United States Environmental Protection February 2006 Agency EPA 600/R-05/004bF 

# EPA Air Quality Criteria for Ozone and Related Photochemical Oxidants

Volume II of IIIEPA 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 (O 3 

### ) in 1979 and a 1-hour O 3 

### NAAQS was set. The 1978 document focused mainly on the air quality criteria for O 3 

### and, to a lesser extent, on those for other photochemi cal 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 O 3 

### 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 O 3 

### 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 O 3 

### air quality criteria document (O 3 

### AQCD) which has completed in 1996 and provided scientific bases supporting the setting by EPA in 1997 of the current 8-h O 3 

### NAAQS. The purpose of this revised air quality criteria document for O 3 

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

assessed in the above 1996 O 3 

### AQCD, with the main focus being on pertinent new information useful in evaluating health and environmental effects data associated with ambient air O 3 

### exposures. However, other scientific data are also discussed in order to provide a better understanding of the nature, sources, distribution, measurement, and concentrations of O 3 

### 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 O 3 

### 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 O 3 

### Staff Paper analyses prepared by EPA’s Office of Air Quality Planning and Standa rds (OAQPS) to pose options for consideration by the EPA Administrator with regard to propos al and, ultimately, promulgation of decisions on potential retention or revision, as appropriate, of the current O 3 

### NAAQS. Preparation of this document was coordina ted by staff of EPA’s National Center for Environmental Assessment in Research Triangl e Park (NCEA-RTP). NCEA-RTP scientific staff, together with experts from other EP A/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 O 3 

### in outdoor (ambient) and indoor environments. It also evaluates the latest data on human exposures to ambient O 3 

### and consequent health effects in exposed human populations, to support decision making regarding the primary, health-related O 3 

### NAAQS. Lastly, the document also evaluates ambient O 3 

### 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

O 3 

### 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

### I I -v ii 

## T ab l e of C on te n ts

P age

L i s t o f T a b l e s

............................................................... I I -xiv L i s t o f F i g u r e s

.............................................................. I I -xix A u t h o r s , C o n t r i b u t o r s , a n d R e v i e w e r s

........................................... I I

- xxxi U.S. Environmental Protection Ag ency Project Tea

m for De velopment of Ai r Q ua lit y

Cr ite ri a fo r O zon e a nd

Re la te d Ph oto c he mic a l O xida nts

. . . . . . . . I I -xxxviii U.S . E nv ir on men tal P rot ect io n Agen cy S cie nce A dv is ory

Board (S AB) Sta ff Of fi c e Cle a n A ir

Sc ie nti fi c Ad

vis or y Com mit te e (C ASA C) O z o n e R e v i e w P a n e l

.................................................. I I -xli A B B R E V I A T I O N S A

N D A C R O N Y M S

......................................... I I -xli v

AX 2. PHY SI CS A

ND CH EM I STR

Y O F OZ ON E I

N T HE AT MO SPH ERE

. . . . . . . . . . AX2-1 A X 2

. 1 I

N T R O D U C T I O N

......................................... AX2-1 AX 2. 2 TRO POS PHE RI C O Z ON E CH EM I STR Y

. . . . . . . . . . . . . . . . . . . . . . AX2-2 A X 2

. 2

. 1 A t m o s p h e r i c S t r u c t u r e

........................... AX2-2 AX2.2.2 Over

view of O zone Chemistry

. . . . . . . . . . . . . . . . . . . . AX2-3 AX 2. 2. 3 I nit ia tio n o f t he Oxid a tio n o f V OC s

. . . . . . . . . . . . . . . . AX2-6 AX2.2.4 Chemistry

of Nitrog en Oxides in the Troposphere

. . . . AX2-11 AX 2. 2. 5 Th e Me tha

ne Oxid a tio n Cy

c le

. . . . . . . . . . . . . . . . . . . . AX2-14 AX2.2.6 The Atmospher ic Chemistry of Alkane s

. . . . . . . . . . . . AX2-20 AX2.2.7 The Atmospher ic Chemistry of Alkene s

. . . . . . . . . . . . AX2-23 AX2.2.8 The Atmospher ic Chemistry of Aroma tic H y d r o c a r b o n s

................................. AX2-31 AX2.2.8.1 Chemical Kinetics a nd Atmospheric L ifetimes of Ar omatic H y d r o c a r b o n s

..................... AX2-32 AX 2. 2. 8. 2 Re a c tio n Pr od uc ts a nd Me c ha nis ms of Aroma tic Hy droca

rbon Oxidation

. . . AX2-36 A X 2

. 2

. 8

. 3 T h e F o r

m a t i o n o f S e c o n d a r y Org anic Ae rosol as a Sink for O z o n e P r e c u r s o r s

.................. AX2-44 AX 2. 2. 9 I mpo rt a nc e of Oxy g e na te d V OC s

. . . . . . . . . . . . . . . . . AX2-44 AX2.2.10 I nfluenc e of Multiphase Chemica l Processes

. . . . . . . . AX2-45

x 

### AX 2. 2. 10 .1 HO a nd

Ae ro so ls

. . . . . . . . . . . . . . . . . AX2-47

x 

### A X 2

. 2

. 1 0

. 2 N O C h e m i s t r y

.................... AX2-50 AX2.2.10.3 Halog en Radica l Chemistry

. . . . . . . . . . AX2-52 AX 2. 2. 10 .4 Re a c tio ns on the Sur fa c e s o f C ru sta l P a r t i c l e s

......................... AX2-56 AX2.2.10.5 Reac tions on the Surface s of

2 4 

### Aqueous H SO Soluti ons

. . . . . . . . . . . AX2-57 AX2.2.10.6 Oxi dant For mation in Particles

. . . . . . . AX2-58 AX2.2.10.7 Ozone Reac tion I ndoors

. . . . . . . . . . . . AX2-60

### I I -v iii 

## T ab l e of C on te n ts (cont’d)

P age

AX2.3 PHYSI CAL PROCES SES I NFL UENCI NG THE A BU

NDANCE O F O Z O N E

............................................. AX2-60 AX 2

. 3

. 1 S t ra t o s p h er i c- T ro p o s p h er i c O z o n e E x ch an ge

. . . . . . . . AX2-62 AX2.3.2 Dee p Convection in the Tropospher e

. . . . . . . . . . . . . . AX2-71

AX2.3.2.1 Observations of the Effe cts of

Convective Tr ansport

. . . . . . . . . . . . . . AX2-73 AX2.3.2.2 Modeling the Eff ects of Conve ction

. . . AX2-76 AX 2. 3. 3 No c tur

na l L ow -L e ve l Jet s

. . . . . . . . . . . . . . . . . . . . . . . AX2-79 AX2.3.4 I nterc ontinental Transpor t of Ozone and Othe r P o l l u t a n t s

.................................... AX2-83 A X 2

. 3

. 4

. 1 T h e A t m o s p h e r e / O c e a n C h e m i s t r y Expe ri me nt, AE RO CE

. . . . . . . . . . . . . AX2-83 AX 2. 3. 4. 2 Th e No rt

h A tla nti c Re g ion a l E x p e r i m e n t , N A R E

................ AX2-86 AX 2. 3. 5 Sma ll- Sc a le Cir c ula tio n Sy ste ms

. . . . . . . . . . . . . . . . . . AX2-89 A X 2

. 3

. 5

. 1 L a n d

- Se a

B r e e ze

. . . . . . . . . . . . . . . . . . AX2-90 AX 2. 3. 6 Th e Re la tio n o f O zon e to S ola r U ltr a vio le t Radiation, Aerosols, and A ir Temper ature

. . . . . . . . . . AX2-90 AX2.3.6.1 Solar Ultraviolet Radiation

a n d O z o n e

....................... AX2-90 AX2.3.6.2 I mpact of A erosols on Radiation

and Photoly sis Rates and At mos ph e ri c Sta

bil ity

. . . . . . . . . . . . . . AX2-91 AX2.3.6.3 Temper ature and Ozone

. . . . . . . . . . . . . AX2-92 AX2.4 THE REL ATI ON OF OZ ONE TO I TS PR ECURSORS AND

O T H E R O X I D A N T S

...................................... AX2-95 AX 2

. 4

. 1 S u m m ar y

o f R es u l t s fo r t h e R el at i o n s Am o n g Ozo ne , it s Pr e c ur so rs a nd Othe r O xida nts fr om R e c e n t F i e l d

E x p e r i m e n t s

....................... AX2-99 AX 2. 4. 1. 1 Re su lts fr om t he Sou the rn

Oxid a nt Stu dy a nd Re la te d E xpe ri me nts

. . . . . . . AX2-99 AX2.4.1.2 Results from Studi es on B ioge nic and

Anthropog enic Hy droca

rbons and O z o n e P r o d

u c t i o n

................ AX2-103 AX2.4.1.3 Results of Studi es on Ozone

Production in Missi ssippi and A l a b a m a

........................ AX2-103 AX2.4.1.4 The Noc turnal Urba n Plume over P o r t l a n d

, O r e g o n

................. AX2-104 AX2.4.1.5 Effe cts of VOCs in Houston on

O z o n e P r o d

u c t i o n

................ AX2-104

### I I -i x 

## T ab l e of C on te n ts (cont’d)

P age

AX 2. 4. 1. 6 Che mic a l a nd Me te or olo g ic a l I nfluenc es on the Phoenix Urban O z o n e P l u m e

.................... AX2-105 AX 2. 4. 1. 7 Tr a ns po rt

of Ozo ne a nd

Pr e c ur so rs

on the Re g ion a l Sc a le

. . . . . . . . . . . . . AX2-105 AX 2. 4. 1. 8 Mo de l Ca lc ulatio ns a nd Ai rc ra ft Observations of Ozone over P h i l a d e l p h i a

..................... AX2-106 AX2.4.1.9 The Two- Reservoir Sy stem

. . . . . . . . . AX2-107 AX2.5 METHODS USED TO CAL CUL ATE REL ATI ONS BET WEEN

O Z O N E A

N D I T S P R E C U R S O R S

.......................... AX2-107 AX 2. 5. 1 Che mis tr

y -T ra ns po rt Mo de ls

. . . . . . . . . . . . . . . . . . . . AX2-109 AX2.5.2 Emissions of Oz one Prec ursors

. . . . . . . . . . . . . . . . . . AX2-123 AX 2. 5. 3 Ob se rv a tio na lly -B a se d M od e ls

. . . . . . . . . . . . . . . . . . AX2-130 AX2.5.4 Chemistry -Tra nsport Model Evaluation

. . . . . . . . . . . AX2-131 AX 2. 5. 4. 1 Ev a lua

tio n o f E mis sio ns I n v e n t o r i e s

...................... AX2-144 AX2.5.4.2 Availability and Ac cura cy

of Am bie nt M e a su re me nts

. . . . . . . . . . . . AX2-146 AX 2. 6 TE CH NI QU ES F OR ME ASU RI

NG OZ ON E A

ND I TS P R E C U R S O R S

......................................... AX2-147 AX2.6.1 Sampling and A naly sis of Ozone

. . . . . . . . . . . . . . . . AX2-147 AX2.6.2 Sampling and A naly sis of Nitrog en Oxides

. . . . . . . . AX2-149

AX2.6.2.1 Calibration Standards

. . . . . . . . . . . . . AX2-150 AX2.6.2.2 Measur ement of N itric Oxi de

. . . . . . . AX2-151 AX2.6.2.3 Measur ements of Nitrog en Dioxide

. . AX2-152

2 

### AX2.6.2.4 Monitoring f or NO Compli ance Ver sus Monitoring for

Ozone F o r m a t i o n

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

3 

### AX2.6.3 Measur ements of Nitric Acid Va por, HNO

. . . . . . . . AX2-154 AX2.6.4 Sampling and A naly sis of Volatile Org anic

C o m p o u n d s

................................. AX2-156 AX2.6.4.1 Polar Volatile Org anic Compounds

. . . AX2-156 R E F E R E N C E S

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

AX3. ENVI RONMENTAL CONCENTRATI ONS, PATTERNS, AND E X P O S U R E E S T I M A T E S

............................................ AX3-1 A X 3

. 1 I

N T R O D U C T I O N

......................................... AX3-1 AX3.2 SURFACE OZ ONE CONCENTRATI ONS

. . . . . . . . . . . . . . . . . . . . . AX3-4

AX3.2.1 Nationwide Distribution of Metric s for Char acte rizing

Ex posures of V eg etation to Ozone

. . . . . . . . . . . . . . . . AX3-27

### I I -x 

## T ab l e of C on te n ts (cont’d)

P age

AX3.3 SPATI AL

VARI AB I L I TY I

N OZ ONE CONCENTRATI ONS

. . . . . AX3-30 AX3.3.1 Spatial Varia bility of Ozone Concentr ations in U r b a n A r e a s

................................. AX3-30 AX3.3.2 Small-scale Hor izont al and Spatial Va riability in O z o n e C o n c e n t r a t i o n s

.......................... AX3-56 AX3.3.3 Ozone Concentra tions at High Ele vations

. . . . . . . . . . . AX3-58 AX3.4 DI URNAL

PATTERNS I

N OZ ONE CONCENTRATI ON

. . . . . . . . AX3-68 A X 3

. 4

. 1 I n t r o d

u c t i o n

.................................. AX3-68 AX3.4.2 Diurnal Patterns in Ur ban Ar eas

. . . . . . . . . . . . . . . . . . AX3-70 AX3.4.3 Diurnal Patterns in Nonur ban Ar eas

. . . . . . . . . . . . . . . AX3-87 AX3.5 SEASONALVARI ATI ONS I N OZ ONE CONCENTRATI ONS

. . . . AX3-95 AX3.5.1 Seasonal Va riations in Urban A rea s

. . . . . . . . . . . . . . . AX3-95 AX3.5.2 Seasonal Va riations in Nonurban A rea s

. . . . . . . . . . . . AX3-98 AX3.6 TRENDS I

N OZ ONE CONCENTRATI ONS

. . . . . . . . . . . . . . . . . . AX3-104 AX3.7 REL ATI ONS BET WEEN OZ ONE, OTH ER OXI DANTS,

A N D O X I D A T I O N P R O D U C T S

........................... AX3-114 AX3.8 REL ATI ONSHI P BETWEEN SURFACE OZ ONE AN D

O T H E R P O L L U T A

N T S

.................................. AX3-121 A X 3

. 8

. 1 I n t r o d

u c t i o n

................................. AX3-121 AX3.8.2 Co-Occ urre nce of Ozone with Nitrog en Oxides

. . . . . AX3-123 AX3.8.3 Co-Occ urre nce of Ozone with Sulfur Diox ide

. . . . . . AX3-125

2.5 

### AX 3. 8. 4 Co- Oc c ur

re nc e of Ozo ne a nd

Da ily PM

. . . . . . . . . . AX3-127 AX3.8.5 Co-Occ urre nce of Ozone with Acid Prec ipitation

. . . . AX3-128 AX3.8.6 Co-Occ urre nce of Ozone with Acid Cloudwater

. . . . . AX3-130 AX3.9 THE METHO DOL OGY F OR DETERMI NI NG POL I CY REL EVANT B ACKGROUND O Z ONE CONCENTRATI ONS

. . . AX3-131 A X 3

. 9

. 1 I n t r o d

u c t i o n

................................. AX3-131 AX3.9.2 Capability

of Global Models to Simulate T r o p o s p h e r i c O z o n e

.......................... AX3-147 AX3.9.3 Mean B ackg round Concentr ations: Spatial and

S e a s o n a l V a r i a t i o n

............................ AX3-150 AX 3. 9. 4 F re qu e nc y

of Hi g h- Ozo ne Oc c ur

re nc e s a t R e m o t e S i t e s

................................ AX3-153 AX3.10 OZ ONE EXPOSURE I N VARI OUS MI CROENVI RONMENTS

... 

