemokine levels. Exposure also resulted in a significant decthe CD4+/CD8+ ratio and the % of activated CD4+ and CD8in BAL fluid.

Host Defense - Mucous Clearance

0.4 784 1 h CE (40 L/min) 15 healthy NS

18 to 35 years old

Subjects inhaled radiolabeled iron oxide particles 2 h after exNo significant O3-induced effect on clearance of particles dur

next 3 h or the following morning.

0.200.40

392784

2 h IE (light treadmill) 7 M,

27.2 ± 6.0 (SD)years old

Subjects inhaled radiolabeled iron oxide particles immediatelexposure. Concentration-dependent increase in rate of particclearance 2 h after exposure, although clearance was confinedprimarily to the peripheral airways at the lower O3 concentrat

AX6-106
Table AX6-13 (cont’d). Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro S

Controlled Human Exposure to Ozonea

Ozone

Concentrationb

Exposure

Duration

Activity Level

(

.

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Host Defense - Epithelial Permeability 

0.00.2

0

392

2 h IE 

4 × 15 minat V

.

E = 20

L/min/m2 BSA

10 M, 12 FHealthy NS;mean 24 years ofage

Clara cell protein (CC16) levels, a biomarker of epithelialpermeability, were elevated by O3 exposure and remained hig

postexposure. By 18 h postexposure, CC16 levels had returnbaseline. No correlation between CC16 and FEV1 decrement

0.150.35

294686

130 min IE

10 exercise/10 rest(

.

VE) . 8×FVC

8M,1FNS

Subjects inhaled 99mTc-DTPA 19 h after exposure to O3. Clea

was increased in the lung periphery. Clearance was not relatspirometry.

0.5 784 2.25 h IE 

(70 L/min) at15-min intervals

16 M, 20 to 30 years old

Similar design and results as earlier study (Kehrl et al., 1987)For the combined studies the average rate of clearance was 6in O3-exposed subjects.

0.4 784 2 h IE 

(70 L/min) at15-min intervals

8 M, 20 to 30 years old

Subjects inhaled 99mTc-DTPA 75 min after exposure. Signifiincreased clearance of 99mTc-DTPA from the lung in O3-expo

subjects. Subjects had expected changes in FVC and SRaw.

Drug Effects on Inflammation

0.25 490 3 h IE

15-min

intervals

4 O3

exposures: 

screening,

placebo, and

two treatments

27 °C56 % RH(values from Holzet al. 1999)

14M, 4FHealthy NS ozone responders31.4 ± 8.4 years old

On average, the screening and placebo O3 exposures caused g

than a 9-fold increase in sputum neutrophils relative to baseliRelative to placebo, the inhaled or oral corticosteroids signifireduced neutrophil levels by 62 and 64%, respectively. Post-

spirometry not significantly different from baseline. 

0.4 784 2 h 23 healthy adults Subjects were exposed to O3 following random selection for a 

daily regimen of antioxidants, including vegetable juice high carotenoid, lycopene, or placebo. Concentrations of lycopenlungs of supplemented subjects increased by 12% following tSupplemented subjects showed a 20% decrease in epithelial cdamage as assessed by the Comet Assay. Effects attributable lycopene could not be separated from those of other antioxida

AX6-107
Table AX6-13 (cont’d). Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro S

Controlled Human Exposure to Ozonea

Oz one

Concentrationb

Exposure

Duration

Activity Level

(

.

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Drug Effects on Inflammation (cont’d)

0.00.4

0

784

2 h IE20 minmild-mod.exercise, 10 min rest

4 M, 5 F Healthy NS

30 ± 3 years old

Subjects previously in Nightingale et al. (2000) study. Placebcontrol: Immediately postexposure decrements in FVC (9%) FEV1 (14%) relative to pre-exposure values. FEV1 decremen

9% at 1 hr postexposure. By 3 h postexposure, recovery in F97% and FEV1 to 98% of preexposure values. Significant inc

8-isoprostane at 4 h postexposure. Budesonide for 2 wk prior exposure did not affect responses. 

0.2 392 2 h

All exposuresseparated by atleast 2 wks(mean . 30d)

IE (15 min/30 min);(

.

VE) . 20

L/min/m2 BSA

Healthy (6 M, 9 F)and mild asthmatic(9 M, 6 F) subjects

Comparison was made of responses in healthy subjects, who higher basal ascorbate (ASC) levels and lower glutathione di

(GSSG) levels than those of asthmatics. 6 h after exposure, Awere decreased and GSSG levels were increased in BAL fluinormals, but not asthmatics. Despite these differences in basantioxidant levels and response to O3, decrements in FEV1 an

neutrophil influx did not differ in the two subject groups.

0.4 784 2 h IE

15-min intervals;

.

VE . 20 L/min/m2

BSA

Placebo group15 M, 1 F Antioxidant group13 M, 2 FMean age 27 years 

All subjects were exposed to FA and then entered a 2 wk regof placebo or 250 mg Vit C, 50IU "-tocopherol, and 12 oz ve

cocktail/day prior to O3 exposure. O3-induced decrements in 

FVC were 30% and 24% less, respectively, in supplemented Percent neutrophils and IL-6 levels in BAL fluid obtained 1 hpostexposure were not different in the two treatment groups.

0.27 529 2 h

All exposuresseparated by atleast 1 wk(mean . 14 d)

Continuousexercise; (

.

VE) . 25

L/min/m2 BSA

7 M, F subjectswith mild asthma;20-50 years of age

Subjects were randomly exposed to FA and to O3 before and 

4 wks of treatment with 400 μg budesonide, b.i.d. Budesonidinhibit the decrement in FEV1 or increase in symptom scores

significantly reduced the increase in % neutrophils and IL-8 iinduced 6 h postexposure.

0.4 784 2 h IE

15-min intervals

.

VE min

. 30 L/min

5 M, 4 F healthy6 M, 7 F asthmatics

Subjects were pretreated for 3 days prior to exposure withindomethacin (75 mg/day) or placebo. Similar reductions in 

FVC were seen in both groups following placebo, whereas mshowed greater decline in asthmatics than normals. Indomethattenuated decrements in FEV1 and FVC in normals, but not

asthmatics. Attenuation of decrements was seen for FEF60p in

asthmatics and for FEF50 in normals.

AX6-108
Table AX6-13 (cont’d). Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro S

Controlled Human Exposure to Ozonea

Ozone

Concentrationb

Exposure

Duration

Activity Level

(

.

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Drug Effects on Inflammation (cont’d)

0.4 784 2 h IE 

(20 min/30 min);workload @50 watts

6 M, 9 F healthyNSmean ~31 yearsof age

Subjects were randomly exposed to FA and to O3 before and 

2 wks of treatment with 800 μg budesonide, b.i.d. O3 caused

significant decrements in FEV1 and FVC immediately follow

exposure, and a small increase in MCh-reactivity and increasneutrophils and myeloperoxidase in sputum induced at 4 hpostexposure. No differences were detected between responstwo treatment groups.

0.00.4

784 2 h IE 

4 × 15 min at 

.

VE = 18

L/min/m2 BSA2 exposures: 25% subjectsexposed to airair, 75% toO3-O3

21 °C40% RH

Weak responders7 M, 13FStrong responders21 M, 21 FHealthy NS20 to 59 years old

Significant O3-induced decrements in spirometric lung functi

Young adults (<35 years) were significantly more responsive older individuals (>35 years). Sufentanil, a narcotic analgesiabolished symptom responses and improved FEV1 in strong

responders. Naloxone, an opioid antagonist, did not affect O

weak responders. See Section AX6.2.5.1

0.4 784 2 h IE

(60 L/min) at15-min intervals

10 M Subjects given 800 mg ibuprofen or placebo 90 min before ex

Subjects given ibuprofen had less of a decrease in FEV1 after 

exposure. BAL fluid 1 h after exposure contained similar levPMNs, protein, fibronectin, LDH, "-1 antitrypsin, LTB4, and 

both ibuprofen and placebo groups. However, subjects given had decreased levels of IL-6, TXB2, and PGE2.

0.4 784 2 h IE 

(15 min/ 30 min);(

.

VE) = 30

L/min/m2 BSA

13 healthy malesubjects

Subjects received either placebo or 150 mg indomethacin/day days prior to O3 exposure. Indomethacin treatment attenuate

O3-induced decrease in FEV1, but had no effect on the O3-indincrease in MCh responsiveness.

0.35 686 1 h Continuous

exercise;(

.

VE) . 60 L/min

14 healthy collegeage males In a placebo- and air-controlled random design, subjects were 

with 75 mg indomethacin every 12 h for 5 days prior to expoIndomethacin significantly reduced O3-induced decrements in 

and FVC.

AX6-109
Table AX6-13 (cont’d). Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro S

Controlled Human Exposure to Ozonea

Ozone

Concentrationb

Exposure

Duration

Activity Level

(

.

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Supportive In Vitro Studies

0.01 to

0.10

19.6 to

196

6 h bronchial

epithelial cells

Nonatopic,nonasthmatic andatopic, mildasthmatic bronchialbiopsy samples

Exposure to 0.01-0.10 ppm O3 significantly decreased the ele

resistance of cells from asthmatic sources, compared to nonassources. This range of O3 concentrations also increased the m

of 14C-BSA across the confluent cultures of “asthmatic” cells 

extent that was greater than that in “nonasthmatic” cells.

0.1 196 24 h Nasal mucosa Allergic and

nonallergic patients

Increased concentrations of neurokinin A and substance P in following O3 exposure. Levels of release of both neuropeptidhigher from tissues derived from allergic compared to nonallepatients.

0.2 392 3 h Nasal epithelial

cells and airwayepithelial cell line

Synergistic effect of O3 exposure on rhinovirus-induced relea

at 24 h through mechanisms abrogated by antioxidant pretreaAdditive enhancement of ICAM-1 expression. 

1 1,690 4 h Macrophage-like

THP-1 cells

THP-1 cells were treated with samples of human surfactant p(SP-A) genetic variants (SP-A1 and SP-A2) that had been preexposed to O3. O3-exposed variants differed in their ability to 

the production of TNF-" and IL-8 by these cells.

0.01 to

0.10

19.6 to

196

6 h bronchial

epithelial cells

Nonatopic,nonasthmatic andatopic, mildasthmatic bronchialbiopsy samples

No difference in constitutive release of IL-8, GM-CSF, sICARANTES from cells from nonasthmatic and asthmatic sourcefor detection of RANTES in latter cells only. Increased releamediators 24 h after 0.05 to 0.10 ppm O3 in “asthmatic” cells

IL-8 and sICAM-1 in “nonasthmatic” cells.

0.120.240.50

235470980

3 h Nasal epithelial

cells

Small dose-response activation of NF-6B coinciding with O3

production of free radicals assessed by electron spin resonancIncreased TNF-" at two higher concentrations of O3 at 16 h

postexposure. 

AX6-110
Table AX6-13 (cont’d). Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro S

Controlled Human Exposure to Ozonea

Ozone

Concentrationb

Exposure

Duration

Activity Level

(

.

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Supportive In Vitro Studies (cont’d)

0.06 to

0.20

118 to 

392

24 h Nasal mucosa 105 surgical

samples fromatopic andnonatopic patients

Increased histamine release correlated with mast cell degranuIncreased release of IL-1, IL-6, IL-8 and TNF-" following O

at 0.10 ppm. Release of IL-4, IL-6, IL-8 and TNF-" at

this concentration was significantly greater from tissues from versus nonatopic patients.

0.5 980 1 h Lung fibroblast

cell line with anairway epithelialcell line

BEAS-2B cells in the presence or absence of HFL-1 cells weexposed and incubated for 11 or 23 h. Steady-state mRNA leof alpha 1 procollagens type I and II, as well as TGF$1, were 

in O3-exposed co-cultured fibroblasts compared to air control

support interactions between the cell types in the presence anabsence of O3-exposure.

0.5 980 1 h tracheal epithelial

cells

O3 exposure caused an increase in ROS formation and a decli

PGE2 production. No differences in mRNA and protein level

prostaglandin endoperoxide G/H synthase 2 (PGHS-2) or the synthesis were detected, suggesting a direct effect of O3-geneoxidants on PGHS-2 activity.

0.4 784 1 h Lung fibroblasts;

airway epithelialcell line

Cells incubated with O3-exposed arachidonic acid (AA) were 

contain DNA single strand breaks. Pretreatment of the expossolution with catalase eliminated the effect on DNA, indicatindependence on H2O2 production. The effect was potentiated 

non-carbonyl component of ozonized AA.

0.250.50

490980

6 h Human nasal

epithelial cells

Increased in ICAM-1, IL-6, IL-1, and TNF expression at 0.5 No increase in IL-8 expression. No increases at 0.25 ppm. 

0.250.501.00

490980

1,960

1 h Airway epithelial

cell line andalveolarmacrophages

Increased secretion of IL-6, IL-8, and fibronectin by epitheliaeven at lowest O3 concentration. No O3-induced secretion of 

compounds by macrophages.

AX6-111
Table AX6-13 (cont’d). Studies of Effects on Host Defense, on Drug Effects and Supportive In Vitro S

Controlled Human Exposure to Ozonea

Ozone

Concentrationb

Exposure

Duration

Activity Level

(

.

VE)

Number and

ppm μg/m Gender of Subjects Observed Effect(s) 

3

Supportive In Vitro Studies (cont’d)

0.20 to

1.0

392 to

1960

2 h or 4 h Airway epithelial

cell line

O3 caused a dose-related loss in cellular replicative activity a

levels that caused minimal cytotoxicity. DNAsingle strand bwere not detected. These effects were different from those of and, thus, not likely related to production of this oxidant withcells.

0.250.501.00

490980

1,960

1 h Airway epithelial

cell line 

Concentration-dependent increased secretion of PGE2, TXB2

PGF2", LTB4, and LTD4. More secretion basolaterally than a

0.301.00

588

1,960

1 h Alveolar

macrophages

Concentration-dependent increases in PGE2 production, and d

in phagocytosis of sheep erythrocytes. No O3-induced secret

1, TNF, or IL-6.

aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3 concentration.

AX6-112
AX6-113

Inflammatory cells of the lung such as alveolar macrophages (AMs), monocytes, and

PMNs also constitute an important component of the pulmonary host defense system. Upon

activation, they are capable of generating free radicals and enzymes with microbicidal

capabilities, but they also have the potential to damage nearby cells. More recently published

studies since the last literature review (U.S. Environmental Protection Agency, 1996) observed

changes in T lymphocyte subsets in the airways following exposure to O3 that suggest

components of the immune host defense also may be affected.

AX6.9.2 Inflammatory Responses in the Upper Respiratory Tract

The nasal passages constitute the primary portal for inspired air at rest and, therefore, the

first region of the respiratory tract to come in contact with airborne pollutants. Nikasinovic et al.

(2003) recently reviewed the literature of laboratory-based nasal inflammatory studies published

since 1985. Nasal lavage (NL) has provided a useful tool for assessing O3-induced inflammation

in the nasopharynx. Nasal lavage is simple and rapid to perform, is noninvasive, and allows

collection of multiple sequential samples. Graham et al. (1988) reported increased levels of

PMNs in the NL fluid of humans exposed to 0.5 ppm O3 at rest for 4 h on 2 consecutive days,

with NL performed immediately before and after each exposure, as well as 22 h after the second

exposure. Nasal lavage fluid contained elevated numbers of PMNs at all postexposure times

tested, with peak values occurring immediately prior to the second day of exposure. Bascom

et al. (1990) exposed subjects with allergic rhinitis to 0.5 ppm O3 at rest for 4 h, and found

increases in PMNs, eosinophils, and mononuclear cells following O3 exposure. Graham and

Koren (1990) compared inflammatory mediators present in both the NL and BAL fluids of

humans exposed to 0.4 ppm O3 for 2 h. Increases in NL and BAL PMNs were similar (6.6- and

eightfold, respectively), suggesting a qualitative correlation between inflammatory changes in

the lower airways (BAL) and the upper respiratory tract (NL), although the PMN increase in NL

could not quantitatively predict the PMN increase in BAL. Torres et al. (1997) compared NL

and BAL in smokers and nonsmokers exposed to 0.22 ppm O3 for 4 h. In contrast to Graham

and Koren (1990), they did not find a relationship between numbers or percentages of

inflammatory cells (PMNs) in the nose and the lung, perhaps in part due to the variability

observed in their NL recoveries. Albumin, a marker of epithelial cell permeability, was

increased 18 h later, but not immediately after exposure, as seen by Bascom et al. (1990). 
AX6-114

Tryptase, a constituent of mast cells, was also elevated after O3 exposure at 0.4 ppm for 2 h

(Koren et al., 1990). McBride et al. (1994) reported that asthmatic subjects were more sensitive

than nonasthmatics to upper airway inflammation at an O3 concentration (0.24 ppm for 1.5 h

with light IE) that did not affect lung or nasal function or biochemical mediators. A significant

increase in the number of PMNs in NL fluid was detected in the asthmatic subjects both

immediately and 24 h after exposure. Peden et al. (1995) also found that O3 at a concentration of

0.4 ppm had a direct nasal inflammatory effect, and reported a priming effect on the response to

nasal allergen challenge, as well. A subsequent study in dust mite-sensitive asthmatic subjects

indicated that O3 at this concentration enhanced eosinophil influx in response to allergen, but did

not promote early mediator release or enhance the nasal response to allergen (Michelson et al.,

1999). Similar to observations made in the lower airways, the presence of O3 molecular

“targets” in nasal lining fluid is likely to provide some level of local protection against exposure. 

In a study of healthy subjects exposed to 0.2 ppm O3 for 2 h, Mudway and colleagues (1999)

observed a significant depletion of uric acid in NL fluid at 1.5 h following exposure. 

An increasing number of studies have taken advantage of advances in cell and tissue

culture techniques to examine the role of upper and lower airway epithelial cells and mucosa in

transducing the effects of O3 exposure. Many of these studies have provided important insight

into the basis of observations made in vivo. One of the methods used enables the cells or tissue

samples to be cultured at the air-liquid interface (ALI), allowing cells to establish apical and

basal polarity, and both cells and tissue samples to undergo exposure to O3 at the apical surfaces

as would occur in vivo. Nichols and colleagues (2001) examined human nasal epithelial cells

grown at the ALI for changes in free radical production, based on electron spin resonance, and

activation of the NF-6B transcription factor following exposure to O3 at 0.12 to 0.5 ppm for 3 h. 

They found a dose-related activation of NF-6B within the cells that coincided with O3-induced

free radical production and increased release of TNF-" at levels above 0.24 ppm. These data

confirm the importance of this oxidant stress-associated pathway in transducing the O3 signal

within nasal epithelial cells and suggest its role in directing the inflammatory response. In a

study of nasal mucosal biopsy plugs, Schierhorn et al. (1999) found that tissues exposed to O3 at

a concentration of 0.1 ppm induced release of IL-4, IL-6, IL-8, and TNF-" that was significantly

greater from tissues from atopic patients compared to nonatopic controls. In a subsequent study,

this same exposure regimen caused the release of significantly greater amounts of the
AX6-115

neuropeptides, neurokinin A and substance P, from allergic patients, compared to nonallergic

controls, suggesting increased activation of sensory nerves by O3 in the allergic tissues

(Schierhorn et al., 2002).

AX6.9.3 Inflammatory Responses in the Lower Respiratory Tract

Seltzer et al. (1986) were the first to demonstrate that exposure of humans to O3 resulted in

inflammation in the lung. Bronchoalveolar lavage fluid (3 h postexposure) from subjects

exposed to O3 contained increased PMNs as well as increased levels of PGE2, PGF2", and TXB2

compared to fluid from air-exposed subjects. Koren et al. (1989a,b) described inflammatory

changes 18 h after O3 exposure. In addition to an eightfold increase in PMNs, Koren et al.

reported a two-fold increase in BAL fluid protein, albumin, and immunoglobulin G (IgG) levels,

suggestive of increased epithelial cell permeability. There was a 12-fold increase in IL-6 levels,

a two-fold increase in PGE2, and a two-fold increase in the complement component, C3a. 

Evidence for stimulation of fibrogenic processes in the lung was shown by significant increases

in coagulation components, Tissue Factor and Factor VII (McGee et al., 1990), urokinase

plasminogen activator and fibronectin (Koren et al., 1989a). Subsequent studies by Lang et al.

(1998), using co-cultures of cells of the BEAS-2B bronchial epithelial line and of the HFL-1

lung fibroblast line, provided additional information about O3-induced fibrogenic processes. 

They demonstrated that steady-state mRNA levels of both alpha 1 and procollagens type I and

III in the fibroblasts were increased following O3 exposure and that this effect was mediated by

the O3-exposed epithelial cells. This group of studies demonstrated that exposure to O3 results in

an inflammatory reaction in the lung, as evidenced by increases in PMNs and proinflammatory

compounds. Furthermore, they demonstrated that cells and mediators capable of damaging

pulmonary tissue are increased after O3 exposure and provided early suggestion of the potential

importance of the epithelial cell-myofibroblast “axis” in modulating fibrotic and fibrinolytic

processes in the airways.

Isolated lavage of the mainstream bronchus using balloon catheters or BAL using small

volumes of saline have been used to assess O3-induced changes in the large airways. Studies

collecting lavage fluid from isolated airway segments after O3 exposure indicate increased

neutrophils in the airways (Aris et al., 1993; Balmes et al., 1996; Scannell et al., 1996). Other

evidence of airway neutrophil increase comes from studies in which the initial lavage fraction
AX6-116

(“bronchial fraction”) showed increased levels of neutrophils (Schelegle et al., 1991; Peden

et al., 1997; Balmes et al., 1996; Torres et al., 1997). Bronchial biopsies show increased PMNs

in airway tissue (Aris et al.,1993) and, in sputum collected after O3 exposure, neutrophil numbers

are elevated (Fahy et al., 1995).

Increased BAL protein, suggesting O3-induced changes in epithelial permeability (Koren

et al., 1989a, 1991 and Devlin et al., 1991) supports earlier work in which increased epithelial

permeability, as measured by increased clearance of radiolabled diethylene triamine pentaacetic

acid (99mTc-DTPA) from the lungs of humans exposed to O3, was demonstrated (Kehrl et al.,

1987). In addition, Foster and Stetkiewicz (1996) have shown that increased permeability

persists for at least 18-20 h and the effect is greater at the lung apices than at the base. In a study

of mild atopic asthmatics exposed to 0.2 ppm O3 for 2 h, Newson et al. (2000) observed a 2-fold

increase in the percentage of PMNs present at 6 hours postexposure, with no change in markers

of increased permeability as assessed by sputum induction. By 24 h, the neutrophilia was seen

to subside while levels of albumin, total protein, myeloperoxidase, and eosinophil cationic

protein increased significantly. It was concluded that the transient PMN influx induced by acute

exposure of these asthmatic subjects was followed by plasma extravasation and the activation of

both PMNs and eosinophils within the airway tissues. Such changes in permeability associated

with acute inflammation may provide better access of inhaled antigens, particulates, and other

substances to the submucosal region.

Devlin et al. (1991) reported an inflammatory response in subjects exposed to 0.08

and 0.10 ppm O3 for 6.6 h. Increased numbers of PMNs and levels of IL-6 were found at

both O3 concentrations, suggesting that lung inflammation from O3 can occur as a consequence

of prolonged exposure to ambient levels while exercising. Interestingly, those individuals who

had the largest increases in inflammatory mediators in this study did not necessarily have the

largest decrements in pulmonary function, suggesting that separate mechanisms underlie these

two responses. The absence of a relationship between spirometric responses and inflammatory

cells and markers has been reported in several studies, including Balmes et al., 1996; Schelegle

et al., 1991; Torres et al., 1997; Hazucha et al., 1996; Blomberg et al., 1999. These observations

relate largely to disparities in the times of onset and duration following single exposures. The

relationship between inflammatory and residual functional responses following repeated or

chronic exposures may represent a somewhat different case (see Section AX6.9.4).
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As indicated above, a variety of potent proinflammatory mediators have been reported to

be released into the airway lumen following O3 exposure. Studies of human alveolar

macrophages (AM) and airway epithelial cells exposed to O3 in vitro suggest that most mediators

found in the BAL fluid of O3-exposed humans are produced by epithelial cells. Macrophages

exposed to O3 in vitro showed only small increases in PGE2 (Becker et al., 1991). In contrast,

airway epithelial cells exposed in vitro to O3 showed large concentration-dependent increases

in PGE2, TXB2, LTB4, LTC4, and LTD4 (McKinnon et al., 1993) and increases in IL-6, IL-8, and

fibronectin at O3 concentrations as low as 0.1 ppm (Devlin et al., 1994). Macrophages lavaged

from subjects exposed to 0.4 ppm (Koren et al., 1989a) showed changes in the rate of synthesis

of 123 different proteins, whereas AMs exposed to O3 in vitro showed changes in only six

proteins, suggesting that macrophage function was altered by mediators released from other

cells. Furthermore, recent evidence suggests that the release of mediators from AMs may be

modulated by the products of O3-induced oxidation of airway lining fluid components, such as

human surfactant protein A (Wang et al., 2002). 

Although the release of mediators has been demonstrated to occur at exposure

concentrations and times that are minimally cytotoxic to airway cells, potentially detrimental

latent effects have been demonstrated in the absence of cytotoxicity. These include the

generation of DNA single strand breaks (Kozumbo et al., 1996) and the loss of cellular

replicative activity (Gabrielson et al., 1994) in bronchial epithelial cells exposed in vitro, and the

formation of protein and DNA adducts. A highly toxic aldehyde formed during O3-induced lipid

peroxidation is 4-hydroxynonenal (HNE). Healthy human subjects exposed to 0.4 ppm O3 for

1 h underwent BAL 6 h later. Analysis of lavaged alveolar macrophages by Western blot

indicated increased levels of a 32-kDa HNE-protein adduct, as well as 72-kDa heat shock protein

and ferritin, in O3- versus air-exposed subjects (Hamilton et al., 1998). In a recent study of

healthy subjects exposed to 0.1 ppm O3 for 2 h (Corradi et al., 2002), formation of 8-hydroxy-2'-

deoxyguanosine (8-OHdG), a biomarker of reactive oxidant species (ROS)-DNA interaction,

was measured in peripheral blood lymphocytes. At 18 h postexposure, 8-OHdG was

significantly increased in cells compared to pre-exposure levels, presumably linked to concurrent

increases in chemical markers of ROS. Of interest, the increase in 8-OHdG was only significant

in a subgroup of subjects with the wild genotype for NAD(P)H:quinone oxidoreductase and the

null genotype for glutathione-S-transferase M1, suggesting that polymorphisms in redox
AX6-118

enzymes may confer “susceptibility’ to O3 in some individuals. The generation of ROS

following exposure to O3 has been shown to be associated with a wide range of responses. In a

recent study, ROS production by alveolar macrophages lavaged from subjects exposed to

0.22 ppm for 4 h was assessed by flow cytometry (Voter et al., 2001). Levels were found to be

significantly elevated 18 h postexposure and associated with several markers of increased

permeability. An in vitro study of human tracheal epithelial cells exposed to O3 indicated that

generation of ROS resulted in decrease in synthesis of the bronchodilatory prostaglandin, PGE2,

as a result of inactivation of prostaglandin endoperoxide G/H synthase 2 (Alpert et al., 1997). 

These and similar studies indicate that the responses to products of O3 exposure in the airways

encompass a broad range of both stimulatory and inhibitory activities, many of which may be

modulated by susceptibility factors upstream in the exposure process, at the level of

compensating for the imposed oxidant stress. 

The inflammatory responses to O3 exposure also have been studied in asthmatic subjects

(Basha et al., 1994; Scannell et al., 1996; Peden et al., 1997). In these studies, asthmatics

showed significantly more neutrophils in the BAL (18 h postexposure) than similarly exposed

healthy individuals. In one of these studies (Peden et al., 1997), which included only allergic

asthmatics who tested positive for Dematophagoides farinae antigen, there was an eosinophilic

inflammation (2-fold increase), as well as neutrophilic inflammation (3-fold increase). In a

study of subjects with intermittent asthma that utilized a 2-fold higher concentration of O3

(0.4 ppm) for 2 h, increases in eosinophil cationic protein, neutrophil elastase and IL-8 were

found to be significantly increased 16 h postexposure and comparable in induced sputum and

BAL fluid (Hiltermann et al, 1999). Scannell et al. (1996) also reported that IL-8 tended to be

higher in post-O3 exposure BAL in asthmatics compared to nonasthmatics (36 vs. 12 pg/mL,

respectively) suggesting a possible mediator for the significantly increased neutrophilic

inflammation in asthmatics relative to healthy subjects (12 vs. 4.5%, respectively). In a recent

study comparing the neutrophil response to O3 at a concentration and exposure time similar to

those of the latter three studies, Stenfors and colleagues (2002) were unable to detect a

difference in the increased neutrophil numbers between 15 mild asthmatic and 15 healthy

subjects by bronchial wash at the 6 h postexposure time point. These results suggest that, at least

with regard to neutrophil influx, differences between healthy and asthmatic individuals develop

gradually following exposure and may not become evident until later in the process. 
AX6-119

In another study, mild asthmatics who exhibited a late phase underwent allergen challenge

24 hrs before a 2 h exposure to 0.27 ppm O3 or filtered air in a cross-over design (Vagaggini

et al., 2002). At 6 h postexposure, eosinophil numbers in induced sputum were found to be

significantly greater after O3 than after air. Studies such as these suggest that the time course of

eosinophil and neutrophil influx following O3 exposure can occur to levels detectable within the

airway lumen by as early as 6 h. They also suggest that the previous or concurrent activation of

proinflammatory pathways within the airway epithelium may enhance the inflammatory effects

of O3. For example, in an in vitro study of epithelial cells from the upper and lower respiratory

tract, cytokine production induced by rhinovirus infection was enhanced synergistically by

concurrent exposure to O3 at 0.2 ppm for 3 h (Spannhake et al, 2002). 

The use of bronchial mucosal biopsies has also provided important insight into the

modulation by O3 of existing inflammatory processes within asthmatics. In a study of healthy

and allergic asthmatic subjects exposed to 0.2 ppm O3 or filtered air for 2 h, biopsies were

performed 6 hr following exposure (Bosson et al., 2003). Monoclonal antibodies were used to

assess epithelial expression of a variety of cytokines and chemokines. At baseline (air

exposure), asthmatic subjects showed significantly higher expression of interleukins (IL)-4

and -5. Following O3 exposure, the epithelial expression of IL-5, IL-8, granulocyte-macrophage

colony-stimulating factor (GM-CSF) and epithelial cell-derived neutrophil-activating peptide

78 (ENA-78) was significantly greater in asthmatic subjects, as compared to healthy subjects. 

In vitro studies of bronchial epithelial cells derived by biopsy from nonatopic, nonasthmatic

subjects and asthmatic subjects also demonstrated the preferential release of GM-CSF and also

of regulated on activation, normal T cell-expressed and -secreted (RANTES) from asthmatic

cells following O3 exposure.

The time course of the inflammatory response to O3 in humans has not been explored fully. 

Nevertheless, studies in which BAL was performed 1-3 h (Devlin et al., 1990; Koren et al.,

1991; Seltzer et al., 1986) after exposure to 0.4 ppm O3 demonstrated that the inflammatory

response is quickly initiated, and other studies (Koren et al., 1989a,b; Torres et al., 1997;

Scannell et al., 1996; Balmes et al., 1996) indicated that, even 18 h after exposure, inflammatory

mediators such as IL-6 and PMNs were still elevated. However, different markers show peak

responses at different times. Ozone-induced increases in IL-8, IL-6, and PGE2 are greater

immediately after O3 exposure, whereas BAL levels of fibronectin and plasminogen activator are
AX6-120

greater after 18 h. PMNs and some products (protein, Tissue Factor) are similarly elevated both

1 and 18 h after O3 exposure (Devlin et al., 1996; Torres et al., 1997). Schelegle et al. (1991)

found increased PMNs in the “proximal airway” lavage at 1, 6, and 24 h after O3 exposure, with

a peak response at 6 h. In a typical BAL sample, PMNs were elevated only at the later time

points. This is consistent with the greater increase 18 h after exposure seen by Torres et al.

(1997). In addition to the influx of PMNs and (in allergic asthmatics) eosinophils, lymphocyte

numbers in BAL were also seen to be elevated significantly at 6 h following exposure of healthy

subjects to 0.2 ppm O3 for 2 h (Blomberg et al., 1997). Analysis of these cells by flow cytometry

indicated the increased presence of CD3+, CD4+ and CD8+ T cell subsets. This same laboratory

later demonstrated that within 1.5 h following exposure of healthy subjects to the same O3

regimen, expression of human leukocyte antigen (HLA)-DR on lavaged macrophages underwent

a significant, 2.5-fold increase (Blomberg et al., 1999). The significance of these alterations in

immune system components and those in IL-4 and IL-5 expression described above in the

studies of Bosson et al. (2003) has not been fully explored and may suggest a role for O3 in the

modulation of immune inflammatory processes.

AX6.9.4 Adaptation of Inflammatory Responses

Residents of areas with high oxidant concentrations tend to have somewhat blunted

pulmonary function responses and symptoms to O3 exposure (Hackney et al., 1976, 1977b, 1989;

Avol et al., 1988; Linn et al., 1988). Animal studies suggest that while inflammation may be

diminished with repeated exposure, underlying damage to lung epithelial cells continues (Tepper

et al., 1989). Devlin et al. (1997) examined the inflammatory responces of humans repeatedly

exposed to 0.4 ppm O3 for 5 consecutive days. Several indicators of inflammation (e.g., PMN

influx, IL-6, PGE2, fibronectin, macrophage phagocytosis) were attenuated after 5 days of

exposure (i.e., values were not different from FA). Several markers (LDH, IL-8, total protein,

epithelial cells) did not show attenuation, indicating that tissue damage probably continues to

occur during repeated exposure. The recovery of the inflammatory response occurred for some

markers after 10 days, but some responses were not normalized even after 20 days. The

continued presence of markers of cellular injury indicates a persistent but not necessarily

perceived response to O3. 
AX6-121

Christian et al. (1998) randomly subjected heathy subjects to a single exposure and to

4 consecutive days of exposure to 0.2 ppm O3 for 4 h. As reported by others, they found an

attenuation of FEV1, FVC and specific airway resistance when comparing the single exposure

with day 4 of the multiday exposure regimen. Similarly, both “bronchial” and “alveolar”

fractions of the BAL showed decreased numbers of PMNs and fibronectin concentration at day

4 versus the single exposure, and a decrease in IL-6 levels in the alveolar fraction. Following a

similar study design and exposure parameters, but with single day filtered air controls, Jörres

et al. (2000) found a decrease in FEV1 and increases in the percentages of neutrophils and

lymphocytes, in concentrations of total protein, IL-6, IL-8, reduced glutathione, ortho-tyrosine

and urate in BAL fluid, but no changes in bronchial biopsy histology following the single

exposure. Twenty hours after the day 4 exposure, both functional and BAL cellular responses

to O3 were abolished. However, levels of total protein, IL-6, IL-8, reduced glutathione and

ortho-tyrosine were still increased significantly. In addition, following the day 4 exposure,

visual scores for bronchitis, erythema and the numbers of neutrophils in the mucosal biopsies

were increased. Their results indicate that, despite reduction of some markers of inflammation

in BAL and measures of large airway function, inflammation within the airways persists

following repeated exposure to O3. 

In another study, Frank and colleagues (2001) exposed healthy subjects to filtered air and

to O3 (0.25 ppm, 2 h) on 4 consecutive days each, with pulmonary function measurements being

made prior to and following each exposure. BAL was performed on day 5, 24 h following the

last exposure. On day 5, PMN numbers remained significantly higher in the O3 arm compared to

air control. Of particular note in this study was the observation that small airway function,

assessed by grouping values for isovolumetric FEF25-75, V0 max50, and V0 max75 into a single value,

showed persistent reduction from day 2 through day 5. These data suggest that methods to more

effectively monitor function in the most peripheral airway regions, which are known to be the

primary sites of O3 deposition in the lung, may provide important information regarding the

cumulative effects of O3 exposure. Holz et al. (2002) made a comparison of early and late

responses to allergen challenge following O3 in subjects with allergic rhinitis or allergic asthma. 

With some variation, both early and late FEV1 and cellular responses in the two subject groups

were significantly enhanced by 4 consecutive days of exposure to 0.125 ppm O3 for 3 h. 
AX6-122

AX6.9.5 Effect of Anti-Inflammatory and Other Mitigating Agents

Studies have shown that indomethacin, a non-steroidal anti-inflammatory agent (NSAID)

that inhibits the production of cyclooxygenase products of arachidonic acid metabolism, is

capable of blunting the well-documented decrements in pulmonary function observed in

humans exposed to O3 (Schelegle et al., 1987; Ying et al., 1990). Indomethacin did not alter

the O3-induced increase in bronchial responsiveness to methacholine (Ying et al., 1990). 