### AX3-161 A X 3

. 1 0

. 1 I n t r o d

u c t i o n

................................. AX3-161 AX 3. 10 .2 Sum ma ry

of the I nf or ma tio n Pr e se nte d in the Exposure Discussion in the 1996 Ozone C r i t e r i a D o c u m e n t

............................ AX3-161 AX3.10.3 Concepts of Huma n Ex posure

. . . . . . . . . . . . . . . . . . . AX3-162 AX3.10.4 Quantifica tion of Ex posure

. . . . . . . . . . . . . . . . . . . . . AX3-162

### I I

- xi 

## T ab l e of C on te n ts (cont’d)

P age

AX3.10.5 Methods to Estimate Personal Exposure

. . . . . . . . . . . AX3-163

AX3.10.5.1 Direc t Measure ment Method

. . . . . . . . AX3-163 AX3.10.5.2 I ndirec t Measure ment Method

. . . . . . . AX3-165 AX 3. 10 .6 Ozo ne Expo su re Mo de ls

. . . . . . . . . . . . . . . . . . . . . . . AX3-167

AX 3. 10 .6 .1 Pop ulatio n E xpos ur e Mo de ls

. . . . . . . . AX3-172 AX 3. 10 .6 .2 Am

bie nt C on c e ntr a tio ns Mo de ls

. . . . . AX3-180 AX3.10.6.3 Microenvir onmental Concentra tion M o d e l s

......................... AX3-182 AX3.10.7 Measur ed Exposures and Monitored

C o n c e n t r a t i o n s

............................... AX3-186 AX 3. 10 .7 .1 Pe rs on a l E xpos ur e Me a su re me nts

. . . . AX3-186 AX 3. 10 .7 .2 Mo nit or e d A mbi e nt

C o n c e n t r a t i o n s

................... AX3-190 AX3.10.7.3 Ozone Concentra tions in

Mic ro e nv ir on me nts

. . . . . . . . . . . . . . . AX3-191 AX3.10.8 Trends in Conce ntrations within

M i c r o e n v i r o n m e n t s

........................... AX3-216 AX3.10.9 Charac terization of Ex posure

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

AX3.10.9.1 Use of A mbient Ozone

C o n c e n t r a t i o n s

................... AX3-217 AX3.10.9.2 Ex posure Selec tion in C ontrolled

E x p o s u r e S t u d i e s

................. AX3-219 AX3.10.9.3 Ex posure to Relate d Photochemical

A g e n t s

......................... AX3-219 R E F E R E N C E S

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

AX 4. DO SI ME TRY OF OZ ON E I N T HE RES PI RA TO RY TRA CT

. . . . . . . . . . . . . . . . AX4-1 A X 4

. 1 I

N T R O D U C T I O N

......................................... AX4-1 AX4.2 EXPERI MENTAL OZ ONE DO SI METRY I NVESTI GATI ONS

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

. . . . . . . . . . . . . . . . . . . . . . . . . AX4-3 AX4.2.2 Gene ral Upta ke Studies

. . . . . . . . . . . . . . . . . . . . . . . . . . AX4-9 A X 4

. 2

. 3 D o s i m e t r

y M o d e l i n g

........................... AX4-11 AX4.3 SPEC I ES HOMOL OGY, SENSI TI VI TY AND

ANI MAL -TO- HUMAN EX TRAPOL ATI ON

. . . . . . . . . . . . . . . . . . . AX4-17 R E F E R E N C E S

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

AX 5. AN

NE X T O C HA PTE R 5 O F OZ ON E A QC D

. . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-1 R E F E R E N C E S

.................................................... AX5-62

### I I -xii 

## T ab l e of C on te n ts (cont’d)

P age

AX6. CONTROL L ED HUMAN EXPOSURE STUDI ES OF OZ ONE AN D R E L A T E D P H O T O C H E M I C A L O X I D A N T S

............................. AX6-1 A X 6

. 1 I

N T R O D U C T I O N

......................................... AX6-1 AX6.2 PUL MONARY F UNCTI ON EF FECTS OF OZ ONE EXPOSURE

I N H E A L T H Y S U B J E C T S

.................................. AX6-2 A X 6

. 2

. 1 I n t r o d

u c t i o n

................................... AX6-2 AX6.2.2 Acute O zone Ex posures for Up to 2 Hours

. . . . . . . . . . . AX6-3 AX6.2.3 Prolonge d Ozone Ex posures

. . . . . . . . . . . . . . . . . . . . . AX6-10

AX6.2.3.1 Effe ct of Exercise V entilation Rate

1 

### on FEV Response to 6.6 h Ozone E x p o s u r e

........................ AX6-13 AX6.2.3.2 Ex erc ise Ventilation Rate as a

1



### Func tion of Body

/L ung Siz e on F EV Response to 6.6 h Ozone Expos ure

. . . . AX6-14 AX6.2.3.3 Comparison of 6.6 h Ozone Exposure

Pulmonary

Responses to Those Observe d in 2 h I ntermittent Ex erc ise O z o n e E x p o s u r e s

.................. AX6-16 AX6.2.4 Triang ular Ozone Exposures

. . . . . . . . . . . . . . . . . . . . . AX6-17 AX6.2.5 Mecha

nisms of Pul monary

Func tion Responses

. . . . . . AX6-21 AX 6. 2. 5. 1 Pa tho ph y sio log ic Me c ha nis ms

. . . . . . . AX6-22 AX6.2.5.2 Mecha

nisms at a Cellular and M o l e c u l a r

L e v e l

................... AX6-28 AX6.3 PUL MONARY F UNCTI ON EF FECTS OF OZ ONE EXPOSURE

I N SU B JECTS WI TH PRE EX I STI NG DI SEA SE

. . . . . . . . . . . . . . . AX6-29 A X 6

. 3

. 1 S u

b j e c t s w i t h C h r o n i c O b s t r

u c t i v e P u l m o n a r

y D i s e a s e

...................................... AX6-29 A X 6

. 3

. 2 S u

b j e c t s w i t h A s t h m a

.......................... AX6-34 AX 6. 3. 3 Sub

je c ts w ithAl le rg ic Rhi nit is

. . . . . . . . . . . . . . . . . . . AX6-38 AX 6. 3. 4 Sub

je c ts w ithCa rd iov a sc ula

r D ise a se

. . . . . . . . . . . . . . AX6-40 AX6.4 I

NTERSUBJECT VARI AB I L I TY AND REPR ODUCI BI L I TY O F R E S P O N S E

.......................................... AX6-41 A X 6

. 5 IN F LU E N C E O F A G E
, G E N D E R
, E T H N IC
, E N V IR O N M E N T A L

A N D O T H E R

F A C T O R S

.................................. AX6-45 A X 6

. 5

. 1 I n f

l u e n c e o f A g e

.............................. AX6-45 AX6.5.2 Gende r and H ormonal I nfluenc es

. . . . . . . . . . . . . . . . . AX6-51 AX6.5.3 Racial, Ethnic, a nd Socioeconomic Status Fa ctors

. . . . AX6-58 AX 6. 5. 4 I nf

lue nc e of Phy sic a l A c tiv ity

. . . . . . . . . . . . . . . . . . . . AX6-59 A X 6

. 5

. 5 E n v i r o n m e n t a l F a c t o r s

.......................... AX6-60 AX6.5.6 Oxi dant-Antioxi dant B alanc e

. . . . . . . . . . . . . . . . . . . . AX6-65 A X 6

. 5

. 7 G e n e t i c F a c t o r s

............................... AX6-68

### I I -xii i 

## T ab l e of C on te n ts (cont’d)

P age

AX6.6 REPEATED EXPOSURES TO OZ ONE

. . . . . . . . . . . . . . . . . . . . . . AX6-70 AX 6. 7 EF F ECT S ON EX ERC I SE PE RF OR MA NC E

. . . . . . . . . . . . . . . . . . AX6-81 A X 6

. 7

. 1 I n t r o d

u c t i o n

.................................. AX6-81 AX6.7.2 Effe ct on Maxim al Oxy g en Uptake

. . . . . . . . . . . . . . . . AX6-82 AX6.7.3 Effe ct on Endura nce E x erc ise Perfor

mance

. . . . . . . . . AX6-84 AX 6. 8 EF F ECT S ON AI RWAY RES PON SI VE NE SS

. . . . . . . . . . . . . . . . . AX6-86 AX 6. 9 EF F ECT S ON I NF L AM MA TI ON AN D H OST DE F EN SE

. . . . . . . . AX6-97 A X 6

. 9

. 1 I n t r o d

u c t i o n

.................................. AX6-97 AX6.9.2 I nflammatory Responses in the Upper R e s p i r a t o r

y T r a c t

............................. AX6-113 AX6.9.3 I nflammatory Responses in the L ower R e s p i r a t o r

y T r a c t

............................. AX6-115 AX6.9.4 Adaptation of Inflammatory Responses

. . . . . . . . . . . AX6-120 AX6.9.5 Effe ct of Anti-I nflammatory and Other M i t i g a t i n g A g e n t s

............................ AX6-122 AX 6

. 9

. 6 C h an ges i n Ho s t De fe n s e C ap ab i l i t y Fo l l o wi n g O z o n e E x p o s u r e.............................. AX6-124 AX6.10 EXTRAPUL MONARY EF FECTS OF OZ ONE

. . . . . . . . . . . . . . . . AX6-126 AX6.11 OZ ONE MI XED WI TH OTHE R POL L UTANTS

. . . . . . . . . . . . . . AX6-129

AX6.11.1 Ozone and Sulfur Oxides

. . . . . . . . . . . . . . . . . . . . . . . AX6-129 AX 6. 11 .2 Ozo ne a nd

Ni tr og e n- Con ta ini ng Pol lut a nts

. . . . . . . . . AX6-135 AX 6

. 1 1

. 3 Oz o n e a n d

Ot h er P o l l u t an t M i x t u re s I n cl u d i n g P a r t i c u l a t e M a t t e r

............................ AX6-137 AX6.12 CONTROL L ED STUDI ES OF AMB I ENT AI R EXPOSURES

. . . . AX6-138

AX6.12.1 Mobile L abora tory Studies

. . . . . . . . . . . . . . . . . . . . . AX6-138 AX6.12.2 Aircr aft Cabin Studies

. . . . . . . . . . . . . . . . . . . . . . . . . AX6-139 R E F E R E N C E S

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

AX 7. EPI DE MI OL OG I C ST UD I ES O F HU MA N H EA L TH EF F ECT S ASS OC I AT ED WI TH AM B I EN T O Z ON E E XPO SUR E

. . . . . . . . . . . . . . . . . . . . AX7-1 AX7.1 TAB L ES OF EPI DEMI OL OGI C STUDI ES OF HU MAN

HEAL TH EF FECTS ASSOCI ATED WI TH AMB I ENT O Z O N E E X P O S U R E

...................................... AX7-2 LIST OF STUDIES BY

AUTHOR

............................. AX7-3 AX7.2 DESCRI PTI ON OF SUMMARY DENSI TY CURVES

. . . . . . . . . . AX7-121 AX7.3 ESTI MATI

NG THE G OMPERTZ CONCENT RATI ONR E S P O N S E M O D E L

.................................... AX7-130

### I I -xiv 

## L i st of T ab l es

Nu m b er P age

AX 2- 1 Com

pa ri so n o f t he At mos ph e ri c L if

e tim e s ( J 

### ) of L ow Molecula r Weig ht

3 3 

### Hy droca rbons Due to Rea ction with OH, NO , Cl, Br, a nd O

. . . . . . . . . . . . AX2-7

AX2-2 Calculated A tmospheric L ifetimes of B ioge nic Volatile Or g anic

C o m p o u n d s

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

AX2-3 Hy droxy l Rate Constants and Atmospheric L ifetimes of Mono- a nd D i

- c y c l i c A r o m a t i c H y d r o c a r b o n s

................................. AX2-34

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

3 

### Evaluation of Pre dicting T ropospher ic O and OH

. . . . . . . . . . . . . . . . . . . AX2-122

AX 2- 5 Em iss ion s o f N itr og e n O xide s b y Va ri ou s So ur c e s in

the Un ite d St a te s i n 1 9 9 9

..................................................... AX2-124

AX2-6 Emissions of Volatile Org anic Compounds by Var ious Sources in the U n i t e d S t a t e s i n 1 9 9 9

.......................................... AX2-125

AX 2- 7 Em iss ion s o f A mmo nia by Va ri ou s So ur c e s in

the Un ite d St a te s i n 1 9 9 9

..................................................... AX2-126

AX 2- 8 Em iss ion s o f C a rb on Mo no xide by

Va ri ou s So ur c e s in

the Un ite d St a te s i n 1 9 9 9

..................................................... AX2-127

A X 3

- 1 O z o n e M o n i t o r i n g S e a s o n s b y S t a t e

................................. AX3-3

AX3-2 Summary

of Perc entiles of Pooled Data Acr oss Monitoring Sites for May to September 2000-2004 Conc entra tions are in ppb

. . . . . . . . . . . . . . . AX3-11

AX3-3 Seasonal (A pril to October) Perce ntile Distribution of Hourly Ozone Con c e ntr a tio ns (p pm) , N umb e r o f H ou rl y Me a n O zon e Oc c ur

re nc e s

$ 

### 0.08 and $ 

### 0.10, Seasonal 7-h A vera g e Conce ntrations, SUM06, and W126 Values for Sites Experiencing L ow Maxim um Hourly Aver ag e Concentra tions with Data Capture of $ 

### 7 5 %

.......................... AX3-18

AX3-4 The Top 10 Da ily Maxi mum 8-h Avera g e Conce ntrations (ppm) for Site s E xpe ri e nc ingL ow Ma ximum Ho ur ly Av e ra g e Con c e ntr a tio ns with Data Capture of $ 

### 7 5 %

...................................... AX3-23

AX3-5 Summary

Statist ics for O zone (in ppm) Spatial Varia bility in Selected U

. S

. U r b a n A r e a s

.............................................. AX3-42

### I I

- xv 

## L i st of T ab l es (cont’d)

Nu m b er P age

AX3-6 Desc ription of Mountain Cloud C hemistry Prog ram Sites

. . . . . . . . . . . . . . . AX3-60

AX3-7 Seasonal (A pril-Octobe r) Per centiles, SUM06, SUM08, and W126 V a l u e s f o r t h e M C C P S i t e s

....................................... AX3-61

AX3-8 Summary

Statist ics for 11 I

nteg rate d For est Study

Sites

. . . . . . . . . . . . . . . . AX3-66

3 

### AX3-9 Trends in Warm Season ( May to September) D aily

Maxi mum 8-h O Concentra tions at National Parks in the United States (1990 to 2004)

. . . . AX3-113

AX 3- 10 Ra ng e of

An nu a l ( Janu a ry -D e c e mbe r) Ho ur ly Ozo ne Con c e ntr a tio ns (ppb) a t Ba ckg round Sites Around the World (CMDL , 2004)

. . . . . . . . . . . AX3-137

AX 3- 11 Ra ng e of

a nnua l ( Janu a ry -D e c e mbe r) Ho ur ly Me dia n a nd Ma ximum Ozo ne Con c e ntr a tio ns (p pb ) at B a c kg ro un d St a tio ns in P ro te c te d A re a s of the United States ( CASTNet, 2004)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-137

AX 3- 12 Ra ng e of

An nu a l ( Janu a ry -D e c e mbe r) Ho ur ly Me dia n a nd Ma ximum Ozo ne Con c e ntr a tio ns (p pb ) at Ca na dia n B a c kg ro un d St a tio ns ( C A P M o N
, 2 0 0 3 )

............................................. AX3-138

3 

### AX 3- 13 Nu mbe r o f H ou rs $ 

### 0.05 ppm for Selec ted Rural O Monitoring in the

United States by

Month for the Period 1988 to 2001

. . . . . . . . . . . . . . . . . . AX3-139

3 

### AX 3- 14 Nu mbe r o f H ou rs $ 

### 0. 06 pp m f or Se le c te d Rura l O Mo nit or ingSite s in the United States by

Month for the Period of

1988 to 2001

. . . . . . . . . . . AX3-141

A X 3

- 1 5 G l o b a l B u d g e t s o f T r o p o s p h e r i c O z o n e ( T g ye a r ) f o r t h e P r e s e n t

- d a y ! 1 

### A t m o s p h e r e

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

AX3-16 Desc ription of Simul ations Used for Source A ttribution

. . . . . . . . . . . . . . . AX3-151

AX3-17 Number of Hours with Ozone Above 50 or 60 ppbv at U.S. C A S T N e t S i t e s i n 2 0 0 1

........................................ AX3-155

A X 3

- 1 8 A c t i v i t y P a t t e r n S t u d i e s In c l u d e d

i n t h e C o n s o l i d a t e d

H u m a n A c t i v i t y D a t a b a s e ( C H A D )............................................. AX3-174

AX3-19 Personal and Population Exposure Models for Ozone

. . . . . . . . . . . . . . . . . AX3-179

AX 3- 20 Pe rs on a l E xpos ur e Me a su re me nts

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-187

### I I -xvi 

## L i st of T ab l es (cont’d)

Nu m b er P age

A X 3

- 2 1 I n d o o r

/ O u t d o o r O z o n e R a t i o s

................................... AX3-192

3 

### AX 3- 22 I nd oo r a

nd Ou tdo or O Con c e ntr a tio ns in B os ton , M A

. . . . . . . . . . . . . . . . AX3-197

3 

### AX3-23 I ndoor and O utdoor O Concentra tions in Hong Kong

. . . . . . . . . . . . . . . . AX3-199

AX3-24 I ndoor and O utdoor Ozone Concentra tions

. . . . . . . . . . . . . . . . . . . . . . . . . AX3-202

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

### D i f f e r e n t I n d o o r

E n v i r o n m e n t s................................... AX3-211

AX4-1 New E x perimenta l Human Studies on Ozone Dosimetry

. . . . . . . . . . . . . . . . AX4-4

AX4-2 New O zone Dosimetry Model I nvestig ations

. . . . . . . . . . . . . . . . . . . . . . . . . AX4-13

AX5-1 Cellular Tar g ets of Ozone I ntera ction

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-2

AX5-2 Effe cts of Ozone on L ung Monoox y g enase s

. . . . . . . . . . . . . . . . . . . . . . . . . . AX5-3

AX5-3 Antiox idants, Antiox idant Metabolism, and Mitochondrial Oxy g en

C o n s u m p t i o n................................................... AX5-4

AX5-4 L ipid Metabolism and Content of the L ung

. . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-5

AX 5- 5 Ef

fe c ts o f O zon e on

Pr ote in S y

nth e sis

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-7

AX5-6 Effe cts of Ozone on Diff ere ntial Gene E x pression

. . . . . . . . . . . . . . . . . . . . . AX5-7

AX5-7 Effe cts of Ozone on L ung Host Defe nses

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-8

AX5-8 Effe cts of Ozone on L ung Permea

bility and I nflammation

. . . . . . . . . . . . . . AX5-17

AX5-9 Effe cts of Ozone on L ung Structure: Ac ute and Subchr onic Exposures

. . . . AX5-27

AX5-10 Effe cts of Ozone on L ung Structure: Subchronic and Chronic Exposures

... 

### AX5-31

AX5-11 Effe cts of Ozone on Pulmonary Func tion

. . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-34

AX 5- 12 Ef

fe c ts o f O zon e on

Ai rw a y Re sp on siv e ne ss

. . . . . . . . . . . . . . . . . . . . . . . . . AX5-36

AX 5- 13 Ef

fe c ts o f O zon e on

Ge no toxic ity

/Ca rc ino g e nic ity

. . . . . . . . . . . . . . . . . . . . AX5-43

### I I -xvi i 

## L i st of T ab l es (cont’d)

Nu m b er P age

A X 5

- 1 4 S y s t e m i c E f f e c t s o f O z o n e

....................................... AX5-44

AX5-15 I ntera ctions of Ozone With Nit rog en Dioxide

. . . . . . . . . . . . . . . . . . . . . . . . AX5-51

AX5-16 I ntera ctions of Ozone with For maldehy de

. . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-53

AX5-17 I ntera ctions of Ozone with Tobac co Smoke

. . . . . . . . . . . . . . . . . . . . . . . . . . AX5-54

AX5-18 I ntera ctions Of Ozone With P article s

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-55

AX 5- 19 Ef

fe c ts o f O the r P ho toc he mic a l O xida nts

. . . . . . . . . . . . . . . . . . . . . . . . . . . AX5-61

AX 6- 1 Con tr oll e d E xpos ur e of He a lth y Hu ma ns to O zon e fo r 1 to 2 Ho ur s D u r i n g E x e r c i s e

................................................ AX6-5

AX6-2 Pulmonary Func tion Effec ts after

Prolonge d Ex posures to Ozone

. . . . . . . . AX6-11

AX 6- 3 Ozo ne Expo su re in S ub je c ts w ithPr e e xistin g Di se a se

. . . . . . . . . . . . . . . . . AX6-30

AX 6- 4 Cla ssi fi c a tio n o f A sth ma Se ve ri ty

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX6-37

AX6-5 Ag e Diff

ere nces in Pulmonary

Func tion Responses to Ozone

. . . . . . . . . . . . AX6-46

AX 6- 6 Ge nd e r a

nd Ho rm on a l D if

fe re nc e s in

Pul mon a ry

F un c tio n Re sp on se s t o O z o n e

..................................................... AX6-52

AX6-7 I nfluenc e of Ethnic, E nvironmental, and O ther F actor s

. . . . . . . . . . . . . . . . . AX6-62

AX6-8 Chang es in For ced E x piratory Volume in One Sec ond After Repea ted D a i l y E x p o s u r e t o O z o n e

........................................ AX6-71

AX6-9 Pulmonary Func tion Effec ts with Repeated Exposures to Ozone

. . . . . . . . . AX6-73

AX6-10 Ozone Effe cts on Exercise Perf ormanc e

. . . . . . . . . . . . . . . . . . . . . . . . . . . . AX6-83

AX6-11 Airwa

y Responsiveness F ollowing Ozone Exposures

. . . . . . . . . . . . . . . . . . AX6-88

AX6-12 Studies of Respiratory Trac t I nflammatory

Effe cts from Controlled H u m a n E x p o s u r e t o O z o n e

....................................... AX6-99

AX6-13 Studies of Effe cts on Host Def ense, on D rug Effe cts and Supportive I n Vitro Studies Relating to Controlled Human Exposure to Ozone

. . . . . . AX6-106

### I I -xvi ii 

## L i st of T ab l es (cont’d)

Nu m b er P age

AX 6- 14 Ozo ne Mixe d w ithOthe r P oll uta nts

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AX6-131

AX6-15 Acute E ffe cts of Ozone in Ambient Air in F ield Studies with a

M o b i l e L a

b o r a t o r y

............................................ AX6-140

3 

### A X 7

- 1 E f

f e c t s o f A c u t e O E x p o s u r e o n L u n g F u n c t i o n a n d R e s p i r a t o r

y S y m p t o m s i n F i e l d

S t u d i e s

........................................ AX7-9

3 

### AX7-2 Effe cts of Ac ute O Ex posure on Car diovascular Outcomes in F i e l d S t u d i e s

.................................................. AX7-33

3 

### AX 7- 3 Ef

fe c ts o f O on

Da ily Em e rg e nc y

De pa rt me nt V isi ts

. . . . . . . . . . . . . . . . . . AX7-40

3 

### AX7-4 Effe cts of O on Daily Hospital Admissions

. . . . . . . . . . . . . . . . . . . . . . . . . AX7-52

3 

### AX 7- 5 Ef

fe c ts o f A c ute O Expo su re on Mo rt a lit y

. . . . . . . . . . . . . . . . . . . . . . . . . . AX7-71

3 

### AX 7- 6 Ef

fe c ts o f C hr on ic O Expo su re on Re sp ir a tor

y He a lth

. . . . . . . . . . . . . . . . AX7-102

3 

### AX7-7 Effe cts of Chronic O Ex posure on Morta lity and I ncidenc e of Canc er

. . . . AX7-118

AX7-8 Ozone-Associa ted Cardiovasc ular Morta lity Risk Esti mates per S t a n d a r d i z e d

I n c r e m e n t

........................................ AX7-126

AX7-9 Estimated Parame ters of the Gompertz Model

. . . . . . . . . . . . . . . . . . . . . . . AX7-131

### I I -xix 

## L i st of F i gu re s

Nu m b er P age

3 

### AX2-1 Schematic ove rview of O photochemistry

in the stratosphere

a n d t r o p o s p h e r e................................................. AX2-4

AX 2- 2 Ge ne ra l c he mic a l me c ha nis m f or the oxida tiv e de g ra da tio n o f V OC s

. . . . . AX2-21

AX2-3 Hy droxy l radica l initi ated oxidation of a) propa ne and b) propene

. . . . . . . . AX2-24

AX2-4 Structures of a selec ted number of

terpe ne and se squiterpene compounds

... 

### AX2-27

3 

### AX2-5 Products from the r eac tion of terpene s with O

. . . . . . . . . . . . . . . . . . . . . . . AX2-30

A X 2

- 6 In i t i a l s t e p s i n t h e p h o t o o x i d a t i o n m e c h a n i s m o f t o l u e n e i n i t i a t e d

b y i t s r e a c t i o n w i t h O H r a d i c a l s

..................................... AX2-39

AX2-7a Cross section throug h a tropopa use folding event on Ma

rch 13, 1978

a t 0 0 0 0 G M T

................................................. AX2-64

AX 2 -7 b Oz o n e m i x i n g ra t i o s p p h m (p ar t s p er h u n d re d m i l l i o n ) c o rr es p o n d i n g t o F i g u r e A X 2

- 7 a

.............................................. AX2-67

AX2-7c Condensation nuclei conc entra tions (particles c m ) cor responding to ! 3 

### F i g u r e A X 2

- 7 a

................................................ AX2-68

AX2-8 Schematic diag ram of a meteorolog ical mec hanism involved in high

3 

### conce ntrations of O found in spring in the lower troposphe re of f the A m e r i c a n e a s t c o a s t

............................................ AX2-71

AX2-9a ,b (a) Contour plot of CO mix ing r atios (ppbv) obser ved in and ne ar the June 15 , 1 98 5, me so sc a le c on ve c tiv e c omp le x in e a ste rn Ok la ho ma

. . . . . . AX2-75

AX2-10 The diurna l evolution of the planeta ry boundary lay er w hile high
p r e s s u r e p r e v a i l s o v e r

l a n d

....................................... AX2-80

AX2-11 L ocations of low leve l jet occur renc es in dec rea sing or der of preva lence ( m o s t f r e q u e n t , c o m m o n , o b s e r

v e d )

................................ AX2-81

3 

### AX2-12 Schematic diag ram showing the diurnal be havior of O and the

3 

### development of

seconda ry O maxi ma re sulting fr om downwar d transport fr om the residual lay er w hen a low- level jet is prese nt

. . . . . . . . . . AX2-82

AX2-13 The noc turnal low-leve l jet occupies a thin sli ce of

the atmosphere

n e a r t h e E a r t h ’ s s u r f

a c e

......................................... AX2-82

### I I

- xx 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 

### A X 2

- 1 4 A s c a t t e r

p l o t o f d a i l y m a x i m u m 8

- h O c o n c e n t r a t i o n v e r s u s d a i l y maxi mum temperature in the Ba ltimore, MD Air Qua lity For eca st Area

. . . AX2-93

3 

### AX 2- 15 A s c a tte r p lot of da ily ma ximum1- h a ve ra g e O c on c e ntr a tio n v e rs us d a i l y m a x i m u m t e m p e r a t u r e i n t h e B a l t i m o r e , M D A i r Q u a l i t y F o r e c a s t A r e a

................................................. AX2-93

3 

### AX 2- 16 A s c a tte r p lot of da ily ma ximum8- h a ve ra g e O c on c e ntr a tio ns ve rs us daily maxi mum temperature downwind of Phoenix, AZ

. . . . . . . . . . . . . . . . AX2-94

3 z y x 

### AX 2- 17 Me a su re d v a lue s o f O a nd NO (N O – N O ) d

ur ingthe a ft e rn oo n a t

ru ra l si te s in

the e a ste rn

Un ite d St a te s ( g ra

y c ir c le s) a nd

in u rb a n a re a s

a nd ur ba n p lum e s a sso c ia te d w ithNa sh vil le , T N ( g ra y da sh e s) , Pa

ri s, F R (b la c k d ia mon ds ) a

nd L os An g e le s, CA (X ’s )