Pretreatment of healthy subjects and asthmatics with indomethacin prior to exposure to 0.4 ppm

for 2 h significantly attenuated decreases in FVC and FEV1 in normals, but not asthmatics

(Alexis et al., 2000). Subjects have also been given ibuprofen, another NSAID agent that blocks

cyclooxygenase metabolism, prior to O3 exposure. Ibuprofen blunted decrements in lung

function following O3 exposure (Hazucha et al., 1996). Subjects given ibuprofen also had

reduced BAL levels of the cyclooxygenase product PGE2 and thromboxane B2, as well as IL-6,

but no decreases were observed in PMNs, fibronectin, permeability, LDH activity, or

macrophage phagocytic function. These studies suggest that NSAIDs can blunt O3-induced

decrements in FEV1 with selective (perhaps drug-specific) affects on mediator release and other

markers of inflammation. 

At least two studies have looked at the effects of the inhaled corticosteroid, budesonide, on

the effects of O3, with differing outcome perhaps associated with the presence of preexistent

disease. Nightingale and colleagues (2000) exposed healthy nonsmokers to 0.4 ppm O3 for 2 h

following 2 wk of treatment with budesonide (800 micrograms, twice daily) or placebo in a

blinded, randomized cross-over study. This relatively high O3 exposure resulted in significant

decreases in spirometric measures and increases in methacholine reactivity and neutrophils and

myeloperoxidase in induced sputum. No significant differences were observed in any of these

endpoints following budesonide treatment versus placebo. In contrast, Vagaggini et al. (2001)

compared the effects of treatment with budesonide (400 micrograms, twice daily) for 4 wk on

the responses of mild asthmatic subjects to exposure to 0.27 ppm O3 for 2 h. Prior to exposure,

at the midpoint and end of exposure, and at 6 h postexposure, FEV1 was measured and a

symptom questionnaire was administered; at 6 h postexposure, sputum was induced. 

Budesonide treatment did not inhibit the decrement in FEV1 or alter symptom score, but

significantly blunted the increase in percent PMNs and concentration of IL-8 in the sputum. The

difference in subject health status between the two studies (healthy versus mild asthmatic) may
AX6-123

suggest a basis for the differing outcomes; however, because of differences in the corticosteroid

dosage and O3 exposure levels, that basis remains unclear.

Holz et al. (2005) investigated the mitigation of O3-induced inflammatory responses in

subjects pretreated with single doses of inhaled fluticasone and oral prednisolone. Eighteen

healthy ozone-responders (>10% increase in sputum neutrophils from O3 exposure) received

corticosteroid treatment or placebo 1-h before being exposed for 3-h with IE (15 min periods

rest/exercise) to 0.25 ppm O3. Sputum was collected 3-h post-O3 exposure. The 18 ozoneresponders were selected from 35 screened subjects. Twelve subjects were disqualified from the

study (6 produced insufficient sputum and 6 had inadequate neutrophil responses to O3), the

remaining 5 subjects were [presumably] qualified but did not participate. The O3 exposure

caused small changes in FEV1 (!3.6% ±6.8%) that were not significantly different from baseline

or between treatment groups (i.e., prescreening, placebo, fluticasone, and prednisolone). 

On average, the prescreening and placebo O3 exposures caused greater than a 9-fold increase in

sputum neutrophils relative to baseline levels. Relative to placebo, the inhaled or oral

corticosteroids significantly reduced neutrophil levels by 62 and 64%, respectively. Total

protein levels were not altered by O3 or corticosteroid treatment. Authors concluded that the

pronounced anti-inflammatory effect of steroids in their study was due to administering the

highest single doses shown to be safe and well tolerated. Furthermore, steroids were

administered so that maximal plasma level would be reached at approximately the beginning of

the O3 exposure. 

Because the O3 exerts its actions in the respiratory tract by virtue of its strong oxidant

activity, it is reasonable to assume that molecules that can act as surrogate targets in the airways,

as constituents of either extracellular fluids or the intracellular milieus, could abrogate the effects

of O3. Some studies have examined the ability of dietary “antioxidant” supplements to reduce

the risk of exposure of the lung to oxidant exposure. In a study of healthy, nonsmoking adults,

Samet and colleagues (2001) restricted dietary ascorbate and randomly treated subjects for

2 weeks with a mixture of vitamin C, "-tocopherol and vegetable cocktail high in carrot and

tomato juices or placebo. Responses to 0.4 ppm O3 for 2 h were assessed in both groups at the

end of treatment. O3 -induced decrements in FEV1 and FVC were significantly reduced in the

supplemented group, whereas the inflammatory response, as assessed by percentage neutrophils

and levels of IL-6 in BAL fluid, were unaffected by antioxidant supplementation. In a study that
AX6-124

focused on supplementation with a commercial vegetable cocktail high in the carotenoid,

lycopene, healthy subjects were exposed for 2 h to 0.4 ppm O3 after 2 wk of antioxidant

supplementation or placebo (Arab et al., 2002). These investigators observed that lung epithelial

cell DNA damage, as measured by the Comet Assay, decreased by 20% in supplemented

subjects. However, the relationships between the types and levels of antioxidants in airway

lining fluid and responsiveness to O3 exposure is likely to be complex. In another study where

differences in ascorbate and glutathione concentrations between healthy and mild asthmatic

subjects were exploited, no relationship between antioxidant levels and spirometric or cellular

responses could be detected (Mudway et al., 2001).

AX6.9.6 Changes in Host Defense Capability Following Ozone Exposure

Concern about the effect of O3 on human host defense capability derives from numerous

animal studies demonstrating that acute exposure to as little as 0.08 ppm O3 causes decrements

in antibacterial host defenses (see Chapter 5). A study of experimental rhinovirus infection in

susceptible human volunteers failed to show any effect of 5 consecutive days of O3 exposure on

the clinical evolution of, or host response to, a viral challenge (Henderson et al., 1988). Healthy

men were nasally inoculated with type 39 rhinovirus (103 TCID50). There was no difference

between the O3-exposed and control groups in rhinovirus titers in nasal secretions, in levels of

interferon gamma or PMNs in NL fluid, or in blood lymphocyte proliferative response to

rhinovirus antigen. However, subsequent findings that rhinovirus can attach to the intracellular

adhesion molecule (ICAM)-1 receptor on respiratory tract epithelial cells (Greve et al., 1989)

and that O3 can up-regulate the ICAM-1 receptor on nasal epithelial cells (Beck et al., 1994)

suggest that more studies are needed to explore the possibility that prior O3 exposure can

enhance rhinovirus binding to, and infection of, the nasal epithelium.

In a single study, human AM host defense capacity was measured in vitro in AMs removed

from subjects exposed to 0.08 and 0.10 ppm O3 for 6.6 h while undergoing moderate exercise. 

Alveolar macrophages from O3-exposed subjects had significant decrements in complementreceptor-mediated phagocytosis of Candida albicans (Devlin et al., 1991). The impairment of

AM host defense capability could potentially result in decreased ability to phagocytose and kill

inhaled microorganisms in vivo. A concentration-dependent decrease in phagocytosis of AMs

exposed to 0.1 to 1.0 ppm O3 in vitro has also been shown Becker et al. (1991). Although the
AX6-125

evidence is inconclusive at present, there is a concern that O3 may render humans and animals

more susceptible to a subsequent bacterial challenge.

Only two studies (Foster et al., 1987; Gerrity et al., 1993) have investigated the effect

of O3 exposure on mucociliary particle clearance in humans. Foster et al. (1987) had seven

healthy subjects inhale radiolabeled particles (5 μm MMAD) and then exposed these subjects to

FA or O3 (0.2 and 0.4 ppm) during light IE for 2 h. Gerrity et al. (1993) exposed 15 healthy

subjects to FA or 0.4 ppm O3 during CE (40 L/min) for 1 h; at 2 h post-O3 exposure, subjects

then inhaled radiolabeled particles (5 μm MMAD). Subjects in both studies had similar

pulmonary function responses (average FVC decrease of 11 to 12%) immediately postexposure

to 0.4 ppm O3. The Foster et al. (1987) study suggested there is a stimulatory affect of O3

on mucociliary clearance; whereas, Gerrity et al. (1993) found that in the recovery period

following O3 exposure, mucus clearance is similar to control, i.e., following a FA exposure. 

The clearance findings in these studies are complementary not conflicting. Investigators in both

studies suggested that O3-induced increases in mucociliary clearance could be mediated by

cholinergic receptors. Gerrity et al. (1993) further suggested that transient clearance increases

might be coincident to pulmonary function responses; this supposition based on the return of

sRaw to baseline and the recovery of FVC to within 5% of baseline (versus an 11% decrement

immediately postexposure) prior to clearance measurements. 

Insofar as the airway epithelial surface provides a barrier to entry of biological, chemical

and particulate contaminants into the submucosal region, the maintenance of barrier integrity

represents a component of host defense. Many of the studies of upper and lower respiratory

responses to O3 exposure previously cited above have reported increases in markers of airway

permeability after both acute exposures and repeated exposures. These findings suggest that O3

may increase access of airborne agents. In a study of bronchial epithelial cells obtained from

nonatopic and mild atopic asthmatic subjects (Bayram et al., 2002), cells were grown to

confluence and transferred to porous membranes. When the cultures again reached confluence,

they were exposed to 0.01-0.1 ppm O3 or air and their permeability was assessed by measuring

the paracellular flux of 14C-BSA. The increase in permeability 24 h following O3 exposure was

observed to be significantly greater in cultures of cells derived from asthmatics, compared to

healthy subjects. Thus, the late increase in airway permeability following exposure of asthmatic
AX6-126

subjects to O3, of the sort described by Newson et al. (2000), may be related to an inherent

susceptibility of ‘asthmatic’ cells to the barrier-reducing effects of O3.

As referenced in Section 6.9.3, the O3-induced increase in the numbers of CD8+ T

lymphocytes in the airways of healthy subjects reported by Blomberg et al. (1997) poses several

interesting questions regarding possible alterations in immune surveillance processes following

exposure. In a subsequent study from the same group, Krishna et al. (1998) exposed healthy

subjects to 0.2 ppm O3 or filtered air for 2 h followed by BAL at 6 h. In addition to increased

PMNs and other typical markers of inflammation, they found a significant decrease in the

CD4+/CD8+ T lymphocyte ratio and in the proportion of activated CD4+ and CD8+ cells. 

Studies relating to the effects of low-level O3 exposure on the influx and activity of

immunocompetent cells in the upper and lower respiratory tracts may shed additional light on

modulation of this important area of host defense. 

AX6.10 EXTRAPULMONARY EFFECTS OF OZONE

Ozone reacts rapidly on contact with respiratory system tissue and is not absorbed or

transported to extrapulmonary sites to any significant degree as such. Laboratory animal studies

suggest that reaction products formed by the interaction of O3 with respiratory system fluids or

tissues may produce effects measured outside the respiratory tract—either in the blood, as

changes in circulating blood lymphocytes, erythrocytes, and serum, or as changes in the structure

or function of other organs, such as the parathyroid gland, the heart, the liver, and the central

nervous system. Very little is known, however, about the mechanisms by which O3 could cause

these extrapulmonary effects. (See Section 5.4 for a discussion of the systemic effects

of O3 observed in laboratory animals.)

The results from human exposure studies discussed in the previous criteria documents

(U.S. Environmental Protection Agency, 1986, 1996) failed to demonstrate any consistent

extrapulmonary effects. Early studies on peripheral blood lymphocytes collected from human

volunteers did not find any significant genotoxic or functional changes at O3 exposures of 0.4 to

0.6 ppm for up to 4 h/day. Limited data on human subjects indicated that 0.5 ppm O3 exposure

for over 2 h caused transient changes in blood erythrocytes and sera (e.g., erythrocyte fragility

and enzyme activities), but the physiological significance of these studies remains questionable. 
AX6-127

The conclusions drawn from these early studies raise doubt that cellular damage or altered

function is occurring to circulating cells at O3 exposures under 0.5 ppm.

Other human exposure studies have attempted to identify specific markers of exposure

to O3 in blood. For example, Schelegle et al. (1989) showed that PGF2" was elevated after O3

exposure (0.35 ppm); however, no increase in "-1 protease inhibitor was observed by Johnson

et al. (1986). Foster et al. (1996) found a reduction in the serum levels of the free radical

scavenger "-tocopherol after O3 exposure. Vender et al. (1994) failed to find any changes in

indices of red blood cell antioxidant capacity (GSH, CAT) in healthy male subjects exposed to

0.16 ppm O3 for 7.5 h while intermittently exercising. Liu et al. (1997, 1999) used a salicylate

metabolite, 2,3-dihydroxybenzoic acid (DHBA), to indicate increased levels of hydroxyl radical

which hydroxylates salicylate to DHBA. Increased DHBA levels after exposure to 0.12 and

0.40 ppm suggest that O3 increases production of hydroxyl radical. The levels of DHBA were

correlated with changes in spirometry.

Only a few experimental human studies have examined O3 effects in other nonpulmonary

organ systems besides blood. Early studies on the central nervous system (Gliner et al., 1979,

1980) were not able to find significant effects on motor activity or behavior (vigilance and

psychomotor performance) from O3 exposures at rest up to 0.75 ppm (U.S. Environmental

Protection Agency, 1986). Drechsler-Parks et al. (1995) monitored ECG, HR, cardiac output,

stroke volume, and systolic time intervals in healthy, older subjects (56 to 85 years of age)

exposed to 0.45 ppm O3 using a noninvasive impedance cardiographic method. No changes

were found at this high O3 concentration after 2 h of exposure while the subjects exercised

intermittently at 25 L/min. 

Gong et al. (1998) monitored ECG, HR, cardiac output, blood pressure, oxygen saturation,

and chemistries, as well as calculating other hemodynamic variables (e.g., stroke volume,

vascular resistance, rate-pressure products) in both healthy (n = 6) and hypertensive (n = 10)

adult males (41-78 years old). Subjects were exposed for 3 h with IE (V0 E . 30 L/min) to FA

and on the subsequent day to 0.3 ppm O3. See Section AX6.3 for more details about this study. 

Statistically significant O3 effects for both groups combined were increases in HR, rate-pressure

product, and the alveolar-to-arterial PO2 gradient. Gong et al. (1998) suggested that by

impairing alveolar-arterial oxygen transfer, the O3 exposure could potentially lead to adverse

cardiac events by decreasing oxygen supply to the myocardium. The subjects in the Gong et al.
AX6-128

(1998) study had sufficient functional reserve so as to not experience significant ECG changes or

myocardial ischemia and/or injury. However, Gong et al. (1998) concluded that O3 exposure

could pose a cardiopulmonary risk to persons with preexisting cardiovascular disease, with or

without concomitant respiratory disease. 

The mechanism for the decrease in arterial oxygen tension in the Gong et al. (1998) study

could be due to an O3 induced ventilation-perfusion mismatch. It is well recognized and

accepted that ventilation and perfusion per unit lung volume increase with progression from the

apex to the base of the lung in normal upright healthy humans (Inkley and MacIntyre, 1973;

Kaneko et al., 1966). But, Foster et al. (1993) demonstrated that even in relatively young

healthy adults (26.7 ± 7 years old), O3 exposure can cause ventilation to shift away from the well

perfused basal lung (see Section AX6.2.3 for more details). This effect of O3 on ventilation

distribution [and by association the small airways] may persist beyond 24-h postexposure (Foster

et al., 1997). Hypoxic pulmonary artery vasoconstriction acts to shift perfusion away from areas

of low ventilation and moderate ventilation-perfusion mismatches (Šantak et al., 1998). This

arterial vasoconstriction is thought to be mediated by protein kinase C, (Barman, 2001; Tsai

et al., 2004). A more generalized (i.e., not localized to poor ventilated areas) increase in

pulmonary vascular resistance in response to O3 exposure would presumably act against the

ability of the hypoxic vasoconstriction in mediating ventilation-perfusion mismatches. Acute

arterial vasoconstriction has been observed clinically in humans (15 M, 10 F; 34.9 ± 10 years

old) exposed for 2-h to O3 (0.12 ppm) in tandem with fine particulate (.150 μg/m3) (Brook et al.,

2002). Delaunois et al. (1998) also found that O3 exposure increases total (arterial, capillary, and

venous segments) pulmonary vascular resistance in rabbits. Hence, vasoconstriction could

potentially be induced by mechanisms other than regional hypoxia during O3 exposure. This

notion is consistent with the O3-induced reduction in alveolar-arterial oxygen transfer observed

by Gong et al. (1998). 

Effects of O3 exposure on alveolar-arterial oxygen gradients may be more pronounced in

patients with preexisting obstructive lung diseases. Relative to healthy elderly subjects, COPD

patients have increased heterogeneity in both regional ventilation and perfusion (Kronenberg

et al., 1973). King and Briscoe (1968) examined the distribution of ventilation and perfusion in

a group of eight patients with severe COPD (mean FEV1/FVC = 36%). In these patients, 68% of

the lung by volume received 45% of the cardiac output, but only 10% of the total alveolar
AX6-129

ventilation. This distribution of ventilation and perfusion in the patients contributed to their low

mean SaO2 of only 82% (inspired oxygen, 20.93%). Thus, even prior to O3 exposure, COPD

patients may have reduced gas exchange and low SaO2. Based on model predictions, increasing

tidal volume increases the O3 dose to the proximal alveolar region (Overton et al., 1996). 

Similarly, with 90% of the alveolar ventilation supplied to only 32% of lung’s volume, the well

ventilated regions of the COPD lung will be subjected to increased peripheral O3 doses. Any

inflammatory or edematous responses due to O3 delivered to the well ventilated regions of the

COPD lung will likely further inhibit gas exchange and reduce oxygen saturation. 

In addition to reducing alveolar-arterial oxygen transfer, O3 induced vasoconstriction could

also acutely induce pulmonary hypertension. Individuals with COPD and coexisting pulmonary

hypertension might be subpopulations sensitive to cardiac effects as a consequence of O3

exposure. Acute pulmonary hypertension could potentially affect cardiac function by increasing

right ventricular workloads. Oral or inhaled vasodilators are used in patients to reduce

pulmonary artery pressure to improve right ventricular function (Šantak et al., 1998). 

Consequently, inducing pulmonary vasoconstriction in these patients would perhaps worsen their

condition, especially if their right ventricular function was already compromised. There are

reduced spirometric and symptom responses to O3 exposure with age (see Section AX6.5.1). It is

conceivable, therefore, that COPD patients and elderly individuals (due to their decreased

symptomatic responses to ambient O3) might further increase their risk of adverse

cardiopulmonary responses by continuing their exposures beyond the point where young healthy

adults might experience discomfort and cease exposure. 

AX6.11 OZONE MIXED WITH OTHER POLLUTANTS

Controlled laboratory studies simulating conditions of ambient exposures have failed for

the most part to demonstrate significant adverse effects either in healthy subjects, atopic

individuals, or in young and middle-aged asthmatics.

AX6.11.1 Ozone and Sulfur Oxides

The difference in solubilities and other chemical properties of O3 and SOx seems to limit

chemical interaction and formation of related species in the mixture of these pollutants either in
AX6-130

liquid or gaseous phase. Laboratory studies reviewed in the previous O3 criteria document

(Table AX6-14) reported, except for one study (Linn et al., 1994), no significant effects on

healthy individuals exposed to mixtures of O3 and SO2 or H2SO4 aerosol. In the study of Linn

et al. (1994), which was a repeated 6.5 h exposure protocol, O3 alone and O3 + H2SO4 induced

significant spirometric decrements in healthy adults and asthmatics, but the magnitude of effects

between exposure atmospheres was not significant. Asthmatic and atopic subjects showed

somewhat enhanced or potentiated response to mixtures or sequential exposure, respectively;

however, the observed effects were almost entirely attributable to O3 (U.S. Environmental

Protection Agency, 1996). Thus, in both healthy and asthmatic subjects, the interactive effects

of O3 and other pollutants were marginal and the response was dominated by O3. 

Since 1994, the only laboratory study that examined the health effects of a mixture of O3

and sulfur oxides (SO2 and H2SO4) has been that of Linn et al. (1997). In this study, the

investigators closely simulated ambient summer haze air pollution conditions in Uniontown, PA

as well as controlled the selection of study subjects with the objective to corroborate earlier

reported findings of an epidemiologic study of Neas et al. (1995). The subjects were 41 children

(22F/19M) 9 to 12 yrs old. Of these, 26 children had history of asthma or allergy. During a

14-day study period, children were exposed on the 4th and 11th day for 4 hrs (IE, 15 min @ avg.

V0 E 22 L/min) in random order to air and a mixture of 0.10 ppm O3, 0.10 ppm SO2 and 42 to

198 mg/m3

 H2SO4 (mean conc. 101 mg/m3, 0.6 mm MMAD). The effects of controlled

exposures were assessed by spirometry. Except for exposure days, children used diaries to

record activity, respiratory symptoms, location, and PEFR. Thus, every exposure day was

bracketed by 3 days of monitoring. Spirometry, PEFR, and respiratory symptoms score showed

no meaningful changes between any condition for a total study population. The symptoms score

reported by a subset of asthmatic/allergic subjects was positively associated with the inhaled

concentration of H2SO4 (p = 0.01). However, the reported symptoms were different from the

ones reported in the Uniontown study (Neas et al., 1995). Although retrospective statistical

power calculations using these study observations for the symptoms score, PEFR, and

spirometric endpoints were sufficient to detect with >80% probability the same magnitude of

changes as observed in Uniontown, the effects were minimal and not significant. The divergent

observations of the two studies have been explained by the presence of an unidentified

environmental factor in Uniontown, differences in physico-chemical properties of acid, 
Table AX6-14. Ozone Mixed with Other Pollutantsa

Concentrationb

Pollutant

Exposure Duration

and Activity

Exposure 

Conditionsc

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Ef

3

Sulfur-Containing Pollutants0.00.1 +0.1 +

0

196b +

262b +

101b

AirO3 +

SO2 +

H2SO4

4 hIE 15' ex/ 15' restVE = 22 L/min

25 °C50% RH

8 M, 7 F1 M, 4 F10 M, 11 F

HealthyAsthmatic AllergicAll NS,9 to 12 yrs. old

Spirometry, PEFR and ssymptoms score showed changes between any cototal study population. score reported by a subsasthmatics/allergics werassociated with inhaled of H2SO4 (p = 0.01).

0.20.3

392564

O3

NO2H2SO4

90 min.V

.

E . 32 L/min

IE 3 × 15 min

21 °C50% RH

24(17 M, 7 F)

Asthmatic NS, 11 to 18 years old

H2SO4/O3/NO2, O3/NO2 

produced similar respon

0.120.300.05

235564

70

O3

NO2H2SO4HNO3

1.5 h with IE for2 consecutive days;V

.

E . 23.2 L/min

22 °C65% RH

22 completedstudy; 15 M, 7 F

Asthmatic NS,adolescents; NS, 12 to19 years old 

No significant pulmonachanges following any ecompared to response to Six additional subjects sstudy, but dropped out duncomfortable symptom

0.12 235

100

O3

H2SO4

6.5 h2 consecutive days50 min exercise/hV

.

E = 29 L/min

21 °C50% RH

8 M, 7 F13 M, 17 F

Nonasthmatic NS, 22 to 41 years oldAsthmatic NS, 18 to 50 years old

Exposure to O3 or O3 + 

significant decrements iforced expiratory functibetween O3 and O3 + H2

best, marginally signific

more important pollutanrespiratory effects. A feand nonasthmatic subjeresponsive to O3 + H2SO

O3 alone.

0.080.120.18

157235353100100

O3

O3O3NaClH2SO4

3-h exposure to aerosol,followed 24 h later by a3-h exposure to O3. IE

(10 min per half hour)V

.

E = 4 times resting

(30 to 364 min)

21 °C

.40% RH

16 M, 14 F10 M, 20 F

Nonasthmatic NS, 18 to 45 years oldAsthmatic NS, 21 to 42 years old

No significant changes lung function with any a

combination in the healIn asthmatics, H2SO4 pr

enhanced the small decrthat occurred following 0.18 ppm O3. Asthmati

significant changes on F

O3 exposures, but symp

greater.

AX6-131 DRAFT-DO NOT QUOTE OR CITE
Table AX6-14 (cont’d). Ozone Mixed with Other Pollutantsa

Concentrationb

Pollutant

Exposure Duration

and Activity

Exposure 

Conditionsc

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Ef

3

Sulfur-Containing Pollutants (cont’d)0.120.10

235262

O3

SO2

1 h (mouthpiece)IE V.

E . 30 L/min

45-min exposure to air orO3, followed by 15-min

exposure to O3 or SO2

22 °C75% RH

8 M, 5 F Allergic asthmatics,

12 to 18 years old,medications withheldfor at least 4 h beforeexposures

Prior exposure to O3 po

pulmonary function resp

decrements in FEV1 we

!8% for the air/O3, O3/Oexposures, respectively

0.25 490

1,200

to 

1,600

O3

H2SO4

2 hIEV

.

E = 30 to 32 L/min

35 °C83% RH

9 M Healthy NS, 

19 to 29 years old

No significant effects o

alone or combined with 

Nitrogen-Containing Pollutants0.00.20.40.2+0.40.10.20.1+0.2

0

392752196376

AirO3

NO2O3+NO2O3NO2O3+NO2

3 h IE 10' ex/ 20' restV

.

E =32 L/min

6 hIE 10' ex/ 20' restV

.

E =32 L/min

T = 25 °CRH = 50%

9 M, 2 F Atopic asthmatics

22 to 41 yrs. old

Exposure to NO2 alone 

effects on FEV1. Howe

in combination elicited greater decline in FEV1 

exposure (higher concenlong (6 h) exposure whewere nonsignificant. Achallenge inhalation sigreduced PD20 FEV1 in a

the long exposures. No potentiating effects havobserved.

0.00.360.360.750.36

0

706677

1,411

943

AirO3

NO2NO2SO2

2 hrest

Head onlyexposure

6 M, 6 F Healthy NS

19 to 33 yrs. old

For NO2 and SO2 the ab

of O3 increased relative whereas after O3 exposuThe differences explainincreased production of 

substrate in ELF due to 

0.450.60

883

1,129

O3

NO2

2-h random exposures toFA, O3, NO2, and O3 +

NO2; IE; V.

E = 26-29

L/min

23.6 °C62% RH

6 M2 F

Healthy, NS, 56 to85 years old

Exercise-induced cardiasmaller with O3 + NO2 e

compared to FA or O3 a

AX6-132 DRAFT-DO NOT QUOTE OR CITE
Table AX6-14 (cont’d). Ozone Mixed with Other Pollutantsa

Concentrationb

Pollutant

Exposure Duration

and Activity

Exposure 

Conditionsc

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Ef

3

Nitrogen-Containing Pollutants (cont’d)0.300.60

589

1,129

O3

NO2

2-h exposure to NO2 or

FA, followed 3 h later by2-h exposure to O3, IEV

.

E = 20 L/min/m2 BSA

21 °C40% RH

21 F Healthy NS, 

18 to 34 years old

No significant effect of 

on any measured paramexposure of NO2 follow

induced small but signifdecrements in FEV1 and 

FA/O3 sequence. Subje

increased airway responmethacholine after both significantly greater resafter the NO2/O3 sequen

the FA/O3 sequence.

0.2 392

500

O3

HNO3H2O

5 hIE (50 min/h exercise)V

.

E . 40 L/min

2 h HNO3 or H2O fog or

air, followed by 1-h break,followed by 3 h O3

20 °C5% RH

6 M, 4 F Healthy NS, 

minimum of 10%decrement in FEV1

after 3 h exposure to0.20 ppm O3 with

50 min exercise/h

Exposure to HNO3 or H

by O3 induced smaller p

function decrements thaby O3.

0.00.120.300.12+0.30

0

235564

AirO3

NO2O3 + NO2

1 h (mouthpiece)IE V

.

E = 33 L/min

V

.

E = 35 L/min

22 °C75% RH

5 M, 7 F9 M, 3 F

Healthy NS, 12 to 17 years oldAsthmatic 13 to 18 years old

Findings inconsistent acand atmospheres. No sidifferences in FEV1 and 

asthmatics and healthy, atmospheres and cohort

0.300.60

589

1,129

O3

NO2

1 h (mouthpiece)CEV

.

E . 70 L/min for men

V

.

E . 50 L/min for women 

20 M, 20 F Healthy NS, 

21.4 ± 1.5 (SD) years old for F, 22.7 ± 3.3 (SD) yearsold for M

No differences between O3 and NO2 + O3 for spi

parameters. Increase in NO2 + O3 was significan

O3 alone.

0.300.300.150.150.150.150.15

589564200294284200294282393200

O3

NO2H2SO4O3NO2H2SO4O3NO2SO2H2SO4

2 h CE for 20 minV

.

. 25 L/min

2 h, 60 min total exerciseV

.

. 25 L/min

2 h, 60 min total exerciseV

.

. 25 L/min

28 to 29 °C50 to 60% RH

6 M6 M3 M

Healthy subjects,some smokers

Possible small decrease 

Possible small decrease Possible small decrease 

AX6-133 DRAFT-DO NOT QUOTE OR CITE
Table AX6-14 (cont’d). Ozone Mixed With Other Pollutantsa

Concentrationb

Pollutant

Exposure Duration

and Activity

Exposure 

Conditionsc

Number and

Gender of

Subjects

Subject

ppm μg/m Characteristics Observed Ef

3

Peroxyacetyl Nitrate0.450.600.13

883

1,129

644

O3

NO2PAN

2 hIEV

.

E . 25 L/min

24 °C55 to 58% RH

8 M, 8 F8 M, 8 F

Healthy NS; 19 to 26 years old;51 to 76 years old

No differences between responses to O3 alone, O

PAN, or O3 + NO2 + PA

0.450.30

883

1,485

O3

PAN

2 hIEV

.

E . 27 L/min

22 °C60% RH

3 M, 5 F Healthy NS, 

mean age = 24 years

No differences between responses to exposure to O3 alone and O3 + PAN

0.4850.27

952

1,337

O3

PAN

2 hIEV

.

E . 25 L/min

21 °CWBGT

10 F Healthy NS, 

19 to 36 years old

Exposure to the mixture 

induced decrements in Faveraging 10% greater tfollowing exposure to O

Particle-Containing Pollutants0.00.12

0

235b +

153b

AirO3 +

PM2.5

2-2.5 hrest

22 °C30% RH

15 M, 10 F Healthy NS

18 to 50 yrs. old

Neither systolic nor diahas been affected by poexposure despite a signiartery constriction and a arterial diameter when cfiltered air (p = 0.03). Aflow- and nitroglycerin-brachial artery dilatation

aSee Appendix A for abbreviations and acronyms.bGrouped by pollutant mixture.cWBGT = 0.7 Twet bult + 0.3 Tdry bulb or globe.

AX6-134 DRAFT-DO NOT QUOTE OR CITE
AX6-135

differences in time course of exposure and history of previous exposure of children to pollutants,

psychological and physiological factors related to chamber exposures, and by other conjectures.

AX6.11.2 Ozone and Nitrogen-Containing Pollutants

Nitrogen dioxide is a key component of the photooxidation cycle and formation of O3. 

Both gases are almost invariably present in ambient atmosphere. Compared to O3, NOx species

have limited solubility and moderate oxidizing capability. Both O3 and NO2 are irritants and

tissue oxidants and exert their toxic actions through many common mechanisms. The regional

dosimetry and the primary sites of action of O3 and NO2 overlap but are not the same. Since

these gases are relatively insoluble in water, they will likely penetrate into the peripheral airways

that are more sensitive to damage than better protected conducting airways. The controlled

studies reviewed in the previous O3 criteria document (Table AX6-14) generally reported only

small pulmonary function changes after combined exposures of NO2 or nitric acid (HNO3) with

O3, regardless if the interactive effects were potentiating or additive. In two of these studies, the

effects reached statistical significance, but they were not coherent. Preexposure with NO2

potentiated both spirometric and nonspecific airway reactivity response following subsequent O3

exposure (Hazucha et al., 1994); however, exposure to NO2 + O3 mixture blunted SRaw increase

as compared to O3 alone (Adams et al.,1987). As with O3 and SOx mixtures, the effects have

been dominated by O3 (U.S. Environmental Protection Agency, 1996).

Combined exposure to O3 and NO2 also blunted the exercise-induced increase in cardiac

output found with FA and O3 exposures alone (Drechsler-Parks, 1995). Eight healthy older

subjects (56 to 85 years of age) were exposed for 2 h to FA, 0.60 ppm NO2, 0.45 ppm O3, and to

0.60 ppm NO2 + 0.45 ppm O3 while alternating 20-min periods of rest and exercise. Cardiac

output, HR, stroke volume, and systolic time intervals were measured by noninvasive impedance

cardiography at the beginning of each exposure, while the subjects were at rest, and again during

the last 5 min of exercise. Metabolic exercise data (V0 E, VO0 2, fB) also were measured. There

were no statistically significant differences between exposures for HR, V0 E, VO0 2, fB, stroke

volume, or systolic time intervals. Exercise increased cardiac output after all exposures;

however, the incremental increase over rest was significantly smaller for the combined O3

and NO2 exposures. The authors speculated that nitrate and nitrite reaction products from the

interaction of O3 and NO2 cross the air/blood interface in the lungs, causing peripheral
AX6-136

vasodilation and a subsequent drop in cardiac output. No major cardiovascular effects of O3

only exposures have been reported in human subjects (see Section AX6.10).

Despite suggested potentiation of O3 response by NO2 in healthy subjects, it is unclear

what response, and at what dose, either sequential or combined gas exposures will induce

in asthmatics. Jenkins et al. (1999) exposed 11 atopic asthmatics in random order to air,

0.1 ppm O3, 0.2 ppm NO2, and 0.1 ppm O3 + 0.2 ppm NO2 for 6 h (IE for 10 min @ 32 L/min

every 40 min). Two weeks later, 10 of these subjects were exposed for 3 h to doubled

concentrations of these gases (i.e., 0.2 ppm O3, 0.4 ppm NO2, and 0.2 ppm O3 + 0.4 ppm NO2)

employing the same exercise regimen. Immediately following each exposure, subjects were

challenged with allergen (D. pteronyssinus) and PD20 FEV1 was determined. Exposure to NO2

alone had minimal effects on FEV1 or airway responsiveness. However, O3 alone or in

combination with NO2 elicited a significantly (p < 0.05) greater decline in FEV1 in a short (3 h)

exposure (higher concentrations) than the long (6 h) exposure, where the effects were not

significant. Allergen challenge inhalation significantly (p = 0.018 to 0.002) reduced PD20 FEV1

in all short, but not the long, exposures. No associations were observed between pollutant

concentrations and physiologic endpoints. The statistical analyses of these data suggest that the

combined effect (O3 + NO2) on lung function (FVC, FEV1) was not significantly greater than the

effect of individual gases for 6-h exposures, thus no additive or potentiating effects have been

observed. Shorter 3-h exposures using twice as high NO2 concentrations, however, showed

significant FEV1 decrements following exposures to atmospheres containing O3. The analysis

also suggests that it is the inhaled concentration, rather than total dose, that determines lung

airway responsiveness to allergen.

The potential for interaction between O3 and other gas mixtures was studied by Rigas et al.

(1997). They used an O3 bolus absorption technique to determine how exposures to O3, NO2,

and SO2 will affect distribution of O3 adsorption by airway mucosa. The selected O3 bolus

volume was set to reach lower conducting airways. Healthy young nonsmokers (6F/6M) were

exposed on separate days at rest in a head dome to 0.36 ppm O3, 0.36 ppm NO2, 0.75 ppm NO2

and 0.75 ppm SO2 for 2 h. The rationale for the selection of these gases was their differential

absorption. Because O3 and NO2 are much less soluble in liquid (i.e., ELF) than SO2, they are

expected to penetrate deeper into the lung than SO2 which is absorbed more quickly in the

epithelial lining fluid of the upper airways. The actual experimental measurements have shown
AX6-137

that during continuous NO2 and SO2 exposure the absorbed fraction of an O3 bolus in lower

conducting airways increased relative to baseline, whereas during continuous O3 exposure the O3

bolus fraction in lower conducting airways decreased. The authors attempted to explain the

differences by suggesting that there may be increased production of an O3-reactive substrate

in epithelial lining fluid due to airway inflammation. As interpreted by the investigators,

during NO2 and SO2 exposures the substrate was not depleted by these gases and so could react

with the O3 bolus, whereas during O3 exposure the substrate was depleted, causing the fractional

absorption of the O3 bolus to decrease. Greater absorption in males than females for all gases

was attributed to anatomical differences in the bronchial tree. 

AX6.11.3 Ozone and Other Pollutant Mixtures Including Particulate Matter

Almost all of the studies published over the last twenty years investigating the health

effects of mixtures of O3 with other air pollutants involved peroxyacetyl nitrate (PAN). These

studies on healthy individuals exposed under laboratory conditions came from the Horvath

laboratory at UC Santa Barbara (Table AX6-13). In the last of this series of studies, DrechslerParks and colleagues (1989) found the same equivocal interaction of O3 and PAN as in previous

studies, which is attributable to O3 exposure alone (U.S. Environmental Protection Agency,

1996). Subsequently, only a couple of studies have investigated the effects of more complex air

pollutant mixtures on human pathophysiology under controlled conditions.

It is not only the interaction between air pollutants in ambient air; but, as Rigas et al.

(1997) has found, an uneven distribution of O3, SO2, and NO2 absorption in the lower conducting

airways of young healthy subjects may modulate pathophysiologic response as well. Exposure

to SO2 and NO2 increased, while exposure to O3 decreased, the absorbing capacity of the airways

for O3. The authors have suggested that SO2 or NO2 -inflamed airways release additional

substrates into the epithelial lining fluid that react with O3, thus progressively removing O3 from

the airway lumen. This mechanism may explain findings of antagonistic response (e.g., Adams

et al., 1987; Dreschler-Parks, 1995) when the two gases are combined in an exposure

atmosphere. 

The mechanisms by which inhalation exposure to other complex ambient atmospheres

containing particulate matter (PM) and O3 induce cardiac events frequently reported in

epidemiologic studies are rarely studied in human subjects under laboratory conditions. 
AX6-138

Recently, Brook et al. (2002) have reported changes in brachial artery tone and reactivity in

healthy nonsmokers following 2-h exposures to a mixture of 0.12 ppm O3 and 153 μg/m3 of

concentrated ambient PM2.5, and a control atmosphere of filtered air with a trace of O3,

administered in random order. Neither systolic nor diastolic pressure was affected by pollutant

exposure despite a significant brachial artery constriction and a reduction in arterial diameter

when compared to filtered air (p = 0.03). The authors postulate that changes in arterial tone may

be a plausible mechanism of air pollution-induced cardiac events. However, the observations of

no changes in blood pressure, and an absence of flow- and nitroglycerin- mediated brachial

artery dilatation, cast some doubt on the plausibility of this mechanism. A number of other

proposed mechanisms advanced to establish a link between cardiac events due to pollution and

changes in vasomotor tone based on the findings of this study are purely speculative.

AX6.12 CONTROLLED STUDIES OF AMBIENT AIR EXPOSURES

A large amount of informative O3 exposure-effects data has been obtained in controlled

laboratory exposure studies under a variety of different experimental conditions. However,

laboratory simulation of the variable pollutant mixtures present in ambient air is not practical. 

Thus, the exposure effects of one or several artificially generated pollutants (i.e., a simple

mixture) on pulmonary function and symptoms may not explain responses to ambient air where

complex pollutant mixtures exist. Epidemiologic studies, which do investigate ambient air

exposures, do not typically provide the level of control and monitoring necessary to adequately

characterize short term responses. Thus, controlled exposures to ambient air using limited

numbers of volunteers have been used to try and bridge the gap between laboratory and

community exposures.

AX6.12.1 Mobile Laboratory Studies

As presented in previous criteria documents (U.S. Environmental Protection Agency, 1986;

1996), quantitatively useful information on the effects of acute exposure to photochemical

oxidants on pulmonary function and symptoms responses originated from field studies using a

mobile laboratory. These field studies involved subjects exposed to ambient air, FA without

pollutants, or FA containing artificially generated concentrations of O3 that are comparable to
AX6-139

those measured in the ambient environment. As a result, measured pulmonary responses in

ambient air can be directly compared to those found in more artificial or controlled conditions. 

However, the mobile laboratory shares some of the same limitations of stationary exposure

laboratories (e.g., limited number of both subjects and artificially generated pollutants for

testing). Further, mobile laboratory ambient air studies are dependent on ambient outdoor

conditions which can be unpredictable, uncontrollable, and not completely characterizable.

As summarized in Table AX6-15, investigators in California used a mobile laboratory and

demonstrated that pulmonary effects of ambient air in Los Angeles residents are related to O3

concentration and level of exercise (Avol et al., 1983, 1984, 1985a,b,c, 1987; Linn et al., 1980,

1983). Avol et al. (1987) observed no significant pulmonary function or symptoms responses in

children (8 to 11 years) engaged in moderate continuous exercise for 1 h while breathing

ambient air with an O3 concentration of 0.113 ppm. However, significant pulmonary function

decrements and increased symptoms of breathing discomfort were observed in healthy

exercising (1 h continuous) adolescents (Avol et al., 1985a,b), athletes, (Avol et al., 1984, 1985c)

and lightly exercising asthmatic subjects (Linn et al., 1980, 1983) at O3 concentrations averaging

from 0.144 to 0.174 ppm. Many of the healthy subjects with a history of allergy appeared to be

more responsive to O3 than “nonallergic” subjects (Linn et al., 1980, 1983), although a

standardized evaluation of atopic status was not performed. Comparative studies of exercising

athletes (Avol et al., 1984, 1985c) with chamber exposures to oxidant-polluted ambient air

(mean O3 concentration of 0.153 ppm) and purified air containing a controlled concentration of

generated O3 at 0.16 ppm showed similar pulmonary function responses and symptoms,

suggesting that acute exposures to coexisting ambient pollutants had minimal contribution to

these responses under the typical summer ambient conditions in Southern California. This

contention is similar to, but extends, the laboratory finding of no significant difference in

pulmonary function effects between O3 and O3 plus PAN exposures (Drechsler-Parks, 1987b). 

Additional supporting evidence is provided in Section AX6.11.

AX6.12.2 Aircraft Cabin Studies

Respiratory symptoms and pulmonary function effects resulting from exposure to O3 in

commercial aircraft flying at high altitudes, and in altitude-simulation studies, have been

reviewed elsewhere (U.S. Environmental Protection Agency, 1986, 1996). Flight attendants, 
Table AX6-15. Acute Effects of Ozone in Ambient Air in Field Studies with a Mobile Labor

Mean Ozone

Concentrationb Ambient

Temperaturec

(°C)

Exposure

Duration

Activity Level

(

.

VE ppm μg/m ) Number of Subjects Observed Effect(s) 

3

0.113 ± .033 221 ± 65 33 ± 1 1 h CE (22 L/min) 66 healthy children, 

8 to 11 years old

No significant changes in forced expifunction and symptoms of breathingdiscomfort after exposure to 0.113 pp

ambient air.

0.144 ± .043 282 ± 84 32 ± 1 1 h CE (32 L/min) 59 healthy

adolescents, 12 to 15 years old

Small significant decreases in FVC (!

FEV0.75 (!4.0%), FEV1 (!4.2%), and 

(!4.4%) relative to control with no re

during a 1-h postexposure rest; no sigincreases in symptoms.

0.153 ± .025 300 ± 49 32 ± 2 1 h CE (53 L/min) 50 healthy adults

(competitivebicyclists)

Mild increases in symptoms scores ansignificant decreases in FEV1 (!5.3%

FVC; mean changes in ambient air wstatistically different from those in pucontaining 0.16 ppm O3.

0.156 ± .055 306 ± 107 33 ± 4 1 h CE (38 L/min) 48 healthy adults,

50 asthmatic adults

No significant changes for total sympscore or forced expiratory performannormals or asthmatics; however, FEV

remained low or decreased further (!

after ambient air exposure in asthmat

0.165 ± .059 323 ± 115 33 ± 3 1 h CE (42 L/min) 60 "healthy" adults

(7 were asthmatic)

Small significant decreases in FEV1 (

and FVC with no recovery during a 1postexposure rest; TLC decreased and 

increased slightly.

0.174 ± .068 341 ± 133 33 ± 2 2 h IE (2 times resting)

at 15-min intervals

34 "healthy" adults,30 asthmatic adults

Increased symptom scores and smallsignificant decreases in FEV1 (!2.4%

PEFR, and TLC in both asthmatic ansubjects; however, 25/34 healthy subjallergic and "atypically" reactive to pambient air.

aSee Appendix A for abbreviations and acronyms.bRanked by lowest level of O3 in ambient air, presented as the mean ± SD.cMean ± SD.

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because of their physical activities at altitude, tend to receive higher exposures. In a series of

hypobaric chamber studies of nonsmoking subjects exposed to 1,829 m (6,000 ft) and O3 at

concentrations of 0.2 and 0.3 ppm for 3 or 4 h (Lategola et al., 1980a,b), increased symptoms

and pulmonary function decrements occurred at 0.3 ppm but not at 0.2 ppm.

Commercial aircraft cabin O3 levels were reported to be very low (average concentration

0.01 to 0.02 ppm) during 92 randomly selected smoking and nonsmoking flights in 1989 (Nagda

et al., 1989). None of these flights recorded O3 concentrations exceeding the 3-h time-weighted

average (TWA) standard of 0.10 ppm promulgated by the Federal Aviation Administration

(FAA, 1980), probably due to the use of O3-scrubbing catalytic filters (Melton, 1990). However,

in-flight O3 exposure can still occur because catalytic filters are not necessarily in continuous use

during flight. Other factors to consider in aircraft cabins, however, are erratic temperature

changes, lower barometric pressure and oxygen pressure, and lower humidity, often reaching

levels between 4 and 17% (Rayman, 2002).

Ozone contamination aboard high-altitude aircraft also has been an interest to the U.S. Air

Force because of complaints by crew members of frequent symptoms of dryness and irritation of

the eyes, nose, and throat and an occasional cough (Hetrick et al., 2000). Despite the lack of

ventilation system modifications as used in commercial aircraft, the O3 concentrations never

exceeded the FAA ceiling limit of 0.25 ppm and exceeded the 3-h TWA of 0.10 ppm only 7% of

the total monitored flight time (43 h). The authors concluded that extremely low average

relative humidity (12%) during flight operations was most likely responsible for the reported

symptoms. 

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ozone-induced increase in bronchial responsiveness in human subjects. Am. Rev. Respir. Dis. 142: 817-821.

Yu, M.; Pinkerton, K. E.; Witschi, H. (2002) Short-term exposure to aged and diluted sidestream cigarette smoke

enhances ozone-induced lung injury in B6C3F1 mice. Toxicol. Sci. 65: 99-106.

Zhang, L.-Y.; Levitt, R. C.; Kleeberger, S. R. (1995) Differential susceptibility to ozone-induced airways

hyperreactivity in inbred strains of mice. Exp. Lung Res. 21: 503-518.
AX7-1

ANNEX AX7. EPIDEMIOLOGIC STUDIES OF HUMAN

HEALTH EFFECTS ASSOCIATED WITH AMBIENT

OZONE EXPOSURE
AX7-2

AX7.1 TABLES OF EPIDEMIOLOGIC STUDIES OF HUMAN HEALTH

EFFECTS ASSOCIATED WITH AMBIENT OZONE EXPOSURE
AX7-3

LIST OF STUDIES BY AUTHOR

Page 

Abbey et al. (1999) ..................................................... AX7-119

Anderson et al. (1996) .................................................... AX7-87

Anderson et al. (1997) .................................................... AX7-61

Anderson et al. (1998) .................................................... AX7-63

Anderson et al. (2001) .................................................... AX7-88

Atkinson et al. (1999a) .................................................... AX7-47

Atkinson et al. (1999b) ................................................... AX7-63

Atkinson et al. (2001) .................................................... AX7-61

Avol et al. (1998) ........................................................ AX7-10

Avol et al. (2001) ....................................................... AX7-107

Ballester et al. (2001) ..................................................... AX7-66

Beeson et al. (1998) ..................................................... AX7-119

Bell et al. (2004) ........................................................ AX7-74

Bell et al. (2005) ........................................................ AX7-71

Borja-Aburto et al. (1997) ................................................. AX7-95

Borja-Aburto et al. (1998) ................................................. AX7-95

Bourcier et al. (2003) ..................................................... AX7-48

Brauer and Brook (1997) .................................................. AX7-18

Brauer et al. (1996) ...................................................... AX7-18

Bremner et al. (1999) ..................................................... AX7-87

Burnett et al. (1995) ...................................................... AX7-57

Burnett et al. (1997a) ..................................................... AX7-57

Burnett et al. (1997b) ..................................................... AX7-58

Burnett et al. (1999) ...................................................... AX7-58

Burnett et al. (2001) ...................................................... AX7-58

Calderón-Garcidueñas et al. (1995) ......................................... AX7-115

Cassino et al. (1999) ..................................................... AX7-41

Castellsague et al. (1995) .................................................. AX7-48

Castillejos et al. (1995) ................................................... AX7-27

Chan and Wu (2005) ..................................................... AX7-32

Chang et al. (2005) ....................................................... AX7-68

Charpin et al. (1999) .................................................... AX7-111

Chen et al. (1998) ........................................................ AX7-31

Chen et al. (1999) ........................................................ AX7-32

Chen et al. (2000) ........................................................ AX7-14

Chen et al. (2002) ....................................................... AX7-110

Chew et al. (1999) ....................................................... AX7-51

Chock et al. (2000) ....................................................... AX7-82

Cifuentes et al. (2000) .................................................... AX7-97

Cuijpers et al. (1994) ..................................................... AX7-25

Dab et al. (1996) ........................................................ AX7-89

De Leon et al. (2003) ..................................................... AX7-82

Delfino et al. (1996) ...................................................... AX7-13
AX7-4

LIST OF STUDIES BY AUTHOR (cont’d)

Page 

Delfino et al. (1997a) ..................................................... AX7-12

Delfino et al. (1997b) ..................................................... AX7-45

Delfino et al. (1998a) ..................................................... AX7-13

Delfino et al. (1998b) ..................................................... AX7-46

Delfino et al. (2003) ...................................................... AX7-12

Delfino et al. (2004) ...................................................... AX7-13

Desqueyroux et al. (2002a) ................................................ AX7-20

Desqueyroux et al. (2002b) ................................................ AX7-20

Díaz et al. (1999) ........................................................ AX7-94

Dockery et al. (1992) ..................................................... AX7-78

Dockery et al. (2005) ..................................................... AX7-36

Dominici et al. (2003) .................................................... AX7-75

Fairley (1999) .......................................................... AX7-77

Fairley (2003) .......................................................... AX7-77

Friedman et al. (2001) .................................................... AX7-42

Frischer et al. (1993) ..................................................... AX7-22

Frischer et al. (1997) ..................................................... AX7-23

Frischer et al. (1999) .................................................... AX7-113

Frischer et al. (2001) .................................................... AX7-113

Fung et al. (2005) ........................................................ AX7-59

Galizia and Kinney (1999) ................................................ AX7-102

Gamble (1998) .......................................................... AX7-78

Garcia-Aymerich et al. (2000) .............................................. AX7-92

Gauderman et al. (2000; 2004a,b) .......................................... AX7-105

Gauderman et al. (2002) ................................................. AX7-105

Gent et al. (2003) ........................................................ AX7-16

Gielen et al. (1997) ...................................................... AX7-25

Gilliland et al. (2001) ..................................................... AX7-11

Gold et al. (1999) ........................................................ AX7-27

Gold et al. (2000) ........................................................ AX7-35

Gold et al. (2003) ........................................................ AX7-35

Goldberg et al. (2001) .................................................... AX7-84

Goldberg et al. (2003) .................................................... AX7-84

Gong et al. (1998b) ..................................................... AX7-109

Goss et al. (2004) ....................................................... AX7-102

Gouveia and Fletcher (2000a) .............................................. AX7-66

Gouveia and Fletcher (2000b) .............................................. AX7-96

Gouveia et al. (2004) .................................................... AX7-115

Greer et al. (1993) ...................................................... AX7-103

Gryparis et al. (2004) ..................................................... AX7-85

Gwynn and Thurston (2001) ............................................... AX7-56

Gwynn et al. (2000) ...................................................... AX7-56

Ha et al. (2001) ........................................................ AX7-116
AX7-5

LIST OF STUDIES BY AUTHOR (cont’d)

Page 

Ha et al. (2003) ........................................................ AX7-100

Hagen et al. (2000) ....................................................... AX7-65

Hajat et al. (1999; 2002) .................................................. AX7-47

Hedley et al. (2002) ..................................................... AX7-101

Hernández-Garduño et al. (1997) ........................................... AX7-49

Hiltermann et al. (1998) ................................................... AX7-26

Hoek (2003) ............................................................ AX7-90

Hoek and Brunekreef (1995) ............................................... AX7-26

Hoek et al. (2000) ....................................................... AX7-90

Hoek et al. (2001) ....................................................... AX7-90

Holguín et al. (2003) ..................................................... AX7-39

Hong et al. (2002) ...................................................... AX7-100

Höppe et al. (1995a,b) .................................................... AX7-23

Höppe et al. (2003) ...................................................... AX7-24

Horak et al. (2002a,b) ................................................... AX7-114

Huang et al. (2005) ...................................................... AX7-75

Hwang and Chan (2002) .................................................. AX7-50

Ihorst et al. (2004) ...................................................... AX7-112

Ilabaca et al. (1999) ...................................................... AX7-50

Ito (2003; 2004) ......................................................... AX7-55

Ito and Thurston (1996) ................................................... AX7-79

Ito et al. (2005) .......................................................... AX7-72

Jaffe et al. (2003) ........................................................ AX7-40

Jalaludin et al. (2000) ..................................................... AX7-30

Jalaludin et al. (2004) ..................................................... AX7-31

Jones et al. (1995) ....................................................... AX7-40

Just et al. (2002) ......................................................... AX7-21

Kim et al. (2004) ........................................................ AX7-98

Kinney and Lippmann (2000) ............................................. AX7-103

Kinney and Özkaynak (1991) .............................................. AX7-76

Kinney et al. (1995) ...................................................... AX7-76

Kinney et al. (1996b) .................................................... AX7-110

Klemm and Mason (2000) ................................................. AX7-83

Koken et al. (2003) ...................................................... AX7-54

Kopp et al. (1999) ....................................................... AX7-24

Kopp et al. (2000) ...................................................... AX7-112

Korrick et al. (1998) ...................................................... AX7-17

Künzli et al. (1997) ..................................................... AX7-108

Kuo et al. (2002) ....................................................... AX7-117

Kwon et al. (2001) ....................................................... AX7-99

Lagerkvist et al. (2004) ................................................... AX7-21

Le Tertre et al. (2002a) ................................................... AX7-88

Le Tertre et al. (2002b) ................................................... AX7-62
AX7-6

LIST OF STUDIES BY AUTHOR (cont’d)

Page 

Lee and Schwartz (1999) .................................................. AX7-99

Lee et al. (1999) ......................................................... AX7-99

Lee et al. (2002) ......................................................... AX7-67

Levy et al. (2005) ........................................................ AX7-73

Liao et al. (2004) ........................................................ AX7-33

Lin et al. (1999) ......................................................... AX7-50

Lin et al. (2003) ......................................................... AX7-59

Lin et al. (2004) ......................................................... AX7-60

Linn et al. (1996) ........................................................ AX7-11

Linn et al. (2000) ........................................................ AX7-53

Lipfert et al. (2000a) ..................................................... AX7-81

Lipfert et al. (2000b; 2003) ............................................... AX7-118

Lippmann et al. (2000) ............................................ AX7-55, AX7-80

Loomis et al. (1999) ...................................................... AX7-96

Luginaah et al. (2005) .................................................... AX7-59

Mann et al. (2002) ....................................................... AX7-52

Martins et al. (2002) ...................................................... AX7-50

McConnell et al. (1999) .................................................. AX7-105

McConnell et al. (2002) .................................................. AX7-106

McConnell et al. (2003) .................................................. AX7-106

McDonnell et al. (1999) .................................................. AX7-104

Metzger et al. (2004) ..................................................... AX7-43

Moolgavkar (2000) ...................................................... AX7-80

Moolgavkar (2003) ...................................................... AX7-79

Moolgavkar et al. (1995) .................................................. AX7-81

Moolgavkar et al. (1997) .................................................. AX7-55

Morgan et al. (1998a) ..................................................... AX7-67

Morgan et al. (1998b) .................................................... AX7-98

Mortimer et al. (2000) .................................................... AX7-10

Mortimer et al. (2002) ..................................................... AX7-9

Naeher et al. (1999) ...................................................... AX7-17

Nauenberg and Basu (1999) ............................................... AX7-53

Neas et al. (1995) ........................................................ AX7-15

Neas et al. (1999) ........................................................ AX7-16

Neidell (2004) .......................................................... AX7-52

Newhouse et al. (2004) ................................................... AX7-14

Oftedal et al. (2003) ...................................................... AX7-65

Ostro (1995) ............................................................ AX7-77

Ostro (2000) ............................................................ AX7-77

Ostro et al. (1996) ....................................................... AX7-97

Ostro et al. (2001) ....................................................... AX7-12

O’Neill et al. (2004) ...................................................... AX7-96

Palli et al. (2004) ....................................................... AX7-114
AX7-7

LIST OF STUDIES BY AUTHOR (cont’d)

Page 

Park et al. (2005) ........................................................ AX7-34

Peel et al. (2005) ........................................................ AX7-43

Pereira et al. (1998) ...................................................... AX7-97

Pereira et al. (2005) ..................................................... AX7-120

Peters et al. (1999a,b) ................................................... AX7-104

Peters et al. (2000a) ...................................................... AX7-33

Peters et al. (2000b) ...................................................... AX7-91

Peters et al. (2001) ....................................................... AX7-34

Petroeschevsky et al. (2001) ............................................... AX7-67

Poloniecki et al. (1997) ................................................... AX7-64

Ponce de Leon et al. (1996) ................................................ AX7-63

Pönkä and Virtanen (1996) ................................................ AX7-66

Pönkä et al. (1998) ....................................................... AX7-91

Pope et al. (2002) ....................................................... AX7-118

Prescott et al. (1998) ............................................. AX7-64, AX7-88

Ramadour et al. (2000) .................................................. AX7-111

Rich et al. (2004) ........................................................ AX7-37

Rich et al. (2005) ........................................................ AX7-37

Ritz and Yu (1999) ..................................................... AX7-107

Ritz et al. (2000) ....................................................... AX7-107

Ritz et al. (2002) ....................................................... AX7-108

Roemer and van Wijinen (2001) ............................................ AX7-90

Romieu et al. (1996) ..................................................... AX7-28

Romieu et al. (1997) ..................................................... AX7-28

Romieu et al. (1998) ..................................................... AX7-29

Romieu et al. (2002) ..................................................... AX7-29

Romieu et al. (2004) ..................................................... AX7-30

Ross et al. (2002) ........................................................ AX7-15

Ruidavets et al. (2005) .................................................... AX7-38

Saez et al. (1999) ........................................................ AX7-92

Saez et al. (2002) ........................................................ AX7-92

Saldiva et al. (1994) ...................................................... AX7-97

Saldiva et al. (1995) ...................................................... AX7-97

Samet et al. (2000) ....................................................... AX7-75

Sartor et al. (1995) ....................................................... AX7-89

Scarlett et al. (1996) ...................................................... AX7-19

Schindler et al. (2001) .................................................... AX7-22

Schouten et al. (1996) .................................................... AX7-65

Schwartz (1996) ......................................................... AX7-54

Schwartz (2005) ......................................................... AX7-76

Schwartz et al. (1996) .................................................... AX7-55

Schwartz et al. (2005) .................................................... AX7-35

Sheppard (2003) ......................................................... AX7-53
AX7-8

LIST OF STUDIES BY AUTHOR (cont’d)

Page 

Sheppard et al. (1999) .................................................... AX7-53

Simpson et al. (1997) ..................................................... AX7-98

Stieb et al. (1996) ........................................................ AX7-46

Sunyer and Basagana (2001) ............................................... AX7-93

Sunyer et al. (1996) ...................................................... AX7-93

Sunyer et al. (1997) ...................................................... AX7-47

Sunyer et al. (2002) ...................................................... AX7-94

Tager et al. (2005) ...................................................... AX7-109

Taggart et al. (1996) ...................................................... AX7-20

Téllez-Rojo et al. (2000) .................................................. AX7-96

Tenías et al. (1998; 2002) ................................................. AX7-49

Thompson et al. (2001) ................................................... AX7-48

Thurston et al. (1997) ..................................................... AX7-17

Tobías et al. (1999) ...................................................... AX7-49

Tolbert et al. (2000) ...................................................... AX7-44

Touloumi et al. (1997) .................................................... AX7-86

Tsai et al. (2003a) ....................................................... AX7-69

Tsai et al. (2003b) ...................................................... AX7-100

Ulmer et al. (1997) ....................................................... AX7-25

Vedal et al. (2003) ....................................................... AX7-83

Vedal et al. (2004) ....................................................... AX7-38

Verhoeff et al. (1996) ..................................................... AX7-91

Villeneuve et al. (2003) ................................................... AX7-83

Ward et al. (2002) ....................................................... AX7-19

Weisel et al. (2002) .............................................. AX7-42, AX7-56

Wilson et al. (2005) ...................................................... AX7-41

Wong et al. (1999a) ...................................................... AX7-69

Wong et al. (1999b) ...................................................... AX7-70

Wong et al. (2001) ...................................................... AX7-101

Wong et al. (2002) ....................................................... AX7-62

Yang et al. (2003) ....................................................... AX7-60

Yang et al. (2004a) ....................................................... AX7-68

Yang et al. (2004b) ..................................................... AX7-100

Zhu et al. (2003) ......................................................... AX7-44

Zmirou et al. (1996) ...................................................... AX7-89

Zmirou et al. (1998) ...................................................... AX7-86
Table AX7-1. Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms in F

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United StatesMortimer et al. (2002)Eight urban areas inthe U.S.: St. Louis, MO;Chicago, IL;Detroit, MI;Cleveland, OH;Washington, DC;Baltimore, MD;East Harlem, NY;Bronx, NY Jun-Aug 1993

National Cooperative InnerCity Asthma Study(NCICAS) cohort. This panelstudy examined 846asthmatic children aged4-9 years for O3 exposure

effects on PEF and morningsymptoms using linear mixedeffects models and GEE.

8-h avg O3

(10 a.m.-6 p.m.):48 ppbSD not provided.Range of mediansacross citiesshown in a figure:Approximately34 to 58 ppb.<5% of daysexceeded 80 ppb.

PM10, NO2,

SO2

No associations were seen betweensingle or multiday O3 measures and any

evening outcome measure. The effectsof O3 on morning outcomes increased

over several days with the strongestassociations seen for multiday lags. Joint modeling of O3 with NO2 or SO2

resulted in slightly reduced estimates foreach pollutant. Closed cohort. Approximately 60% of NCICAS cohortreturned diary, characterizations similarto entire cohort.

8-h % cLag All St. ChiDetCleWaBalEasBroOddMoLag All St. ChiDetCleWaBalEasBro

AX7-9
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Mortimer et al. (2000)Eight urban areas inthe U.S.: St. Louis, MO;Chicago, IL;Detroit, MI;Cleveland, OH;Washington, DC;Baltimore, MD;East Harlem, NY; Bronx, NY Jun-Aug 1993

A cohort of 846 asthmaticchildren aged 4-9 yearsexamined for effects ofsummer O3 exposure on PEF

and morning symptoms. Twosubgroups were compared: (1) low birth weight orpremature and (2) normalbirth weight or full-term.Analysis using GEE andlinear mixed effects models. Panel study.

8-h avg O3

(10 a.m.-6 p.m.):48 ppbSD not provided.See Mortimeret al. (2002).

None Low birth weight and premature

asthmatic children had greater declinesin PEF and higher incidence of morningsymptoms than normal birth weight andfull-term asthmatic children.

8-h 

% cLow Lag NorLag 

Intep < OddMoLow Lag NorLag Intep < 

Avol et al. (1998)Southern CaliforniacommunitiesSpring-summer 1994

Three panels of children (age10-12 years): (1) asthmatic(n = 53); (2) wheezy (n = 54);and (3) healthy (n = 103). Examined for symptoms,medication use, outdoor time,physical activity, andpulmonary function measuresin relation to O3 exposure, via

logistic regression and GLM.

Stratified analysisof low and highO3: 

Fixed site 1-hmax O3:

Low: <100 ppb High: >100 ppbPersonal 24-havg O3:

Low: #15.6 ppb

High: $32.4 ppb

None The three groups responded similarly. 

Few pulmonary function or symptomassociations. Asthmatic children hadthe most trouble breathing, the mostwheezing, and the most inhaler use onhigh O3 days in the spring. Ozone levels

were considered too low during theperiod of the study. Noncomplianceby subjects may have been a problem. Other analysis methods may have beenmore appropriate.

Muconresp

AX7-10
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Gilliland et al. (2001)12 SouthernCaliforniacommunitiesJan-Jun 1996

Time-series study of 1,9334th grade children (age9-10 years) followed forschool absences. Eachabsence classified as illnessrelated or not. Amongformer, classified intorespiratory or gastrointestinal. Respiratory absences furtherclassified into upper or lower. Pollution measured in centralsite in each town. Analysis ofdistributed lag effectscontrolling for time, day ofweek, and temperature in aPoisson model.

8-h avg O3

(10 a.m.-6 p.m.):Levels notreported.Figure depictsmean range ofapproximately35 to 55 ppbacross the12 communities.

PM10, NO2 Ozone strongly associated with illnessrelated and respiratory absences. PM10

only associated with upper respiratoryabsences. Long distributed lag effectsfor O3 raise questions about adequacyof control for seasonal changes.

8-h 

% cAll 62.9Non37.3Res82.9Upp45.Low173

Linn et al. (1996)Three towns inCalifornia: Rubidoux,Upland, TorranceFall-spring 1992-1993and 1993-1994

Panel study of 269 schoolchildren, each followed formorning/afternoon lungfunction and symptoms for1 week in fall, winter, andspring during their 4th and5th grade school years. Personal exposure monitoringin a subset. Analyzedafternoon symptoms vs. sameday pollution and morningsymptoms vs. 1-daylag pollution.

24-h avg O3:

Personal:5 ppb SD 3Range 1-16Central site:23 ppbSD 12Range 3-53

PM2.5, NO2 Central site O3 correlated with personal

exposures, r = 0.61. Ozone effectsobserved on lung function but onlysignificant for FEV1 in one analysis. 

No effects on symptoms. Ozone effectswere not robust to NO2 or PM2.5. Power

may have been limited by short followupwithin seasons (limiting both persondays and variability in exposures).

ChaFEV

!0.

FEV

!0.

FEV

!0.

FVC 

!0.

FVC 

!0.

FVC 

!0.

AX7-11
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Ostro et al. (2001)Central Los Angelesand Pasadena, CAAug-Oct 1993

Panel study of 138 AfricanAmerican children aged8-13 years with doctordiagnosed asthma requiringmedication in past yearfollowed for daily respiratorysymptoms and medicationuse. Lags of 0 to 3 daysexamined.

1-h max O3:

Los Angeles: 59.5 ppbSD 31.4Pasadena:95.8 ppbSD 49.0

PM10, NO2,

pollen, mold

Correlation between PM10 and O3 was

r = 0.35. Significant O3 effect seen for

extra medication use (above normal use). No O3 effect on symptoms in expected

direction observed. Inverse associationseen for cough. PM10 effects seen at a

lag of 3 days. Time factors not explicitlycontrolled in analysis; may have led toconfounding of O3 effects.

1-h 

OddExtLag ResShoLag WhLag CouLag 

Delfino et al. (2003)Los Angeles, CANov 1999-Jan 2000

A panel study of 22 Hispanicchildren with asthma aged10-16 years. Filled outsymptom diaries in relation topollutant levels. Analysisusing GEE model.

1-h max O3:

25.4 ppbSD 9.6

NO2, SO2, CO,

volatileorganiccompounds,PM10

Support the view that air toxics inthe pollutant mix from traffic mayhave adverse effects on asthma inchildren.

1-h 

OddSymdailLag 

Delfino et al. (1997a)Alpine, CAMay-Aug1994

Panel study of 22 asthmaticsaged 9-46 years followed forrespiratory symptoms,morning-afternoon PEF, and

$2 agonist inhaler use. 

Personal O3 measured for

12 h/day using passivemonitors. GLM mixedmodel.

Ambient:12-h avg O3(8 a.m.-8 p.m.): 64 ppbSD 17Personal:12-h avg O3: 

(8 a.m.-8 p.m.)18 ppbSD 14

PM10, pollen,

fungi

No O3 effects observed. No 

AX7-12
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Delfino et al. (1998a)Alpine, CAAug-Oct 1995

A panel of 24 asthmatics aged9-17 years followed for dailysymptoms. Analysis usingGEE model.

1-h max O3:

90 ppbSD 18

PM10 Asthma symptoms were significantly

associated with both ambient O3 and

PM10 in single-pollutant models. Ozone

effects generally robust to PM10. Current

day O3 effects strongest in asthmatics noton anti-inflammatory medication. Effects of O3 and PM10 were largely

independent. The largest effects forPM10 were seen for a 5-day distributed

lag. For O3 effects, there were no lag

day effects; current day results showedthe greatest effect.

1-h 

OddO3 o

Lag O3 w

Lag 

Delfino et al. (2004)Alpine, CAAug-Oct 1999, AprJun 2000

Panel study of 19 asthmaticchildren (age 9-17 years)followed daily for 2 weeks todetermine relationshipbetween air pollutants,namely PM, and FEV1. 

Linear mixed model used foranalysis.

8-h max O3:

62.8 ppbSD 15.1IQR 22.0

PM2.5, PM10,NO2

Significant declines in FEV1 associated

with various PM indices (personal,indoor home, etc.), but not ambient O3

levels.

No 

Delfino et al. (1996)San Diego, CASep-Oct 1993

Panel study of 12 wellcharacterized moderateasthmatics aged 9-16 years(7 males, 5 females) followedover 6 weeks for medicationuse and respiratorysymptoms. Allergy measuredat baseline with skin pricktests. Personal O3

measured with passive badge. Analysis with GLM mixedmodel.

Ambient:1-h max O3:68 ppbSD 30Ambient:12-h avg O3:

43 ppbSD 17Personal:12-h avg O3:11.6 ppbSD 11.2

PM2.5, SO42!,

H+, HNO3,

pollen, fungalspores

No effect of ambient O3 on symptom

score. Personal O3 significant for

symptoms, but effect disappeared whenconfounding day-of-week effect wascontrolled with weekend dummyvariable. $2 inhaler used among

7 subjects was significantly related topersonal O3. Results of this small study

suggest the value of personal exposuredata in providing more accurateestimates of exposures. However, nearly50% of personal O3 measurements were

below limits of detection, diminishingvalue of these data. Pollen and fineparticulate (low levels) were notassociated with any of the outcomes.

Cha

(per 

0.0p = 

AX7-13
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Chen et al. (2000)Washoe County, NV1996-1998

Time-series study of schoolabsenteeism examined among27,793 students (kindergartento 6th grade) from 57elementary schools.First-order autoregressionmodels used to assessrelationship between O3 and

school absenteeism afteradjusting for weather, day ofweek, month, holidays, andtime trends. Ozone levelsfrom the current day, andcumulative lags of 1-14 days,1-21 days, and 1-28 daysexamined.

1-h max O3: 37.45 ppbSD 13.37

PM10, CO Multipollutant models were examined. 

Ozone concentrations in the preceding14 days were significantly associatedwith school absenteeism for studentsin grades 1 through 6, but not those inkindergarten. Both PM10 and CO

concentrations on the concurrent daywere associated with school absenteeism,but the estimate for PM10 was a negativevalue.

1-h 

TotO3 w

Lag 

Newhouse et al.(2004)Tulsa, OKSep-Oct 2000

Panel study of 24 subjectsaged 9-64 years withphysician diagnosis ofasthma. Performed PEFtwice daily (morning andafternoon), and reported dailyrespiratory symptoms andmedication use. Forwardstepwise multiple regressionmodels and Pearsoncorrelation analyses.

24-h avg O3:

30 ppbRange 10-70

PM2.5, CO,

SO2, pollen,

fungal spores

Among ambient air pollutants, O3

seemed to be most significant factor. Morning PEF values significantlyassociated with average and maximumO3 levels on the previous day. Individualsymptoms, including wheezing,headache, and fatigue, also significantlyrelated to average and maximum dailyO3. Multiple regression analysesproduced complex models with differentpredictor variables for each symptom.

PeaMoMe

Lag Max

Lag 

AX7-14
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Ross et al. (2002)East Moline, IL andnearby communitiesMay-Oct 1994

Panel study of 59 asthmaticsaged 5-49 years recruited. 19 lost to follow-up, yieldingstudy population of 40. Assessment of PEFand respiratory symptoms. Analytical methods unclear interms of control fortime factors.

8-h max O3:

41.5 ppbSD 14.2IQR 20

PM10, SO2,

NO2, pollen,

fungi

Saw significant associations betweenO3 and both PEF declines and

symptom increases. Most but not alleffects remained after controlling fortemperature, pollen and fungi. Ozoneeffect on morning PEF disappeared afteradjusting for temperature. No PM10effects observed.

8-h 

ChaMoLag 

AftLag 

SymMoLag AftLag 

Neas et al. (1995)Uniontown, PASummer 1990

Panel study of 83 4th and 5thgrade children reported twicedaily PEF and the presence ofcold, cough, or wheeze. Relationship to pollutants wasanalyzed by an autoregressivelinear regression model/GEE. The number of hours eachchild spent outdoors duringthe preceding 12-h period wasevaluated.