. . . . . . . . . . . . . . . . . . . . . . . . AX2-98

AX2-18 Conceptual two-r eser voir model showing conditions in the PBL and

3 

### in the lower f

ree troposphere during a multiday O episode

. . . . . . . . . . . . AX2-108

3 

### AX2-19 Seasonal va riability in O conce ntrations observe d at a number of
pressure surfa ces a t six ozonesonde sites and the pre dictions of 13 g lob a l sc a le c he mis tr

y -t ra ns po rt mod e ls

. . . . . . . . . . . . . . . . . . . . . . . . . AX2-120

3 

### AX2-20 Seasonal va riability in O conce ntrations observe d at a number of
pressure surfa ces a t six ozonesonde sites and the pre dictions of 13 g lob a l sc a le c he mis tr

y -t ra ns po rt mod e ls

. . . . . . . . . . . . . . . . . . . . . . . . . AX2-121

3 

### AX2-21a ,b I mpact of mode l uncer tainty on control strate g y

predic tions for O for two day s (Aug ust 10[ a] and 11[b] , 1992) in Atlanta, GA

. . . . . . . . . . . . . . AX2-134

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

vera g e emission rate

x 

### f o r N O a n d V O C ( 1 0 mo le c

. c m s ) in ze r o d im e n s io n a l b o x 12

! 2

! 1



### m o d e l c a l c u l a t i o n s

............................................ AX2-135

AX 2- 23 a Ti me se ri e s f or me a su re d g a s- ph a se sp e c ie s in c omp a ri so n w ithre su lts f r o m a p h o t o c h e m i c a l m o d e l

.................................... AX2-136

AX 2- 23 b Ti me se ri e s f or me a su re d g a s- ph a se sp e c ie s in c omp a ri so n w ithre su lts f r o m a p h o t o c h e m i c a l m o d e l

.................................... AX2-137

3 z y x 

### AX 2- 24 Cor

re la tio ns fo r O ve rs us NO (N O – N O ) i n p pb fr om c he mic a l transport models for

the northea st corridor, L ake Mic higa n, Nashville, the San J oaquin Valley , and L os Ang eles

. . . . . . . . . . . . . . . . . . . . . . . . . . . AX2-139

### I I

- xxi 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 y 

### AX 2- 25 a ,b Ev a luatio n o f m od e l ve rs us me a su re d O ve rs us NO fo r t wo mod e l

s c e n a r i o s f

o r A t l a n t a

........................................... AX2-140

3 z 

### AX2-26a ,b Evaluation of model ve rsus: (a) measure d O versus NO and

3 2 2 z 

### (b) O versus the sum 2H O + NO for Na shville, TN

. . . . . . . . . . . . . . . . AX2-142

2 2 

### AX 2- 27 Ti me se ri e s o f c on c e ntr a tio ns of RO , H O , a

nd OH ra dic a ls, loc a l

3 x 

### O ph oto c he mic a l pr od

uc tio n r a te a nd

c on c e ntr a tio ns of

NO fr om

m e a s u r e m e n t s m a d e d

u r i n g B E R L I O Z

............................. AX2-143

3 

### AX3-1 County

wide mea n daily maxi mum 8-h O conce ntrations, May to S e p t e m b e r

2 0 0 2 t o 2 0 0 4

.......................................... AX3-6

3 

### AX3-2 County

wide 95th per centile va lue of da ily maxi mum 8-h O

conce ntrations, May

to September 2002 to 2004

. . . . . . . . . . . . . . . . . . . . . . . AX3-7

AX 3- 3 L oc a tio ns of mon ito ri ng sit e s u se d f

or c a lc ulatin g c ou nty

wi de a ve ra g e s

a c r o s s t h e U n i t e d

S t a t e s

.......................................... AX3-8

3 

### AX 3- 4 Di str ibu tio n o f n a tio nw ide da ily ma ximum

1- h a ve ra g e O c on c e ntr a tio ns f r o m M a y t o S e p t e m b e r

2 0 0 0 t o 2 0 0 4

............................... AX3-9

3 

### AX 3- 5 Di str ibu tio n o f n a tio nw ide da ily ma ximum

8- h a ve ra g e O c on c e ntr a tio ns f r o m M a y t o S e p t e m b e r

2 0 0 0 t o 2 0 0 4

............................... AX3-9

3 

### AX 3- 6 Di str ibu tio n o f n a tio nw ide 24 -h a ve ra g e O c on c e ntr a tio ns fr om M a y t o S e p t e m b e r

2 0 0 0 t o 2 0 0 4

................................... AX3-10

3 

### AX3-7 Box plots s howing O aver ag ed by month from 1993 to 2002 in the five
reg ions in the easter

n United States derive d by L ehman e t al. (2004)

. . . . . . AX3-12

3 

### AX 3- 8 Ho ur ly

a ve ra g e O c on c e ntr a tio ns ob se rv e d a t se le c te d r ur a l- a g ri c ult

ur a l

s i t e s f r o m A p r i l t o O c t o b e r

2 0 0 1

.................................. AX3-13

3 

### AX 3- 9 Ho ur ly

a ve ra g e O c on c e ntr a tio ns ob se rv e d a t se le c te d r ur a l- fo re st s ite s f r o m A p r i l t o O c t o b e r

2 0 0 1

...................................... AX3-14

3 

### AX 3- 10 Ho ur ly

a ve ra g e O c on c e ntr a tio ns ob se rv e d a t se le c te d r ur a l- c omm e rc ia l

or -r esidential sites from Apr il to October 2001

. . . . . . . . . . . . . . . . . . . . . . . AX3-15

3 

### AX 3- 11 a -d Da ily

8- h ma ximumO c on c e ntr a tio ns ob se rv e d a t se le c te d n a tio na l
p a r k s i t e s

..................................................... AX3-16

### I I -xxii 

## L i st of F i gu re s (cont’d)

Nu m b er P age

AX 3- 12 Se a so na l SU M0 6 a nd W12 6 e xpos ur e ind ic e s f or the Ou a c hit a

Na tio na l F o r e s t f o r t h e p e r i o d

o f 1 9 9 1 t o 2 0 0 1

............................... AX3-27

A X 3

- 1 3 Si x- mo n th ( A p r il to Se p te mb e r ) 2 4

- h c u mu lati v e W1 2 6 e xp o s u r e in d e x wi th t he nu mbe r o f h ou rl y

a ve ra g e c on c e ntr a tio ns $ 

### 0.10 ppm (N100)

occur ring during 2001 for the e astern U nited States

. . . . . . . . . . . . . . . . . . . AX3-29

A X 3

- 1 4 Si x- mo n th ( A p r il to Se p te mb e r ) 2 4

- h c u mu lati v e SU M 0 6 e xp o s u r e in d e x wi th t he nu mbe r o f h ou rl y

a ve ra g e c on c e ntr a tio ns $ 

### 0.10 ppm (N100)

occur ring during 2001 for the e astern U nited States

. . . . . . . . . . . . . . . . . . . AX3-31

A X 3

- 1 5 Si x- mo n th ( A p r il to Se p te mb e r ) 2 4

- h c u mu lati v e W1 2 6 e xp o s u r e in d e x wi th t he nu mbe r o f h ou rl y

a ve ra g e c on c e ntr a tio ns $ 

### 0.10 ppm (N100)

occur ring during 2001 for the c entra l United States

. . . . . . . . . . . . . . . . . . . . AX3-32

A X 3

- 1 6 Si x- mo n th ( A p r il to Se p te mb e r ) 2 4

- h c u mu lati v e SU M 0 6 e xp o s u r e in d e x wi th t he nu mbe r o f h ou rl y

a ve ra g e c on c e ntr a tio ns $ 

### 0.10 ppm (N100)

occur ring during 2001 for the c entra l United States

. . . . . . . . . . . . . . . . . . . . AX3-33

A X 3

- 1 7 Si x- mo n th ( A p r il to Se p te mb e r ) 2 4

- h c u mu lati v e W1 2 6 e xp o s u r e in d e x wi th t he nu mbe r o f h ou rl y

a ve ra g e c on c e ntr a tio ns $ 

### 0.10 ppm (N100)

occur ring during 2001 for the w estern U nited States

. . . . . . . . . . . . . . . . . . . AX3-34

A X 3

- 1 8 Si x- mo n th ( A p r il to Se p te mb e r ) 2 4

- h c u mu lati v e SU M 0 6 e xp o s u r e in d e x wi th t he nu mbe r o f h ou rl y

a ve ra g e c on c e ntr a tio ns $ 

### 0.10 ppm (N100)

occur ring during 2001 for the w estern U nited States

. . . . . . . . . . . . . . . . . . . AX3-35

AX3-19 The 95% c onfidenc e interva l for the 6- month (April to September)

24-h cumulative W126 exposure index for 2001 for the e astern U n i t e d S t a t e s

.................................................. AX3-36

AX3-20 The 95% c onfidenc e interva l for the 6- month (April to September)

24-h cumulative SUM06 exposure index for 2001 for the easte rn U n i t e d S t a t e s

.................................................. AX3-36

AX3-21 The 95% c onfidenc e interva l for the 6- month (April to September)

24-h cumulative N 100 exposure index for 2001 for the e astern U n i t e d S t a t e s

.................................................. AX3-37

AX3-22 The 95% c onfidenc e interva l for the 6- month (April to September)

24 -h c umu la tiv e W12 6 e xpos ur e ind e x for 20 01 fo r t

he c e ntr a l U n i t e d S t a t e s

.................................................. AX3-37

### I I -xxiii 

## L i st of F i gu re s (cont’d)

Nu m b er P age

AX3-23 The 95% c onfidenc e interva l for the 6- month (April to September)

24 -h c umu la tiv e SUM 06 e xpos ur e ind e x for 20 01 fo r t

he c e ntr a l U n i t e d S t a t e s

.................................................. AX3-38

AX3-24 The 95% c onfidenc e interva l for the 6- month (April to September)

24 -h c umu la tiv e N1 00 e xpos ur e ind e x for 20 01 fo r t

he c e ntr a l U n i t e d S t a t e s

.................................................. AX3-38

AX3-25 The 95% c onfidenc e interva l for the 6- month (April to September)

24-h cumulative W126 exposure index for 2001 for the w estern U n i t e d S t a t e s

.................................................. AX3-39

AX3-26 The 95% c onfidenc e interva l for the 6- month (April to September)

24-h cumulative SUM06 exposure index for 2001 for the wester n U n i t e d S t a t e s

.................................................. AX3-39

AX3-27 The 95% c onfidenc e interva l for the 6- month (April to September)

24-h cumulative N 100 exposure index for 2001 for the we stern U n i t e d S t a t e s

.................................................. AX3-40

3 

### AX3-28 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

corr elation statistics (c) f

or the Char lotte, NC-Gastonia-Roc k Hill, S C M S A

..................................................... AX3-44

3 

### AX3-29 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the B a ton

Rou g e , L A M SA

. . . . . . . . . . . . . . . . AX3-45

3 

### AX3-30 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the De tr oit -A nn

Ar bo r- F lin t, M I CMSA

. . . . . . AX3-46

3 

### AX3-31 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the St. L ou is, MO -I L MSA

. . . . . . . . . . . . . . . . . AX3-47

3 

### AX3-32 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the Pho e nix- Me sa , A Z MSA

. . . . . . . . . . . . . . . AX3-49

3 

### AX3-33 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the F re sn o, CA MSA

. . . . . . . . . . . . . . . . . . . . . AX3-50

3 

### AX3-34 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the B a ke rs fi e ld, CA MSA

. . . . . . . . . . . . . . . . . . AX3-51

### I I -xxiv 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 

### AX3-35 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

corr elation statistics (c) f

or the L os Ang eles-O rang e County
, C A C M S A

................................................... AX3-52

3 

### AX3-36 L ocations of O sampling sites (a ) by AQS I D# (b) a

nd intersite

c or re la tio n s ta tis tic s ( c ) f

or the Riv e rs ide -O ra

ng e County , CA CMSA

. . . . . AX3-54

3 

### AX3-37 Ver

tical profile of

O obtained over

low veg etation

. . . . . . . . . . . . . . . . . . . . AX3-58

3 

### AX 3- 38 Ve rt ic a l pr of ile of O ob ta ine d in

a sp ru c e fo re st

. . . . . . . . . . . . . . . . . . . . . . AX3-59

AX3-39a -d Seven- a

nd 12-h sea sonal means a t (a) Whitefa ce Mounta in and (b) Shena ndoah Na tional Park for Ma y to September 1987, a

nd integ rate d exposures at (c) Whit efa ce Mounta in and (d) Shena ndoah National Park f

or May to September 1987

. . . . . . . . . . . . . . . . . . . . . . . . . . . AX3-64

A X 3

- 4 0 a

- e C u m u l a t i v e e x p o s u r e s f o r t h r e e n o n

- M o u n t a i n C l o u d C h e m i s t r y Prog ram Shena

ndoah Na tional Park sites, 1983 to 1987

. . . . . . . . . . . . . . . . AX3-65

3 

### AX3-41 Composit e, nationwide diur nal var iability

in hourly aver ag ed O in

u r b a n a r e a s

................................................... AX3-70

3 

### AX3-42 Composit e, nationwide diur nal var iability

in 8 hour ave rag e O in

u r b a n a r e a s

................................................... AX3-71

3 

### AX3-43a -f Diurnal va riability in hourly aver ag ed O in selecte d urban a rea s

. . . . . . . . . AX3-72

3 

### AX3-43g -l Diurnal va riability in hourly aver ag ed O in selecte d urban a rea s

. . . . . . . . . AX3-73

3 

### AX3-44a -f Diurnal va riability in 8 hour ave rag ed O in selecte d urban a rea s

. . . . . . . . . AX3-74

3 

### AX3-44g -l Diurnal va riability in 8 hour ave rag ed O in selecte d urban a rea s

. . . . . . . . . AX3-75

3 

### AX3-45a -d Time of occ urre nce of daily maxi mum 1-h O conce ntration in four cities, ave rag ed fr om April to October, 2000 to 2004

. . . . . . . . . . . . . . . . . . AX3-77

3 

### AX3-46a -d Time of occ urre nce of daily maxi mum 8-h aver ag e O conce ntration in four c ities, avera g ed fr om April to October, 2000 to 2004