12-h avg O3:

Daytime (8 a.m.-8 p.m.):50.0 ppbOvernight(8 p.m.-8 a.m.):24.5 ppb

SO2, PM10, H+ Evening cough was associated with O3

levels weighted by hours spent outdoorsduring the prior 12 h. A decrease in PEFwas associated with O3 levels weighted

by hours spent outdoors. When particlestrong acidity was added to the model,the decrement was decreased and nolonger significant.

12-h 

Eve

!2.OddEve1.36 ConpropdurEve!2.OddEve2.20 

AX7-15
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Neas et al. (1999)Philadelphia, PAJul-Sep 1993

Panel study of 156 childrenaged 6-11 years at twosummer camps followed fortwice-daily PEF. Analysisusing mixed effects modelsadjusting for autocorrelatederrors.

Daytime 12-h avg O3

(9 a.m-9 p.m.):SW camp:57.5 ppbIQR 19.8NE camp:55.9 ppbIQR 21.9

H+, SO42!,

PM2.5, PM10,

PM10-2.5

Some O3 effects detected as well as PM

effects. Similar O3-related decrements

observed in both morning and afternoonPEF. Ozone effects not robust to SO42!

in two-pollutant models, whereas SO42!effects relatively robust to O3.

12-h 

MoO3 o

Lag 

!1.

Lag 

!2.O3 w

Lag 

!0.

Gent et al. (2003)Southern NewEnglandApr-Sep 2001

Panel study of 271 children(age <12 years) with active,doctor-diagnosed asthmafollowed over 183 days forrespiratory symptoms. Foranalysis, cohort split into twogroups: 130 who usedmaintenance medicationduring follow-up and141 who did not, onassumption that medicationusers had more severeasthma. Logistic regressionanalyses performed. 

1-h max O3:

58.6 ppbSD 19.08-h max O3:51.3 ppbSD 15.5

PM2.5 Correlation between 1-h max O3 and

daily PM2.5 was 0.77 during this warmseason study. Large numbers of

statistical tests performed. Significantassociations between symptoms and O3

seen only in medication users, asubgroup considered to be moresensitive. PM2.5 significant for somesymptoms, but not in two-pollutantmodels. Ozone effects generally robustto PM2.5. Study limitations include

limited control for meteorological factorsand the post-hoc nature of the populationstratification by medication use.

1-h 

OddRegCheO3 o

Lag O3 w

Lag ShoO3 o

Lag 

AX7-16
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Korrick et al. (1998)Mount Washington,NHSummers 1991, 1992

Cross-sectional studyevaluating the acute effects ofambient O3 on pulmonary

function of exercising adults. 530 hikers (age 15-64 years)monitored before and aftertheir hike. Analysis using ageneral linear regressionmodel. 

Avg of hourly O3during each hike: 40 ppbSD 12Range 21-74

PM2.5, smoke,

acidity

With prolonged outdoor exercise lowlevel exposures to O3 were associated

with significant effects on pulmonaryfunction. Hikers with asthma had a4-fold greater responsiveness to exposureto O3.

% c(per 

FEV

FVC

Thurston et al. (1997)Connecticut RiverValley, CTJune 1991, 1992, 1993

Panel study of children (age7-13 years) with moderate-tosevere asthma followed formedication use, lungfunction, and medicalsymptoms at a summerasthma camp for 1 week in1991 (n = 52), 1992 (n = 58),and 1993 (n = 56). Analysiswas conducted using bothPoisson modeling and GLM.

1-h max O3:

1991: 114.0 ppb1992: 52.2 ppb1993: 84.6 ppb1991-1993: 83.6 ppb

H+, SO42! Ozone was most consistently associated

with acute asthma exacerbation, chestsymptoms, and lung functiondecrements. Pollen was poorlyassociated with any adverse effect. Consistent results were obtained betweenthe aggregate and individual analyses.

1-h 

Rel$2-a

CheCha

!0.

Naeher et al. (1999)Vinton, VA Summers 1995, 1996

Panel study evaluated therelationship between O3 and

daily change in PEF studiedin a sample of 473 nonsmoking women aged19-43 years who recentlydelivered babies. PEFperformed twice daily for a2-week period. Mixed linearrandom coefficient model.

8-h max O3:53.69 ppbRange17.00-87.6324-h avg O3:

34.87 ppbRange 8.74-56.63

PM2.5, PM10,

SO42!, H+

Ozone was the only exposure related toevening PEF with 5-day cumulative lagexposure showing the greatest effect.

24-h MoLag 

!2.

Lag 

!3.

EveLag 

!2.

Lag 

!7.

AX7-17
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

CanadaBrauer et al. (1996)Fraser Valley, BritishColumbia, CanadaJun-Aug 1993

Panel study of 58 berrypickers aged 10-69 years hadlung function measuredbefore and after a seriesof outdoor work shifts(average duration = 11 h)over 59 days. Analysis usingpooled regression withsubject-specific intercepts,with and without temperaturecontrol.

1-h max O3:

40.3 ppbSD 15.2Work shift O3:26.0 ppbSD 11.8

PM2.5, SO42!,

NO3!, NH4+,

H+

End shift FEV1 and FVC significantly

diminished in relation to O3 levels. 

PM2.5 also related to lung function

declines, but O3 remained significant in

two-pollutant models. Next morninglung function remained diminishedfollowing high O3 days. Ozone effects

still evident at or below 40 ppb. Therewas an overall decline of lung functionof roughly 10% over course of study,suggesting subchronic effect. Levels ofother pollutants low during study. 

Cha1-h 

EndFEV

FVC

NexFEV

FVC

Brauer and Brook(1997)Fraser Valley, BritishColumbia, CanadaJun-Aug 1993

Additional analysis of Braueret al. (1996) with personalexposure presented for threegroups, stratified by timespent outdoors.Group 1: 25 individuals whospent most of the day indoors.Group 2: 25 individuals whospent much of the dayindoors, but still spent severaldaylight hours outdoors.Group 3: 15 individuals whospent the entire work dayoutdoors.

1-h max O3:

Ambient:40 ppbSD 15Range 13-84

PM2.5, SO42!,

NO3!, NH4+,

H+

Group 1: 9.0% sampling time (24-h)outdoors. Personal to ambient O3 ratio

was 0.28.Group 2: 25.8% sampling time (24-h)outdoors. Personal to ambient O3 ratiowas 0.48.Group 3: 100% sampling time(11-h work shift) outdoors. Personalto ambient O3 ratio was 0.96.

One of the first direct demonstrationsthat magnitude of personal exposure toO3 is related to amount of time spent

outdoors. Further showed that, onaverage, outdoor fixed O3 monitors were

representative of day-to-day changes inO3 exposure experienced by the study

population.

SamBra

AX7-18
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

EuropeScarlett et al. (1996)Surrey, EnglandJun-Jul 1994

Panel study examined154 children aged 7 years in aprimary school next to amajor motorway for O3

exposure effects on PEF0.75,

FVC, and FEV1 using

autoregression for %change in function.

8-h max O3: 

50.7 ppbSD 24.48

PM10, NO2,

pollen

No significant association was seenbetween pulmonary function measuresand O3 levels. No pollen effects.

Cha

weiFEVLag 

FVCLag FEV

Lag 

Ward et al. (2002)Birmingham andSandwell, EnglandJan-Mar 1997May-Jul 1997

A panel study of 162 children(age 9 years at time ofenrollment in Sept 1996). 39of 162 children (24%)reported wheezing in the past12 months. Examinedassociation of ambient acidspecies with PEF and symptoms. Single-day lags of0 to 3 days and a 7-daycumulative lag wereinvestigated. Linearregression used for PEF andlogistic regression used forsymptoms.

24 h-avg O3: 

Winter:Median 13.0 ppb Range 2-33Summer:Median 22.0 ppbRange 10-41

PM10, PM2.5,

SO2, H+, Cl!,

HCl, HNO3,

NH3, NH4+,

NO3! SO42!

Pollutants levels were generally low,even in the summer. Significantassociations were noted betweenrespiratory health outcomes and airpollutants, but no consistent patternswere identified. The association betweenO3 and PEF was generally negative in thesummer and positive in the winter. Moreassociations between O3 and symptoms

were observed in the winter. Ozone wasassociated with a significant increase incough, shortness of breath, and wheezeduring the winter. Results did notindicate that children with atopy or ahistory of recent wheezing were moresusceptible to short-term effects of airpollutants.

24-h 

winChaMoWinSum

AftWin

Sum

OddSymCouWinSumShoWinSumWhWinSum

AX7-19
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Taggart et al. (1996)Runcorn and Widnesin NW EnglandJul-Sep 1993

Panel study investigated therelationship of asthmaticbronchialhyperresponsiveness andpulmonary function withsummertime ambient airpollution among 38 adultnonsmoking asthmatics (age18-70 years) using log-linearmodels. Analysis limitedto investigation of withinsubject variance of thedependent variables.

1-h avg O3:

Maximum61 μg/m3

24-h avg O3:

Maximum24.5 μg/m3

SO2, NO2,

smoke

No association found for O3. Changesin bronchial hyperresponsiveness werefound to correlate significantly withchange in the levels of 24-h mean SO2,NO2, and smoke.

24-h 

% chypLag 

Lag 

Desqueyroux et al.(2002a)Paris, FranceNov 1995-Nov 1996

Panel study of 60 severeasthmatics (mean age 55years) were monitored bytheir physicians for asthmaattacks. Asthma attacks werebased on medical datacollected by a pulmonaryphysician at time of clinicalexamination. Analysis usingGEE.

8-h avg O3(10 a.m.-6 p.m.):Summer:41 μg/m3SD 18Winter:11 μg/m3SD 10

PM10 Significant associations between PM10,

O3, and incident asthma attacks were

found. Low O3 levels raise plausibilityconcerns.

8-h 

OddLag 

Desqueyroux et al.(2002b)Paris, FranceOct 1995-Nov 1996

Panel study of 39 adultpatients with severe COPD(mean age 67 years) followedover 14 months by physiciansfor exacerbations. Logistic regression with GEE,examining exposure lagsof 0 to 5 days.

8-h avg O3(10 a.m.-6 p.m.):Summer:41 μg/m3SD 18Winter:11 μg/m3SD 10

PM10, SO2,

NO2

50 COPD exacerbations observed overfollow-up period. 1-, 2-, and 3-day lag O3 significantly related to exacerbations. No other pollutants significant. Low O3levels raise plausibility and confoundingconcerns.

8-h 

OddLag Effesmoexc

AX7-20
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Just et al. (2002)Paris, FranceApr-Jun 1996

Panel study of 82 medicallydiagnosed asthmatic children(mean age 10.9 years)followed for O3 exposure and

PEF, asthmatic attacks,cough, supplementary use of

$2-agonists, and symptoms of

airway irritation. Analysis byGEE.

24-h avg O3: 58.9 μg/m3

SD 24.5Range 10.0-121.0

PM10, NO2 In asthmatic children, O3 exposure was

related to the occurrence of asthmaattacks and additional bronchodilatoruse. O3 was the only pollutant associated

with changes in lung function, as shownby an increase in PEF variability anddecrease in PEF.

24-h 

% cLag OddSup

on dwerLag 

Lagerkvist et al.(2004)Brussels, BelgiumMay 2002

Panel study of 57 children(mean age 10.8 years)stratified by swimming poolattendance. Pulmonaryfunction test performed andClara cell protein levelsmeasured in blood before andafter light exercise outdoorsfor 2 h. Analysis usingStudent’s t test and Pearsoncorrelation test. For dosecalculations, O3 levels indoors

assumed to be 50% of themean outdoor O3concentration.

Daytime outdoorO3: Range 77-116μg/m3Exposure dose:Range 352-914μg/m3·h

None Ozone levels did not have any adverse

effect on FEV1 after 2 h of outdoor

exercise. In addition, no significantdifferences were observed between Claracell protein levels before and afterexercise. A marginally significantpositive correlation between ambient O3

dose and Clara cell protein levelsobserved among the nonswimmers,indicating increased antioxidant activityfollowing O3 exposure in this group. 

The lack of a clear relationship betweenClara cell protein levels and O3 dose may

be attributable to the short period of timebetween measurements and diurnalvariability of the protein levels.

PeaO3 e

protAll r = Nonr = Swir = 

AX7-21
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Schindler et al. (2001)Eight communitiesof Switzerland May-Sep 1991

A random sample of 3,912adult never-smokers, aged18-60 years, examined forshort-term O3-related changes

in lung function. Naturallogarithms of FVC, FEV1,

and FEF25-75 were regressed

against the individualpredictor variables and O3. 

Spline functions were used tocontrol potential trends. Sensitivity analyses for grassand pollens, and NO2 and

TSP involved lineartime-trend variables.

8 h-avg O3

(10 a.m.-6 p.m.): 90.3 μg/m3

Range 2.9-247.1

NO2, TSP Daily average concentrations of O3 were

associated with daily sample means ofFEV1 and FEF25-75 in this random adult

cross-sectional sample. The associationsbetween daily O3 levels and daily means

of lung function were smaller inmagnitude than the association betweenannual O3 levels in the previous analyses(Ackermann and Liebrich et al., 1997). This analytic approach was designed tofilter out long-term components. Sensitive analyses indicated that majorconfounding by uncontrolled effects ofpollen, NO2, and TSP was unlikely.

8-h 

% cFEVFVC

FEF

Frischer et al. (1993)Umkirch, GermanyMay-Oct 1991

Panel study of nasal lavagerepeatedly performed on44 school children (age 9-11years) according to protocolpublished by Koren et al.(1990). Samples collectedmorning after “low” and“high” O3 days. Nasal lavage

samples analyzed forpolymorphonuclear leukocytecounts, albumin, tryptase,eosinophil cationic protein,and myeloperoxidase. Analysis using individualregression methods. 

Stratified analysisof 1⁄2-h avg O3 at

3 p.m.:Low: <140 μg/m3High: >180 μg/m3

None Significant higher polymorphonuclear

leukocyte counts after high O3 days. In children without symptoms of rhinitis,significantly elevated myeloperoxydaseand eosinophil cationic proteinconcentrations detected. Results suggestthat ambient O3 produces aninflammatory response in the upperairways of healthy children.

ChirhinMyLow Hig

p < EosLow 

Hig

p < 

AX7-22
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Frischer et al. (1997)Umkirch, GermanyMay-Oct 1991

Panel study examined 44school children aged 9-11years for ratio of orthotyrosine to para-tyrosine in

nasal lavage as a marker ofhydroxyl radical attack. Nasal lavage performedaccording to protocolpublished by Koren et al.(1990). Concomitant lungfunction tests performed. Analysis using individualregression methods. 

Stratified analysisof 1⁄2-h avg O3 at

3 p.m.:Low: <140 μg/m3High: >180 μg/m3

None Ambient O3 was associated with the

generation of hydroxyl radicals in theupper airways of healthy children andsignificant lung function decrements. However, the ortho/para ratio was not

related to polymorphonuclear leukocytecounts. Passive smoking was not relatedto outcomes.

FEV

LowHig

): 

Ort

LowHig

): 

Höppe et al. (1995a,b)Munich, GermanyApr-Sep 1992-1994

Panel study of five studygroups (age 12-95 years): (1) senior citizens (n = 41);(2) juvenile asthmatics(n = 43); (3) forestry workers(n = 41); (4) athletes (n = 43);and (5) clerks (n = 40) as acontrol group. Examined forlung function (FVC, FEV1,

PEF) and questions onirritated airways. Eachsubject tested 8 days, 4 dayswith elevated or high O3 and4 days with low O3. Analysis

using Wilcoxon matchedpairs signed rank test andlinear regression.

1⁄2-h max O3(1 p.m.-4 p.m.):Seniors:High: 70 ppbLow: 31 ppbAsthmatics:High: 74 ppbLow: 34 ppbForestry workers:High: 64 ppbLow: 32 ppbAthletes:High: 71 ppbLow: 28 ppbClerks:High: 68 ppbLow: 15 ppb

None No indication that senior citizens

represent a risk group in this study. Senior citizens had the lowest ventilationrate (mean 10 L/min). Athletes andclerks experienced significantdecrements in lung function parameters. Well-medicated juvenile asthmatics havea trend toward large pulmonarydecrements. Forestry workers wereexposed to motor tool exhaust, whichmight be a potential promoting factor. 

1⁄2-h 

ChaSenFEV

PEFAstFEVPEF

ForFEV

PEF

AthFEV

PEF

CleFEV

PEF

*p < 

AX7-23
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Höppe et al. (2003)Munich, GermanyApr–Sep 1992-1995

Three of the same studygroups examined in Höppeet al. (1995a,b): asthmatics(n = 43), athletes (n = 43),and elderly = 41). Oneadditional risk group, children(n = 44), was examined.Over 80% of the elderly andasthmatic groups tookmedications on a daily basis. Eye and airway symptomswere assessed, as werepulmonary function test. GLM analyses wasconducted.

1⁄2-h max O3

(1 p.m.-4 p.m.):Asthmatics:High: 66.9 ppbLow: 32.5 ppbAthletes:High: 65.9 ppbLow: 27.2 ppbChildren: High: 70.4 ppbLow: 29.8 ppbElderly:High: 66.1 ppbLow: 30.6 ppb

NO2 Stratified analyses by group did not show

consistent O3 effects at the concentrationlevel of this study; lack of power mayhave made it difficult to detect small O3effects. Analyses on an individual basisshow clearly different patterns of O3sensitivity. Ozone responders aredefined as individuals with relevant lungfunction changes of at least 10% forFEV1, FVC, and PEF, and 20% for

sRaw. Most of the responders werefound in the asthmatic and childrengroups. In these responders, a significantO3 concentration-response relationship

was observed in individual regressions(results not presented). The sample sizemay limit quantitative extrapolation tolarger populations, but may allowcautious first estimates.

1⁄2-h 

% cAstFEV

PEF

AthFEV

PEF

ChiFEV

PEF

EldFEVPEF

OzoAstAthChiEld

Kopp et al. (1999)Two towns in BlackForest, GermanyMar-Oct 1994

Panel study of 170 schoolchildren (median age9.1 years) followed over11 time points with nasallavage sampling. Subjectswere not sensitive to inhaledallergens. Nasal lavagesamples analyzed foreosinophil cationic protein,albumen, and leukocytes. Analysis using GEE. 

1⁄2-h max O3: 

Villingen:64 μg/m3

5th %-95th % 1-140 Freudenstadt:105 μg/m35th %-95th % 45-179

PM10, NO2,

SO2, TSP

Eosinophil cationic protein andleukocyte levels peaked soon after firstmajor O3 episode of summer, but did not

show response to later, even higher,O3 episodes. These observations are

consistent with an adaptive responsein terms of nasal inflammation.

Chaprot

O3)

Ear0.97 Lat

!0.

AX7-24
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Ulmer et al. (1997)Freudenstadt andVillingen, GermanyMar-Oct 1994

Panel study of 135 childrenaged 8-11 years in two townswere evaluated. Pulmonaryfunction was associated withthe highest O3 concentration

in the previous 24 h. An initial cross-sectionalanalysis was followed bya longitudinal analysisusing GEE with the dataat four time periods(Apr, Jun, Aug, Sep). 

1⁄2-h max O3: 

Freudenstadt:Median 50.6 ppb10th %-90th % 22.5-89.7Villingen:Median 32.1 ppb10th %-90th % 0.5-70.1

None In the cross-sectional analysis,

a significant negative associationbetween O3 exposure and FVC was onlyshown at the June testing. For FEV1,

no significant associations were detected. In contrast, the longitudinal analysisobtained a statistically significantnegative correlation between O3

exposure, and FVC and FEV1 for the

subpopulation living in the town withhigher O3 levels, Freudenstadt. The

associations were more pronouncedin males than females. 

Cha1⁄2-h 

FEV

Freu

!1.

Vill

!0.

FVCFreu

!1.

Vill0.02 

Cuijpers et al. (1994)Maastricht, theNetherlandsNov-Dec 1990(baseline),Aug 8-16, 1991 (smogepisode)

During episode, 212 children(age unspecified) randomlychosen from 535 reexaminedfor lung function andsymptoms. Correctedbaseline lung functioncompared by paired t test. Difference in prevalence ofrespiratory symptomsexamined.

Baseline:8-h avg O3: 

Range 2-56 μg/m3

Smog episode: 1-h max O3: Exceeded160 μg/m3 on11 days

PM10, SO2,

NO2

Small decrements in FEV1 and FEF25-75were found in the 212 children. However, significant decreases inresistance parameters also were noted. Each day a different group of 30 childrenwere measured. The results of the lungfunction are contradictory in thatspirometry suggest airflow obstructionwhile impedance measurement suggestotherwise. Respiratory symptomsimpacted by low response rate of 122 of212 children due to summer holidays. No increase was observed.

ChaimpsmoFEV

!0.

FEF

!0.

Res

!0.p # 

Gielen et al. (1997)Amsterdam, theNetherlandsApr-Jul 1995

Panel study of 61 childrenaged 7-13 years from twospecial schools forchronically ill children,followed for twice-daily PEF,symptoms, and medicationusage. 77% of cohort haddoctor-diagnosed asthma.

1-h max O3:77.3 μg/m3SD 15.78-h max O3:67.0 μg/m3SD 14.9

PM10, BS,

pollen

Morning PEF significantly associatedwith 8-h max O3 at a lag of 2 days. 

BS also associated with PEF. Among14 symptom models tested, only oneyielded a significant O3 finding (for

upper respiratory symptoms). PM10

and BS, but not O3, were related to$2-agonist inhaler use.

8-h % cMoLag AftLag 

AX7-25
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Europe (cont’d)Hiltermann et al.(1998)Bilthoven, theNetherlandsJul-Oct 1995

Panel study of 60 adultnonsmoking intermittent tosevere asthmatics (age18-55 years) followed over96 days. Measured morningand afternoon PEF,respiratory symptoms, andmedication use. Analysiscontrolled for time trends,aeroallergens, environmentaltobacco smoke exposures,day of week, temperature. Lags of 0 to 2 days examined. 

8-h max O3:

80.1 μg/m3Range 6-94

PM10, NO2,

SO2, BS

Ozone had strongest association withsymptoms of any pollutant analyzed. PEF lower with O3 but not statistically

significant. No effect on medication use. No effect modification by steroid use orhyperresponsiveness. 

8-h 

OddResShoLag SleeLag Pain Lag CouLag BroLag 

Hoek and Brunekreef(1995)Deurne andEnkhuizen, theNetherlandsMar-Jul 1989

The occurrence of acuterespiratory symptomsinvestigated in children aged7-11 years (Deurne n = 241;Enkhuizen n = 59). Symptoms included cough,shortness of breath, upper andlower respiratory symptoms,throat and eye irritation,headache and nausea. Ozonerelated symptom prevalenceand incidence were examined. Lags of 0 and 1 day, andmean O3 concentration from

previous week wereinvestigated. Analyses using1st-order autoregressivemodels and logistic regressionmodels.

1-h max O3:Deurne:57 ppbSD 20Range 22-107Enkhuizen:59 ppbSD 14Range 14-114

PM10, NO2,

SO2

No consistent association betweenambient O3 concentrations and theprevalence or incidence of symptoms ineither city. The one significant positivecoefficient in Enkhuizen for prevalenceof upper respiratory symptoms was notconfirmed by the Deurne results. No associations of daily symptomprevalence or incidence found with anyof the other copollutants examined.

1-h 

PrevDeuAny Lag 

CouLag UppLag EnkAny Lag CouLag UppLag *p < 

AX7-26
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Latin AmericaCastillejos et al.(1995)SW Mexico City Aug 1990-Oct 1991

Panel study of children aged71⁄2-11 years (22 males, 18females) tested up to 8 timesfor FEV1 and FVC, before

and after exercise. Targetminute ventilation was35 L/min/m2. Analysis using

GEE models.

1-h max O3:

112.3 ppbRange 0-3655th quintile mean229.1 ppb

PM10 The mean % decrements in lung function

were significantly greater than zero onlyin the fifth quintile of O3 exposure

(183-365 ppb).

% c5th 

(18FEV

FVC

Gold et al. (1999)SW Mexico City1991

Panel study of 40 schoolchildren aged 8-11 years inpolluted community followedfor twice-daily PEF andrespiratory symptoms. PEFdeviations inmorning/afternoon fromchild-specific means analyzedin relation to pollution,temperature, season, and timetrend. Morning symptomsanalyzed by Poissionregression.

24-h avg O3:

52.0 ppbIQR 25

PM2.5, PM10 Reported significant declines in PEF

in relation to 24-h avg O3 levels. 

Effects did not vary by baselinesymptom history. Lags chosen tomaximize effects and varied by outcome. Ozone generally robust to PM2.5. 

Morning phlegm significantly related to24-h avg O3 at a 1-day lag.

24-h 

% cMoLag AftLag % cMoLag 

AX7-27
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Latin America (cont’d)Romieu et al. (1996)N Mexico CityApr-Jul 1991,Nov 1991-Feb 1992

Panel study of 71 mildlyasthmatic children aged5-13 years followed for PEFand respiratory symptoms. Lower respiratory symptomsincluded cough, phlegm,wheeze and/or difficultybreathing.

1-h max O3:

190 ppbSD 80

PM2.5, PM10,

NO2, SO2

Ozone effects observed on both PEF andsymptoms. Symptom, but not PEF,effects robust to PM10 in two-pollutant

models. Symptoms related to O3

included cough and difficulty breathing.

1-h 

ChaMoLag Lag 

Lag AftLag Lag Lag OddLowLag Lag Lag 

Romieu et al. (1997)SW Mexico CityApr-Jul 1991,Nov 1991-Feb 1992

Same period as Romieu et al.,1996, but in different sectionof city. 65 mildly asthmaticchildren aged 5-13 yearsfollowed for twice-daily PEF,and respiratory symptoms. Up to 2 months follow-up perchild. Analysis includedtemperature and looked at0- to 2-day lags. No timecontrols. Lower respiratorysymptoms included cough,phlegm, wheeze and/ordifficulty breathing. Panelstudy.

1-h max O3: 196 ppbSD 78

PM10 Ozone had significant effects on PEF and

symptoms, with largest effects at lags 0and 1 day. Symptoms related to O3included cough and phlegm. Ozoneeffects stronger than those for PM10. 

1-h 

ChaMoLag 

Lag Lag AftLag 

Lag Lag 

OddLowLag Lag Lag 

AX7-28
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Latin America (cont’d)Romieu et al. (1998)Mexico CityMar-May 1996(1st phase)Jun-Aug 1996(2nd phase)

Panel study of 47 streetworkers aged 18-58 yearsrandomly selected to take adaily supplement (vitamin C,vitamin E, and beta carotene)or placebo during 1st phase ofstudy. Following washoutperiod, the use ofsupplements and placeboswas reversed during 2ndphase. Pulmonary functiontest performed twice a weekat end of workday. Plasmaconcentrations of betacarotene and "-tocopherol 

measured. Analysis usingGEE models.

1-h max O3: 

123 ppbSD 4055% of days >110ppb.Workday hourlyaverage duringworkday prior topulmonaryfunction test:67.3 ppbSD 24

PM10, NO2 During the 1st phase, O3 levels were

significantly associated with declines inlung function parameters. Noassociations were observed in the dailysupplement group. A significantsupplement effect was observed. Ozonerelated decrements also were observedduring the 2nd phase, however theassociations were not significant. Supplementation with antioxidantsduring the 1st phase may have had aresidual protective effect on the lung.

1-h 

Plac1st FEV

Lag 

FVCLag 2nd FEV

Lag 

FVCLag No 

obs

Romieu et al. (2002)Mexico CityOct 1998-Apr 2000

Panel study of 158 asthmaticchildren aged 6-16 yearsrandomly given a vitamin (Cand E) supplement or placebofollowed for 12 weeks. Peakflow was measured twice aday and spirometry wasperformed twice per week inthe morning. Double blindstudy. Plasma concentrationof vitamin E levels measured. Analysis using GEE models.

1-h max O3: 

102 ppbSD 47

PM10, NO2 Ozone levels were significantly

correlated with decrements in FEF25-75in the placebo group, but not in thesupplement group. When analysis wasrestricted to children with moderate-tosevere asthma, amplitudes of decrementswere larger and significant for FEV1,

FEF25-75, and PEF in the placebo group. 

Supplementation with antioxidants maymodulate the impact of O3 exposure on

the small airways of children withmoderate to severe asthma.

1-h 

ChiasthPlacO3 wFEV

Lag 

FEF

Lag 

PEFLag 

No vita

AX7-29
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Latin America (cont’d)Romieu et al. (2004)Mexico CityOct 1998-Apr 2000

Additional analysis ofRomieu et al., 2002 with dataon glutathion S-transferaseM1 polymorphism (GSTM1null genotype) in158 asthmatic children. Analysis performed usingGEE models, stratified byGSTM1 genotype (null vs.positive) within the twotreatment groups (placeboand antioxidantsupplemented). Panel study.

1-h max O3: 

102 ppbSD 47

None In the placebo group, O3 exposure was

significantly and inversely associatedwith FEF2.5-75 in children who had theGSTM1 null genotype, with largereffects seen in children with moderateto-severe asthma. No significantdecrements were seen in the GSTM1positive children. These results providepreliminary evidence that asthmaticchildren who may be geneticallyimpaired to handle oxidative stress aremost susceptible to the effect of O3 on

small airways function.

1-h 

FEF

sevPlacGSTLag GSTLag SupGSTLag GSTLag 

AustraliaJalaludin et al. (2000)Sydney, AustraliaFeb-Dec 1994

Panel study of three groups ofchildren (mean age 9.6years): (1) n = 45 withhistory of wheeze 12 months,positive histamine challenge,and doctor-diagnosed asthma;(2) n = 60 with history ofwheeze and doctor-diagnosedasthma; (3) n = 20 with onlyhistory of wheeze. Examinedfor evening PEF and daily O3

using GEE model andpopulation regression models.

Mean daytime O3(6 a.m.-9 p.m.):12 ppbSD 6.8Maximum daytime O3(6 a.m.-9 p.m.):26 ppbSD 14.4

PM10, NO2 A significant negative association was

found between daily mean deviation inPEF and same-day mean daytime O3concentration after adjusting forcopollutants, time trend, meteorologicalvariables, pollen count, and Alternariacount. The association was stronger ina subgroup of children with bronchialhyper-reactivity and doctor-diagnosedasthma. In contrast, the same-daymaximum O3 concentration was not

statistically associated.

Chaday

All O3 o

!0.

O3 w

!0.

O3 w

!0.

AX7-30
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Australia (cont’d)Jalaludin et al. (2004)Sydney, AustraliaFeb-Dec 1994

Same three groups of childrenas studied in Jalaludin et al.,2000. Examined relationshipbetween O3 and evening

respiratory symptoms(wheeze, dry cough, and wetcough), evening asthmamedication use (inhaled

$2-agonist and inhaled

corticosteroids), and doctorvisits for asthma. Analysisusing GEE logistic regressionmodels. Panel study.

Mean daytime O3

(6 a.m.-9 p.m.):12 ppbSD 6.8Maximumdaytime O3(6 a.m.-9 p.m.):26 ppbSD 14.4

PM10, NO2 No significant O3 effects observed on

evening symptoms, evening asthmamedication use, and doctors visits. Also, no differences in the response ofchildren in the three groups. A potentiallimitation is that the use of eveningoutcome measures rather than morningvalues may have obscured the effect ofambient air pollutants. Only consistentrelationship was found between meandaytime PM10 concentrations and doctor

visits for asthma.

Me

OddAll WhLag Dry Lag WeLag InhLag InhLag DocLag 

Chen et al. (1998)Six communities inTaiwan1994-1995

4,697 school children (ageunspecified) from a rural area(Taihsi), urban areas(Keelung and Sanchung), andpetrochemical industrial areas(Jenwu, Linyuan, and Toufen)cross-sectionally examinedfor respiratory symptoms anddiseases using parentcompleted questionnaires. Multiple logistic regressionmodels used to compare oddsof symptoms and diseases inurban or petrochemical areasto the rural area aftercontrolling for potentialconfounding factors. Cross-sectional panel study.

24-h avg O3: 

Rural area:52.56 ppbUrban area:Mean range38.34-41.90 ppbPetrochemicalindustrial area:Mean range52.12-60.64 ppb

SO2, CO,

PM10, NO2

School children in urban communities,but not in petrochemical industrial areas,had significantly more respiratorysymptoms and diseases vs. those livingin the rural community. However, meanO3 levels in the urban communities werelower than that of the rural community. No causal relationship could be derivedbetween O3 and respiratory symptoms

and diseases in this cross-sectional study. 

UrbOddResMo1.33 Day 1.67 Sho1.40 Wh1.68 

AX7-31
Table AX7-1 (cont’d). Effects of Acute O3 Exposure on Lung Function and Respiratory Symptoms 

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

AsiaChen et al. (1999)Three towns inTaiwan: Sanchun,Taihsi, LinyuanMay 1995-Jan 1996

Valid lung function dataobtained once on each of895 children (age 8-13 years)in three towns. Examinedrelation between lungfunction and pollutionconcentrations on same dayand over previous 1, 2, and7 days. Multipollutantmodels examined. Cross-sectional panel study.

1-h max O3:

Range 19.7-110.3ppbSD not provided.

SO2, CO,

PM10, NO2

FEV1 and FVC significantly associated

with day 1-day lag O3. FVC also related

to NO2, SO2, and CO. No PM10 effects

observed. Only O3 remained significant

in multipollutant models. No PM10effects. A significant O3 effect was not

evident at O3 levels below 60 ppb.

ChaO3 o

Lag FEV

FVC

O3 w

Lag FEVFVC

*p < 

Chan and Wu (2005)Taichung City,TaiwanSep 2001(Questionnairesurvey)Nov-Dec 2001(Field study)

A cohort of mail carriers(mean age 39 years)examined for effects of O3

exposure on PEF. Theirexposure periods werebetween 9 a.m. and 5 p.m.every working day. PEFmeasurements taken twicedaily. Single-day lags from0 to 3 days examined. A twostep statistical model wasused, a multiple linearregression without airpollutants followed by alinear mixed effects model toestimate pollution effects.

8-h avg O3(9 a.m.-5 p.m.):35.6 ppbSD 12.1Range 7.6-65.1

PM10, NO2 Significant associations observed

between evening PEF and O3concentrations at lags of 0, 1 and 2 days. Largest effect observed at a day 1-daylag. Similar O3 effects on morning PEF

also noted (data not presented). NeitherPM10 nor NO2 showed consistent

associations with PEF. Ozone resultswere robust to adjustment for PM10 and

NO2.

8-h % cLag Lag Lag 

AX7-32
Table AX7-2. Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field Stud

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United StatesLiao et al. (2004)Three locations in U.S.: Minneapolis, MN;Jackson, MS; ForsythCounty, NC1996-1998

Cross-sectional study of5,431 cohort members ofthe Atherosclerosis Risk inCommunities study, menand women aged 45-64years at entry in 1987. Association between O3 and

cardiac autonomic controlassessed using 5-min heartrate variability indicescollected over a 4-h period. Analysis usingmultivariable linearregression models, adjustingfor individualcardiovascular disease riskfactors and meteorologicalfactors.

8-h avg O3

(10 a.m.-6 p.m.): 41 ppbSD 16

PM10, CO,

SO2, NO2

Significant interaction between O3 and

ethnicity in relation to high-frequencypower (p < 0.05). Ambient O3

significantly associated with highfrequency power among whites, but notblacks. No significant O3 effect on other

heart rate variability indices, includinglow-frequency power and SD of normalR-R intervals. More consistentrelationships observed between PM10

and heart rate variability indices.

8-h a

Log-poweWhitLag 

BlacLag Log-poweLag SD oLag *p < 

Peters et al. (2000a)Eastern Massachusetts1995-1997

Records of detectedarrhythmias and therapeuticinterventions weredownloaded fromdefibrillators implanted incardiac clinic patients aged22-85 years (n = 100).Analysis was restricted todefibrillator dischargesprecipitated by ventriculartachycardias or fibrillation.Data were analyzed bylogistic regression modelsusing fixed effect modelswith individual intercepts.

24-h avg O3:

18.6 ppbIQR 14.0

PM2.5, PM10,

BC, CO, NO2,

SO2

No significant O3 effects observed fordefibrillator discharge interventions. For patients with 10 or moreinterventions, increased arrhythmiaswere associated significantly withPM2.5, CO, and NO2 at various lag

periods, but not O3.

24-h 

Odds DefibPatieLag PatieLag 

AX7-33
Table AX7-2 (cont’d). Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field S

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Peters et al. (2001)Greater Boston area,MAJan 1995-May 1996

Case-crossover studydesign used to investigateassociation between airpollution and triggering ofmyocardial infarction in772 patients (mean age61.6 years). For eachsubject, one case periodwas matched to threecontrol periods 24 h apart. Conditional logisticregression used for analysis.

1-h max O3:

19.8 ppbSD 1485th%-95th%1-4624-h avg O3:

19.9 ppbSD 10.05th%-95th%6-36

PM2.5, PM10,

PM10-2.5, BC,

CO, NO2, SO2

None of the gaseous pollutants, includingO3, were significantly associated with

the triggering of myocardial infarctions.Significant associations reported forPM2.5 and PM10. Note that the use of

unidirectional referent sampling may leadto time trend bias and overlap bias (i.e.,biased conditional logistic regressionestimating equations), which can result inoverestimated effects of exposure.

Odds Myo2-h a

Lag 1.31 24-h Lag 20.94 

Park et al. (2005)Greater Boston area,MANov 2000-Oct 2003

Cross-sectional studyexamining the effect of O3

on heart rate variability in497 adult males (mean age72.7 years). Subjects weremonitored during a 4-minrest period between 8 a.m.and 1 p.m. Ozone levelsmeasured at central site 1km from study site. Exposure averaging timesof 4, 24, and 48 hinvestigated. Modifyingeffects of hypertension,ischemic heart disease,diabetes, and use of cardiac/antihypertensivemedications also examined. Linear regression analyses.

24-h avg O3: 

23.0 ppbSD 13.0

PM2.5, particle

numberconcentration,BC, NO2, SO2,

CO

Of the pollutants examined, only PM2.5

and O3 showed significant associationswith heart rate variability outcomes. The 4-h averaging period was moststrongly associated with heart ratevariability indices. The O3 effect was

robust in models including PM2.5. The

associations between O3 and heart rate

variability indices were stronger insubjects with hypertension (n = 335) andischemic heart disease (n = 142). In addition, calcium-channel blockerssignificantly influenced the effect of O3

on low frequency power. Majorlimitations of this study are the use of ashort 4-min period to monitor heart ratevariability and the lack of repeatedmeasurements for each subject.

4-h a

ChanAll s

!11.

Subj

!12.Subj!5.4Subjdisea!25.

Subjdisea

!4.8

AX7-34
Table AX7-2 (cont’d). Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field S

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Gold et al. (2000;reanalysis Gold et al.,2003)Boston, MAJun-Sep 1997

Panel study of repeatedmeasurements of heart ratevariability in subjects aged53-87 years (n = 21, 163observations). Twenty-fiveminute protocol included5 min each of rest, standing,exercise outdoors, recovery,and 20 cycles of slowbreathing. Ozone levelsmeasured at central site4.8 miles from study site. Analyses using randomeffects models and GAMwith stringent convergencecriteria.

1-h avg O3

during HRVmeasurement:25.7 ppbIQR 23.0

PM2.5, NO2,

SO2

Increased levels of O3 were associated

with reduced r-MSSD (square root of themean of the squared differences betweenadjacent normal RR intervals) during theslow breathing period after exerciseoutdoors. The estimated O3 effects were

similar to those of PM2.5. Results suggest

that O3 exposure may decrease vagal

tone, leading to reduced heart ratevariability.

1-h a

ChanDuriO3 on

!3.0 

DuriO3 on

!5.8 

O3 w

!5.4 

Schwartz et al. (2005)Boston, MA12 weeks during thesummer of 1999

A panel study of 28 elderlysubjects (age 61-89 years).Various HRV parameterswere measured for 30 minonce a week. Analysisusing linear mixed modelswith log-transformed HRVmeasurements. To examineheterogeneity of effects,hierarchical model wasused.

1-h avg O3

during HRVmeasurement:Median 34 ppbIQR 26

BC, PM2.5,

CO, SO2, NO2

HRV parameters examined included: standard deviation of normal RR intervals(SDNN), root mean squared differencesbetween adjacent R-R intervals(r-MSSD), proportion of adjacent NNintervals differing by more than 50 ms(PNN50), and low frequency/high

frequency ratio (LFHFR). Ozone wasweakly associated with HRV parameters. Strongest association seen for BC, anindicator of traffic particles. The randomeffects model indicated that the negativeeffect of BC on HRV was not restrictedto a few subjects. Subjects with MIexperienced greater BC-relateddecrements in HRV parameters. Authorsnoted that in this study ambient O3 might

represent a secondary particle effect andnot a true O3 effect, and suggested that

personal exposure measurements mightbe necessary to assess the effect of O3 on

cardiovascular outcomes.

1-h a

ChanSDN

!3.1 

r-MS

!8.5 

PNN

!6.5

AX7-35
Table AX7-2 (cont’d). Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field S

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Dockery et al. (2005)Boston, MAJul 1995-Jul 2002

Effect of air pollution onincidence of ventriculararrhythmias was examinedin 203 patients withimplantable cardioverterdefibrillators using timeseries methods. Meanfollow-up period was3.1 year/subject. Allsubjects located <40 km ofair pollution monitoringsite. Two-day mean airpollution level used inanalysis. Results analyzedby logistic regression usingGEE with random effects. Modifying effects ofprevious arrhythmia within3 days also examined.

48-h avg O3:

Median 22.9 ppbIQR 15.4

PM2.5, BC,

SO42!, particle

number, CO,NO2, SO2

No associations were observed betweenair pollutants and ventricular arrhythmiaswhen all events were considered. When only examining ventriculararrhythmias within 3 days of a priorevent, positive associations were foundfor most pollutants except for O3. 

Suggestive evidence of a concentrationresponse relationship between ventriculararrhythmias and increasing quintilesof O3.

48-h 

Odds All e1.09 Prior 1.01 Prior 1.14 

AX7-36
Table AX7-2 (cont’d). Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field S

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

United States (cont’d)Rich et al. (2005)Boston, MAJul 1995-Jul 2002

Same study population asDockery et al. (2005). Case-crossover study designused to examine associationbetween air pollution andventricular arrhythmias. For each case period,3-4 control periods wereselected. Various movingaverage concentrations ofexposure considered ! lags

0-2, 0-6, 0-23, and 0-47 h. Analysis using conditionallogistic regression models.

1-h avg O3:

Median 22.2 ppbIQR 21.724-h avg O3:Median 22.6 ppbIQR 15.7

PM2.5, BC,

CO, NO2, SO2

Associations observed for PM2.5 and O3with a 24-h moving average, and for NO2and SO2 with a 48-h moving average. In

two-pollutant analyses, only PM2.5 and O3

appeared to act independently. Incontrast to results from other pollutants,stratified analyses indicated that O3 was

associated with increased risk amongsubjects without a recent event, but notthose with recent events. The odds ratiofor the 24-h moving averageconcentration was larger than that for thesame-calendar day concentration. Thissuggested that using calendar dayconcentrations might result in greaterexposure misclassification which couldlead to underestimation of risk. Findingsof an association with 24-h movingaverage concentrations but not withshorter time periods could imply acumulative effect across the previous24 h.

Odds 24-h 

15.9 O3 on

All e1.21 Prior 1.04 Prior 1.28 O3 wAll e1.18 24-h 

(per O3 on

All e0.96 

CanadaRich et al. (2004)Vancouver, BritishColumbia, CanadaFeb-Dec 2000

Case-crossover studydesign used to investigateassociation between airpollution and cardiacarrhythmia in patients aged15-85 years (n = 34) withimplantable cardioverterdefribillators. Controlsperiods were selected 7 daysbefore and after each caseday. Analysis usingconditional logisticregression.

1-h max O3:

27.5 ppbSD 9.7IQR 13.4

PM2.5, PM10,

EC, OC,SO42!, CO,NO2, SO2

No consistent association between anyof the air pollutants, including O3, andimplantable cardioverter defribillatorsdischarges. No significant associationobserved in all-year data, however,significant relationship found in wintermonths at a 3-day lag. Overall, littleevidence that air pollutants affect riskof cardiac arrhythmias, however, powerwas limited to study subtle effects.

No q

AX7-37
Table AX7-2 (cont’d). Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field S

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Canada (cont’d)Vedal et al. (2004)Vancouver, BritishColumbia, Canada1997-2000

Retrospective, longitudinalpanel study of 50 patients(age 12-77 years) withimplantable cardioverterdefribillators. Occurrenceof cardiac arrhythmia wasassociated with airpollutants over 4-yearperiod. GEE used foranalysis.

1-h max O3:

28.2 ppbSD 10.2IQR 13.8

PM10, CO,

NO2, SO2

No consistent association between anyof the air pollutants and % change inarrhythmia. Among patients with at least2 arrhythmia event-days per year, asignificant negative relationship betweenO3 and arrhythmias was observed at lag

3-day during the summer, but noassociations were found during thewinter. These results do not provideevidence for an O3 effect on cardiacarrhythmias in susceptible patients.

No q

EuropeRuidavets et al. (2005)Toulouse, FranceJan 1997 - Jun 1999

MONICA Project. Examined short-term effectsof pollution on acute MIusing case-crossover studydesign. The studypopulation included395,744 inhabitants aged35 to 64 years. Acute MIwas examined usingclinical, electrocardiograms,and enzymatic data. Fourcase definitions were used;there were a total of 635cases for the most inclusivedefinition. Deaths werevalidated. Age, gender,history of ischemic heartdisease, and survival statusevaluated. Analyses usingfixed-effects method withconditional logisticregression. 

8-h max O3:

74.8 μg/m3

SD 28.1Range 3.8-160.2

NO2, SO2 After adjustment for temperature, relative

humidity, and influenza epidemics, anassociation between O3 and acute MI was

found for 0- and 1-day lags, but not forlonger lags. Older age was an importantrisk factor. Subjects with no personalhistory of ischemic heart disease yieldeda stronger association. Moderate levelsof NO2 and SO2 were observed. NO2 and

SO2 were not associated with acute MI. 

No PM data was reported.

8-h m

RelaAll cLag Lag Age Age Lag Age Lag HistoYes Lag No (n Lag Age of isc225)Lag Lag 

AX7-38
AX7-39

Table AX7-2 (cont’d). Effects of Acute O3 Exposure on Cardiovascular Outcomes in Field S

Reference, StudyLocation and Period Outcomes and Methods Mean O3 Levels

Copollutants

Considered Findings, Interpretation 

Latin AmericaHolguín et al. (2003)Mexico CityFeb-Apr 2000

Panel study of theassociation between O3

and heart rate variabilityexamined in 34 elderlysubjects (mean age79 years) in a nursing home. Subjects were monitoredduring a 5-min rest periodbetween 8 a.m. and 1 p.m.every other day for a 3-moperiod. A total of 595observations were collected. Ambient O3 levels obtained

from central site 3 kmupwind from study site. Analysis performed usingGEE models adjusting forpotential confoundingfactors including age andaverage heart rate.

1-h max O3: 

149 ppbSD 40

PM2.5 (indoor,

outdoor,total), NO2,

SO2, CO

Only PM2.5 and O3 were significantly

associated with heart rate variabilityoutcomes. A significant effect of O3 on

heart rate variability was limited tosubjects with hypertension (n = 21).In two-pollutant models, the magnitudeof the PM2.5 effect decreased slightly but

remained significant, whereas O3 was

no longer associated with heart ratevariability indices.

1-h m

Log1

powe

All s

!0.0

Subj

!0.0Subj0.002 

Log1

powe

All s

!0.0

Subj

!0.0Subj0.00

AX7-39
Table AX7-3. Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United StatesJaffe et al. (2003)Cincinnati, Cleveland,and Columbus, OHJun-Aug 1991-1996

Daily time-seriesstudy of emergencydepartment visits forasthma amongMedicaid recipientsaged 5-34 years.

8-h max O3: 

Cincinnati: 60 ppb SD 20Cleveland: 50 ppb SD 17 Columbus: 57 ppb SD 16

PM10, NO2,

SO2

1, 2, 3 Poisson regression with control

for city, day of week, week,year, minimum temperature,overall trend, and a dispersionparameter. No specific effortto control cycles, butregression residuals wereuncorrelated, presumably dueto seasonal restriction. Resultsshown for individual cities andoverall. PM10 available only

every 6th day. Positiverelationships betweenemergency department visitsfor asthma and 8-h max O3

levels lagged 2 to 3 days. Results of borderline statisticalsignificance. Other pollutantsalso related to asthmaemergency department visitsin single-pollutant models.

8-CiLaClLaCoLaTh1.

Jones et al. (1995)Baton Rouge, LAJun-Aug 1990

Daily emergencydepartment visits forrespiratory complaintsover a 3-month periodin pediatric(age 0-17 years), adult(age 18-60 years),and geriatric(age >60 years)subgroups. Time-series study.

1-h max O3: 69.1 ppb SD 28.724-h avg O3: 

28.2 ppb SD 11.7

Mold, pollen Not specified. Relatively simple statistical

approach using ordinary leastsquares regression to modeleffects of O3 by itself and of O3

along with pollen counts, moldcounts, temperature, andrelative humidity. No directcontrol of cycles but authorsreported nonsignificantautocorrelations among modelresiduals. Data restriction to3-month period may havereduced any cyclic behavior. Significant associationsbetween respiratory emergencydepartment visits and O3observed for adult age grouponly in multiple regressionmodels.

24

PeAdGe

AX7-40
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Wilson et al. (2005)Portland, ME1998-2000Manchester, NH1996-2000

Daily emergencyroom visits for totalrespiratory and asthmaexamined for all agesand age groups 0-14,15-64, and 65+ years. Time-series study.

8-h max O3:

Portland:Spring:43.7 ppbSD 10.2Summer:46.1 ppbSD 15.4Manchester:Spring:43.4 ppbSD 9.7Summer:42.8 ppbSD 14.6

SO2 0 Poisson GAM with stringent

convergence criteria. Positiveassociations for asthma in thelarger city, Portland. Authorsexpressed the view that largercities might be needed toconduct such studies.

8-

WAlPoTo0.9As1.0MTo0.9As0.9

Cassino et al. (1999)New York CityJul 1992-Dec 1995

Daily time-seriesstudy of emergencydepartment visits in acohort of 1,115 adultasthmatics aged18-84. Stratified into552 never-smokers,278 light smokers, and285 heavy smokers. 

1-h max O3: 37.2 ppb IQR 2824-h avg O3: 

17.5 ppbIQR 14

CO, NO2,

SO2

0, 1, 2, 3 Used Poisson GAM with

default convergence criteria. No warm-season resultspresented. Significant O3

effects seen only at lag 2among heavy-smokers. Copollutants did not haveeffects. Short-term cycles andepisodic variations in asthmamay not have been controlledadequately with 3-monthperiod LOESS. Multiple testsperformed, and inconsistentresults across smoking strataand lags raise possibility ofchance findings. No PMresults included.

1-NeLaLiLaHeLa24

AlLaNeLaLiLaHeLa

AX7-41
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Weisel et al. (2002)New JerseyMay-Aug 1995

Daily asthmaemergency departmentvisits for all ages. Time-series study.

1-h max O3;

5-h avg O3(10 a.m.-3 p.m.);and 8-h avg O3(2 p.m.-10 p.m.)analyzed.Levels notreported.

Pollen, spores 0, 1, 2, 3 No control for time, but

authors report noautocorrelation, whichalleviates concerns about lackof control. Significant O3effects reported, even afteradjusting for potentialconfounding by pollen. Allthree O3 indices gaveessentially same results.

Sl(vExwhO3 LaO3 La

Friedman et al. (2001)Atlanta, GAJun-Sep 1996

Emergencydepartment visits andhospital admissionsfor asthma in childrenaged 1-16 years. Outcomes measuresduring 1996 SummerOlympics werecompared to abaseline period of4 weeks before andafter the OlympicGames. Time-seriesstudy.

1-h max O3: Baseline:81.3 ppbSD not provided.Interventionperiod:58.6 ppbSD not provided.

NO2, SO2,

CO, PM10,

mold

0, 0-1, 0-2 Analysis using Poisson GEE

models addressing serialautocorrelation. An overalldecrease was observed whencomparing the number of visitsand hospitalizations during theOlympic Games to the baselineperiod. However, significantassociations between O3 and

asthma events were foundduring the Olympic Games.

1-

PedeLaLaLa

AX7-42
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Metzger et al. (2004)Atlanta, GA1993-2000

Emergencydepartment visits fortotal and causespecificcardiovasculardiseases by age groups19+ years and 65+years. Time-seriesstudy.

8-h max O3: 

Mar-Nov:Median 53.9 ppb10th %-90th %13.2-44.7

NO2, SO2,

CO, PM2.5,

PM10,

PM10-2.5,

ultrafine PMcount, SO42!,

H+, EC, OC,

metals,oxygenatedhydrocarbons

0-2 Poisson GLM regression used

for analysis. A priori modelsspecified a lag of 0 to 2 days. Secondary analyses performedto assess alternative pollutantlag structures, seasonalinfluences, and age effects. Cardiovascular visits weresignificantly associated withseveral pollutants, includingNO2, CO, and PM2.5, but

not O3. 

8-

AlTo1.0Dy1.0Co0.9Isc1.0Pece1.0

Peel et al. (2005)Atlanta, GA1993-2000

Emergencydepartment visits fortotal and causespecific respiratorydiseases by age groups0-1, 2-18, 19+, and65+ years. Timeseries study.

8-h max O3: Mar-Nov:55.6 ppbSD 23.8

NO2, SO2,

CO, PM2.5,

PM10, PM10-

2.5, ultrafine

PM count,SO42!, H+,

EC, OC,metals,oxygenatedhydrocarbons

0-2 Poisson GEE and GLM

regression used for analysis. A priori models specified a lagof 0 to 2 days. Also performedsecondary analyses estimatingthe overall effect of pollutionover the previous 2 weeks. Seasonal analyses indicatedstronger associations withasthma in the warm months. Quantitative results notpresented for multipollutant,age-specific, and seasonalanalyses.

8-

AlAlTo1.0Up1.0As1.0Pn1.0CO1.0WAs1.0

AX7-43
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Tolbert et al. (2000)Atlanta, GAJun-Aug 1993-1995

Pediatric (aged0-16 years) asthmaemergency departmentvisits over threesummers in Atlanta. A unique feature ofthe study wasassignment of O3

exposures to zip codecentroids based onspatial interpolationfrom nine O3monitoring stations. Time-series study.

1-h max O3: 68.8 ppbSD 21.18-h max O3: 59.3 ppb SD 19.1

PM10, NO2,

mold, pollen

1 A priori specification of

model, including a lag of 1 dayfor all pollutants andmeteorological variables. Secondary analysis usinglogistic regression of theprobability of daily asthmavisits, referenced to total visits(asthma and nonasthma). Significant association withO3 and PM10 in 1-, but not in

2-pollutant models (correlationbetween O3 and PM10: 

r = 0.75). Secondary analysisindicated nonlinearity, with O3

effects clearly significant onlyfor days $100 ppb vs. days

<50 ppb.

8-

PoO3 1.0LoO3 1.0O3 

1.0

Zhu et al. (2003)Atlanta, GAJun-Aug 1993-1995

Asthma emergencydepartment visits inchildren (age 0-16years) over threesummers in Atlanta. Time-series study.

8-h max O3:

Levels notreported.

None 1 Used Bayseian hierarchical

modeling to address modelvariability and spatialassociations. Data wereanalyzed at the zip code levelto account for spatiallymisaligned longitudinal data. A positive, but nonsignificantrelationship between O3 and

emergency room visits forasthma.

8-Po1.0

AX7-44
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

CanadaDelfino et al. (1997b)Montreal, Quebec,CanadaJun-Sep 1992-1993

Daily time-seriesecologic study ofemergency departmentvisits for respiratorycomplaints within fiveage strata (<2, 2-18,19-34, 35-64,>64 years).

1-h max O3: 

1992: 33.2 ppbSD 12.61993: 36.2 ppbSD 13.88-h max O3: 1992: 28.8 ppbSD 11.31993: 30.7 ppbSD 11.5

PM10, PM2.5,SO42!, H+

0, 1, 2 Used ordinary least squares,

with 19-day weighted movingaverage pre-filter to controlcycles; weather also controlled. Significant effects reported for1-day lag O3 in 1993 only for

age >64 years. This O3 effect

reported to be robust in twopollutant models. Low O3

levels raise plausibilityconcerns. Short data series,multiple tests performed, andinconsistent results acrossyears and age groups raisepossibility of chance findings. 

191-La8-LaNo 

19the tak

AX7-45 tes
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Canada (cont’d)Delfino et al. (1998b)Montreal, Quebec,CanadaJun-Aug 1989-1990

Daily time-seriesecologic study ofemergency departmentvisits for respiratorycomplaints across allages and within fourage strata (<2, 2-34,35-64, >64 years).

1-h max O3: 

1989: 44.1 ppbSD 18.31990: 35.4 ppbSD 12.98-h max O3: 1989: 37.5 ppbSD 15.51990: 29.9 ppbSD 11.2

EstimatedPM2.5

0, 1, 2 Same analytical approach used

in Delfino et al., 1997. Resultspresented only for 1989. Significant effects reported for1-day lag O3 in 1989 only for

age >64 years. This O3 effect

reported to be robust in2-pollutant models. Ozoneconcentrations weresignificantly higher in 1989than 1990 (p < 0.001).

191-

La8-LaNo 

19the 

Stieb et al. (1996)Saint John, NewBrunswick, CanadaMay-Sep 1984-1992

Daily emergencydepartment visits forasthma in all ages,age <15 years and15+ years. Timeseries study.

1-h max O3: 

41.6 ppbRange 0-16095th % 75

SO2, NO2,

SO42!, TSP

0, 1, 2, 3 Poisson analysis with control

of time based on 19-daymoving average filter. Alsocontrolled day of week andweather variables. Ozone wasonly pollutant consistentlyassociated with emergencydepartment visits for asthma,but effect appeared nonlinear,with health impacts evidentonly above 75 ppb O3.

Al1-

La1-

ppLa

AX7-46
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

EuropeSunyer et al. (1997)Four European cities:Barcelona, Helsinki,London, and Paris1986-1992

Emergencyadmissions for asthmain children (<15years) and adults (15-64 years). Timeseries study.

1-h max O3:

Barcelona:Median 72 μg/m3Range 7-283Helsinki:Median 27 μg/m3Range 1-78London:Median 40 μg/m3Range 1-188Paris:Median 36 μg/m3Range 1-230

BS, SO2, NO2 0, 1, 2, 3 Poisson analysis using APHEA

methodology. Significant O3

effects on emergencyadmissions for asthmaobserved among 15-64 yearolds in Barcelona and London. Across all cities, there was nostrong evidence forassociations involving O3. 

1-

Wlag Ag3-(Bav1.0Ag4-1.0

Atkinson et al. (1999a)London, England1992-1994

Emergencydepartment visitsfor respiratorycomplaints, asthma forall ages and age 0-14,15-64, and 65+ years. Time-series study.

8-h max O3: 

17.5 ppbSD 11.5

NO2, SO2,

CO, PM10

0, 1, 2, 3

0-1, 0-2, 0-3

Poisson GLM regression usedfor analysis. No warm-seasonanalysis attempted. PM10

positively associated.

8-AlToLaAsLa

Hajat et al. (1999;2002)London, England1992-1994

Daily doctor consultsfor asthma, lowerrespiratory diseases,and upper respiratorydiseases for age 0-14,15-64, and $65 years. 

Time-series study.

8-h max O3: 

All year: 17.5 ppbSD 11.5 Warm season:22.7 ppbSD 12.2Cold season: 12.1 ppbSD 7.6

BS, SO2,NO2, CO,PM10, pollen

0-3 Used Poisson GAM with

default convergence criteria. Conducted all-year andseasonal analyses. Single- andtwo-pollutant models analyzed. Significant negative effects forO3. This may reflect residualconfounding by seasonalfactors or highly negativecorrelation with otherpollutants.

Upag

Al8-

La

W8-

LaCo8-La

AX7-47
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Thompson et al. (2001)Belfast, N Ireland1993-1995

Asthma emergencydepartmentadmissions in children(age unspecified). Time-series study.

24-h avg O3:

Warm season:18.7 ppbIQR 9Cold season:17.1 ppb IQR 12

PM10, SO2,

NO2, CO,benzene

0, 0-1, 0-2, 0-3 GLM with sinusoids. 

Pre-adjustment. Very low O3levels in both seasons. No O3effect in warm season. Significant inverse O3associations in full-year andcold-season models. Afteradjusting for benzene in modelO3 was no longer negativelyassociated with asthma visits. 

24

AlO3 

LaO3 LaWO3 LaCoO3 La

Bourcier et al. (2003)Paris, France Jan 1999-Dec 1999

Ophthalmologicalemergencyexamination;conjunctivitis andrelated ocular surfaceproblems. Timeseries study.

24-h avg O3: 

35.7 μg/m3

Range 1-97

PM10, SO2,NO2

0, 1, 2, 3 Logistic Regression Re

rel

24

CoLa

Castellsague et al.(1995)Barcelona, Spain1985-1989

Daily emergencydepartment visits forasthma in personsaged $14 years. 

Time-series study.

1-h max O3: Summer: 43 ppbIQR 22Winter: 29 ppbIQR 16

BS, SO2, NO2 Not specified. Poisson regression with year

and month dummy variablesand extensive control forweather factors (minimum,maximum, mean temperature,relative humidity, dewpointtemperature; continuous andcategorical parameterizations)

1-

Su0.9W1.0

AX7-48
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Tobías et al. (1999)Barcelona, Spain1986-1989

Daily asthmaemergency departmentvisits. Investigatedsensitivity of resultsto four alternativemethods forcontrolling asthmaepidemics. Timeseries study.

Levels notreported.

BS, NO2, SO2 Not specified. Poisson analysis using

APHEA methodology. Asthma epidemics eithernot controlled, or controlledwith one, six, or individualepidemic dummy variables.

O3 

measregrandeOnha

Tenías et al.(1998; 2002)Valencia, Spain1994-1995

Daily emergencydepartment visits forasthma and COPDin persons aged>14 years. Timeseries study.

1-h max O3: 

All year: 62.8 μg/m3Range 13.3-157.3Warm season:74.0 μg/m3Cool season:51.4 μg/m3

BS, NO2,

SO2, CO

0, 1, 2, 3, 4, 5 Poisson analysis using APHEA

methodology. Comparedwarm and cold season effects. GAM explored in sensitivityanalysis. For asthma, both O3

and NO2 significant in singleand two-pollutant models, andO3 effect larger in warmseason. For COPD, both O3and CO significant in bothsingle- and two-pollutantmodels and no difference in O3effects by season.

1-

AsAlLaWLaCoLaCOAlLa

Latin AmericaHernández-Garduñoet al. (1997)Mexico CityMay 1992-Jan 1993

Visits to clinics forrespiratory diseases inpersons aged 1 monthto 92 years. Timeseries study.

Percent timeexceeding 1-hmax O3 of 120

ppb: 6.1-13.2% bylocation

SO2, NO2,

CO

0, 1, 2, 3, 4, 5 GLM with pre-adjustment. 

Ozone at lags 0 and 5 dayssignificantly associated withdaily visits for all ages,age <14 years, and 15+ years. Neither O3 nor NO2 significant

in two-pollutant model.

1-lesgivLap < Lap < 

AX7-49
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Latin America (cont’d)Lin et al. (1999)São Paulo, BrazilMay 1991-Apr 1993

Daily pediatric (ageunspecified)respiratory emergencydepartment visits. Time-series study.

1-h max O3: 

34 ppbSD 22

SO2, CO,

PM10, NO2

0, 1, 0-1, 0-2,

0-3, 0-4, 0-5

Seasonal control using monthdummy variables. Alsocontrolled day of week,temperature. Both O3 and

PM10 associated with outcome

alone and together.

1-O3 LaO3 

La

Martins et al. (2002)São Paulo, BrazilMay 1996-Sep 1998

Daily emergencydepartment visitsfor chronic lowerrespiratory diseasesin personsaged >64 years. Time-series study.

1-h max O3: 

34 ppbSD 21IQR 21

CO, NO2,

SO2, PM10

0-1, 0-2, 0-3,0-4, 0-5, 0-6.

Analyzed using Poisson GAMwith default convergencecriteria. Only O3 and SO2significant in single-pollutantmodels. Ozone effectremained significant when SO2included in two-pollutantmodel.

1-La

Ilabaca et al. (1999)Santiago, ChileFeb 1995-Aug 1996

The associationbetween pollutantlevels and emergencyvisits for pneumoniaand other respiratoryillnesses amongchildren. Time-seriesstudy.

1-h max O3:Warm season:66.6 μg/m3

SD 25.2Cold season: 27.6 μg/m3

SD 20.2 

PM10, PM2.5,SO2, NO2

1, 2, 3, 1-7 Poisson regression analysis. W

1-

LaCo1-La

AsiaHwang and Chan(2002)50 communitiesin Taiwan 1998

Daily clinic visits forlower respiratoryillnesses for all ages. Time-series study.

1-h max O3:

Means for50 communities:54.2 ppbSD 10.2Range 38.9-78.3

NO2, SO2,

PM10, CO

0, 1 Analysis using general linear

regressions withmoving-average residualprocesses and Bayesianhierarchical modeling. Allpollutants except O3 were

associated with daily clinicvisits.

1-Ba1.0

AX7-50
Table AX7-3 (cont’d). Effects of O3 on Daily Emergency Department Visits

Reference, StudyLocation and Period

Outcomes and

Design Mean O3 Levels

Copollutants

Considered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Asia (cont’d)Chew et al. (1999)SingaporeJan 1990-Dec 1994

Emergencydepartment visits forasthma in personsaged 3-21 years. Time-series study.

1-h max O3: 

23 ppbSD 15

TSP, PM10,

SO2, NO2

0, 1, 2 Simplistic but probably

adequate control for time byincluding 1-day laggedoutcome as covariate. In adjusted models thatincluded covariates, O3

had no significant effect.

No pr

AX7-51
Table AX7-4. Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United StatesNeidell (2004)California1992-1998

Asthma hospitaladmissions within fiveage strata (0-1, 1-3,3-6, 6-12, and12-18 years). Time-series study. 

O3 (index not

specified): 38.9 ppbSD 17.8Low SES:40.1 ppbHigh SES:38.3 ppb

CO, NO2, PM10;multipollutantmodels

Not specified. Statistical analysis using

naturally occurring seasonalvariations in pollutantconcentrations within zipcodes. Linear regressionanalyses. Consistentsignificant positive effectsonly observed for CO. Negative O3 effect observed

in all age groups. Number ofsmog alerts was negativelyassociated with asthmahospitalizations, indicatingavoidance behavior on highO3 days. Interaction term

with indicator variable forlow SES was positive in allage groups and statisticallysignificant in age 3-6 yearsand 12-18 years, afteradjusting for number of smogalerts.

SlnuO3 moAg!0

Ag

!0

Ag

!0

O3 

terAg0.0Ag0.0Ag0.0

Mann et al. (2002)South Coast air basin,CA1988-1995

Ischemic heart diseaseadmissions for age40+ years. Time-seriesstudy.

8-h max O3:

50.3 ppbSD 30.1IQR 39.6

PM10, CO, NO2 0, 1, 2, 3, 4, 5,

0-1, 0-2, 0-3,

0-4

Poisson GAM with cubicB-splines; co-adjustment. No significant O3 effects

observed overall or in warmseason. CO and NO2significant in full-yearanalyses. 

O3 bueff

AX7-52
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Linn et al. (2000)Los Angeles, CA1992-1995

Total respiratory andtotal cardiovascularadmissions for age30+ years. Time-seriesstudy.

24-h avg O3:

Winter: 14 ppbSD 7Spring: 32 ppbSD 10Summer: 33 ppbSD 8Fall: 15 ppbSD 9

PM10, CO, NO2 0 Poisson GLM;

co-adjustment. Onlysignificant O3 effects

observed were inverseassociations with totalcardiac admission in full-yearand winter season, suggestingresidual confounding. No significant effects of O3

on respiratory admissions.

24

AlRe1.0Ca0.9SuRe1.0Ca1.0

Nauenberg and Basu(1999)Los Angeles, CA1991-1994

Unscheduled asthmaadmissions for all ages. Time-series study.

24-h avg O3:

All year:19.88 ppbSD 11.13Nov-Mar:7.52 ppbSD 4.34

PM10 0, 0-7 Poisson GLM with preadjustment. No significant

effects of O3. Nowarm-season resultspresented.

24

NoLa

Sheppard et al.(1999; reanalysisSheppard, 2003)Seattle, WA1987-1994

Asthma admissions forage <65 years. Time-series study.

8-h max O3:

30.4 ppbIQR 20

PM2.5, PM10,

PM10-2.5, SO2,

CO

1, 2, 3 Poisson GAM, reanalyzed

with stringent convergencecriteria; Poisson GLM. Results stratified by season. Ozone significant predictorof outcome. No twopollutant model resultsreported for O3.

8-

GLLa

AX7-53
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Schwartz (1996)Spokane, WAApr-Oct 1988-1990

Total respiratoryadmissions in personsaged 65+ years.

1-h max O3:

79 μg/m3IQR 2324-h avg O3:

56 μg/m3

IQR 17

PM10 2 Poisson GAM with default

convergence criteria. Resultsavailable only for warmseason. Ozone and PM10

both significant predictors ofoutcome. No two-pollutantmodels reported. Ozoneeffects robust to moreextensive temperaturespecification.

1-

La24

La

Koken et al. (2003)Denver, COJul-Aug 1993-1997

Cause-specificcardiovascularadmissions for age>65 years. Causecategories includeacute MI, coronaryatherosclerosis,pulmonary heartdisease, cardiacdysrhythmia, andcongestive heartfailure. Time-seriesstudy. 

24-h avg O3:

25.0 ppbSD 6.61Range 5.4-40.2

PM10, NO2,

SO2, CO

0, 1, 2, 3, 4 Analysis using Poisson

GLM. Results suggest thatO3 increases the risk of

hospitalization for coronaryatherosclerosis andpulmonary heart disease. No association was found forPM10. Strong O3 effects

observed in this seasonalstudy compared to otherstudies examining year-rounddata. Male gender andhigher temperatures werefound to be important riskfactors for cardiovasculardisease. No multipollutantanalyses were reported.

24

Ac0.8Co1.Pu1.2

AX7-54
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Moolgavkar et al.(1997)Minneapolis/St. Paul,MN and Birmingham,AL1986-1991

Pneumonia and COPDadmissions for age65+ years. Time-seriesstudy.

24-h avg O3:

Minneapolis/St. Paul: 26.2 ppbIQR 15.3Birmingham: 25.1 ppbIQR 12.7

PM10, SO2, NO2 0, 1, 2, 3 Poisson GLM with coadjustment. Both O3 and

PM10 significant in MN; not

in AL. Ozone, but not PM10,

effects were robust to NO2

and SO2.

24

MPnLaPnLaCOLaBiPnLa

Lippmann et al. (2000;reanalysis Ito, 2003,2004)Detroit, MI 1992-1994

Pneumonia, COPD,ischemic heart disease,dysrhythmias, heartfailure, and strokeadmissions for age65+ years. Time-seriesstudy.

24-h avg O3:

25 ppbMaximum 55

PM10, PM2.5,

PM10-2.5, SO42!,

H+, NO2, SO2,

CO

0, 1, 2, 3, 0-1,

0-2, 0-3

Poisson GAM, reanalyzedwith stringent convergencecriteria; Poisson GLM. Atvarious lags, no consistent O3effect observed for anycause-specific hospitaladmission. No two-pollutantmodels reported.

24

PoPnLaCOLaIscLaDyLaHeLaStLa

Schwartz et al. (1996)Cleveland, OHApr-Oct 1988-1990

Total respiratoryadmissions for age65+ years. Time-seriesstudy.

1-h max O3:

56 ppbIQR 28

PM10, SO2 1-2 Poisson GLM with sinusoids;

co-adjustment. Resultsavailable only for warmseason. Ozone and PM10

both significant predictors ofoutcome. No two-pollutantmodels reported.

1-

1.0

AX7-55
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

United States (cont’d)Gwynn and Thurston(2001)New York City1988-1990

Respiratory admissionsfor all ages, stratifiedby race and insurancestatus. Time-seriesstudy.

24-h avg O3:

22.1 ppbIQR 14.1Maximum 80.7

H+, SO42!, PM10 1 GLM with high-pass filter. 

Ozone associated withrespiratory admissions;effects larger for nonwhitesand for those uninsured or onmedicaid.

24

W1.0No1.Un1.

Gwynn et al. (2000)Buffalo, NYMay 1988-Oct 1990

Total respiratoryadmissions for all ages. Time-series study.

24-h avg O3:

26.2 ppbIQR 14.8

PM10, SO42– ,

H+, COH, CO,NO2, SO2

0, 1, 2, 3 Used Poisson with GAM

default convergence criteriafor control of temperature;moving average control fortime. Ozone significantpredictor of outcome. Notwo-pollutant modelsreported.

24

La

Weisel et al. (2002)New JerseyMay-Aug 1995

Asthma admissions forall ages. Time-seriesstudy.

1-h max O3;

5-h avg O3

(10 a.m.-3 p.m.);and 8-h avg O3(2 p.m.-10 p.m.)analyzed.Levels notreported.

Pollen, spores 0, 1, 2, 3 No control for time, but

authors report noautocorrelation, whichalleviates concerns aboutlack of control. SignificantO3 effects reported after

adjusting for potentialconfounding by pollen.