. . . . . . . . . . . . . . AX3-78

3 

### AX3-47a -d Diurnal va riations in hourly

aver ag ed O on wee kday s and we ekends i n f o u r c i t i e s

.................................................. AX3-80

### I I

- xxv 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 

### AX 3- 47 e -h Di ur

na l va ri a tio ns in h ou rl y

a ve ra g e d O on

we e kd a y s a nd we e ke nd s i n f o u r c i t i e s

.................................................. AX3-81

3 

### AX3-48a -d Diurnal va riations in 8-h ave rag ed O on wee kday s and we ekends in f o u r c i t i e s

.................................................... AX3-82

3 

### AX3-48e -h Diurnal va riations in 8-h ave rag ed O on wee kday s and we ekends in f o u r c i t i e s

.................................................... AX3-83

3 

### AX3-49a Diurnal va riations in hourly

aver ag ed O at a site in downtown D e t r o i t , M I

................................................... AX3-84

3 

### AX3-49b Diurnal va riations in hourly

aver ag ed O at a site downw ind of d o w n t o w n D e t r o i t

.............................................. AX3-84

3 

### AX3-50a Diurnal va riations in hourly

aver ag ed O at a site in downtown S t

. L o u i s , M O

................................................. AX3-85

3 

### AX3-50b Diurnal va riations in hourly

aver ag ed O at a site downw ind of d o w n t o w n S t

. L o u i s

............................................ AX3-85

3 

### AX3-51a Diurnal va riations in hourly

aver ag ed O at a site in S a n B e r n a d i n o , C A

............................................. AX3-86

3 

### AX3-51b Diurnal va riations in hourly

aver ag ed O at a site in Riverside C o u n t y w e l l d o w n w i n d

o f s o u r c e s

................................. AX3-87

3 

### AX 3- 52 a Di ur

na l va ri a tio ns in 8 -h

a ve ra g e O a t a

sit e in d ow nto wn

De tr oit , M I

. . . . AX3-88

3 

### AX3-52b Diurnal va riations in 8-h ave rag e O at a site downw ind of downtown D e t r o i t , M I

................................................... AX3-88

AX3-53a Diurnal va riations in 8-h ave rag e ozone at a site in downtown S t

. L o u i s , M O

................................................. AX3-89

3 

### AX3-53b Diurnal va riations in 8-h ave rag e O at a site downw ind of downtown S t

. L o u i s , M O

................................................. AX3-89

3 

### AX 3- 54 a Di ur

na l va ri a tio ns in 8 -h

a ve ra g e O a t a

sit e in S a n B e rn a din o, CA

. . . . . . . AX3-90

3 

### A X 3

- 5 4 b D i u r

n a l v a r i a t i o n s i n 8

- h a v e r a g e O a t a s i t e i n R i v e r s i d e C o u n t y

w e l l d o w n w i n d

o f s o u r c e s

....................................... AX3-90

### I I -xx vi 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 

### AX3-55 Composit e diurna l variability in hourly O conce ntrations observe d

a t C A S T N E T s i t e s

............................................. AX3-91

3 

### AX 3- 56 Com

po sit e diu rn a l va ri a bil ity in 8 -h a ve ra g e O c on c e ntr a tio ns

o b s e r v e d a t C A S T N E T s i t e s

...................................... AX3-91

AX3-57 The c omparison of the se asonal diurna l patterns for urban- influence d (Jeffer son County , KY) a nd a rur al-influenc ed (O liver County , ND) monitoring sites using 2002 hourly data f or April-O ctober

. . . . . . . . . . . . . . AX3-93

3 

### AX 3- 58 a -d Di ur

na l be ha vio r o f O a t r

ur a l si te s in

the Un ite d St a te s in

July

. . . . . . . . . . AX3-94

3 

### AX3-59 Composit e diurna l O pattern a t selecte d national fore st sites in t he

Un ite d St a te s u sin g 20 02 ho ur ly a ve ra g e c on c e ntr a tio n d a ta

. . . . . . . . . . . . . AX3-95

AX3-60a ,b Composit e diurna l pattern a t (a) Whitefa ce Mounta in, NY and

(b ) t he Mo un ta in C lou d Ch e mis tr y Pr og ra m Sh e na nd oa h N a tio na l P a r k s i t e f o r M a y t o S e p t e m b e r

1 9 8 7

............................... AX3-96

3 

### AX3-61a -h Seasonal va riations in O conce ntrations as indicate d by the 1-h maxi mum in each month at sele cted sites, 2002

. . . . . . . . . . . . . . . . . . . . . . AX3-97

3 

### AX3-62a -f Diurnal va riability in 1-h ave rag e O conce ntrations in EPA’s 12 cities

. . . . AX3-99

3 

### AX3-62g -l Diurnal va riability in 1-h ave rag e O conce ntrations in EPA’s 12 cities

. . . AX3-100

3 

### AX3-63a -f Diurnal va riability in 8-h ave rag e O conce ntrations in EPA’s 12 cities

. . . AX3-101

3 

### AX3-63g -l Diurnal va riability in 8-h ave rag e O conce ntrations in EPA’s 12 cities

. . . AX3-102

3 

### AX3-64 Yea

r-to-y ear varia bility in nationwide mean da ily maxi mum 8-h O

c o n c e n t r a t i o n s

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

AX3-65 Yea

r-to-y ear varia bility in nationwide 95th perc entile value of the

3 

### d a i l y m a x i m u m 8

- h O c o n c e n t r a t i o n s

............................. AX3-106

3 

### AX 3- 66 a -h Ye a r- to- y e a r v a ri a bil ity in m e a n d a ily

ma ximum8- h O c on c e ntr a tio ns at selec ted national par

k (NP), national wildlife r efug e (N WR ), and

n a t i o n a l m o n u m e n t ( N M ) s i t e s

................................... AX3-107

### I I -xxvii 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 

### AX 3- 66 i- p Ye a r- to- y e a r v a ri a bil ity in m e a n d a ily

ma ximum8- h O c on c e ntr a tio ns at selec ted national par

k (NP), national wildlife r efug e (N WR ), and

n a t i o n a l m o n u m e n t ( N M ) s i t e s

................................... AX3-108

3 

### AX 3- 66 q- v Ye a r- to- y e a r v a ri a bil ity in m e a n d a ily

ma ximum8- h O c on c e ntr a tio ns at selec ted national par

k (NP), national wildlife r efug e (N WR ), and

n a t i o n a l m o n u m e n t ( N M ) s i t e s

................................... AX3-109

3 

### AX3-67a -h Yea

r-to-y ear varia bility in 95th perce ntile of daily maxi mum 8-h O

conce ntrations at selec ted national par k (NP), national wildlife r efug e (NWR), and national monument (NM) sites

. . . . . . . . . . . . . . . . . . . . . . . . AX3-110

3 

### AX3-67i-p Yea

r-to-y ear varia bility in 95th perce ntile of daily maxi mum 8-h O

conce ntrations at selec ted national par k (NP), national wildlife r efug e (NWR), and national monument (NM) sites

. . . . . . . . . . . . . . . . . . . . . . . . AX3-111

3 

### AX3-67q- v Yea

r-to-y ear varia bility in 95th perce ntile of daily maxi mum 8-h O

conce ntrations at selec ted national par k (NP), national wildlife r efug e (NWR), and national monument (NM) sites

. . . . . . . . . . . . . . . . . . . . . . . . AX3-112

3 

### AX 3 -6 8 a- d M ea s u re d

O (p p b v ) v er s u s P AN (p p t v ) i n T en n es s ee , i n cl u d i n g (a) airc raf t measure ments, and (b, c , and d) subur ban sites nea

r N a s h v i l l e

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

y 

### AX3-69 Measur ed cor rela tion between be nzene and NO at a mea surement site i n B o u l d e r , C O

............................................... AX3-118

2.5 3 

### AX3-70 Binne d mean PM conce ntrations versus binned me an O

conce ntrations observe d at For t Meade , MD from July

1999 to J u l y 2 0 0 1.................................................... AX3-121

3 2 

### AX3-71 The c o-occ urre nce pa ttern for O and NO

. . . . . . . . . . . . . . . . . . . . . . . . . . AX3-124

3 2 

### AX 3- 72 Th e c o- oc c ur re nc e pa tte rn

fo r O a nd

NO us ing20 01 da ta

fr om t h e A Q S

.................................................... AX3-125

3 2 

### AX 3- 73 Th e c o- oc c ur re nc e pa tte rn

fo r O a nd

SO

. . . . . . . . . . . . . . . . . . . . . . . . . . AX3-126

3 2 

### AX3-74 The c o-occ urre nce pa ttern for O and SO using 2001 da ta from AQ S

. . . . AX3-127

3 2.5 

### AX3-75 The c o-occ urre nce pa ttern for O and PM using 2001 da ta from AQ S

. . . AX3-128

### I I -xxvii i 

## L i st of F i gu re s (cont’d)

Nu m b er P age

3 

### AX3-76a Monthly

maxi mum hourly

aver ag e O conce ntrations at Yellowstone National Park, Wy oming in 1998, 1999, 2000, and 2001

. . . . . . . . . . . . . . AX3-133

3 

### AX3-76b Hourly

aver ag e O conce ntrations at Yellowstone N ational Park, Wy oming f

or the pe riod J anuar

y to Dece mber 2001

. . . . . . . . . . . . . . . . . . AX3-133

AX3-77 (a) Contour plot of CO mix ing r atios (ppbv) obser ved in and ne ar the June 15 , 1 98 5, me so sc a le c on ve c tiv e c omp le x in e a ste rn Ok la ho ma

. . . . . AX3-135

3 

### AX3-78 Maxi mum hourly aver ag e O conce ntrations at rura l monitoring sites in Canada and the United States in F ebrua ry from 1980 to 1998

. . . . . . . . . . . AX3-143

AX3-79 Schematic diag ram of a meteorolog ical mec hanism involved in high

3 

### conce ntrations of O found in spring in the lower troposphe re of f the A m e r i c a n E a s t C o a s t

.......................................... AX3-145

AX3-80 Ozone vertica l profile at B oulder, Colorado on Ma y 6, 1999 at 1802 U T C ( 1 1 0 2 L S T )

............................................. AX3-148

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

. . . . . . . . . . . . AX3-152

AX 3- 82 Mo nth ly

me a n a ft e rn oo n ( 13 00 to 1 70 0 h ou rs L T) c on c e ntr a tio ns (p pb v) in s ur fa c e a ir

a ve ra g e d o ve r t

he CA STN e t st a tio ns (F igur e AX3- 81) in ea ch U.S. quadr ant for Ma rch to Oc tober 2001

. . . . . . AX3-153

AX3-83 Probability distributions of daily

mean a fternoon ( 1300 to 1700 L T)

3 

### O c on c e ntr a tio ns in s ur fa c e a ir fo r M a rc h th ro ug h O c tob e r 2 00 1 a t U.S. CASTNet sites (Fig ure A X3-83): obse rvations (thick solid line)

are compar ed with model re sults (thin sol id line)

. . . . . . . . . . . . . . . . . . . . AX3-157

3 

### AX3-84 Daily

mean a fternoon ( 13 to 17 L T) O conce ntrations in surfac e air at Voy ag eurs Na

tional Park (NP), Minnesota in mid-May throug h J u n e o f 2 0 0 1

................................................. AX3-157

AX 3 -8 5 S am e a s Fi gu re AX 3 -8 4 b u t fo r Y el l o ws t o n e N at i o n al P ar k

, W y o m i n g

i n M a r c h t o M a y

2 0 0 1

......................................... AX3-159

AX3-86 Same as F igur e AX3- 84 but for Mar ch of 2001 a t selecte d wester n (left c olumn) and southeaste rn (r ight c olumn) sites

. . . . . . . . . . . . . . . . . . . AX3-160

AX3-87a Detailed dia g ram illustrating components of a n exposure model

. . . . . . . . AX3-170

### I I -xxix 

## L i st of F i gu re s (cont’d)

Nu m b er P age

AX3-87b Detailed dia g ram illustrating components of a n exposure model

. . . . . . . . AX3-171

3 

### AX3-88 Measur ed outdoor O conce ntrations (thin line) and modele d indoor

c o n c e n t r a t i o n s ( b o l d

l i n e )

....................................... AX3-185

3 

### AX 3 -8 9 Ai r e x ch an ge r at es an d o u t d o o r a n d

i n d o o r O co n ce n t ra t i o n s d u ri n g the su mme r at a

te le ph on e sw itc hin g sta tio n in B ur ba nk , CA

. . . . . . . . . . . AX3-200

3 

### AX 3 -9 0 Ai r e x ch an ge r at es an d o u t d o o r a n d

i n d o o r O co n ce n t ra t i o n s d u ri n g the fa ll a t a

te le ph on e sw itc hin g sta tio n in B ur ba nk , CA

. . . . . . . . . . . . . . . AX3-201

3 

### AX 3- 91 Di ur

na l va ri a tio n o f i nd oo r a

nd ou tdo or O a nd PAN c on c e ntr a tio ns

measure d in a private residenc e, F reising , Ger many , Aug ust 11-12, 1995

. . 

### AX3-203

3 

### AX3-92 I ndoor and outdoor O conce ntration in moving c ars

. . . . . . . . . . . . . . . . . . AX3-205

AX3-93 I ndoor/outdoor conc entra tion ratios for PAN at 10 souther n C a l i f o r n i a m u s e u m s

........................................... AX3-206

AX 3- 94 Ozo ne de c a y pr oc e sse s v e rs us tim e me a su re d f or se ve ra l in do or

ro oms

. . . AX3-212

1 3 

### AX6-1 FEV decr ements as a function of O conce ntration following a 2 h

e xpos ur e wi th i nc re me nta l e xer c ise (1 5 mi n in te rv a ls) or re st

. . . . . . . . . . . . . AX6-8

1 

### AX6-2 Aver ag e F EV decr ements (±SE) for prolong ed 6.6 h exposures to

3 E 

### 0.12 ppm O as a function of exercise V

. . . . . . . . . . . . . . . . . . . . . . . . . . . 

## 0 AX6-15

1 

### AX6-3 The for ced e x piratory volume in 1 s (FEV ) is shown in relation to exposure duration (hour s) under three exposure conditions

. . . . . . . . . . . . . . AX6-18

AX 6- 4a ,b Re c ov e ry

of sp ir ome tr ic re sp on se s f

oll ow inga

2 h e xpos ur e to 0 .4 pp m

3 

### O w i t h I E

.................................................... AX6-23

1 

### AX 6- 5 Plo t of

the me a n F EV (% ba se lin e ) v s. tim e fo r o zon e e xpos e d c oh or ts

. . . AX6-26

1 

### AX 6- 6 F re qu e nc y dis tr ibu tio ns of

F EV de c re me nts fo llo wi ng 6. 6- h e xpos ur e s

3 

### t o O o r f i l t e r e d a i r

............................................. AX6-42

3 1 

### AX6-7 Effe ct of O exposure (0.42 ppm for 1.5 h w ith I E) on F EV as a f unction

o f s u b j e c t a g e

................................................. AX6-50

### I I

- xxx 

## L i st of F i gu re s (cont’d)

Nu m b er P age

1 

### AX 6- 8 Re g re ssi on c ur ve s w e re fi tte d to da

y -b y -d a y po ste xpos ur e F EV va lue s

3 

### obtained af

ter re peate d daily

acute exposures to O for 2 to 3 h with

E 

### int e rm itt e nt e xer c ise a t a

V of 24 to 4 3 L

/mi n ( a da ptatio n s tud ie s)

. . . . . . . AX6-81

3 

### AX7-1 Density

curve s of the O -assoc iated excess risk of c ardiova scular mortality in the war

m season per

standardized incr ement

. . . . . . . . . . . . . . AX7-127

AX7-2 Fitted der ivative cur ve of the Gompertz model to the reg ression

c oe ff ic ie nts ( $ 

### = log rela tive risk per 1,000 ppb) for the a ssociation

3 

### b e t w e e n m o r t a l i t y a n d

a c u t e e x p o s u r e t o O p l o t t e d a g a i n s t c o m m u n i t y3 

### sp e c if ic lon g -t e rm

a ve ra g e 24 -h

a vg O c on c e ntr a tio ns us ingda ta fr om t h e U

. S

. 9 5 c o m m u n i t i e s s t u d y

................................... 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 Agenc y, 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 Agenc y, 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 Atmos pheric Administration/Geophysical Fluid Dynamics Laboratory, Princeton, NJ

Mr. Chris Geron—National Risk Management Res earch 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 Oceanogra phy, 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 Atmo spheric 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 Agenc y, Research Triangle Park, NC 27711

Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

### II-xxxiii 

## Authors, Contributors, and Reviewers (cont’d)

Principal Authors (cont’d)

Dr. Arlene Fiore—National Oceanic and Atmos pheric 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 Agenc y, Research Triangle Park, NC 27711

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Timothy Lewis—National Center fo r Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, 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 Oceanogra phy, 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 Meteorol ogy, 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 Agenc y, Research Triangle Park, NC 27711

Dr. Lori White—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, 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 Environm ental 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, Res earch Triangle Park, NC 27711 (Retired)

Dr. Deepak Bhalla—Department of Occupati onal and Environmental Health Sciences, Wayne State University, Detroit, MI

Dr. Carroll Cross—School of Medicine, Un iversity 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 Envir onmental Health, University of Cincinnati, Cincinnati, OH

Dr. David Basset—Department of Occupational a nd 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 Envi ronment, University of California, Davis, CA

Dr. Edward Schelegle—Department of Anat omy, Physiology, and Cell Biology, University of California, Davis, CA

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

Dr. Paul Reinhart—National Center for Envir onment (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 Agenc y, 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 Me dicine, 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 E nvironmental 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 Agenc y, Research Triangle Park, NC 27711

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, 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, Mailm an 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 Protect ion Agency Project Team

for Development of Air Quality Criteria for Ozone and Related Photochemical Oxidants

Executive Direction

Dr. Lester D. Grant (Director)—National Cent er for Environmental Assessment-RTP Division, (B243-01), U.S. Environmental Protection Ag ency, Research Triangle Park, NC 27711

Scientific Staff

Dr. Lori White(Ozone Team Leader)—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Joseph Pinto—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Ms. Beverly Comfort—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Brooke Hemming—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. James S. Brown—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Dennis Kotchmar—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Jee Young Kim—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. David Svendsgaard—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Srikanth Nadadur—National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

Dr. Timothy Lewis—National Center fo r Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, 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 Protect ion 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 Environm ental 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 Manage r, National Center for Environmental Assessment (B243-01), U.S. Environmental Protec tion Agency, Research Triangle Park, NC 27711

Mr. Douglas B. Fennell—Technical Information Sp ecialist, National Center for Environmental Assessment (B243-01), U.S. Environmental Protec tion Agency, Research Triangle Park, NC 27711

Ms. Emily R. Lee—Management Analyst, National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Ag ency, Research Triangle Park, NC 27711

Ms. Diane H. Ray—Program Specialist, National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Ag ency, Research Triangle Park, NC 27711

Ms. Donna Wicker—Administrative Officer, National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711 (retired)

Mr. Richard Wilson—Clerk, National Center for Environmental Assessment (B243-01), U.S. Environmental Protection Agenc y, Research Triangle Park, NC 27711

### II-xl 

## U.S. Environmental Protect ion 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 Scie nces Corporation, 2803 Slater Road, Suite 220, Morrisville, NC 27560

Mr. John A. Bennett—Technical Information Sp ecialist, 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 Sc iences Corporation, 2803 Slater Road, Suite 220, Morrisville, NC 27560

Dr. Barbara Liljequist—Technical Editor, Comput er 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 Specia list, InfoPro, Inc., 8200 Greensboro Drive, Suite 1450, McLean, VA 22102

Mr. Carlton Witherspoon—Graphic Artist, Comput er Sciences Corporation, 2803 Slater Road, Suite 220, Morrisville, NC 27560

### II-xli 

## U.S. Environmental Protection Agen cy Science Advisory Board (SAB) Staff Office Clean Air Scientifi c 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 Medi cine, 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 Pr eventive 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 Developm ent Scientist , Environmental Sciences Division, Oak Ridge National Laboratory (ORNL), Beth el 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 Agen cy Science Advisory Board (SAB) Staff Office Clean Air Scientifi c Advisory Committee (CASAC) Ozone Review Panel (cont’d)

Members (cont’d)

Dr. Philip Hopke, Bayard D. Clarkson Distingui shed Professor, Department of Chemical Engineering, Clarkson University, B ox 5708, Potsdam, NY, 13699-5708, Phone: 315-268-3861, Fax: 315-268-4410, (hopkepk@clarkson.edu) (Fed Ex: 8 Clarkson Avenue, Potsdam, NY 136995708)

Dr. Michael T. Kleinman, Professor, Departme nt 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 Solu tions, 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 E nvironmental Science & Occupational Health, Department of Environmental Sciences, School of Public Health, University of Texas - Houston Health Science Center, 1200 Herman Pressl er Street, Houston, TX, 77030, Phone: 713-500-9288, Fax: 713-500-9249, (mmorandi@sph.uth.tmc.edu) (F edEx: 1200 Herman Pressler, Suite 624)

Dr. Charles Plopper, Professor, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of Califor nia - 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, Sc hool 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 Agen cy Science Advisory Board (SAB) Staff Office Clean Air Scientifi c Advisory Committee (CASAC) Ozone Review Panel (cont’d)

Members (cont’d)

Dr. Elizabeth A. (Lianne) Sheppard, Research Asso ciate 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 Engin eering, 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, Depa rtment 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 , Di vision 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 Fede ral 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. Butte rfield, 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 Scien tific 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

AH 2 

### 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

B scatter 

### 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

C dyn 

### 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)

CH 3 

### ammonia

CH 4 

### methane

C 2 

### H 4 

### ethene

C 5 

### H 8 

### isoprene

C 6 

### H 6 

### benzene

CHAD Consolidated Human Activities Database

CH 2 

### =C(CH 3 

### )–CHO methacrolein

CH 3 

### –CCl 3 

### methyl chloroform

C 6 

### H 5 

### CH 3 

### toluene

CH 3 

### –CHO acetaldehyde

CH 3 

### CH(ONO 2 

### )CHO 2-nitratopropanol

CHCl 3 

### chloroform

CH 3 

### CN acetonitrile

CH 3 

### –CO acetyl

CH 3 

### –C(O)–CH=CH 2 

### methyl vinyl ketone

### II-xlvii CH 3 

### C(O)CH 2 

### ONO 2 

### 1-nitratopropanone

CH 3 

### –C(O)O 2 

### , CH 3 

### –C(O)OO acetyl peroxy, peroxyacetyl

CHO Chinese hamster ovary (cells)

CH 3 

### O methoxy

CH 3 

### O 2 

### methyl peroxy

CH 3 

### OH methanol

CH 3 

### –O(O)CH 3 

### acetone

CH 3 

### OOH 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

CO 2 

### 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

EC 0.05% 

### 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 , f

B 

### frequency of breathing F344 Fischer 344 (rat)

FA filtered air FA fractional absorption; absorbed fraction

FAA Federal Aviation Administration FEF forced expiratory flow

FEF 25-75 

### , FEF 25%-75% 

### forced expiratory flow between 25 and 75% of vital capacity

FEF

x 

### forced expiratory flow after X% vital capacity (e.g., after 25, 50, or 75% vital capacity)

FEV 1 

### 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

H 2 

### CO, HCHO formaldehyde HDMA house dust mite allergen

HF Howland Forest site

H 2 

### O 2 

### hydrogen peroxide

H 2 

### SO 4 

### sulfuric acid HCs hydrocarbons HHP-C9 1-hydroxy-1-hydroperoxynonane 5-HIAA 5-hydroxyindolacetic acid

HIST histamine HLA human leukocyte antigen HNE 4-hydroxynonenal

HNO 2 

### nitrous acid

HNO 3 

### nitric acid

HNO 4 

### pernitric acid HO hydroxy

### II-li HO 2 

### hydroperoxy

H 2 

### O 2 

### hydrogen peroxide

H 3 

### O + 

### protonated water

HOCH 2 

### OOH hydroxymethylhydroperoxide

HONO nitrous acid HOONO pernitrous acid

HO 2 

### NO 2 

### peroxynitric acid

HO

x 

### hydrogen oxides HPLC high-pressure liquid chromatography

HR heart rate

HR
max 

### maximum heart rate HRV heart rate variability 5-HT 5-hydroxytryptamine

h v 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(NO 2 

### ) photolysis rate coefficient for O 3 

### to NO 2 

### j(O 3 

### ) photolysis rate coefficient for O 3 

### to O( 1 

### D)

K
a 

### intrinsic mass transfer coefficient/parameter KM particle optical reflectance

KO knockout

K TB 

### 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., LTB 4 

### , LTC 4 

### , LTD 4 

### , LTE 4 

### )

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

MEF 50 

### 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 phosphateNADPH-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- 6 

### B nuclear factor kappa B

NH 3 

### ammonia

NH 4 + 

### ammonium ion

### II-lv NHAPS National Human Activity Pattern Survey NHBE cultured human bronchial epithelial (cells) (NH 4 

### ) 2 

### SO 4 

### 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

NO 2 

### nitrogen dioxide

NO 3 

### nitrate (radical)

NO 3 ! 

### nitrate (ion)

N 2 

### O 5 

### dinitrogen pentoxide NOAA National Oceanic and Atmospheric Administration

NOAEL non-observable-adverse-effect level NOS nitric oxide synthase

NO

x 

### nitrogen oxides

NO y 

### total reactive nitrogen; sum of NO

x 

### and NO

z 

### ; odd nitrogen species

NO

z 

### nitrogen-containing species, the sum of the products of the oxidation of NO

x 

### NP national park NQO1 NAD(P)H-quinone oxidore ductase (genotype) NQO1wt NAD(P)H-quinone oxidoreducta se 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)

O 2 

### molecular oxygen

O 2 ! 

### superoxide

O 3 

### ozone

18 

### O radiolabeled oxygen atom OC organic carbon OAQPS Office of Air Quality Planning and Standards OBMs observationally based methods O( 1 

### D) electronically excited oxygen atom OH hydroxy 8-OHdG 8-hydroxy-2 N 

### -deoxyguanosine OLS ordinary least squares O( 3 

### P) ground-state oxygen atom OPE ozone production efficiency

OVA ovalbumin

O

x 

### odd oxygen species; total oxidants p probability

P 90 

### 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

P
a 

### O 2 

### 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)

PC 20 

### provocative concentration that produces a 20% decrease in forced expiratory volume in 1 second

PC 50 

### 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
pCO 2 

### partial pressure of carbon dioxide

PD 20 

### , PD 20 

### FEV 1 

### provovative dose that produces a 20% decrease in FEV 1 

### PC 20 

### FEV 1 

### provovative concentration that produces a 20% decrease in FEV 1 

### PD 100 

### SRaw provocative dose that produces a 100% increase in SRaw
PE postexposure PEF peak expiratory flow

PEF 0.75 

### 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., PGD 2 

### , PGE, PGE 1 

### , PGE 2 

### PGF 1 " 

### , PGF 2 " 

### ) 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

Pm 0.1 

### pressure at mouth at 0.1 second of inspiration against a transiently occluded mouthpiece (an index of inspiratory drive)

PM 2.5 

### fine particulate matter (mass median aerodynamic diameter

# 

### 2.5 μm)

PM 10 

### combination of coarse and fine particulate matter (mass median aerodynamic diameter # 

### 10 μm)

PM 10-2.5 

### coarse particulate matter (mass median aerodynamic diameter between 10 and 2.5 μm)

PM 15 

### 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

PNN 50 

### 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

R 2 

### 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)

R
aw 

### , 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)

R L 

### total pulmonary resistance RMR resting metabolic rate rMSSD square root of the mean of the squared difference between adjacent normal R-R intervals

RO 2 

### organic peroxy ROI reactive oxygen intermediate/superoxide anion

RONO 2 

### organic nitrate

ROONO 2 

### , RO 2 

### NO 2 

### peroxy nitrate

### II-lx ROS reactive oxygen species

RR relative risk RRMS relatively remote monitoring sites RT respiratory tract

R T 

### transepithelial resistance

F g 

### sigma-g; geometric standard deviation

S smoker

SAC Staphylococcus aureus Cowan 1 strain SAI Systems Applications International

S
a 

### O 2 

### 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])

SAW grp 

### 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

SO 2 

### sulfur dioxide

SO 4 2

! 

### sulfate

### II-lxi SOA secondary organic aerosol SOD superoxide dismutase SOS Southern Oxidant Study

SO

x 

### 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

T 3 

### triiodothyronine

T 4 

### thyroxine TAR Third Assessment Report

TB terminal bronchiole TB tracheobronchial (region)

TBA thiobarbituric acid

TBARS thiobarbituric acid reactive substances

99m 

### Tc-DTPA radiolabeled diethylenetriaminepentaacetic acid

T CO 

### core temperature TDLAS tunable-diode laser absorption spectroscopy

### II-lxii T
e 

### expiratory time TEM transmission electron microscopy
Tg teragram

TGF $ 

### 1 transforming growth factor-beta 1

T i 

### 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., TXA 2 

### , TXB 2 

### )

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 V D 

### anatomic dead space

V D 

### deposition velocity

0 

### V E 

### minute ventilation; expired volume per minute

0 

### V Emax 

### maximum minute ventilation

0 

### V max25% 

### maximum expiratory flow at 25% of the vital capacity

0 

### V max50% 

### maximum expiratory flow at 50% of the vital capacity

0 

### V max75% 

### maximum expiratory flow at 75% of the vital capacity

VMD volume median diameter

0 

### VO 2 

### oxygen consumption

0 

### VO 2max 

### maximal oxygen uptake (maximal aerobic capacity) VOCs volatile organic compounds

V T 

### tidal volume

V TB 

### tracheobronchial region volume

V Tmax 

### 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 (O 3 

### ) 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 O 3 

### formation. A very brief overview of atmospheric structure is presented in Section AX2.2.1. An overview of O 3 

### 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 O 3 

### production are best understood by considering the oxidation of methane, structurally the simplest VOC. The CH 4 

### 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 CH 4 

### 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 O 3 

### formation in polluted areas. Multiphase chemical processes influencing O 3 

### are discussed in

### AX2-2 Section AX2.2.10. Meteorological processes that control the formation of O 3 

### and other oxidants and that govern their transport and dispersion, and the sensitivity of O 3 

### 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 O 3 

### in the troposphere is presented in Section AX2.3.1. The importance of deep convection in redistributing O 3 

### 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 O 3 

### 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 O 3 

### to solar ultraviolet radiation and temperature is given in Section AX2.3.5. The relations of O 3 

### 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 O 3 

### its precursors and other oxidants are given in Section AX2.5. Chemistry-transport models are discussed in Section AX2.5.1.