Sl(ad5-

O3 

LaAl

O3 

La

AX7-56
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

CanadaBurnett et al. (1997a)16 Canadian cities1981-1991

Total respiratoryadmissions for all ages,age <65 years and65+ years. Time-seriesstudy.

1-h max O3:

All year:31 ppb95th % 60Mean rangeacross cities:26-38 ppb95th % 45-84Jan-Mar:26 ppbApr-Jun: 40 ppbJul-Sep: 38 ppbOct-Dec:21 ppb9.6% of O3 data

missing.

SO2, NO2,

CO, coefficientof haze

0, 1, 2, 0-1, 0-2,

1-2

Poisson GLM with coadjustment. Results stratifiedby season. Significant O3

effect observed in warmseason only. No O3 effects

on control outcomes. Resultsconsistent across cities.

1-

AlJaLaApLaJuLaOcLa

Burnett et al. (1995)168 Hospitals inOntario, Canada1983-1988

Respiratory andcardiovascularadmissions for allages and within agestrata. Study focusedmainly on testing forsulfate effects. Timeseries study.

1-h max O3:

36.3 ppb

SO42! 1 GLM with pre-adjustment of

outcome variables. Resultsstratified by season. Authorsreport that O3 associated with

respiratory admission inwarm season only.

No pr

AX7-57
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Canada (cont’d)Burnett et al. (1997b)Toronto, Ontario,CanadaSummers 1992-1994

Unscheduledrespiratory andcardiovascularadmissions for all ages. Time-series study.

1-h max O3:

41.2 ppbIQR 22

PM2.5, PM10,

H+, SO42!, SO2,

NO2, CO,

coefficientof haze

0, 1, 2, 3, 4,

2 to 5 multiday

periods lagged

1 to 4 days

Poisson GLM with coadjustment. Results stratifiedby season. Ozone andcoefficient of haze strongestpredictors of outcomes. Ozone effects on bothoutcomes were robust to PM. PM effects were not robust toO3.

12

(pMtemReLaCaLa

Burnett et al. (1999)Toronto, Ontario,Canada1980-1994

Cause-specificrespiratory andcardiovascular admissions for all ages. Cause categoriesincluded asthma,COPD, respiratoryinfections, heart failure,ischemic heart disease,and cerebrovasculardisease. Time-seriesstudy.

24-h avg O3:

19.5 ppbIQR 19

EstimatedPM2.5, PM10,

PM10-2.5, CO,

NO2, SO2

0, 1, 2, 0-1, 0-2,

1-2, 1-3, 2-3,

2-4

Poisson GAM with LOESSpre-filter applied to pollutionand hospitalization data. Ozone effects seen forrespiratory outcomes only. Ozone effect robust to PM;not vice versa. No seasonalstratification.

24

AsLaCOLaReLa

Burnett et al. (2001)Toronto, Ontario,Canada1980-1994

Acute respiratorydisease admissions forage <2 years. Timeseries study.

1-h max O3:

Summer:45.2 ppbIQR 25

EstimatedPM2.5, PM10,

PM10-2.5, CO,

NO2, SO2

0, 1, 2, 3, 4,

5, 0-4

Poisson GAM with LOESSpre-filter applied to pollutionand hospitalization data. Sensitivity analyses using coadjustment. Results stratifiedby season. Ozone effectssignificant only in summer. Ozone effect robust to PM;not vice versa.

1-

SuO3 LaO3 La

AX7-58
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Canada (cont’d)Lin et al. (2003)Toronto, Ontario,Canada1981-1993

Asthma admission forage 6-12 years. Case-crossover design.

1-h max O3:

30 ppbIQR 20

CO, SO2, NO2 0, 0-1, 0-2, 0-3,

0-4, 0-5, 0-6

Conditional logisticregression model analysis. No O3 effects observed. 

Positive relations to CO, SO2

and NO2 observed.

1-OdMLaFeLa

Fung et al. (2005)Windsor, Ontario,CanadaApr 1995-Dec 2000

Cardiovascular hospitaladmissions for age<65 and $65 years. 

Time-series study.

1-h max O3: 39.3 ppbSD 21.4Range 1-129

NO2, SO2, CO,PM10,coefficientof haze, totalreduced sulfurcompounds

0, 0-1, 0-2 Conducted both time-series

analysis using Poisson GLMwith natural splines. Strongest effect observed forSO2 in individuals aged

$65 years. No associations

were found any otherpollutant, including O3.

1-

AgLaLaAg

LaLa

Luginaah et al. (2005)Windsor, Ontario,CanadaApr 1995-Dec 2000

Respiratory hospitaladmissions by genderfor all ages and age0-14, 15-64, and65+ years. Time-seriesstudy.

1-h max O3: 

39.3 ppbSD 21.4Range 1-129

NO2, SO2, CO,PM10,coefficientof haze, totalreduced sulfurcompounds

0, 0-1, 0-2 Conducted both time-series

analysis using Poisson GLMwith natural splines andbidirectional case-crossoveranalysis using conditionallogistic regression models. For case-crossover analysis,control periods selected 2weeks before and after thecase period. Results wereconsistent for the time-seriesand case-crossover analyses. Significant associations werefound for all pollutantsexcept O3 and total reduced

sulfur compounds.

1-

AlTiMLaFeLaCaMLaFeLa

AX7-59
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Canada (cont’d)Lin et al. (2004)Vancouver, BritishColumbia, Canada1987-1998

Asthma admissions forage 6-12 years. Timeseries study.

1-h max O3:

28.02 ppb SD 11.54IQR 14.81

CO, SO2, NO2 0, 0-1, 0-2, 0-3,

0-4, 0-5, 0-6

Poisson GAM with LOESS(using default convergencecriteria). Repeated analysiswith natural cubic splinesusing 1,000 iterations withconvergence criteria 10-15. 

Results were similar for bothanalyses. NO2 exposure

associated for males in lowSES but not high. Noassociation for CO and O3 in

either SES group.

1-

MLoLaHiLaFeLoLaHiLa

Yang et al. (2003) Vancouver, BritishColumbia, CanadaJan 1986-Dec 1998

Daily respiratoryadmissions in childrenaged <3 years andadults aged 65+ years. Bidirectionalcase-crossover. Conditional logisticregression.

24-h avg O3:

13.41 ppbSD 6.61IQR 9.74

CO, NO2, SO2,

coefficientof haze

1, 2, 3, 4, 5 Used bidirectional casecrossover analysis,

comparing air pollution onday of admission to levels1 week before and after. SESevaluated. Ozone waspositively associated withrespiratory hospitaladmissions among youngchildren and the elderly. 

24

OdAgLaAgLa

AX7-60
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

EuropeAnderson et al. (1997)Five European cities:London, Paris, Amsterdam,Rotterdam, BarcelonaStudy periods vary bycity, ranging from1977-1992

Emergency COPDadmissions for all ages. Each city analyzedpreviously byindividual teams. Results combined herevia meta-analysis. Time-series study.

1-h max O3:

Median rangeacross five cities:All year:36-77 μg/m3

Warm season:48-91 μg/m3Cool season:20-64 μg/m3

TSP, SO2, NO2,

BS

0, 1, 2, 3, 4, 5 Poisson GLM using APHEA

methodology. Resultsstratified by season. Ozone most consistent andsignificant predictor ofadmissions. Warm-seasoneffect larger.

1-

WfivfoAl1.0W1.0Co1.0

Atkinson et al. (2001)Eight European cities: Barcelona,Birmingham, LondonMilan, Netherlands,Paris, Rome, andStockholmStudy periods vary bycity, ranging fromearly to middle 1990s

Total respiratory,asthma, and COPDadmissions for all agesand age 0-14,15-64 and 65+ years. Time-series study.

8-h max O3:

Mean range:26.0 μg/m3

(Rome) to 66.6 μg/m3(Stockholm)

PM10, NO2,

SO2, CO

N/A Study focused on PM10

effects. Copollutantsincluded only as effectmodifiers. No direct O3results shown. Ozoneappeared to modify the PM10effect on respiratoryadmissions for persons overage 64 years of age.

No 

AX7-61
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Le Tertre et al.(2002b)Eight European cities: Barcelona,Birmingham, LondonMilan, Netherlands,Paris, Rome, andStockholmStudy periods vary bycity, ranging fromearly to middle 1990s

Total cardiovascular,ischemic heart disease,and stroke admissionsfor all ages and age0-64 and 65+ years. Time-series study.

8-h max O3:

Mean range:26.0 μg/m3

(Rome) to 66.6μg/m3(Stockholm)

PM10, BS, NO2,

SO2, CO

N/A Main focus on PM10 and BS. 

Gaseous copollutantsevaluated as effect modifiers. Greater PM10 effects seen in

cities with lower annual O3levels. No risk estimatespresented for O3.

No 

Wong et al. (2002)London, England1992-1994Hong Kong 1995-1997

Total respiratory(>64 years), asthma(15-64 years), totalcardiovascular (allages), and ischemicheart disease (all ages)admissions. Timeseries study.

8-h max O3:London:All year:34.9 μg/m3

SD 23.1Warm season:45.3 μg/m3Cool season:24.0 μg/m3Hong Kong:33.5 μg/m3SD 23.0Warm season:32.0 μg/m3Cool season: 35.1 μg/m3

PM10, NO2, SO2 0, 1, 2, 3

0-1

Poisson GAM with defaultconvergence criteria. Mostconsistent associations foundwith total respiratoryadmissions. Ozoneassociated with totalrespiratory admissions inall-year and warm-seasonanalyses in both cities. Associations in cool-seasonanalyses observed only inHong Kong. All-year O3effects robust to copollutants.

8-

ToLoAlLaWLaCoLaHoAlLaWLaCoLa

AX7-62
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Anderson et al. (1998)London, England1987-1992

Admissions for asthmain all ages andage 0-14, 15-64,and 65+ years. Time-series study.

8-h max O3:

15.5 ppbIQR 131-h max O3:20.6 ppbIQR 16

SO2, NO2,BS, pollens

0, 1, 2, 0-1,

0-2

Poisson GLM using APHEAmethod; co-adjustment. Ozone significantlyassociated with asthmaadmissions in the warmseason for all ages and forage 15-64 years. Warmseason O3 effect robust in

two-pollutant models. Inverse associations observedin the cool season for someage groups.

8-AlWLaCoLa

Atkinson et al. (1999b)London, England1992-1994

Total and causespecific respiratory andcardiovascularadmissions in all agesand in all ages andage 0-14, 15-64, and65+ years. Time-seriesstudy.

8-h max O3:

17.5 ppbSD 11.5

NO2, SO2, CO,PM10, BS

0, 1, 2, 3, 0-1,

0-2, 0-3

Poisson GLM using APHEAmethodology. No significantassociations seen between O3

and respiratory admissions. Ozone was positivelyassociated with totalcardiovascular admissions inage 65+ years. Seasonalanalyses were not conducted.

8-AlToLaToLa

Ponce de Leon et al.(1996)London, EnglandApr 1987-Feb 1992

Total respiratoryadmissions in severalage strata: all ages,0-14, 15-64, 65+ years. Time-series study.

8-h avg O3

(9 a.m.-5 p.m.):15.6 ppbSD 12IQR 14

BS, SO2, NO2 0, 1, 2, 0-1, 0-2,

0-3,

Poisson GLM using APHEAco-adjustment methodology. Ozone significant predictoroverall. Effect larger andmore significant in warmseason. Effect robust tocopollutants. Effects variedby age.

AlAl8-

LaW8-LaCo8-La

AX7-63
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Poloniecki et al.(1997)London, England Apr 1987-Mar 1994

Cause-specific and totalcirculatory admissionsfor all ages. Timeseries study.

8-h avg O3

(9 a.m.-5 p.m.):Median 13 ppbRange 0-94

BS, NO2,

SO2, CO

0 Poisson regression using

APHEA methodology. Noassociation was foundbetween O3 and circulatory

diseases in all-year analyses. Results from acute MIsuggest potential seasonaleffect.

8-

ToAl0.9AcAl0.9W1.0Co0.9

Prescott et al. (1998)Edinburgh, Scotland1992-1995

Total respiratory andcardiovascularadmissions for age<65 years and65+ years. Time-seriesstudy.

24-h avg O3:

14.5 ppbRange 1-37

BS, PM10, NO2,

SO2, CO

0, 1, 1-3 Poisson GLM, month dummy

variables; co-adjustment. NoO3 or other pollution effects

on respiratory admissions. Significant inverseassociation of O3 with

cardiac admissions in olderage group. Very low O3

concentrations.

24

ReAgLaAgLaCaAgLaAgLa

AX7-64
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Schouten et al. (1996)Amsterdam andRotterdam,the Netherlands1977-1989

Unscheduled totalrespiratory, asthma, andCOPD admissions inall ages. Time-seriesstudy.

8-h max O3:

Amsterdam:Summer:86 μg/m3

5th % to 95th % 28-152Winter:53 μg/m3

5th % to 95th % 3-104Rotterdam:Summer:81 μg/m35th % to 95th % 25-199Winter:45 μg/m35th % to 95th %3-96

SO2, NO2, BS 0, 1, 2, 0-1, 0-2,

0-3, 0-4, 0-5

Poisson GLM using APHEAmethodology; co-adjustment. No consistent O3 effects. 

Concern regarding multiplecomparisons.

1-

AmToSuLaWLa

Hagen et al. (2000)Drammen, NorwayNov 1994-Dec 1997

Total respiratoryadmissions for all ages. Time-series study.

24-h avg O3:

44.48 μg/m3

SD 18.40IQR 26.29

PM10, NO2,

SO2, benzene,

toluene,formaldehyde

0 Poisson GAM with partial

splines; co-adjustment. Single and multipollutantmodels evaluated. No O3

effects. Ozone levels lowand cycles may not havebeen adequately controlled.

24

(p

La

Oftedal et al. (2003)Drammen, Norway1995-2000

Admissions forrespiratory disease. Time-series study.

24-h avg O3:

44.6 μg/m3

SD 19.2IQR 26.9

Benzene,formaldehyde,toluene, PM10,NO2, SO2

0 Benzene had the strongest

association.

24

0.9

AX7-65
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Europe (cont’d)Pönkä and Virtanen(1996)Helsinki, Finland1987-1989

Asthma admissions forage 0-14 years and15-64 years. Timeseries study.

8-h max O3: 

All year: 22 μg/m3

Winter:20 μg/m3Spring: 30 μg/m3Summer:23 μg/m3Fall:15 μg/m3

TSP, SO2, NO2 0, 1, 2, 3, 4, 5 Poisson GLM using APHEA

methodology. Reportedsignificant O3 effect for age

0-14 years, but also forcontrol (digestive disease)conditions. Ozone levelsvery low.

No

Ballester et al. (2001)Valencia, Spain1994-1996

Emergency totalcardiovascularadmissions for all ages. Time-series study.

8-h max O3:

23 ppbRange 5-64

SO2, NO2,CO, BS

0, 1, 2, 3, 4, 5 Poisson GLM using APHEA

methodology. Resultsstratified by season. No O3

effects. 

8-La

Latin AmericaGouveia and Fletcher(2000a)São Paulo, BrazilNov 1992-Sep 1994

Total respiratory,pneumonia, and asthmaadmissions for age<5 years. Time-seriesstudy.

1-h max O3:63.4 μg/m3SD 38.1IQR 50.3

PM10, NO2,

SO2, CO

0, 1, 2 Poisson GLM with coadjustment using sine/cosine

waves. Significant O3 effects

on total respiratory andpneumonia admissions. Ozone effects fairly robustto NO2 and PM10.

1-

ToLaPnLaAsLa

AX7-66
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

AustraliaMorgan et al. (1998a)Sydney, Australia 1990-1994

Admissions for asthma(age 1-14 years,15-64 years), COPD(age 65+ years), andheart disease (all ages,0-64 years, 65+ years). Time-series study.

1-h max O3: 

25 ppbSD 13IQR 11

Bscatter, NO2 0, 1, 2, 0-1,

0-2

Poisson with GEE. No significant effects of O3in single or multipollutantmodels. 

1-AsLaAsLaCOLaHeLa

Petroeschevsky et al.(2001)Brisbane, Australia1987-1994

Unscheduled asthma,total respiratory andtotal cardiovascularadmissions in severalage strata: all ages,0-4, 5-14, 15-64,65+ years. Timeseries study.

8-h avg O3(10 a.m.-6 p.m.):All year:19.0 ppbRange 1.7-64.7 Winter:16.1 ppbSpring:23.3 ppbSummer:19.9 ppbFall:16.7 ppb

Bscatter, SO2,

NO2

0, 1, 2, 3, 0-2,

0-4

Poisson GLM using APHEAco-adjustment methodology. Seasonal variations in O3

effects also investigated. Only a few significantinteractions observed betweenO3 and season. Strong O3effects observed in all-yearmodels. Ozone significantlyrelated to asthma and totalrespiratory admissions, notfor cardiac admissions. Effects varied by age group. Ozone effects robust tocopollutants.

8-

AlToLaAsLaToLa

AsiaLee et al. (2002)Seoul, KoreaDec 1997-Dec 1999

Asthma admissionsfor age <15 years. Time-series study.

1-h max O3:

36.0 ppbSD 18.6IQR 21.7

SO2, NO2, CO,

PM10

0, 1, 2, 3, 4, 

0-1, 1-2, 2-3, 

3-4

Poisson GAM using defaultconvergence criteria. Ozoneassociated with asthmaadmissions in single- andtwo-pollutant models.

1-

O3 LaO3 

La

AX7-67
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Asia (cont’d)Chang et al. (2005)Taipei, Taiwan1997-2001

Total cardiovascularhospital admissions forall ages. Cool days(<20 °C) and warmdays ($20 °C) were

evaluated. Casecrossover approach.

24-h avg O3:19.74 ppbIQR 10.87Range 2.30-53.93

PM10, SO2,

NO2, CO

0-2 Conditional logistic

regression. Allcardiovascular admissionschosen because similar riskshave been observed for majorsubcategories and combiningcounts provide greater power. Subtropical climate in Taipei. In the analysis of warm daysonly, all pollutants exceptSO2 were associated with

cardiovascular admissions. Ozone effect slightlydiminished in two-pollutantmodel adjusting for PM10.

24

OdO3 

WCoO3 

WCo

Yang et al. (2004a)Kaohsiung, Taiwan1997-2000

Total cardiovascularhospital admissions forall ages. Cool days(<25 °C) and warmdays ($25 °C) wereevaluated. Casecrossover approach.

24-h avg O3:25.02 ppb IQR 21.20Range 1.25-83.00

PM10, SO2,

NO2, CO

0-2 Conditional logistic

regression. All pollutantsexcept SO2 associated with

cardiovascular admissions onwarm days. On cool days, O3

effect was diminished. Ozone effect was robust toadjustment to copollutants. Results from tropical citymay restrict generalization toother locations.

24

OdO3 

WCoO3 

WCo

AX7-68
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Asia (cont’d)Tsai et al. (2003a)Kaohsiung, Taiwan1997-2000

Stroke admissions(subarachnoidhemorrhagic stroke,primary intracerebralhemorrhage, ischemicstroke, and others) forall ages. Cool days(<20 °C) and warmdays ($20 °C) were

evaluated. Casecrossover approach.

24-h avg O3:25.02 ppb IQR 21.20Range 1.25-83.00

PM10, SO2,

NO2, CO

0-2 Conditional logistic

regression. Warm dayassociations were positivewhile cool days weregenerally negative with somepositive associations. Ozoneeffect was robust toadjustment for SO2 and CO,but not PM10.

24

OdO3 

PrheWCoIscWCoO3 

PrheWIscW

Wong et al. (1999a)Hong Kong1994-1995

Total and causespecific respiratory andcardiovascularadmissions in severalage strata: all ages,0-4, 5-64, 65+ years. Time-series study.

8-h max O3: 

20.2 μg/m3Median 24.15 IQR 31.63

NO2, SO2,

PM10

0, 1, 2, 3, 4, 5,

0-1, 0-2, 0-3,

0-4, 0-5

Poisson GLM using APHEAmethodology. Ozonesignificantly associated withtotal and cause specificrespiratory and cardiacoutcomes. Ozone resultsrobust to adjustment for highPM10, but not high NO2. 

Effects of O3 persisted in

cold season.

8-

AlToLaToLa

AX7-69
Table AX7-4 (cont’d). Effects of O3 on Daily Hospital Admissions

Reference, StudyLocation and Period Outcomes and Design Mean O3 Levels 

CopollutantsConsidered

Lag Structure

Examined

Method, Findings,

Interpretation

(R

Asia (cont’d)Wong et al. (1999b)Hong KongJan 1995-Jun 1997

Cause-specificcardiovascularadmissions for age

$65 years. Time-series

study.

8-h avg O3:

Warm season:31.2 μg/m3

Cool season: 34.8 μg/m3

NO2, SO2,

respirable PM

0, 1, 2, 3, 4, 5,

0-1, 0-2, 0-3,

0-4, 0-5

GLM with sinusoids;co-adjustment. Ozonesignificantly associated withtotal and cause-specificcardiovascular admissions incool season only, when O3

levels are higher in HongKong. Details missing inbrief report.

O3 O3 

ToAlLaWLaCoLa

AX7-70
Table AX7-5. Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Meta-analysisBell et al. (2005)Various U.S. andnon-U.S. citiesVarying study periods 

All cause;cardiovascular;respiratory; allages; age 64+ or65+ years.

Not applicable. Various PM

indices 

0, 1, 2, or 0-1 Meta-analysis. 

Bayesian hierarchicalmodel; included up to144 estimates from39 studies.Risk estimates obtainedfor yearly vs.warm-season data;cause-specific; PMadjustment; U.S. vs.non-U.S.;various lags;and GAM vs. nonGAM.Comparisons withNMMAPS estimates(Bell et al., 2004).

AX7-71
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Meta-analysis (cont’d)Ito et al. (2005)Various U.S. andnon-U.S. citiesVarying study periods

All cause Not applicable. Various PM

indices

Reported lags

up to 3-day lags

Meta-analysis. DerSimonian-Lairdapproach; included upto 43 estimates from38 studies.Risk estimates obtainedfor yearly vs.warm-season data; PMadjustment; correctionfor asymmetry infunnel plot; and GAMvs. non-GAM.Seven U.S. cities timeseries study withvarious sensitivityanalyses.

AX7-72
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Meta-analysis (cont’d)Levy et al. (2005)Various U.S., Canadianand European citiesVarying study periods

All cause Not applicable. PM10, PM2.5, SO2,

NO2, CO

0, 1-2 Meta-analysis. 

Empirical Bayesmetaregression;included up to48 estimates from28 studies.Risk estimates obtainedby season; copollutantadjustment; NorthAmerica vs. Europe;various lags;temperatureadjustment; GAM vs.non-GAM; and annualmean O3.Examined relationshipbetween O3personal exposure andambient concentrationsusing coolingdegree days andresidential central airconditioningprevalence.

AX7-73
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United StatesBell et al. (2004)95 U.S. communities1987-2000

All cause;cardiopulmonary;all ages; age<65 years;age 65-74 years;age $75 years

24-h avg O3: 

26 ppb across the95 communities. 55 communitieswith all-year data: Median range:14.38 ppb (Newark, NJ)to 37.30 ppb(Bakersfield, CA)40 communitieswith warm-seasononly data: Median range:20.41 ppb (Portland, OR)to 36.15 ppb(Memphis, TN) 

PM10, PM2.5; twopollutant models 0, 1, 2, 3, 0-6 Poisson GLM; Bayesian hierarchical

model. Time-seriesstudy.

AX7-74
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Samet et al. (2000;reanalysis Dominici et al.,2003)90 U.S. cities (80 U.S.cities with O3 data)

1987-1994

All cause;cardiopulmonary

24-h avg O3: 

Mean range: Approximately12 ppb(Des Moines, IA)to 36 ppb(San Bernardino,CA) 

PM10, NO2, SO2,

CO; two-pollutantmodels

0, 1, 2 Poisson GAM,

reanalyzed withstringent convergencecriteria; Poisson GLM. Time-series study.

Huang et al. (2005)19 large U.S. citiesJun-Sept 1987-1994

Cardiopulmonary 24-h avg O3: 

Mean range:Approximately18 ppb (Oakland,CA) to 56 ppb(San Bernardino,CA)Daily range across19 U.S. cities:0-100 ppb 

PM10, PM2.5; twopollutant models 0, 1, 2, 0-6 Poisson GLM; Bayesian hierarchical

model. Time-seriesstudy.

AX7-75
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Schwartz (2005) 14 U.S. cities1986-1993

All cause 1-h max O3:

Median range:35.1 ppb (Chicago,IL) to 60.0 ppb(Provo, UT)

PM10; twopollutant models 0 Case-crossover analysis; conditional

logical regression controlled fortemperature usingnonlinear regressionsplines and matching

Kinney and Özkaynak(1991)Los Angeles County, CA1970-1979

All cause;respiratory;circulatory 

1-h max totaloxidants (Ox): 

75 ppbSD 45 

KM (particleopticalreflectance), NO2,

SO2, CO;

multipollutantmodels

1 OLS (ordinary least

squares) on high-passfiltered variables. Time-series study.

Kinney et al. (1995)Los Angeles County, CA1985-1990

All cause 1-h max O3: 

70 ppbSD 41

PM10, NO2, SO2,

CO; two-pollutantmodels

1 Linear, log-linear, and

Poisson. Time-seriesstudy.

AX7-76
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Ostro (1995)San Bernardino County andRiverside County, CA1980-1986

All cause 1-h max O3:

140 ppbRange 20-370

PM2.5 0 Autoregressive linear;

Poisson. Time-seriesstudy.

Ostro et al. (2000)Coachella Valley, CA1989-1998

All cause;respiratory;cardiovascular

1-h max O3:

Palm Springs:67 ppbRange 0-190Indio:62 ppbRange 0-180

PM10, PM2.5,

PM10-2.5, NO2, CO 

0 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

Fairley (1999; reanalysisFairley, 2003)Santa Clara County, CA1989-1996

All cause;respiratory;cardiovascular

8-h max O3:

29 ppb SD 1524-h avg O3:

16 ppbSD 9O3 ppb-h >60 ppb:

Levels not reported.

PM10, PM2.5,

PM10-2.5, SO42!,

coefficient ofhaze, NO3-, NO2,

SO2; two-pollutant

models 

0 Poisson GAM,

reanalyzed withstringent convergencecriteria; Poisson GLM. Time-series study.

AX7-77
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Gamble (1998)Dallas, TX1990-1994

All cause;respiratory;cardiovascular;cancer; other

24-h avg O3:

All year:22 ppbRange 0-160Summer:30 ppbRange 0-160Winter:12 ppbRange 0-75

PM10, NO2, SO2,

CO; two-pollutantmodels

1-2 Poisson GLM. Timeseries study. 

Dockery et al. (1992)St. Louis, MO and EasternTennessee1985-1986

All cause 24-h avg O3:

St. Louis, MO:22.5 ppbSD 18.5Eastern Tennessee:23.0 ppbSD 11.4

PM10, PM2.5,SO42!, H+, NO2,

SO2

1 Poisson with GEE. 

Time-series study.

AX7-78
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Ito and Thurston (1996)Cook County, IL1985-1990

All cause;respiratory;circulatory; cancer;race/gendersubcategories

1-h max O3:

38.1 ppbSD 19.9

PM10, NO2, SO2,

CO; two-pollutantmodels

0-1 Poisson GLM. Timeseries study. 

Moolgavkar (2003)Cook County, IL and LosAngeles County, CA1987-1995

All cause;cardiovascular

24-h avg O3:Cook County:Median 18 ppbRange 0.2-67Los AngelesCounty:Median 24 ppbRange 0.6-77

PM2.5, PM10, NO2,

SO2, CO; twopollutant models

0, 1, 2, 3, 4, 5 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

AX7-79
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Moolgavkar (2000)Cook County, IL; LosAngeles County, CA; andMaricopa County, AZ1987-1995

Cardiovascular;cerebrovascular;COPD

24-h avg O3:

Cook County:Median 18 ppbRange 0.2-67Los AngelesCounty:Median 24 ppbRange 0.6-77Maricopa County:Median 25 ppbRange 1-50

PM2.5, PM10, NO2,

SO2, CO; two- and

three-pollutantmodels

0, 1, 2, 3, 4, 5 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

Lippmann et al. (2000;reanalysis Ito, 2003, 2004)Detroit, MI 1985-19901992-1994

All cause;respiratory;circulatory;cause-specific

24-h avg O3:1985-1990:20.9 ppbIQR 12.0-27.51992-1994:25 ppbIQR 18-30

PM10, PM2.5,PM10-2.5, SO42!, H+,NO2, SO2, CO;

two-pollutantmodels

0, 1, 2, 3, 0-1,

0-2, 0-3

Poisson GAM,reanalyzed withstringent convergencecriteria; Poisson GLM. Time-series study.

AX7-80
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Lipfert et al. (2000a)Seven counties inPhiladelphia, PA area1991-1995

All cause;respiratory;cardiovascular;all ages; age65+ years; age<65 years; varioussubregionalboundaries

1-h max O3:

44.76 ppbSD 25.6824-h avg O3:

23.44 ppbSD 13.86 

PM10, PM2.5,

PM10-2.5, SO42!, 

NO3-, other PMindices, NO2, SO2,

CO; two-pollutantmodels

0-1 Linear with 19-day

weighted averageShumway filters. Time-series study.

Moolgavkar et al. (1995)Philadelphia, PA 1973-1988

All cause 24-h avg O3:

Spring: 25.9 ppbRange 2.9-74.0Summer:35.5 ppbRange 1.3-159.0Fall:16.2 ppbRange 0.2-63.8Winter:11.9 ppbRange 0.0-32.9

TSP, SO2;multipollutantmodels

1 Poisson; GEE and

nonparametricbootstrap methods. Time-series study.

AX7-81
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Chock et al. (2000)Pittsburgh, PA1989-1991

All cause; age<74 years;age 75+ years

1-h max O3: 

Levels not reported.

PM10, NO2, SO2,

CO; two-, five-,and six-pollutantmodels

0 Poisson GLM. Timeseries study. 

De Leon et al. (2003)New York City1985-1994

Circulatory andcancer with andwithoutcontributingrespiratory causes

24-h avg O3:

21.59 ppb5th %-95th % 7.00-44.97

PM10, NO2, SO2,

CO; two-pollutantmodels

0 or 1 Poisson GAM with

stringent convergencecriteria; Poisson GLM. Time-series study.

AX7-82
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

United States (cont’d)Klemm and Mason (2000);Klemm et al. (2004)Atlanta, GAAug 1998-July 2000

All cause;respiratory;cardiovascular; cancer; other; age<65 years; age65+ years

8-h max O3: 

47.03 ppbSD 24.71

PM2.5, PM10-2.5,

EC, OC, NO2,

SO42!,NO3-, SO2, CO

0-1 Poisson GLM using

quarterly, monthly, orbiweekly knots fortemporal smoothing. Time-series study.

CanadaVedal et al. (2003)Vancouver, BritishColumbia, Canada1994-1996

All cause; respiratory;cardiovascular

1-h max O3:

27.3 ppbSD 10.2

PM10, NO2, SO2,

CO

0, 1, 2 Poisson GAM with

stringent convergencecriteria. Time-seriesstudy.

Villeneuve et al. (2003)Vancouver, BritishColumbia, Canada1986-1999

All cause;respiratory;cardiovascular;cancer;socioeconomicstatus

24-h avg O3: 

13.4 ppbRange 0.6-38.6

PM2.5, PM10, PM2.5-10, TSP,

coefficient ofhaze, SO42!, SO2,

NO2, CO

0, 1, 0-2 Poisson GLM with

natural splines. Timeseries study.

AX7-83
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Canada (cont’d)Goldberg et al. (2003)Montreal, Quebec, Canada1984-1993

Congestive heartfailure asunderlying cause ofdeath vs. thoseclassified as havingcongestive heartfailure 1 year priorto death

24-h avg O3: 

29.0 μg/m3

SD 17.1

PM2.5, coefficient

of haze, SO42!,

SO2, NO2, CO

0, 1, 0-2 Poisson GLM with

natural splines. Timeseries study.

Goldberg et al. (2001)Montreal, Quebec, Canada1984-1993

All cause; causespecific; all ages;age <65 years; age

$65 years

24-h avg O3: 

29.0 μg/m3

SD 17.1

PM2.5, coefficient

of haze, SO2, NO2,

NO, CO

0, 1, 0-2 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

AX7-84
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

EuropeGryparis et al. (2004)23 European citiesStudy periods vary by city,ranging from 1990-1997

All cause;respiratory;cardiovascular 

1-h max O3: 

Median range: Warm season: 44 ppb (Tel Aviv,Israel) to 117 ppb(Torino, Italy)Cold season: 11 ppb (Milan,Italy) to 57 ppb(Athens, Greece)8-h max O3: Median range: Warm season: 30 ppb (Rome,Italy) to 99 ppb(Torino, Italy) Cold season: 8 ppb (Milan, Italy)to 49 ppb (Budapest,Hungary)

PM10, NO2, SO2,

CO; two-pollutantmodels

0-1 Poisson GAM with

stringent convergencecriteria; Bayesianhierarchical model. Time-series study.

AX7-85
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Touloumi et al. (1997)Four European cities:London, ParisBarcelona, AthensStudy periods vary by city,ranging from 1986-1992

All cause 1-h max O3:

London:41.2 μg/m3SD 26.0Paris:46.1 μg/m3SD 32.9Barcelona:72.4 μg/m3SD 34.9Athens:93.8 μg/m3SD 42.8

BS, NO2; twopollutant models 0, 1, 2, 3, 0-1, 0-2, 0-3 Poisson autoregressive. Time-series study. 

Zmirou et al. (1998)Four European cities: London, Paris, Lyon,Barcelona Study periods vary by city,ranging from 1985-1992

Respiratory;cardiovascular 

8-h avg O3(9 a.m.-5 p.m.):London:Cold: 21.0 μg/m3

Warm: 40.8 μg/m3Paris:Cold: 11.5 μg/m3Warm: 42.7 μg/m3Lyon: Cold: 21.0 μg/m3Warm: 40.8 μg/m3Barcelona:Cold: 51.5 μg/m3Warm: 89.7 μg/m3

BS, TSP, SO2,

NO2

0, 1, 2, 3, 0-1,

0-2, 0-3

Poisson GLM. Timeseries study. 

AX7-86
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Anderson et al. (1996)London, England1987-1992

All cause;respiratory;cardiovascular

1-h max O3: 

20.6 ppbSD 13.28-h avg O3(9 a.m.-5 p.m.): 15.5 ppbSD 10.9

BS, NO2, SO2;

two-pollutantmodels 

0 Poisson GLM. Timeseries study. 

Bremner et al. (1999)London, England1992-1994

All cause;respiratory;cardiovascular; allcancer; all others;all ages; agespecific (0-64, 65+,65-74, 75+ years)

1-h max O3:

22.6 ppbSD 13.48-h max O3:17.5 ppbSD 11.5

BS, PM10, NO2,SO2, CO; twopollutant models

Selected best

from 0, 1, 2, 3,

(all cause);

0, 1, 2, 3, 0-1,

0-2, 0-3

(respiratory,

cardiovascular)

Poisson GLM. Timeseries study. 

AX7-87
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Anderson et al. (2001)West Midlands region,England1994-1996

All cause;respiratory;cardiovascular; allages; age 0-14years; age 15-64years; age 65+years

8-h max Ox:

24.0 ppbSD 13.8 

PM10, PM2.5, 

PM2.5-10, BS, SO42-,

NO2, SO2, CO

0-1 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

Prescott et al. (1998)Edinburgh, Scotland1992-1995

All cause;respiratory;cardiovascular; allages; age <65years; age $65

years

24-h avg O3:

14.5 ppbSD 2.3

BS, PM10, NO2,

SO2, CO; twopollutant models

0 Poisson GLM. Timeseries study. 

Le Tertre et al. (2002a)Le Havre, Lyon, Paris,Rouen, Strasbourg, andToulouse, FranceStudy periods vary by city,ranging from 1990-1995

All cause;respiratory;cardiovascular

8-h max O3:

Le Havre:43.4 μg/m3Lyon:52.0 μg/m3Paris:26.0 μg/m3Rouen:57.9 μg/m3Strasbourg:37.0 μg/m3Toulouse:68.0 μg/m3

BS, NO2, SO2 0-1 Poisson GAM with

default convergencecriteria. Time-seriesstudy. 

AX7-88
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Dab et al. (1996)Paris, France1987-1992

Respiratory 1-h max O3: 

43.9 μg/m35th %-99th % 6.0-147.08-h max O3: 27.7 μg/m35th %-99th % 3-110

BS, PM13, NO2,SO2, CO

0 Poisson autoregressive. 

Time-series study.

Zmirou et al. (1996)Lyon, France1985-1990

All cause; respiratory;cardiovascular;digestive

1-h max O3:

15.23 μg/m3Range 0-1528-h avg O3(9 a.m.-5 p.m.):9.94 μg/m3Range 0-78.92

PM13, SO2, NO2 Selected best

from 0, 1, 2, 3

Poisson GLM. Timeseries study. 