Emissions of O 3 

### 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 O 3 

### are given in Section AX2.6.1, NO and NO 2 

### in Section AX2.6.2, HNO 3 

### 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 CO 2 

### . 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 O 3 

### , 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 CO 2 

### , H 2 

### O, and O 3 

### . 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 O 3 

### 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 O 3 

### -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 O 3 

### would be found in the troposphere due to downward transport from the stratosphere. Tropospheric photochemistry leading to the formation of O 3 

### and other photochemical air pollutants is complex, involving thousands of chemical reac tions and thousands of stable and reactive intermediate products. Other photochemical oxida nts, 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 NO

x 

### and SO

x 

### to form nitric (HNO 3 

### ) and sulfuric acid (H 2 

### SO 4 

### ), respectively. Ozone participates directly in the oxidation of unsaturated hydrocarbons, via th e ozonolysis mechanism, yielding secondary organic compounds that contribute to aerosol formation and mass, as well as formaldehyde (H 2 

### CO) and other carbonyl compounds, such as aldehydes and ketones.

### AX2-4 Figure AX2-1. Schematic overview of O 3 

### photochemistry in the stratosphere and troposphere.

There is a rapid photochemical cycle in the troposphere that involves the photolysis of nitrogen dioxide (NO 2 

### ) by solar UV-A radiation to yield n itric oxide (NO) and a ground-state oxygen atom, O( 3 

### P),

O( 3 

### P) then reacts with molecular oxygen to form O 3 

### : A molecule from the surrounding air collides with the newly-formed O 3 

### molecule, removing excess energy to allow it to stabilize. (AX2-1)

### AX2-5 (AX2-4) Reaction AX2-2 is the only significant reaction forming O 3 

### in the troposphere.

NO and O 3 

### react to reform NO 2 

### :

This reaction is responsible for O 3 

### 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 NO 2 

### without the participation of O 3 

### (as in reaction AX2-3).

O 3 

### can, therefore, accumulate as NO 2 

### 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” (O

x 

### ) family can be defined as 3 

### (O( 3 

### P) +O( 1 

### D)+ O 3 

### + NO 2 

### ) in much the same way as the NO

x 

### (NO + NO 2 

### ) family is defined. We can then see that production of O

x 

### 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 O

x 

### . 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 NO z, 

### which is the sum of the products of the oxidation of NO

x 

### = 3 

### (HNO 3 

### + PAN (CH 3 

### CHO-OO-NO 2 

### ) + HNO 4 

### + other organic nitrates + particulate nitrate); and NO y 

### , which is the sum of NO

x 

### and NO

z 

### . (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 O 3 

### (e.g., CH 3 

### Br, hydroclorofluorocarbons), and those which contribute to the greenhouse effect (e.g., CH 4 

### ). 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 O 3 

### . In addition to OH radicals, there are several other atmospheric species such as NO 3 

### , Cl, and Br radicals and O 3 

### 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 O 3 

### 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 O 3 

### by solar ultraviolet radiation at wavelengths < 340 nm (solar radiation at wavele ngths < 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( 3 

### P) atom by collisions with N 2 

### and O 2 

### , 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 Due to Reaction withOH, NO3, Cl, Br, and O3Hydrocarbonk, cm3molecule!1s!1OH NO3Cl Br O3k× 1012Jk×1012Jk× 1010Jk× 1012Jk× 1018JAlkanesEthane 0.24 48 d < 1.0 x 10!5> 13 y 0.57 6.7 mo 3.1 × 10!71.0 × 106y2< 0.01 > 3.2 yPropane 1.1 11 d 0.00021 > 0.60 1.3 90 d 0 6.5 × 103y2< 0.01 > 3.2 y2-Methylpropane 2.1 5.6 d < 0.00007 > 18 y 1.3 90 d < 1.0 × > 3.2 × 107y2< 0.01 > 3.2 yn-Butane 2.3 5.2 d 0.000046 2.8 y 2.3 50 d < 1.0 × > 3.2 × 107y2< 0.01 > 3.2 y2-Methylbutane 4 2.9 d 0.00016 0.79 y 2 60 d NA NA NA NAn-Pentane 3.8 3.0 d 0.000081 1.6 y 2.5 46 d NA NA NA NA2,2-Dimethylbutane 2.7 4.3 d NA NA NA NA NA NA NA NA2,3-Dimethylbutane 6.4 1.8d 0.00041 110 d 2 60 d 0.0064 50 y NA NA2-Methylpentane 5.6 2.1 d 0.000017 7.5 y 2.5 47 d NA NA NA NA3-Methylpentane 5.8 2.0 d 0.00002 6.3 y 2.5 46d NA NA NA NAn-Hexane 5.2 2.2 d 0.00011 1.2 y 3.1 38 d NA NA NA NA2,2,4-Trimethylpentane 3.8 3.0 d 0.000075 1.7 y 2.3 50 d 0.0068 47 y NA NA



### AX2-7Table AX2-1 (cont’d). Comparison of the Atmospheric Lifetimes (J) of Low Molecular Weight Hydrocarbons Due toReaction with OH, NO3, Cl, Br and O3Hydrocarbonk, cm3molecule!1s!1OH NO3Cl Br O3k× 1012Jk× 1012Jk× 1010Jk× 1012Jk× 1018JAlkenesEthene 8.5 33 h 0 230 d 0.99 3.8 m 0.18 1.8 y 1.6 7.2 dPropene 26 11 h 0.01 4.9 d 2.3 50 d 5.3 22 d 10 1.2 d2-Methylpropene 51 5.4 h 0.34 3.3 h 0.42 9.0 m NA NA 11 1.1 d1-Butene 31 9.0 h 0.013 3.6 d 1.4 65 d 3.4 34 d 9.6 1.2 dtrans-2-Butene 64 4.3 h 0.39 2.8 h NA NA 0.23 1.4 y 190 1.5 hcis-2-Butene 56 5.0 h 0.35 3.2 h NA NA 6.3 18 d 125 2.3 h1,3-Butadiene 67 4.1 h 0.1 11 h 4.2 28 d 57 2.0 d 6.3 1.8 dIsoprene 100 2.8 h 0.68 1.6 h 5.1 23 d 74 1.6 d 13 21 h2-Methyl-2-butene 87 3.2 h 9.4 0.12 h NA NA 19 6.1 d 400 0.69 h1-Pentene 31 9.0 h 0.7 1.6 h NA NA NA NA 11 1.1 dtrans-2-Pentene 67 4.1 h 1.6 0.69 h NA NA NA NA 320 0.86 hcis-2-Pentene 65 4.3 h 1.4 0.79 h NA NA NA NA 210 1.3 h2,4,4-Trimethyl-1-pentene 65 4.3 h 0.51 2.2 h NA NA NA NA NA NANotes: 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 equilibrium with BrO = 1 ppt.1Rate 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 Evaluationof Calvert et al. (2000).2Lifetimes 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 O 3 

### in the Huggins and Chappuis bands or formed from deactivation of O( 1 

### D) atoms reform O 3 

### 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, CH 4 

### ) to produce HO 2 

### 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 × 10 6 

### molecules /cm 3 

### 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 (CH 3 

### CCl 3 

### ) and the rate constant for

the reaction of the OH radical with CH 3 

### CCl 3 

### . Krol et al. (1998) derived a global average OH

concentration of 1.07 × 10 6 

### molecules /cm 3 

### for 1993 along with an upward trend of about 0.5%/yr between 1978 and 1993. Using an integrated data set of observed O 3 

### , H 2 

### O, NO y 

### , CO, VOCs, temperature and cloud optical depth, Spiv akovsky et al. (2000) calculated a global annual

mean OH concentration of 1.16 × 10 6 

### molecules cm -3 

### , consistent to within 10% of the value obtained by Krol et al. (1998).

HO 2 

### radicals do not initiate the oxidation of hydrocarbons, but serve to recycle OH mainly by way of reaction with NO, O 3 

### , and itself (the latter produces H 2 

### O 2 

### , which can photolyze to yield OH). The HO 2 

### 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 (Wesel y and Hicks, 2000) or degrade further by photolysis and reaction with OH (Jet Propulsion Laboratory, 2003). At night, NO 3 

### 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 NO 3 

### 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 NO 3 

### 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 NO 3 

### , generating an enhanced supply of odd hydrogen radicals leading to O 3 

### production in the presence of

sufficient NO

x 

### . 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 O 3 

### to form ClO and BrO radicals, providing a sink for odd oxygen if they do not react with NO to form NO 2 

### (e.g., Pszenny et al., 1993). As with other oxidants pres ent in the atmosphere, Cl chemistry provides a

modest net sink for O 3 

### when NO

x 

### is less than 20 pptv, and is a net source at higher NO

x 

### . 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 invol ving chlorine containing molecules (HCl, CH 3 

### Cl,

CHCl 3 

### , 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 (C MBO), 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 hydr ocarbons measured at Pt. Arena, CA were consistent with loss by reaction with OH radicals a nd 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 ra dicals 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 cont ributions 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 10 3 

### /cm 3 

### using the globally averaged OH concentration of

about 10 6 

### /cm 3 

### given above. In contrast Wingenter et al. (1996) and Singh et al. (1996a) inferred significantly higher concentrations of atomic Cl (10 4 

### to 10 5 

### 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 (10 3 

### 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, NO 2 

### , and O 3 

### are interrelated by the following reactions:

The reaction of NO 2 

### with O 3 

### leads to the formation of the nitrate (NO 3 

### ) radical,

(AX2-7)

which in the lower troposphere is nearly in equilibrium with dinitrogen pentoxide (N 2 

### O 5 

### ): (AX2-3)

(AX2-1)

(AX2-2)

### AX2-12 (AX2-10)

(AX2-11) However, because the NO 3 

### 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 × 10 7 

### to 1 × 10 10 

### molecules cm -3 

### (< 2 to 430 ppt) over continental areas influenced by anthropogenic emissions of NO

x 

### (Atkinson et al., 1986). This leads to an increase

of N 2 

### O 5 

### concentrations during the night by reaction (AX2-8). The tropospheric chemical removal processes for NO

x 

### involve the reaction of NO 2 

### with the OH radical and the hydrolysis of N 2 

### O 5 

### in aqueous aerosol solutions to produce HNO 3 

### .

The gas-phase reaction of the OH radical with NO 2 

### initiates the major and ultimate removal process for NO

x 

### in the troposphere. This reaction removes radicals (OH and NO 2 

### ) and competes with hydrocarbons for OH radicals in areas characterized by high NO

x 

### 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 NO 2 

### 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 HNO 3 

### formed from reaction AX2-10 undergoes wet and dry deposition to the surface and uptake by ambient aerosol particles. The tropospheric lifetime of NO

x 

### 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 NO

x 

### 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 N 2 

### O 5 

### 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 (HNO 2 

### ):

In the daytime, HNO 2 

### is rapidly photolyzed back to the original reactants:

(AX2-13)

At night, HNO 2 

### can be formed by heterogeneous reactions of NO 2 

### 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; Lamme l and Perner, 1988; Notholt et al., 1992a,b).

This results in accumulation of HNO 2 

### during nighttime. Modeling studies suggest that photolysis of this HNO 2 

### following sunrise, could provide an important early-morning source of

OH radicals to drive O 3 

### formation (Harris et al., 1982). Another important process controlling NO

x 

### concentrations is the formation of organic nitrates. Oxidation of VOCs produces organic peroxy radicals (RO 2 

### ), as discussed in the hydrocarbon chemistry subsections to follow. Reaction of these RO 2 

### radicals with NO and NO 2 

### produces organic nitrates (RONO 2 

### ) and peroxynitrates (RO 2 

### NO 2 

### ):

Reaction (AX2-14) is a minor branch for the reaction of RO 2 

### with NO (the major branch produces RO and NO 2 

### , 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 NO

x 

### and can therefore be viewed as a permanent sink for NO

x 

### . This sink is usually small compared to HNO 3 

### formation, but the formation of isoprene nitrates may be a significant sink for NO

x 

### 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 NO

x 

### . 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 fr om ~1 hour at room temperature to several weeks at 250K. They can thus provide an effective sink of NO

x 

### at cold temperatures, but also a reservoir allowing eventual release of NO

x 

### as air masses warm, in particular by subsidence. By far the most important of these PANs compounds is peroxyacetylnitrate (PAN), with formula

CH 3 

### C(O)OONO 2 

### . 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 O 3 

### enhancement in the U.S. from Asian pollution (Hudman et al., 2004).



## AX2.2.5 The Methane Oxidation Cycle
The photochemical cycles leading to O 3 

### production are best understood by considering the oxidation of methane, structurally the simplest VOC. The CH 4 

### 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 CH 4 

### 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 CH 4 

### 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 O 2 

### to yield the methyl peroxy (CH 3 

### O 2 

### A 

### ) radical (Atkinson et al., 1992):

In the troposphere, the methyl peroxy radical can react with NO, NO 2 

### , HO 2 

### radicals, and other organic peroxy (RO 2 

### ) radicals, with the reactions with NO and HO 2 

### radicals being the most important (see, for example, World Meteorol ogical Organization, 1990). The reaction with NO leads to the formation of the methoxy (CH 3 

### O . ) radical,

The reaction with the HO 2 

### radical leads to the formation of methyl hydroperoxide (CH 3 

### OOH),

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 (H 2 

### O 2 

### ), and so wet deposition after incorporation into cloud droplets is much less important as a removal process

than it is for H 2 

### O 2 

### . CH 3 

### OOH can also be removed by dry deposition to the surface or transported by convection to the upper troposphere. The lifetime of CH 3 

### OOH 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 (CH 3 

### O . ) is

The HO 2 

### radicals produced in (AX2-22) can react with NO, O 3 

### , or other HO 2 

### radicals according

to,

Formaldehyde (H 2 

### CO) 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 H ˆ 

### O (formyl) radical produced in these reactions react solely with O 2 

### to form

the HO 2 

### radical:

The lifetimes of H 2 

### CO 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 H 2 

### CO for overhead sun conditions (Rogers, 1990). The final step in the oxidation of CH 4 

### involves the oxidation of CO by reaction with the

OH radical to form CO 2 

### :

The lifetime of CO in the lower troposphere is . 