Sartor et al. (1995)BelgiumSummer 1994

All cause; age<65 years;age 65+ years

24-h avg O3:

Geometric mean:During heat wave(42-day period): 72.4 μg/m3

Range 34.5-111.5Before heat wave(43-day period): 52.4 μg/m3Range 30.7-92.0After heat wave(39-day period): 38.6 μg/m3Range 18.8-64.9

TSP, NO, NO2,SO2

0, 1, 2 Log-linear regression. 

Time-series study.

AX7-89
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Hoek et al. (2000;reanalysis Hoek, 2003)The Netherlands: entirecountry, four urban areas1986-1994

All cause; COPD;pneumonia;cardiovascular 

8-h avg O3

(12 p.m.-8 p.m.):Median: 47 μg/m3

Range 1-226

PM10, BS, SO42!,NO3-, NO2, SO2,

CO; two-pollutantmodels

1, 0-6 Poisson GAM,

reanalyzed withstringent convergencecriteria; Poisson GLM. Time-series study.

Hoek et al. (2001;reanalysis Hoek, 2003)The Netherlands1986-1994

Totalcardiovascular;myocardialinfarction;arrhythmia; heartfailure;cerebrovascular;thrombosis-related

8-h avg O3

(12 p.m.-8 p.m.):Median: 47 μg/m3

Range 1-226

PM10, NO2, SO2,

CO

1 Poisson GAM,

reanalyzed withstringent convergencecriteria; Poisson GLM. Time-series study.

Roemer and van Wijinen(2001)Amsterdam, theNetherlands1987-1998

All cause 8-h max O3: 

Background sites:43 μg/m3Maximum 221Traffic sites: 36 μg/m3Maximum 213

BS, PM10, NO2,SO2, CO

1, 2, 0-6 Poisson GAM with

default convergencecriteria (only onesmoother). Time-seriesstudy.

AX7-90
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Verhoeff et al. (1996)Amsterdam, theNetherlands1986-1992 

All cause; all ages;age 65+ years

1-h max O3:

43 μg/m3Maximum 301

PM10, NO2, SO2,

CO; multipollutantmodels

0, 1, 2 Poisson. Time-series

study.

Peters et al. (2000b)NE Bavaria, Germany1982-1994Coal basin in CzechRepublic1993-1994

All cause;respiratory;cardiovascular;cancer

24-h avg O3:

Czech Republic:40.3 μg/m3

SD 25.0Bavaria, Germany:38.2 μg/m3SD 21.9

TSP, PM10, NO2,SO2, CO

0, 1, 2, 3 Poisson GLM. 

Time-series study.

Pönkä et al. (1998)Helsinki, Finland1987-1993

All cause;cardiovascular; age<65 years, age 65+years

24-h avg O3: 

Median 18 μg/m3

5th %-95th % 3-51

TSP, PM10, NO2,SO2

0, 1, 2, 3, 4, 5,

6, 7

Poisson GLM. Timeseries study. 

AX7-91
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Saez et al. (2002)Barcelona, Spain1991-1995Madrid, Spain1992-1995Valenica, Spain1994-1996

All cause;respiratory;cardiovascular

8-h max O3:

Barcelona:67.5 μg/m3SD 32.2Madrid:42.1 μg/m3SD 27.8Valencia:45.5 μg/m3SD 19.7

NO2, PM, SO2,

CO; multipollutantmodels

0-5 Poisson GAM with

default convergencecriteria. Time-seriesstudy. 

Garcia-Aymerich et al.(2000)Barcelona, Spain1985-1989

All cause;respiratory;cardiovascular;general population;patients with COPD

1-h max O3:

Levels not reported.

BS, NO2, SO2, Selected best

single-day lag

Poisson GLM. Time-series study.

Saez et al. (1999)Barcelona, Spain1986-1989

Asthma mortality;age 2-45 years

1-h max O3:

Levels not reported.

BS, NO2, SO2, 0-2 Poisson with GEE. 

Time-series study.

AX7-92
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Sunyer et al. (1996)Barcelona, Spain1985!1991

All cause;respiratory;cardiovascular;all ages;age 70+ years

1-h max O3:Summer:86.5 μg/m3Range 9.5-283.5Winter:55.2 μg/m3Range 7-189.2

BS, SO2, NO2 Selected best

single-day lag

AutoregressivePoisson. Time-seriesstudy.

Sunyer and Basagana(2001)Barcelona, Spain1990-1995

Mortality in acohort of patientswith COPD

1-h max O3: 

Mean not reportedIQR 21 μg/m3

PM10, NO2, CO 0-2 Conditional logistic

(case-crossover)

AX7-93
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Europe (cont’d)Sunyer et al. (2002)Barcelona, Spain1986-1995

All cause,respiratory, andcardiovascularmortality in acohort of patientswith severe asthma

1-h max O3:

Median 69.3 μg/m3Range 6.6-283.08-h max O3:Median 54.4 μg/m3Range 3.9-244.5

PM10, BS, SO2,

NO2, CO, pollen

0-2 Conditional logistic

(case-crossover)

Díaz et al. (1999)Madrid, Spain1990-1992

All cause;respiratory;cardiovascular

24-h avg O3: 

Levels not reported.

TSP, NO2, SO2,

CO

1, 4, 10 Autoregressive linear. 

Time-series study.

AX7-94
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Latin AmericaBorja-Aburto et al. (1997)Mexico City1990-1992

All cause;respiratory;cardiovascular; allages; age <5 years;age >65 years

1-h max O3:

Median 155 ppb8-h max O3:Median 94 ppb10-h avg O3

(8 a.m.-6 p.m.):Median 87 ppb24-h avg O3:Median 54 ppb

TSP, SO2, CO;two-pollutantmodels

0, 1, 2 Poisson iteratively

weighted and filteredleast-squares method. Time-series study.

Borja-Aburto et al. (1998)SW Mexico City1993-1995

All cause;respiratory;cardiovascular;other; all ages;age >65 years

1-h max O3:

163 ppbSD 5724-h avg O3:

44.0 ppbSD 15.7

PM2.5, NO2, SO2;two-pollutantmodels

0, 1, 2, 3, 4, 5,

1-2

Poisson GAM withdefault convergencecriteria (only onesmoother). Time seriesstudy.

AX7-95
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Latin America (cont’d)O’Neill et al. (2004)Mexico City1996-1998

All cause; all ages;age 65+ years;SES gradient

24-h avg O3:

35.3 ppbSD 11.0

PM10 0-1 Poisson GAM with

stringent convergencecriteria. Time-seriesstudy.

Téllez-Rojo et al. (2000)Mexico City1994

Respiratory;COPD mortality;age 65+ years;within medicalunit; outside ofmedical unit

1-h max O3:

134.5 ppbSD 33.4

PM10, NO2, SO2 1, 2, 3, 4, 5, 1-3,

1-5, 1-7

Poisson, iterativelyweighted and filteredleast-squares method. Time-series study.

Loomis et al. (1999)Mexico City1993-1995

Infant mortality 24-h avg O3:

44.1 ppbSD 15.7

PM2.5, NO2 0, 1, 2, 3, 4, 5,

2-3

Poisson GAM withdefault convergencecriteria. Time-seriesstudy. 

Gouveia and Fletcher(2000b)São Paulo, Brazil1991-1993

All ages (all cause);age <5 years(all cause,respiratory,pneumonia);age 65+ years(all cause,respiratory,cardiovascular)

1-h max O3:

67.9 μg/m3SD 42.1

PM10, NO2, SO2,

CO

0, 1, 2 Poisson GLM. Timeseries study. 

AX7-96
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Latin America (cont’d)Pereira et al. (1998)São Paulo, Brazil1991-1992

Intrauterinemortality

1-h max O3:

67.5 μg/m3SD 45.0

PM10, NO2, SO2,

CO

0 Poisson, linear with

M-estimation. Timeseries study.

Saldiva et al. (1994)São Paulo, Brazil1990-1991 

Respiratory; age<5 years

24-h avg O3:

12.14 ppbSD 9.94

PM10, NO2, SO2,

CO; multipollutantmodels

0-2 OLS of transformed

data. Time-seriesstudy.

Saldiva et al. (1995)São Paulo, Brazil1990-1991 

All cause;age 65+ years

1-h max O3: 

38.3 ppbSD 29.724-h avg O3:

12.5 ppbSD 11.5

PM10, NO2, SO2,

CO; two-pollutantmodels

0-1 OLS; Poisson with

GEE. Time-seriesstudy.

Cifuentes et al. (2000)Santiago, Chile 1988-1966

All cause 1-h max O3: 

Summer: 108.2 ppbIQR 48.0

PM2.5, PM10-2.5,

CO, SO2, NO2

0, 1, 2, 3, 4, 5,

1-2, 1-3, 1-4,

1-5

Poisson GAM withdefault convergencecriteria; Poisson GLM. Time-series study.

Ostro et al. (1996)Santiago, Chile 1989-1991

All cause 1-h max O3:

52.8 ppbRange 11-264

PM10, NO2, SO2;

two-pollutantmodels

1 OLS, several other

methods. Time-seriesstudy.

AX7-97
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

AustraliaMorgan et al. (1998b)Sydney, Australia1989-1993

All cause;respiratory;cardiovascular 

1-h max O3: 

24 ppbSD 13

PM bynephelometer,NO2;

multipollutantmodels

0 Poisson with GEE. 

Time-series study.

Simpson et al. (1997)Brisbane, Australia1987-1993

All cause;respiratory;cardiovascular;all ages; age<65 years;age 65+ years

8-h avg O3

(10 a.m.-6 p.m.):All year:18.1 ppbRange 1.7-63.4Summer:20.2 ppbRange 2.7-63.4Winter:16.1 ppbRange 1.7-56.9

PM10, PM by

nephelometer,NO2, SO2, CO

0 Autoregressive Poisson

with GEE. Time-seriesstudy.

AsiaKim et al. (2004)Seoul, Korea1995-1999

All cause 1-h max O3: 

All year:35.16 ppbSD 18.31Summer:46.87 ppbSD 22.46Winter:21.26 ppbSD 6.92

PM10, NO2, SO2,

CO; two-pollutantmodels

1 Poisson GAM with

stringent convergencecriteria (linear model);GLM with cubicnatural spline; GLMwith B-mode spline(threshold model). Time-series study.

AX7-98
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Asia (cont’d)Lee et al. (1999)Seoul and Ulsan, Korea1991-1995

All cause 1-h max O3: 

Seoul:32.4 ppb10th %-90th %14-55Ulsan: 26.0 ppb10th %-90th %16-39

TSP, SO2 0 Poisson with GEE. 

Time-series study.

Lee and Schwartz (1999)Seoul, Korea1991-1995

All cause 1-h max O3: 

Seoul:32.4 ppb10th %-90th %14-55

TSP, SO2 0 Conditional logistic

regression. Casecrossover withbidirectional controlsampling.

Kwon et al. (2001)Seoul, Korea1994-1998

Mortality in acohort of patientswith congestiveheart failure

1-h max O3:

31.8 ppbIQR 20.5Range 4.3-102.8

PM10, NO2, SO2,

CO

0 Time-series analysis

using Poisson GAMwith defaultconvergence criteria;case-crossover analysisusing conditionallogistic regression. 

AX7-99
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Asia (cont’d)Ha et al. (2003)Seoul, Korea1995-1999

All cause;respiratory;postneonatal(1 month to 1 year);age 2-64 years; age

$65 years 

8-h avg O3: 

21.2 ppbSD 11.6Range 2.9-69.1

PM10, NO2, SO2,

CO

0 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

Hong et al. (2002)Seoul, Korea1995-1998

Acute strokemortality

8-h avg O3:

22.6 ppbSD 12.4IQR 9.3

PM10, NO2, SO2,

CO

0 Poisson GAM with

default convergencecriteria. Time-seriesstudy. 

Tsai et al. (2003b)Kaohsiung, Taiwan1994-2000

All cause;respiratory;cardiovascular;tropical area

24-h avg O3:

23.6 ppbRange 1.2-83.0

PM10, SO2, NO2,

CO

0-2 Conditional logistic

regression. Casecrossover analysis.

Yang et al. (2004b)Taipei, Taiwan1994-1998

All cause;respiratory;cardiovascular;subtropical area

24-h avg O3:

17.18 ppb Range 2.3-43.47

PM10, SO2, NO2,

CO

0-2 Conditional logistic

regression. Casecrossover analysis.

AX7-100
Table AX7-5 (cont’d). Effects of Acute O3 Exposure on Mortality

Reference, StudyLocation and Period Outcome Measure Mean O3 Levels

Copollutants

Considered

Lag Structure

Reported Method/Design 

Asia (cont’d)Wong et al. (2001)Hong Kong1995-1997

All cause;respiratory;cardiovascular

8-h avg O3

(9 a.m.-5 p.m.):Warm:32.0 ppbSD 24.5Range 0-168.9Cool:35.1 ppbSD 21.3Range 0-101.6

PM10, NO2, SO2;

two-pollutantmodels

3, 4, 5 Poisson GAM with

default convergencecriteria. Time-seriesstudy.

Hedley et al. (2002)Hong Kong1985-1995Intervention Jul 1990(switch to low sulfurcontent fuel)

All cause;cardiovascular;respiratory;neoplasms andother causes;all ages;age 15-64 years;age 65+ years

Average monthlyO3:

Baseline:18.5 μg/m3SD 7.5 1 year afterintervention: 21.3 μg/m3SD 9.12-5 years afterintervention:22.1 μg/m3SD 10.2

SO2 (mainpollutant ofinterest, 45%reduction observed5 years afterintervention),PM10, SO42-, NO2

Monthly

averages

considered

without lags

Poisson regression ofmonthly averages toestimate changes in theincrease in deaths fromwarm to cool season. Annual proportionalchange in death ratebefore and after theintervention was alsoexamined.

AX7-101
Table AX7-6. Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United StatesGalizia and Kinney(1999; exposure dataKinney et al., 1998)U.S. nationwide 1995

1-h max O3:

10-year mean Jun-Aug: 61.2 ppbSD 15.5Range 13-185

Cross-sectional study of a nationwide sample of520 young adults. Subjects were nonsmokers, aged17-21 years, 50% males. Each subject provided onespirometric lung function measurement in the springof their 1st year at Yale College in New Haven, CT,and completed a questionnaire addressingresidential history, respiratory diseases, and activitypatterns. Long-term O3 exposure was treated as a

high/low dichotomous variable, with subjectsassigned to the high O3 category if they lived for4+ years in counties with 10-year summer mean O3

levels greater than 80 ppb. Four lung functionvariables (FVC, FEV1, FEF25-75, FEF75) were

regressed on O3 exposure, controlling forage, height, height squared, sex, race, parentaleducation, and maternal smoking history. Respiratory symptom histories (cough, phlegm,wheeze apart from colds, and composite index forany of the three symptoms) were logisticallyregressed on O3 exposure, controlling for sex, race,parental education, and maternal smoking. 

Significant decrements in FEV1 and FE

exposure were observed for all subjectnot for females alone. Similar patterns FEF75, but not with statistical significa

Percent difference in lung function for 

groups:FEV1:

All subjects: !3.07% (!0.22, !5.92)

Females: !0.26% (3.79, !4.31)

Males: !4.71% (!0.66, !8.76)

FEF25-75:

All subjects: !8.11% (!2.32, !13.90)

Females: !1.96% (6.39, !10.30)

Males: !13.02% (!4.87, !21.17)

Wheeze and respiratory symptom indefor high O3 exposure group. 

Odds ratios for symptoms:Wheeze: 1.97 (1.06, 3.66)Respiratory symptom index: 2.00 (1.1

Goss et al. (2004)U.S. nationwide1999-2000

1-h max O3:

51.0 ppbSD 7.3

Cohort study of 11,484 cystic fibrosis patients overthe age of 6 years. Exposure to O3, PM2.5, PM10,

NO2, SO2, and CO assessed by linking Aerometric

Information Retrieval System with patients’ homezip code. Studied exacerbation and lung function. Mortality was also of interest, but study wasunderpowered to examine this outcome. Logisticregression models were used to analyze theexacerbations and multiple linear regression wasused to study lung function. O3 monitoring season

and regional effects also were examined.

Ozone may increase the risk for pulmofibrosis patients. Odds ratios for two or more exacerbati1-h max O3):

O3 only model: 1.10 (1.03, 1.17)

O3 with PM2.5 model: 1.08 (1.01, 1.15PM2.5, but not O3, was significantly ass

lung function in these patients.

AX7-102
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

Kinney and Lippmann(2000)Fort Sill, OK;Fort Leonard Wood,MO; Fort Dix, NJ; Fort Benning, GA;West Point, NYApr-Sep 1990

1-h max O3: 

Mean during 5-weeksummer trainingperiod:Fort Benning, GA:55.6 ppb (0 h O3 >100 ppb)

Fort Dix, NJ:71.3 ppb(23 h O3 >100 ppb)Fort Leonard Wood,MO: 55.4 ppb(1 h O3 >100 ppb)Fort Sill, OK:61.7 ppb (1 h O3 >100 ppb)

Prospective cohort study of 72 nonsmoking students(mean age 20.25 years) at the U.S. MilitaryAcademy at West Point, NY were measured forlung function and respiratory symptoms before(Apr) and after (Aug-Sep) taking part in anintensive, largely outdoor, summer training over 5weeks (Jul 11-Aug 15) at four U.S. military bases. Ozone levels in the Fort Dix, NJ area wereconsistently higher than at the three remaining threelocations. Analysis assessed change in lungfunction and respiratory symptoms measured beforeand soon after the summer training, and examinedwhether adverse trends would be more pronouncedin students exposed to higher O3 levels during

summer training.

Mean FEV1 declined significantly ove

points for all subjects combined, which effects of O3 with exposures to dust, ve

environmental tobacco smoke as reporlocations in the post-summer questionnmean decline was seen at the higher O

remaining three sites, suggesting an inA larger decline was observed in subjemeasurements in the 1st and 2nd weektraining vs. those measured in the 3rd consistent with the lung function effecChange in lung function over the summFEV1:All locations: !44 mL (SE 21), p = 0.

Fort Dix: !78 mL (SE 41), p = 0.07

Forts Sill, Leonard Wood, and Bennin!31 mL (SE 24), p = 0.21

Greer et al. (1993)California1973-1987

Annual mean O3:

Levels not reported.

Prospective cohort study of 3,914 nonsmokingadults aged 25+ years at enrollment in 1977completed questionnaires at two time points, 1977and 1987. To be eligible, subjects had to have lived10 or more years within 5 miles of currentresidence. Residential histories used to interpolateair pollution levels to zip centroids over a 20-yearperiod (1966-1987). New asthma cases defined asanswering yes to doctor diagnosed asthma at 1987followup among those answering no at enrollmentin 1977. Multiple logistic regression used to test forassociations between new-onset asthma and longterm exposures to air pollution, controlling for age,education, pneumonia or bronchitis before age 16years, and years worked with a smoker through1987. All models stratified by gender.

There were 27 incident cases of asthm51 incident cases among 2,272 femaleanalyses, long-term O3 exposures were 

risk of incident asthma among males bRelative risks for incident cases of asthin annual mean O3):

Males: 3.12 (1.61, 5.85)Females: 0.94 (0.65, 1.34)

AX7-103
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

McDonnell et al.(1999)California1973-1992

8-h avg O3

(9 a.m.-5 p.m):20-year mean:46.5 ppbSD 15.3

This prospective cohort study continued the work ofGreer et al. (1993). 3,091 nonsmoking adultscompleted questionnaires at one additional timepoint, 1992. Residential histories used to interpolateair pollution levels to zip centroids over the period1973-1992, yielding annual mean exposureestimates for O3, PM10, SO2, and NO2. New asthma

cases defined as answering yes to doctor diagnosedasthma at either 1987 or 1992. Multiple logisticregression used to test for associations betweennew-onset asthma and long-term exposures to airpollution, controlling for age, education, pneumoniaor bronchitis before age 16, and ever smoking. All models run separately for males and females.

There were 32 incident cases of asthm79 incident cases among 1,786 femaleanalyses, long-term O3 exposures were risk of incident asthma among males bpollutants were neither associated with were confounders of the O3 association 

Relative risks for incident cases of asthin annual mean 8-h avg O3 ):Males: 2.09 (1.03, 4.16)Females: 0.86 (0.58, 1.26)

Peters et al. (1999a,b)12 SouthernCaliforniacommunities1993-1994

1-h max O3: 

Mean range:1986-1990:30.2 ppb (Santa Maria)to 109.2 ppb(San Dimas)1994:35.5 ppb (Santa Maria)to 97.5 ppb(Lake Gregory) 

3,676 children aged 9-16 years enrolled intothe 1st cohort of the Children’s Health Study in1993. Subjects provided questionnaire data onrespiratory disease histories and symptoms. 3,293 subjects also underwent pulmonary functiontesting, of which 2,781 were used in air pollutionregressions. Air pollution data for O3, PM10, PM2.5,

NO2, and inorganic acid vapors analyzed from

1986-1990 and 1994. For cross-sectional analysisof respiratory diseases, individual pollutants weretested for associations with ever asthma, currentasthma, bronchitis, cough, and wheeze aftercontrolling for covariates. For analysis of lungfunction, individual pollutants and pairs ofpollutants were regressed with FVC, FEV1, FEF25-75,

and PEF, controlling for usual demographic andanthropometric covariates. 

Acids and NO2, but not O3, were assoc

prevalence of wheeze. No association

respiratory diseases or symptoms.Decreased lung function was associateamong females but not males. For O3 

lung function variables declined with iAssociations were stronger for current to previous (1986-1990) exposure. In outdoors, FVC and FEV1 declined sign

exposure to O3.

Change in lung function (per 40 ppb 1

Females:PEF: !187.2 mL/s (SE 50.1), p < 0.00

FEF25-75: !102.2 mL/s (SE 28.8), p < 0

Males:PEF: 31.1 mL/s (SE 48.8), p > 0.05FEF25-75: 11.7 mL/s (SE 26.7), p > 0.0

AX7-104
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

Gauderman et al.(2000; 2004a,b)12 SouthernCaliforniacommunities1993-2001

8-h avg O3

(10 a.m.-6 p.m.): Mean range: Approximately 28 ppb(Long Beach) to 65 ppb(Lake Arrowhead) 

Analysis of longitudinal lung function changein relation to long-term air pollution levels inthe Children’s Health Study cohort. Children from4th (n = 1,498), 7th (n = 802), and 10th (n = 735)grade enrolled in 1993. Children enrolled in 7th and10th grade were followed until 1997; 4th graderswere followed until 2001. Baseline questionnairescompleted and annual pulmonary function tests(FVC, FEV1, FEF25-75, FEF75) performed. 

Air pollution monitoring stations established in the12 study communities beginning in 1994 to measureO3, NO2, PM10, PM2.5, and inorganic acid. Analysis using adjusted linear regression models.

In the 7th and 10th grade cohorts, diffegrowth from the least to the most polluassociated with any of the air pollutant

4th graders, decreased lung growth wato PM2.5, NO2, acid vapor, and elementIt should be noted, however, that there 2.5-fold difference in O3 concentrationpolluted communities, compared to the a 4- to 8-fold difference in concentratiresults should be interpreted with cautisubstantial misclassification of O3 exp

Gauderman et al.(2002)12 SouthernCaliforniacommunities1996-1999

8-h avg O3

(10 a.m.-6 p.m.): Mean range: Approximately 27 ppb(Long Beach) to 67 ppb(Lake Gregory) 

Second cohort of the longitudinal cohort Children’sHealth Study. 2,081 4th graders (mean age 9.9years) enrolled in 1996. Baseline questionnaireswere completed and annual pulmonary functiontests (FVC, FEV1, FEF25-75, FEF25-75/FVC, PEF)

were performed. 1,672 children had at least twopulmonary function test data. Air pollutantsexamined include O3, NO2, PM10, PM2.5, inorganic

acid, elemental carbon, and organic carbon. Adjusted linear regression model was used.

In this cohort, a significant association 

FVC was noted in children spending mPercent difference in annual increases to most polluted community (per 36.6 8-h avg O3):

PEF:All children: !1.21% (!2.06, !0.36)

Children more outdoors: !1.62% (!2.

Children less outdoors: !0.87% (!2.0

McConnell et al.(1999)12 SouthernCaliforniacommunities 1993

1-h max O3:

Estimated annual mean:65.6 ppbRange 35.5-97.5

First cohort of the Children’s Health Study. Association of O3 with prevalence of chronic lower

respiratory tract symptoms among children with ahistory of asthma was examined in a cross-sectionalstudy in 12 communities. Questionnaires werecompleted by parents of 3,676 4th, 7th, and 10thgraders, of which 493 had asthma. Exposure data(O3 NO2, PM10, PM2.5, and inorganic acid vapors)

collected in 1994 used to estimate exposure. Analysis using logistic regression method.

Children with asthma were much more 

related symptoms than children withouasthmatic children, significant relationphlegm and all pollutants studied, with 

AX7-105
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

McConnell et al.(2003)12 SouthernCalifornia communities1996-1999

8-h avg O3

(10 a.m.-6 p.m.): 4-year average across12 communities:47.2 ppbSD 11.3Range 28.3-65.8Range of yearlyvariability within the12 communities:5.3 ppbSD 3.2Range 1.7-13.2

A total of 475 children with asthma from the1st and2nd cohorts of the Children’s Health Study wererecruited to examine the relationship betweenbronchitic symptoms and air pollutants. Analysisinvolved three stages using logistic mixed effectsmodels. Within-community variability in airpollution was assessed in the first stage; individuallevel time-independent confounders were assessedin the second stage; and the effects of 4-yearaverage air pollutants were examined in the thirdstage. Other copollutants examined include NO2,

PM10, PM2.5, PM10-2.5, inorganic acid, organic acid,

EC, and OC.

Symptoms were generally associated wpollutants. Within-community effects between-community effects. Authors community effect estimates are correc(between-community) studies may haveffect of air pollution on respiratory sydifferences may be attributable to confor unmeasured risk factors that vary beeffect estimates were markedly reduce(odds ratios not provided).Odds ratios for bronchitic symptoms (p

Within-community effects: 1.06 (1.00Between-community effects: 0.99 (0.9

McConnell et al.(2002)12 SouthernCaliforniacommunities 1993-1998

1-h max O3:

4-year average(1994-1997):Low-pollutioncommunities (n = 6):50.1 ppbRange 37.7-67.9High-pollutioncommunities (n = 6):75.4 ppbRange 69.3-87.2

Prospective cohort study of 3,535 children (age9-16 years) without a history of asthma recruited in1993 and 1996, and followed with annual surveysthrough 1998 to determine incidence of new onsetasthma. Participation in sports assessed at baseline. Copollutants included PM10, PM2.5, NO2, and

inorganic acid vapors. Asthma incidence wasexamined as a function of number of sports playedin high- and low-pollution communities, controllingfor age, sex, and ethnic origin.

Asthma incidence was not higher in thcommunities as compared with the lowregardless of the pollutant used to defithe high-O3 communities had generally 

However, in high-O3 communities, the

asthma in children playing three or mono sports; no such increase was observcommunities. No other pollutant showresults suggest that high levels of physwith risk of new asthma development in communities with high O3 levels.Relative risk of developing asthma in cmore sports vs. those playing no sportsLow-pollution communities: 0.8 (0.4, High-pollution communities: 3.3 (1.9, 

AX7-106
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

Avol et al. (2001)12 SouthernCaliforniacommunities and sixwestern statesBaseline 1994Follow-up 1998

8-h avg O3

(10 a.m.-6 p.m.): Mean range of baselinelevels:30.4 ppb for SantaMaria to 70.8 ppb forLake GregoryMean range of changes:11.7 ppb increase to27.0 ppb decrease inO3 levels

110 children enrolled in Children’s Health Study in1993 and 1994 followed after moving to differentwestern states. Age 10-11 years at time ofenrollment). Follow-up pulmonary function testingcarried out in 1998. Change in lung function overtime tested in relation to change in exposures toPM10, NO2, and O3.

Negative but nonsignificant associatio

function parameters and changes in O3

strongest with PM10. Subjects who mo

showed greater increases in FEV1 comto areas with higher PM10.

Change in lung function (per 10 ppb inmean 8-h avg O3):

FEV1: 0.1 mL (!8.7, 8.9)

FVC: !1.4 mL (!10.8, 8.0)

MMEF (maximal midexpiratory flow)

PEF: !8.9 mL/s (!41.6, 23.8)

Ritz and Yu (1999)Southern California1989-1993

Last trimester average:20.9 ppbRange 3.0-49.4

125,573 births within 2 miles of an air monitoringstation were examined to determine associationsbetween CO and low birth weight. Copollutantsincluded only as potential confounders.

Exposure to higher levels of ambient Cwas associated with a significantly incweight. Effects of CO appeared more for concurrent exposures to NO2, PM10

estimates were not reported.

Ritz et al. (2000)Southern California1989-1993

8-h avg O3

(9 a.m.-5 p.m.):1st month ofpregnancy:36.9 ppbSD 20.7Range 2.6-1246 weeks before birth:36.9 ppbSD 19.4Range 3.3-117

Data on 97,158 singleton births over period1989-1993 linked to air monitoring data duringdifferent periods of pregnancy to determineassociations between pollution exposures andpreterm birth. Besides O3, pollutants of interestincluded PM10, NO2, and CO. Multiple regression

analysis used, controlling for maternal age, race,education, parity, and other factors.

Both PM10 and CO during early or late 

with increased risk for preterm birth. Nwith O3.

AX7-107
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

Ritz et al. (2002)Southern California1987-1993

24-h avg O3: 

Quartile means:1st month of gestation: 6.4, 15.2, 23.9,34.2 ppb2nd month:6.4, 15.6, 24.2,34.9 ppb3rd month:6.8, 16.6, 24.9,34.9 ppb

The effect of air pollution on the occurrence of birthdefects was examined using a case-control studydesign. Analyses focused on CO and O3. Six typesof cardiac birth defects were investigated ! aortic

defects, defects of the atrium and atrium septum,endocardial and mitral valve defects, pulmonaryartery and valve defects, conotruncal defects, andventricular septal defects. A 1:10 case-control ratiowas achieved for defect-specific analyses. Analyseswere conducted using polytomous logisticregression. A two-stage hierarchical regressionmodel was used to adjust for multiple comparisons. 

Concentration-response patterns were 

concentrations during the 2nd month oand valve defects, pulmonary artery anconotruncal defects. CO during the 2nfound to be associated with ventricular were inconclusive for NO2 and PM10. 

suggest that there may be a vulnerable human malformations.Odds ratios for birth defects (per 10 ppgestation):Aortic defects: 1.56 (1.16, 2.09)Pulmonary valve defects: 1.34 (0.96, Conotruncal defects: 1.36 (0.91, 2.03)

Künzli et al. (1997);Tager et al. (1998)Los Angeles and SanFrancisco, CA;Berkeley, CA1995

8-h avg O3

(10 a.m.-6 p.m.):Lifetime monthlyaverage:Los Angeles:Median 51.5 ppbRange 25-74San Francisco:Median 22.5 ppbRange 16-33

A pilot cohort study of 130 freshman students(age 17-21 years) at the University of California atBerkeley measured for lung function and historiesof residential locations and indoor/outdoor activitypatterns and levels. By design, students hadpreviously resided in one of two metropolitan areasthat differed greatly in O3 concentrations,

San Francisco or Los Angeles. A key goal was totest whether measures of small airways function(e.g., nitrogen washout, FEF25-75, FEF75) were

sensitive measures of long-term O3 impacts. 

Lifetime exposures to O3, PM10 and NO2 assigned

by interpolation to sequence of residence locationsfrom available monitoring stations. Multipleexposure measures were derived with varyingdegrees of incorporation of time-activityinformation, going from ecological concentrationto individual time-activity weighted exposure. Performed linear regression analysis of lungfunction on O3 exposures, controlling for height,

ethnicity, gender, and region.

Decreased FEF25-75 and FEF75 were ass

exposures. Results were similar wheth

ecologic or incorporated time-activity 

and nitrogen washout were generally n

No evidence for PM10 or NO2 main eff

Similar patterns results using O3 hours instead of daily 8-h avg O3. Surprising

a major negative confounder as lung fuaverage among students from the low 

among those who had lived in Los Angwere significant predictors only after ceffect.Change in lung function (per 20 ppb in8-h avg O3):

FEF25-75: !420 mL/s (!886, 46); 7.2% 

FEF75: !334 mL/s (!657, !11); 14% 

AX7-108
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

Tager et al. (2005)Los Angeles andSan Francisco, CA;Berkeley, CA2000-2002

8-h avg O3

(10 a.m.-6 p.m.):Lifetime monthlyaverage:Men:36 ppbRange 19-64Women:33 ppbRange 18-65Difference in medianexposure betweenLos Angeles andSan Francisco:17 ppb

Similar study design to that of Künzli et al. (1997). A cohort study of 255 freshman students (age16-19 years) at the University of California atBerkeley who previously resided in San Franciscoor Los Angeles measured for lung function betweenFeb and May. Subjects were lifetime never-smokerswithout history of chronic respiratory diseases. Histories of residential locations, andindoor/outdoor activity patterns and levels alsoevaluated. Lifetime exposures to O3, PM10, and NO2assigned by interpolation to sequence of residencelocations from available monitoring stations. Multiple exposure measures were derived withvarying degrees of incorporation of time-activityinformation, going from ecological concentrationto individual time-activity weighted exposure. Thebase lung function model consisted of genderspecific linear regressions of each lung functionmeasure on age, height, and weight. Modificationof the air pollution effect on lung function by theFEF25-75/FVC ratio (a measure of intrinsic airway

size) was also examined. 

In the models examining only the main 

associations were observed between li

lung function parameters in either men including an interaction term for FEF2

inverse associations between increasin

and FEF25-75 and FEF75 were observed 

The adverse impact of increased lifetim

to decrease with increasing FEF25-75/FV

regressions with PM10 and NO2 showe

PM10 and NO2 were added to the O3 m

meaningful changes in the effect estimO3 or the interaction term while the eff

NO2 were reduced substantially. The p

measurement error from the use of queestimate exposure to O3 was assessed. 

correction did not have a meaningful ethe association with O3.

Change in lung function (per 17 ppb in

avg O3), after including interaction term FEV1: !19% (!39, 1)

FEF75: !37% (!41, !32)

FEF25-75: !29% (!33, 24)

Gong et al. (1998b)Glendora, CA1977-1987

1-h max O3:

Annual means range(1983-1987): 109-134 ppb

Longitudinal cohort study of 164 adults (mean age45 years; 34% males) from a high O3 community

underwent lung function testing in 1986-1987 (T3). Subjects were recruited from a cohort of 208nonsmoking adults who had been tested on twoprevious occasions: 1977-1978 (T1) and 1982-1983(T2). Analyzed changes in lung function at threetime points. Subjects were also asked to undergocontrolled exposures to 0.40 ppm O3 over 2 h with

intermittent exercise. 45 subjects agreed toparticipate. Investigators hypothesized that acutelyresponsive subjects would show more rapid declinesin function over the study period.

Mean FVC and FEV1 showed nonsign

T3, whereas an earlier analysis of the Tsignificant decline in function (Detels evidence for “regression to the mean,” declines in function from T1 to T2 tenin function from T2 to T3. A consisten

was observed at all three time points (p Acute changes in lung function, determexposures, were not associated with ch

AX7-109
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

United States (cont’d)

Chen et al. (2002)Washoe County, NV1991-1999

8-h max O3:

27.23 ppbSD 10.62Range 2.76-62.44

Birth weight for 36,305 single births analyzedin relation to mean PM10, O3, and CO levels in 1st,

2nd, and 3rd trimesters.

PM10 was the only air pollutant associa

weights. Ozone levels quite low throu

Kinney et al. (1996b)New York City1992-1993

1-h max O3: 

Summer(Jul-Sep 1992): 58 ppbMaximum 100Winter (Jan-Mar 1992): 32 ppbMaximum 64Summer (Jul-Sep 1993):69 ppbMaximum 142

Study of 19 healthy adult joggers (age 23-38 years;18 males) from the Governors Island U.S. CoastGuard facility in New York harbor underwent aseries of two bronchoalveolar lavages, first in thesummer of 1992 and then again in the winter of1992. Because the summer of 1992 had lower thanaverage O3 levels, six subjects underwent a third

bronchoalveolar lavage in the summer of 1993. Study tested whether inflammatory markers inbronchoalveolar lavage fluid were elevated duringthe summer O3 season among adults who regularly

exercised outdoors. Outcomes included celldifferentials, release of IL-8 and TNF-" inbronchoalveolar lavage cells supernatants, releaseof reactive oxygen species by macrophages, andconcentrations of protein, lactate dehydrogenase,IL-8, fibronectin, a1-antitrypsin (a1-AT),complement fragments (C3a), and PGE2 in bronchoalveolar lavage fluids.

There was no evidence of acute inflam1992 compared to the winter; i.e., neutTNF-" showed no significant differenc

cell damage, lactate dehydrogenase, wsuggesting possible O3-mediated dama

with repeated exposures to O3 while ex

the summer of 1992 were atypically loAmong six subjects who agreed to undlavage test in the summer of 1993, lactagain elevated compared to winter. In in the summer of 1993, suggesting acu

AX7-110
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

EuropeCharpin et al. (1999)Seven towns inSE FranceJan-Feb 1993

8-h max O3:

Range of means:30.2-52.1 μg/m324-h avg O3:

Range of means:20.1-42.1 μg/m3

Cross-sectional cohort study of 2,073 children (age10-11 years) from seven towns tested for atopybased on skin prick testing (house dust mite, catdander, grass pollen, cypress pollen, andAlternaria). Towns represented a range of ambientO3 and other pollutant (NO2 and SO2) levels. Tested

hypothesis that atopy is greater in towns with higherphotochemical pollution levels. To be eligible,subjects must have resided in current town for atleast 3 years. Authors stated that Jan to Febpollution levels correlated with levels observedthroughout the year, though no data was given tosupport this. 

In this cross-sectional analysis, no diffseen across the seven towns. Authors exposures to oxidant pollution do not fcommon allergens. The very low wint

lack of long-term exposure data make conclusion in a definitive manner.

Ramadour et al.(2000)Seven towns inSE FranceJan-Feb 1993

8-h max O3:

Range of means:30.2-52.1 μg/m3

Cross-sectional cohort study of 2,445 children(age 13-14 years) who had lived at their currentresidence for at least 3 years were recruited fromschools in seven towns in SE France. This regionhas highest O3 levels in France. Subjects completed

ISAAC survey of asthma and respiratory symptoms. In addition to O3 also collected data on SO2 andNO2. Analyzed relationships between asthma and

other respiratory conditions with mean air pollutionlevels across the seven towns using logisticregression, controlling for family history of asthma,personal history of early-life respiratory diseases,and SES. Also did simple univariate linearregressions.

In logistic regressions, no significant aand 12-mo history of wheezing, historinduced asthma and/or dry cough in laIn simple bivariate scatterplots of respO3 levels in the seven towns, there apprelationships (r = 0.71 for wheezing in for asthma attacks). No data on slope about potential confounding across towof this study.

AX7-111
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

Europe (cont’d)

Ihorst et al. (2004) Nine communities inLower AustriaApr 1994-Oct 1997Six communities inGermanyFeb 1996-Oct 1999

1⁄2-h avg O3:

Semi-annual mean:Quartile ranges:Summer:1st quartile: 22-30 ppb2nd quartile: 30-38ppb3rd quartile: 38-46 ppb4th quartile: 46-54 ppbWinter:1st quartile: 4-12 ppb2nd quartile: 12-20ppb3rd quartile: 20-28 ppb4th quartile: 28-36 ppb

Longitudinal cohort study of 2,153 children (medianage 7.6 years) were studied for the effects of semiannual and 31⁄2-year mean O3 concentrations on

FVC and FEV1. As a measure of lung growth,

the difference between two consecutive values foreach child was divided by the number of daysbetween tests. The effect of O3 exposure on lung

growth was analyzed by linear regression models,after adjusting for sex, age, height at start of thetime period, and passive smoking exposure.

Higher semi-annual mean O3 levels we

diminished lung function growth durinincreased lung function growth in the wChange in lung function (4th quartile vO3 mean):Summer:FEV1 (mL/100 days): !18.5 (!27.1, !FVC (mL/100 days): !19.2 (!27.8, !

Winter:FEV1 (mL/100 days): 10.9 (2.1, 19.7)

FVC (mL/100 days): 16.4 (8.3, 24.6)No associations between longer term O

O3 over a 31⁄2-year period) and lung fun

Kopp et al. (2000)Ten communities inAustria and SWGermanyMar 1994-Nov 1995

1⁄2-h avg O3:Mean from Apr-Oct1994:Stratified by low,medium, highexposure:Low: 24-33 ppbMedium: 35-38 ppbHigh: 44-52 ppb

Longitudinal cohort study of 797 children with amean age of 8.2 years. Four pulmonary functiontests (FVC, FEV1) performed on each child over twosummers. Examined association between averagedaily lung function growth and exposure to O3,

PM10, NO2, and SO2. Analysis using linearregression models.

Lower FVC and FEV1 increases were 

to high ambient O3 levels vs. those exp

during the summer. During the winter

showed a slightly greater increase in F

the low O3 areas, which might reflect t

lung function deficits during the winteChange in lung function for high vs. lo

ppb O3):

FEV1:

Summer of 1994: !0.303 mL/day, p = 

Winter of 1994/1995: 0.158 mL/day, Summer of 1995: !0.322 mL/day, p = 

AX7-112
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

Europe (cont’d)

Frischer et al. (1999)Nine communities inAustria1994-1996

24-h avg O3:

Summer:34.8 ppb SD 8.7Winter:23.1 ppbSD 7.7

Longitudinal cohort study of communities from twocounties chosen to represent a broad range of O3

concentrations; a 2-fold range in mean levels wasobserved. 1,150 children (mean age 7.8 years;52% males) from grades 1 and 2 performedspirometry in spring and fall over 3 years (total ofsix measurements per child) to determine if seasonalexposure to O3 would be associated with diminishedlung function growth, especially over the summerseasons. Ozone levels were low during lungfunction testing periods. Participation rates werehigh. At baseline, respiratory histories werecollected and subjects were tested for allergy byskin prick. Examined association between O3 levels

and change in lung function (FVC, FEV1, and

MEF50 [maximal expiratory flow at 50% of vital

capacity]) over each season, controlling for baselinefunction, atopy, gender, site, environmental tobaccosmoke exposure, season, and change in height. Other pollutants studied included PM10, SO2, andNO2.

Seasonal mean O3 exposures were asso

growth in all three lung function measu

seen for other pollutants. Summer seadecrements per unit O3 were larger wh

who spent whole summer in their comnonlinear O3 effect. No confounding o

ETS, or acute respiratory illnesses. Change in lung function (per ppb O3):

FEV1 (mL/day):

All subjects:Summer: !0.029 (SE 0.005), p < 0.00

Winter: !0.024 (SE 0.006), p < 0.001

Restricted to subjects who stayed in coSummer: !0.034 (SE 0.009), p < 0.00

FVC (mL/day):All subjects:Summer: !0.018 (SE 0.005), p < 0.00Winter: !0.010 (SE 0.006), p = 0.08

Restricted to subjects who stayed in coSummer: !0.033 (SE 0.007), p < 0.00

Frischer et al. (2001)Nine communities inAustriaSep-Oct 1997

1⁄2-h avg O3:30-day mean:31.57 ppbIQR 20.61

A cross-sectional cohort study of 877 schoolchildren (mean age 11.2 years). Analyzedfor urinary eosinophil protein as a markerof eosinophil activation determined from a singlespot urine sample using linear regression models.

Log-transformed urinary eosinophil prfound to be significantly associated wi

for gender, site, and atopy. Change in log urinary eosinophil prote

0.007 μg/mmol creatinine (SE 0.02), p 

AX7-113
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

Europe (cont’d)

Horak et al. (2002a,b)Eight communities inAustria1994-1997

Seasonal mean O3:Summer: 31.8 ppbRange 18.7-49.3Winter: 19.8 ppbRange 12.7-35.9 

This longitudinal cohort study continued the workof Frischer et al., 1999 by including one additionalyear of data, 1997. The major hypothesisconsidered PM10. For this study, 80.6% ofthe 975 children (mean age 8.11 years) performedall six lung function tests. A total of 860 childrenwere included in the GEE analysis. Multipollutantanalysis for PM10, SO2, and NO2.

Seasonal mean O3 showed a negative e

growth, confirming the previous shorterobust to inclusion of PM10 into the mo

winter, the O3 effect slightly diminishe

Taking into account only children who summer period did not affect the resultChange in lung function (per ppb O3):

FEV1 (mL/day):

O3 only models:

Summer: !0.021, p < 0.001

Winter: !0.020, p < 0.001

O3 with PM10 models:

Summer: !0.020, p < 0.001

Winter: !0.012, p = 0.04

Palli et al. (2004)Florence, Italy1993-1998

24-h avg O3:

Range of monthlymeans from 1993-1998:Approximately25-125 ppb

Cohort study of 320 residents (age 35-64 years) inthe metropolitan area of Florence enrolled in a studyinvestigating the correlation between levels of DNAbulky adducts and cumulative O3 exposure. One blood sample was collected for each subject. Various time windows of exposure were examined,ranging from 0-15 days to 0-90 days prior to theblood draw. Simple Spearman correlations betweenDNA adduct levels and different O3 exposure time

windows were calculated after stratifying bysmoking history, area of residence, and populationtype (random sample or exposed workers). 

Consistent relationships between O3 ex

levels were observed only among nevewere highest among never smokers whand were not occupationally exposed tAssociations were significant up to a tprior to the blood draw in the subgroup strongest relationships observed betwe

AX7-114
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

Latin AmericaCalderón-Garcidueñaset al. (1995)SW Mexico City Nov 1993Manzanillo, MexicoJan 1994

1-h max O3:

SW Mexico City(urban):4.4 h/day >120 ppbMaximum 307 ppbManzanillo, Pacificport (control):No detectable airpollutants.

A cohort study in which nasal lavage samplescollected from 38 urban (mean age 12.2 years) and28 control (mean age 11.7 years) children. Urbanchildren monitored four times in November;controls monitored twice in January. Samplesanalyzed for polymorphonuclear leukocyte counts,expression of human complement receptor type3 (CD11b) on nasal polymorphonuclear leukocytes,and nasal cytologies.

Nasal cytologies revealed that children abnormal nasal mucosae, including mudecreases in the numbers of ciliated-tyand squamous metaplasia. Exposed children had significantly higpolymorphonuclear leukocyte counts (expression (p < 0.001) vs. controls. H

response did not seem to correlate with 

exposure, suggesting that there might binflammatory mechanism at the bronchthese results suggest that ambient O3 p

response in chronically exposed childrnoted that urban children were exposed mix, making it difficult to attribute eff

Gouveia et al. (2004)São Paulo, Brazil1997

1-h max O3:

63.0 ppbSD 33.5

Birth weight for 179,460 single births analyzedin relation to PM10, SO2, CO, NO2, and O3 levels in

1st, 2nd, and 3rd trimesters. GAM and logisticregression models used for analysis.

Exposures to PM10 and CO during 1st 

have significant negative associations No associations observed for the other 

AX7-115
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

AsiaHa et al. (2001)Seoul, Korea1996-1997

8-h avg O3:

1st trimester:Median 22.4 ppbIQR 13.63rd trimester:Median 23.3 ppbIQR 16.1

Examined association between air pollutionexposure during pregnancy and low birth weightamong all full-term births for a 2-year period. These associations were evaluated after adjustingfor gestational age, maternal age, parentaleducational level, parity, and infant sex. Analysisusing GAM with default convergence criteria.

Exposures during the 1st and 3rd trimeexamined separately. For the 1st trimepositive associations with risk of low bfor CO, NO2, SO2, and TSP, but not O

exposure estimates, a positive associat

not the other pollutants. When exposuwere examined simultaneously, the risremained positive for CO, NO2, SO2, a

trimester. However for O3, the positivtrimester exposure was diminished. Thexposures to CO, NO2, SO2, and TSP irisk factors for low birth weight.Relative risk of low birth weight (per 1

trimester; per 16.1 ppb 8-h avg O3 for 

Stratified analyses by trimester:1st trimester: 0.92 (0.88, 0.96)3rd trimester: 1.09 (1.04, 1.14)Combined analyses of both trimesters:1st trimester: 0.96 (0.87, 1.07)3rd trimester: 1.06 (0.94, 1.18)

AX7-116
Table AX7-6 (cont’d). Effects of Chronic O3 Exposure on Respiratory Health

Reference, StudyLocation, and Period Mean O3 Levels Study Description Results and Com

Asia (cont’d)Kuo et al. (2002)Central Taiwan1996

1-h max O3:

Annual mean rangeacross 7 of 8 schools:18.6-27.3 ppb

Cross-sectional study. Respiratory questionnaireadministered to 12,926 children aged 13-16 years ateight junior high schools in central Taiwan, todetermine asthma prevalence. The associationbetween asthma prevalence and air pollutionexposure analyzed by simple Pearson correlations ofprevalence with annual mean air pollution levels(O3, SO2, PM10, and NO2), and by multiple logistic

regression. The 775 asthmatics who were identifiedthen provided follow-up data on symptoms andexacerbations over a 1-year period. Simple Pearsoncorrelations were computed between monthlyhospital admissions and air pollution levels, notcontrolling for covariates such as season or weather. 

Asthma prevalence ranged from 5.5% schools. Based on simple Pearson cor

and NO2 (r = 0.63) levels were correla

prevalence. However, only NO2 rema

logistic regression analyses after adjusconfounding factors. Longitudinal hospital admissions resulto analytical limitations. Monthly corradmissions for asthmatics yielded variwould be confounded by temporal fact

AX7-117
Table AX7-7. Effects of Chronic O3 Exposure on Mortality and Incidence of Cancer

Reference, Location,Study Period Mean O3 Levels Study Description Results and 

United StatesPope et al. (2002)U.S. nationwide1982-1998 

1-h max O3:

Mean from Jul-Sep:59.7 ppbSD 12.8

Prospective cohort study of approximately 500,000members of American Cancer Society cohort enrolledin 1982 and followed through 1998 for all cause,cardiopulmonary, lung cancer, and all other causemortality. Age at enrollment was 30+ years. Airpollution concentrations in urban area of residence attime of enrollment assessed from 1982 through 1998. Other pollutants considered include TSP, PM15 , PM10,

PM2.5, PM15-2.5, SO42-, SO2, NO2, and CO.

No significant effect of O3 o

association of Jul-Sep O3 con

and cardiopulmonary mortalsignificant.Residential location was knostudy in 1982. Thus, exposulikely to be high.

Lipfert et al. (2000b;2003)32 VeteransAdministration hospitalsnationwide in the U.S.1976-1996

95th % O3: 

1960-1974: 132 ppb1975-1981: 140 ppb1982-1988: 94 ppb1989-1996: 85 ppb

Cohort study of approximately 50,000 U.S. veterans(all males) diagnosed with hypertension. Mean age atrecruitment was 51 years. Exposure to O3 during four

periods (1960-1974, 1975-1981, 1982-1988, 1989-1996) associated with mortality over three periods(1976-1981, 1982-1988, 1989-1996). Long-termexposures to TSP, PM15 , PM10, PM2.5, PM15-2.5, SO42!,

NO2, and CO also analyzed. Used Cox proportional

hazards regression, adjusting for race, smoking, age,systolic and diastolic blood pressure, body mass index,and socioeconomic factors. 

Positive average concurrent 

NO2, O3 in individual period 

significant for overall. Two-that responses to peak O3 are 

Relative risks (per mean 95th 

background level, value not Averaged over all four perioExposure concurrent with mO3 only model:

9.4% (SE 4.6), p < 0.05O3 with NO2 model:

12.2%, p < 0.05 Exposure before mortality:O3 only model:

!0.2% (SE 6.3) p > 0.05

Analyses were robust to the pressure in the models, indicbetween mortality and O3 wablood pressure.

AX7-118
Table AX7-7 (cont’d). Effects of Chronic O3 Exposure on Mortality and Incidence of Can

Reference, Location,Study Period Mean O3 Levels Study Description Results and 

United States (cont’d)Abbey et al. (1999)Three California airbasins: San Francisco,South Coast (Los Angelesand eastward), San Diego 1977-1992

24-h avg O3:

Monthly average from1973 to censor date: 26.11 ppbSD 7.65 IQR 12.0O3 h/year >100 ppb: 

330 h/yearSD 295 IQR 551

Prospective cohort study of 6,338 nonsmoking nonHispanic white adult members of the Adventist HealthStudy followed for all cause, cardiopulmonary,nonmalignant respiratory, and lung cancer mortality. Participants were aged 27-95 years at enrollment in1977. 1,628 (989 females, 639 males) mortality eventsfollowed through 1992. All results were stratified bygender. Used Cox proportional hazards analysis,adjusting for age at enrollment, past smoking,environmental tobacco smoke exposure, alcohol use,education, occupation, and body mass index. Analyzedmortality from all natural causes, cardiopulmonary,nonmalignant respiratory, and lung cancer. Ozoneresults were presented for both metrics. 

Of 16 regressions involving 

four mortality causes; two O

and one was statistically signmales for O3 h/year >100 pp

Relative risks for lung cance24-h avg O3 (per 12.0 ppb):2.10 (0.99, 4.44)O3 h/year >100 ppb (per 551 

4.19 (1.81, 9.69)Inconsistency across outcompossibility of spurious findincardiopulmonary effects rais

Beeson et al. (1998)Three California airbasins: San Francisco,South Coast (Los Angelesand eastward), San Diego1977-1992

24-h avg O3: 

Monthly average from1973 to 1992:26.2 ppbSD 7.7O3 h/year >100 ppb:

333 h/yearSD 297IQR 556

Prospective cohort study of 6,338 nonsmoking nonHispanic white adult members of the Adventist HealthStudy aged 27-95 years at time of enrollment. 36 (20 females, 16 males) histologically confirmed lungcancers were diagnosed through 1992. Extensiveexposure assessment, with assignment of individuallong-term exposures to O3, PM10, SO42-, and SO2, was a

unique strength of this study. All results were stratifiedby gender. Used Cox proportional hazards analysis,adjusting for age at enrollment, past smoking,education, and alcohol use. 

Males, but not females, showfor O3 and incident lung can

Relative risks for lung canceO3 h/year >100 ppb (per 556 

All males: 3.56 (1.35, 9.42)Never smokers: 4.48 (1.25, Past smokers: 2.15 (0.42, 10

AX7-119
Table AX7-7 (cont’d). Effects of Chronic O3 Exposure on Mortality and Incidence of Can

Reference, Location,Study Period Mean O3 Levels Study Description Results and 

Latin AmericaPereira et al. (2005)São Paulo, BrazilExposure period1981-1990Case period1997

Mean avg of days/yearwhen O3 levels exceeded

air quality standards (unitsnot provided):Lapa: 40.2Moema: 19.6Moóca: 67.1Sé: 28.2

Annual records on larynx and lung cancer diseasesobtained from the São Paulo Cancer Registry. Thecorrelation between average air pollution data from1981-1990 and cases of larynx and lung cancer from1997 were assessed using Pearson correlationcoefficients. Other pollutants examined included PM10,

NO2, NOx, SO2, and CO.

Results from this ecologic stevaluation of the relationship cancer. There was a significincidence of larynx and lung Paulo city districts.Of all the pollutants examine

with cases of larynx and lung Pearson correlation coefficieLarynx cancer: 0.9929 (p = Lung cancer: 0.7234 (p = 0.

AX7-120
AX7-121

AX7.2 DESCRIPTION OF SUMMARY DENSITY CURVES

Introduction

The summary density was used in various figures in Chapter 7. It is important that the

reader not confuse a summary density with an error density, which was also used in Chapter 7

figures. This section will explain the relationship between these two densities, previous use of

similar densities, the theory behind the summary density, and how to interpret the graph of the

summary density.

In explaining the equation for the summary density and the interpretation of it, the

discussion will explain the need for the summary density and its construction. First, the

preliminaries will be discussed. The statistically experienced reader can skip this portion except

to read the definition of the error density.

The summary density has been used before (Flachaire and Nuñez, 2002). There, summary

density was weighted by the population size and was used in an economic context to estimate

income distributions. A meta-analytic method for use in the presence of non-normal

distributions of effects with varying precision has been developed (Burr and Doss, 2005). This

was used in an analysis of effects from multiple studies concerning the association of the platelet

P1A polymorphism of glycoprotein IIIa and risk of coronary heart disease. A related density

estimate, the kernel density estimate, has also been used in a publication (Kochi et al., 2005)

referenced in a White Paper (Dockins et al., 2004) presentation to the U.S. EPA Science

Advisory Board–Environmental Economics Advisory Board.

Preliminaries

The error density is the curve describing the distribution of uncertainty about the mean (or

posterior mean) or the slope estimate. For a normal density, this is sometimes referred to as the

“bell-shaped curve.” With a two-sided test, the area under the curve and to the left of the

no-effect value for a positive (or right of the value for negative) estimate is less than 2.5% when

the effect estimate is statistically significant.

The log odds and the log relative risk estimates are usually considered to have a normal

distribution when the estimate is based on a large number of observations. Many times when the

health effect is a continuous variable, the estimate (or a transformation of it) is assumed to have

a normal distribution. 
AX7-122

The two-sided confidence intervals for a health effect estimate are based on the error

density of the estimate. The confidence intervals include 95% of the area under the error

density, with equal portions of area beyond the intervals.

In displaying confidence limits for effect estimates obtained under different conditions

(relative risk for different cities or studies), the stick diagram is often used (for an example, see

Figure 7-1 in Section 7.2.3.2). The length of the line (stick) represents the confidence limit, with

the estimated mean at the midpoint of this line. With confidence limits for relative risks or odds

ratios, the mean estimates may not be at the midpoint, because their distributions are skewed. 

What is Summary Density?

The summary density is the average of the error densities at each possible value of the

estimate. Since each estimate is different, the summary density usually will not appear as a

normal density. The summary density may have many modes (bumps) or appear skewed.

The summary density is used to portray the distribution of the heterogeneous effects while

accounting for the differing error densities. Other graphics can also be used for the same

purpose. The stick diagram (also called Forest Plots) also portrays the heterogeneity, but it is not

easy to interpret. The stick diagram gives a distorted view, because the effects with the poorest

estimates, and consequently the least informative, have the longest confidence intervals; thus,

they are more eye catching than the most informative effects, which have shorter confidence

intervals. A histogram could be constructed from these estimates, but it weights each estimate

equally although some are more precise than others. Summary density curves can be viewed as

smoothed histograms. However, unlike a histogram, summary density curves account for the

varying standard errors of the individual mean effect estimates.

Many readers interpret stick diagrams by noting the fraction of significant effects. This

method has limitations, as there may be an overall significant effect detectable by meta-analysis

despite the many nonsignificant effects due to low power in the individual studies. The

summary density of these effects may show a mode at a value different from zero. This suggests

that the nonsignificant effects tend to cluster around a value other than zero. The summary

density can also show two or more modes, indicating disagreement between estimates or the

presence of a factor (or multiple factors) that varies between estimates.
AX7-123

Any summary density that does not appear to look similar to a normal density may be

reflecting a distribution that is not normal. This is important because most meta-analyses

assume that the heterogeneity distribution is normal. However, it should be noted that there may

be too few estimates or too much uncertainty to determine the normality of the heterogeneity

distribution based on the shape of the summary density.

Another method for portraying a distribution of effects that have different precision is the

radial plot developed by Galbraith (1994). This is also a good method to summarize various

effect estimates, but it may require more statistical experience to understand.

Theory of Summary Density

Statistical science has studied Kernel density estimates (Silverman, 1986), and the

summary density belongs to the class called the Gaussian Variable Kernel Density. Gaussian is

another name for the normal distribution. The summary density has a variable kernel: variances

of each kernel differ because of the unequal lengths of the confidence intervals of the estimates. 

The kernel is the shape of the distribution used for each estimate. For example, other than the

normal density, a triangular density could be used. The histogram is also a kernel density

estimate. The kernel in this case is rectangular (a uniform density). The rectangular shape is not

considered a good kernel, because as the number of observations increase, the histogram

converges more slowly to the true density compared to other kernels.

The summary density is presented as a graphical description of the heterogeneity. It does

not converge to the true distribution of the heterogeneity. To do so in an optimal way, the

variance of the error density would have to decrease with the number of effects being studied

and the standard deviation among them.

Rather than the summary density being only a descriptive tool, it can be used for inference. 

Research has yielded a formula for fixing the variance of the Gaussian kernel so that there is less

than a 5% chance of erroneously concluding that a sample from a normal density is multimodal

(has more than one bump) (Jones, 1983). As the kernel of the summary density does not use this

formula, the significance of a multimodal summary density is unknown. Also because of the

varying kernel of the summary density, the formula does not apply and likely calculates too

small a value. However, a simulation could be carried out to compute the p value for each

application of the summary density to data.
AX7-124

(AX7-1)

(AX7-2)

(AX7-3)

Extending the Summary Density to an Optimal Kernel Density Estimate

The Gaussian kernel density estimate is an average of normal density estimates and is

given by the equation

where x is the value (in this case a possible value of the effect) at which the density is to be

evaluated, μi is the effect estimate, n is the number of samples (number of effects) and h is the

standard deviation of each Gaussian density. The value of h is a constant for each density

estimate but varies depending on n. As n increases, smaller values of h are used so that the

kernel density estimate converges to the true density.

The definition of the summary density is the same as the Gaussian kernel density except

where is the estimate of the standard error of the ith sample (effect estimate). In this case, the σ$i

summary density is called a variable kernel density estimate, as hi varies depending on the

standard error of each estimate. 

To extend the summary density to an optimal density consider hi of the form

where k is a constant to be determined, Fg is the geometric mean of the estimated standard

errors and 

where is the standard deviation and IQRi

 is the interquartile range of the samples (effect σ$i

estimates). Both and IQRi / 1.34 are estimates of the true standard deviation when the σ$i

A IQR i i = min(σ$ , /. ) 134 (AX7-4)
AX7-125

distribution of the effects is normal. The extension of the summary density to an optimal kernel

density will be referred to as the extension.

Next, the choice of the hi

 for the extension will be explained. Jones (1983) has shown for

the (constant) kernel that 

(AX7-5)

where k = 1.25. A normally distributed sample will have a multimodal kernel estimate 5% of the

time with this choice of k. However, for the extension, a larger k is required to achieve the same

critical value (5%) as Jones has achieved. This is due to the kernel being variable and prone to

having more than one mode. Also, A is used rather than the more common estimate of F, since A

is used with the optimal kernel.

Another simpler, but somewhat unsatisfactory approach, is to use Jones’ result directly on

the effect size (the ratio of the effect estimate to its standard error). The variability of this ratio

is approximately constant for effects estimated from long sampling periods. 

Probably the best and yet somewhat subjective method is to adopt aspects of Silverman’s

method (Silverman, 1986). A multiple of the standard deviation is considered. This multiple is

either increased or decreased until the density becomes visually multimodal. The effects are

simulated using A as defined by Equation AX7-4 for the standard error and the mean of the

effects for the error densities. 

An Example of Calculating the Summary Density

Table AX7-8 shows the O3-associated excess risk estimates for cardiovascular mortality in

the warm season from select studies (see Figure 7-25 in Section 7.4.7 for the stick diagram of

these estimates).

The estimated log relative risk is considered normally distributed, so the percent change is

converted to log relative risk per standard unit (RR) by Equation AX7-6:

(AX7-6)
AX7-126

Table AX7-8. Ozone-Associated Cardiovascular Mortality Risk Estimates

per Standardized Incrementa

Reference Study Location

% Excess Risk in Mortality

(95% CI)

Moolgavkar (2003) b Los Angeles, CA 1.61 (!0.24, 3.50)

Moolgavkar (2003) b Cook County, IL 6.82 (4.38, 9.32)

Lippmann et al. (2000) c Detroit Area, MI 1.52 (!3.64, 6.95)

Vedal et al. (2003) Vancouver, British Columbia, Canada 16.37 (!1.14, 36.98)

Anderson et al. (1996) London, England 4.46 (1.30, 7.72)

Sunyer et al. (1996) Barcelona, Spain 6.70 (2.15, 11.50)

Simpson et al. (1997) Brisbane, Australia 7.37 (!3.41, 19.36)

a The standardized increment is 40 ppb for 1-h max O3; 30 ppb for 8-h max O3; and 20 ppb for 24 h avg O3. b Indicates use of Poisson GAM with default convergence criteria. c

 Reanalysis by Ito (2004) using Poisson GLM.

Then the above equation is applied to the confidence limits of the percent excess risks to

get confidence limits for log(RR). The difference of these limits divided by 3.92 is used as the

standard error of the log(RR).

The equation of the normal density is

For each of the seven effect estimates, the log(RR) is substituted for μi

 and its standard error is

substituted for Fi. These densities are calculated over a range of x. For Figure AX7-1, x has

been calculated every 0.0004 units of log(RR) from !0.2 to 0.2. Then the densities for each

value of x are averaged, resulting in the summary density. 

Figure AX7-1 shows each of the seven error densities and the summary density curve. 

The summary density is multiplied by the number of estimates (n = 7) to better illustrate the

shape of the curve. In the figure, the summary density appears bimodal, but there are too few

effects to confirm this statistically. 

(AX7-7)
AX7-127

In Chapter 7, the summary density curves in Figures 7-29 and 7-30 were calculated using

equation AX7-3 with A equal to the estimated standard deviation of the effects. Simulation

indicated that the all-year curve in Figure 7-29 was not significantly multimodal.

Significance of a Summary Density

When there is no significant difference between effect estimates and the pooled analysis

finds the overall effect to be significantly positive, the error density of the overall effect would

have less than 2.5% of its area under the curve beyond the value of no effect. However, the

summary density of the individual error densities will generally show more than 2.5% beyond

the no-effect value. Results from Mortimer et al. (2002) reported in Chapter 7 found no

significant effects of O3 on PEF and incidence of symptoms in the individual cities, but indicated

a significant overall effect when the data from all cities were combined (see Figures 7-4 and 7-7

in Sections 7.2.3.2 and 7.2.4, respectively). The summary density of the error densities from the

eight cities had about 20 to 25% of the area beyond zero. Simulation under these conditions

verified that these larger percentages of the area beyond the value of no effect are common. One

of the reasons for this result is that the summary density does not treat each estimate as derived

from random estimates of the same single true estimate. 

Figure AX7-1. Density curves of the O3-associated excess risk of cardiovascular mortality

in the warm season per standardized increment. The thicker curve is the

summary density curve of the seven effect estimates.
AX7-128

Rather than treating the area beyond the value of no effect in a summary density as an

indication of significance, it should be treated as an indication of disagreement. For example,

there might be a mode at zero and a mode at a positive value. This could be due to some cities

being always below the threshold and other cities being above the threshold. In this case, there

could be appreciable area below zero while some of the cities indicate a positive effect. Even if

this simple case were the true state, the summary density might appear normal due to wide error

densities. 

“Apples and Oranges” Issue

The argument that a summary analysis is mixing apples and oranges is based on a variety

of reasons. One reason is the uncertainty arising when the analysis includes effects that vary

with factors other than the factor of interest. Another reason is the combining of effects that lack

commonality. That is, the effects may vary with a number of factors, but an average effect is

estimated through some process. The summary density does not average effects; instead it

considers common location through a clustering of effects. This allows a weaker assumption

concerning the commonality of the effects. 

Consider a summary density based on estimates of high precision that cluster together and

one estimate of low precision that is significantly different from the rest (the confidence intervals

do not overlap) and based on an older measurement method. The summary density could

average out the outlying value while forming a high mode based on the other effects. Such a

graph would lead one to ignore the results of the old measurement method. Disregarding

previous results when more precise measurements become available is often practical under such

circumstances. 

Masking of Heterogeneity

When the variances are very large, the kernel density appears to be very similar to a normal

density. Thus, large error densities can mask the true pattern of heterogeneity. There may be

good reasons to suppose that the heterogeneity is other than normal, and the failure of the

summary density to show this pattern is due to wide error densities. When such masking occurs,

the summary density cannot reject the assumption of normality of heterogeneous effects in a

meta-analysis. 
AX7-129

Another reason that masking may occur with the summary density is the use of the

standard error of the effect for the standard deviation of the effects error density. Kernel density

theory permits decreasing the standard deviation when more effects are available. Narrower

error densities should clarify the heterogeneity distribution. However, the ideal reduction in

variance due to increasing observation size is not large for the numbers of effects usually

considered. For example, ideally h decreases as n-1/5 increases, which is rather slowly.

Conclusion

The summary density is not new. As it stands, it is a kernel density estimate without a

fixed value of h. Others have fixed h either using graphics (Kochi et al., 2005) or ad hoc values

(Burr and Doss, 2005). Flachaire and Nuñez (2002) used a weighted average of error densities,

with the weights based on the population size. This and other types of weighting should be

considered in the future. Also, efforts should be made to unmask the heterogeneity distribution

in a statistically justified manner.

The summary density is a simple graphical method for portraying the distribution of

heterogeneous effects in the presence of effects estimated with different precision. It has

graphical advantages over both the stick diagram and the histogram. The summary density can

be put on a more firm statistical footing. Inference concerning the presence of modes could be

made reliably if p values were generated from simulations. The summary density is a graphicaldiagnostic tool for the normality assumption in meta-analyses. A meta-analysis method has

been developed for use when the distribution of effects is not normal and the precision varies

(Burr and Doss, 2005). There is a need to develop other improvements to unmask the

heterogeneity distribution in a statistically justified manner. 

The summary density overcomes some issues with reliance on statistical tests. If effects

were nonsignificant, one would expect them to cluster on either side of the no-effect value. If

the summary density indicates a mode at a positive effect value, a tentative conclusion is that

there is a positive nonrandom effect. Confirmation that the mode is statistically significant may

need further study, mindful that effects can include spurious components. 
AX7-130

AX7.3 ESTIMATING THE GOMPERTZ CONCENTRATIONRESPONSE MODEL

Estimating the Gompertz Concentration-Response Model for Mortality 

Risk and Long-Term O3 Concentrations

A three-parameter Gompertz concentration-response model was fit to examine the

association between mortality risk from acute O3 exposure and long-term O3 concentrations

using data from the U.S. 95 communities study (Bell et al., 2004). Most single-city studies fit a

linear relationship, not a Gompertz model, to mortality times-series data. This may be due to the

limited range of the O3 concentrations within a city, so that all the features (i.e., linear portion

and two flat regions) of the Gompertz model cannot be estimated. The mortality risk estimates

from the 95 communities are also linear effects, and they are assumed to be tangential to the

Gompertz curve for the long-term average 24-h avg O3. To estimate the Gompertz model

parameters, the effect estimates were fit to a derivative of the Gompertz model. Figure AX7-2

shows the fitted derivative curve using only communities with warm-season data (n = 40). The

derivative model does not have the flexibility to estimate negative $ (log relative risk per

1,000 ppb) estimates and can only estimate them with a value near zero. The area under the

derivative curve is the Gompertz curve, which is shown in Figure 7-33 in Chapter 7. 

The equation of the Gompertz model is as follows:

The estimated parameters of the Gompertz model are listed in Table AX7-9.

The result is a model with essentially a threshold at low concentrations and a flat curve at

higher concentrations. The curve has shallower slopes above the median effective concentration

(inflection point) than below that concentration point. The horizontal line is the 95% confidence

interval on the long-term average 24-h avg O3 associated with a 0.05% excess risk in mortality

(EC0.05%). The EC0.05% is a risk that is believed to be low enough to be in the noise band. The

upper 95% confidence limit on the EC0.05% was 27.6 ppb, which may be considered the lowest

concentration for which the data support a no-threshold association. The Gompertz model

presents a threshold of effects at low concentrations and a flat curve at higher concentrations. 

(AX7-8)
AX7-131

Table AX7-9. Estimated Parameters of the Gompertz Model

Parameter Estimate SE (95% CI)

100 × b1 0.63 0.21 (0.20, 1.06)

EC0.05% 25.8 0.9 (24.0, 27.6)

b2 0.79 0.36 (0.06, 1.53)

The actual curve would not be flat indefinitely as the concentration increases, but there is no data

to model what is probably a very complex portion of curve. To the extent that the estimated

concentration associated with a 0.05% excess risk is realistic, the fit of the model supports the

observed relationship between greater mortality risk at lower long-term O3 concentrations. 

Figure AX7-2. Fitted derivative curve of the Gompertz model to the regression

coefficients ($ = log relative risk per 1,000 ppb) for the association

between mortality and acute exposure to O3 plotted against communityspecific long-term average 24-h avg O3 concentrations using data from the 

U.S. 95 communities study (Bell et al., 2004). Only the 40 communities

with warm-season data are included.
AX7-132

The best method of estimating the EC0.05% would be to estimate the Gompertz model

directly from the pooled data from all the communities. Some of the disadvantages of estimating

the EC0.05% by using the community-specific regression coefficients are (1) other possibly

important factors have not been used to adjust the estimate; (2) regression coefficients may not

be tangents to the curve at the long-term average O3 level, but rather have some other

relationship; and (3) the data points represent a sampling of communities rather than individuals.

To compare O3 levels from a 24-h avg to a 1-h max, one could multiply the x-axis by a

factor of two as is done to obtain comparable incremental changes between the metrics (a 20 ppb

increase in 24-h avg O3 corresponds to a 40 ppb increase in 1-h max O3). Many researchers

believe that short spike exposures are more toxic than longer averages. However, the 24-h avg

O3 may be a more stable exposure estimate and still correlate with the shorter metrics of

exposure.
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