### 2 months at midlatitudes.

NO and HO 2 

### radicals compete for reaction with CH 3 

### O 2 

### and HO 2 

### radicals, and the reaction route depends on the rate constants for these two reactions and the tropospheric concentrations

of HO 2 

### and NO. The rate constants for the reaction of the CH 3 

### O 2 

### A 

### radicals with NO (reaction AX2-18) and HO 2 

### radicals (reaction AX2-19) are of comparable magnitude (e.g., Jet Propulsion Laboratory, 2003). Based on expected HO 2 

### radical concentrations in the troposphere, Logan et al. (1981) calculated that the reaction of the CH 3 

### O 2 

### A 

### radical with NO dominates for NO mixing ratios of >30 ppt. For NO mixing ratios <30 ppt, the reaction of the CH 3 

### O 2 

### A 

### radical with HO 2 

### dominates. The overall effects of methane oxidation on O 3 

### formation for the case when NO >30 ppt can be written as: (AX2-28)

(AX2-29)

(AX2-30)

(AX2-29)

### AX2-18 Further O 3 

### formation occurs, based on the subsequent reactions of H 2 

### CO, 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 O 3 

### and HO 2 

### radicals leads to the net destruction of tropospheric O 3 

### :

Using the rate constants reported for reactions AX2-23 and AX2-24 (Atkinson et al., 1992) and the background tropospheric O 3 

### mixing ratios given above, the reaction of HO 2 

### radicals with NO

dominates over reaction with O 3 

### 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 HO 2 

### radical reaction with NO will be favored over the self-reaction of HO 2 

### radicals. Consequently, there are two regimes in the “relatively clean” troposphere, depending on the local NO concentration: (1) a “very low-NO

x 

### ” regime in which HO 2 

### and CH 3 

### O 2 

### radicals combine (reaction AX2-19), and HO 2 

### radicals undergo self-reaction (to form H 2 

### O 2 

### ) and react

with O 3 

### (reactions AX2-25 and AX2-24), leading to net destruction of O 3 

### and inefficient OH radical regeneration (see also Ehhalt et al., 1991; Ayers et al., 1992); and (2) a “low-NO

x 

### ” regime (by comparison with much higher NO

x 

### concentrations found in polluted areas) in

which HO 2 

### and CH 3 

### O 2 

### radicals react with NO to convert NO to NO 2 

### , 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 NO 2 

### , produce O 3 

### . In the “low NO

x 

### ” regime there still may be significant competition from peroxy-peroxy reac tions, depending on the local NO concentration. Nitric oxide mixing ratios are sufficiently low in the remote marine boundary layer relatively unaffected by transport of NO

x 

### from polluted continental areas (< 15 ppt) that

oxidation of CH 4 

### will lead to net destruction of O 3 

### , as discussed by Carroll et al. (1990) and Ayers et al. (1992). In continental and marine areas affected by transport of NO

x 

### from combustion sources, NO mixing ratios are high enough (of the order of ~one to a few hundred ppt) for the oxidation of CH 4 

### , nonmethane hydrocarbons (NMHCs) and CO to lead to net O 3 

### formation (e.g., Carroll et al., 1990; Dickers on 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 oxidati on of peroxides, carbon monoxide and acetone transported upward by convection, in the presence of this NO, can lead to local O 3 

### 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 CH 4 

### is oxidized occur in the oxidation of other, even more reactive and more complex VOCs. As in the CH 4 

### oxidation cycle, the conversion of NO

to NO 2 

### during the oxidation of VOCs results in the production of O 3 

### 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 O 3 

### 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 alka nes 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 NO y 

### exist as alkyl and hydroxy alkyl nitrates (Calvert and Madronich, 1987; Athe rton and Penner, 1988; Trainer et al., 1991).

In NO

x 

### - and VOC-rich urban atmospheres, 100 di fferent 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 NO 2 

### . These uncertainties affect modeling predictions of NO

x 

### concentrations, NO-to-NO 2 

### conversion and O 3 

### formation during photochemical degradation of the VOCs. Discrepancies between observations and theory have been found in aircraft

measurements of NO y 

### (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 NO y 

### 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 O 3 

### formation.

The oxidation of alkanes can also be initiated by other oxidizing agents such as NO 3 

### 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)O 2 

### ) are formed by the addition of O 2 

### . As an example, the oxidation of ethane (C 2 

### H 5 

### –H) yields acetaldehyde (CH 3 

### –CHO). Acetyl (CH 3 

### –CO) and acetylperoxy (CH 3 

### –C(O)O 2 

### ) radicals can then be formed. Acetylperoxy radicals can combine with NO 2 

### 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 NO 2 

### . Upon the decomposition of PAN, either locally
or elsewhere, NO 2 

### is released to participate in the O 3 

### formation process again. During the oxidation of propane, the relatively long-lived intermediate acetone (CH 3 

### –C(O) CH 3 

### ) 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 O 3 

### production. The alkenes emitted from anthropogenic sources are mainly ethene, propene, and the butenes, with lesser amounts of the $ 

### C 5 

### alkenes. The major biogenic alkenes emitted from vegetation are isoprene (2-methyl-1,3-butadiene) and C 10 

### H 16 

### 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 NO 3 

### radicals and with O 3 

### . 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 al kyl nitrates and nitratocarbonyls, and decomposition products from the high energy biradicals formed in alkene-O 3 

### reactions. Table AX2-2 provides estimated atmospheric lifetimes for biogenic alkenes with respect to oxidation by OH, NO 3 

### and O 3 

### . 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 O 3 

### , especially the yields of OH radicals, H 2 

### O 2 

### , and secondary organic aerosol in both outdoor and indoor envi ronments. 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 oxi dation 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 

### O 3 c 

### NO 3 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

Acetone e 

### 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 

### O 3 c 

### NO 3 d



### Oxygenates (cont’d)

Methanol l2 d f 

### > 3.2 y g 

### 2.0 y f



### 2-Methyl-3-buten-2-ol 2.4 h l 

### 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 × 10 6 molecule cm -3

.
c Assumed O 3 concentration: 1 × 10 12 molecule cm -3 , 24-h average.

d Assumed NO 3 radical concentration: 2.5 × 10 8 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, CH 3 

### CHCH 2 

### OH continues to react — producing several smaller, “second generation,” reactive VOCs.

### AX2-27 Figure AX2-4. Structures of a selected num ber of terpene and sesquiterpene compounds.

Source: Atkinson and Arey (2003).

### AX2-28 For the simple # 

### C 4 

### 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

CH 3 

### CHO, 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 (CH 2 

### = C(CH 3 

### )-CHO) and methyl vinyl ketone (CH 3 

### -C(O)-CH=CH 2 

### have been identified as the major products of the OH-isoprene reaction. These products also react with OH ra dicals and undergo photolysis. Yields of these products(and others) are sensitive to the concentration of NO

x 

### used in laboratory experiments.

For NO

x 

### ~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 NO

x 

### ~1 ppb, the yields

of methacrolein are similar to those for NO

x 

### ~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, CO 2 

### , hydroxyacetone, formaldehyde and methacryloylperoxynitrate (MPAN) in their experi ment. 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 oxi dation of isoprene and its products can oxidize

NO to NO 2 

### , initiating photochemical O 3 

### 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 NO

x 

### $ 

### 1 ppb. The

values are much lower for lower NO

x 

### 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

NO 3 

### 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 (CH 3 

### CHO), 2-nitratopropanal (CH 3 

### CH(ONO 2 

### )CHO), and 1-nitratopropanone (CH 3 

### C(O)CH 2 

### ONO 2 

### ). By analogy to OH, conjugated dienes like butadiene and isoprene will react with NO 3 

### to form d-nitrooxyalkyl radicals (Atkinson, 2000). If NO 3 

### is available for reaction in the atmosphere, then NO concentrations will be low, owing to the rapid reaction between NO 3 

### and NO. Consequently, nitrooxyalkyl peroxy radicals are expected to react primarily with NO 2 

### , yielding thermally unstable peroxy nitrates, NO 3 

### , HO 2 

### , and organoperoxy radicals (Atkinson, 2000). Several studies have undertaken the quantification of the products of NO 3 ! 

### initiated degradation of several of the important biogenic alkenes in O 3 

### 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 O 3 

### . 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 O 3 

### .

Source: Atkinson and Arey (2003). 

### of O 3 

### 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 fr om 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 yi elds 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 O 3 

### 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 NO 2 

### also participates to a very small degree in the oxidation of alkenes by addition to

double bonds in a manner similar to O 3 

### . 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 O 3 

### 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 Chemistr y 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 O 3 

### . Reaction with OH radicals serves as the major atmospheric loss process of aromatic hydrocarbons. Atmospheric losses of alkyl aromatic compounds by O 3 

### 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.

### AX2-32Two comprehensive reviews, which provide a detailed understanding of the current stateof-science of aromatic hydrocarbons have been wr itten 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 O 3 

### 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 O 3 

### 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 O 3 

### , which are much longer

than that due to reactive loss with either OH or NO 3 

### . Thus, the atmospheric lifetimes and reaction products of O 3 

### 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 

### cm 3

### AX2-33 molec

! 1 

### s ! 1 

### . Atkinson (1989) recommended a value of 1.4 × 10

! 12 

### cm 3 

### molec

! 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 

### cm 3 

### molec

! 1 

### s ! 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 

### cm 3 

### 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 

### cm 3 

### molec

! 1 

### s ! 1



### . Similarly, the three isomers of ethyltoluene have recommended OH rate constants ranging from

1.2 to1.9 × 10

! 11 

### cm 3 

### 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 

### cm 3 

### molec

! 1 

### s ! 1



### . OH rate constants for the C 9 

### 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 

### cm 3 

### molec

! 1 

### s ! 1



### . While concentrations for numerous other trisubstituted benzene compounds have been reported (e.g., 1,2-dimethyl-4-ethylbenzene), OH rate consta nts 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 C 8 

### AHC, styrene. This compound reacts rapidly with OH and has a recommended

rate constant of 5.8 × 10

! 11 

### cm 3 

### 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 (×10 12 

### ) J OH 

### (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

Styrene 3 

### 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 cm 3 /molec-sec.

2 Lifetime for zero and single alkyl substituted aromatic based on OH concentration of 1× 10 6 molec cm

! 3

. 3 Lifetime for reaction of styrene with NO 3 is estimated to be 44 min based on a nighttime NO 3 concentration of 2.5 × 10 8 molec cm

! 3 and a rate coefficient of 1.5 × 10

! 12 cm 3 /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 NO 3 

### radicals can also be important, particularly at night when photolysis does not substantially reduce the NO 3 

### 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 si ngle 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 ha ve 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 

### cm 3 

### molec

! 1 

### s ! 1 

### (benzaldehyde) to 4.8 × 10

! 11 

### cm 3 

### 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 

### cm 3



### molec

! 1 

### s ! 1 

### ) at room temperature. Five dimet hylphenols and two trimethylphenols have OH reaction rates ranging between 6.6 × 10

! 11 

### and 1.25 × 10 -10 

### cm 3 

### 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, give n 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 NO 3 

### 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 NO 3 

### to the double bond. For these compounds, NO 3 

### rate constants are on the

order of 10

! 12 

### cm 3 

### molec

! 1 

### s ! 1 

### . This leads to atmospheric lifetimes on the order of about 1 h for typical night time atmospheric NO 3 

### levels of 2.5 × 10 8 

### molec cm -3 

### (Atkinson, 2000). The most important reactions of NO 3 

### 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 NO 3 

### + phenol rate has been given as 3.8 × 10

! 12 

### cm 3 

### molec

! 1 

### s ! 1 

### . Similarly, the cresol isomers each has an extremely rapid reaction rate with NO 3 

### ranging from 1.1 to

1.4 × 10

! 11 

### cm 3 

### molec

! 1 

### s ! 1 

### . As a result, these compounds, particularly the cresol isomers, can show rapid nighttime losses due to reaction with NO 3 

### with nighttime lifetimes on the order of a

few minutes. There is little data for the reaction of NO 3 

### 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 O 3 

### 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 NO 2 

### reactions do not dominate the removal of the OH-aromatic adduct. (2) As noted, the reaction mechanism can change as the ratio of NO 2 

### to O 2 

### changes in the system (Atkinson and

### AX2-37 Aschmann, 1994). Thus, reaction product distributions that may be measured in the laboratory at high NO 2 

### (or NO

x 

### ) concentrations may not be applicable to atmospheric conditions. This also limits the usefulness of models to predict O 3 

### 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 O 3 

### 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, whic h reacts with nitric oxide (NO) leading to the stable products benzaldehyde, with an average yiel d 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 O 2 

### to give a cresol, as in reaction (5); an addition reaction with O 2 

### , as in reaction (6); or reaction with NO 2 

### to give m -nitrotoluene as in reaction (7). The simplest fate for the adduct (I) is reaction with O 2 

### to form o -cresol. Data from a number of studies (e.g., Kenley et al., 1981; At kinson et al., 1980; Smith et al., 1998; Klotz et al., 1998; summarized by Calvert et al., 2002) over a wide range of NO 2 

### 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 NO 2 

### concentration (Atkinson and Aschmann, 1994; Moschonas et al., 1999), but the data tend to be scattered. This finding suggests that the addition of NO 2 

### to the hydroxy methylcyclo-hexadienyl radical does not c ontribute 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 photooxidati on mechanism of toluene initiated by its reaction with OH radicals.

### AX2-40 The OH-toluene adduct also reacts with O 2 

### 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 l ead 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 O 2 

### 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 ben zene 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 identif y 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 inve stigators reported 27 photooxidation products from toluene, with 15 reportedly from ring fragmenta tion processes. However, the study was purely qualitative and product yields could not be obtaine d. 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 differentiate d. 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; Sh epson et al., 1984) included glyoxal, methyl glyoxal, butenedial, 4-oxo-2-pentenal, hydroxybut enedial, 1-pentene-3,4-dione, 1-butene-3,4- dione, and methyl vinyl ketone. Additional ev idence (Shepson et al., 1984) for fragmentation processes came from the detection of 2-met hylfuran and furfural. These compounds, although cyclic in structure, result from a bridged oxygen intermediate. Yields of the detected fragmentation products were subsequently measur ed 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 NO 2 

### to give isomers of nitrotoluene. A yield of approximately 0.015 at NO 2 

### 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 NO 2 

### concentration; however, the data were considerably scattered. The positive intercept has been interpreted as suggesting that the OH-toluene adduct does not add O 2 

### . 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 OHradical 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 O 2 

### , a rapid decay reflective of the initial adduct formation and a slower decay reflecting loss of the adduct by O 2 

### or other scavengers. From the decay data in the presence

of O 2 

### , they determine a loss rate for the OH-toluene of 5.4 × 10 -16 

### cm 3 

### 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 NO 2 

### (with a nominal atmospheric concentration of 0.1 ppmv) of about 100 s

! 1 

### . This finding suggests that removal of the OHtoluene adduct by O 2 

### is a far more important loss process than removal by NO 2 

### under atmospheric conditions which is in contrast ot her 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-at om 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; At kinson 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 NO

x 

### at 2 to 5 ppmv. At atmospheric ratios of NO 2 

### and O 2 

### , 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%, respectiv ely. Kwok et al. (1997) also measured products

from the OH + m- and p -xylene systems using atmospheric pressure ionization-tandem mass spectrometry. Complementary ring-fragmenta tion 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 frag mentation 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 ri ng-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-reta ining products, 3,5-dimethyl-benzaldehyde and 2,4,6-trimethylphenol, given its molecular symmetr y. 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 NO

x 

### 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 O 2 

### 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 ) 

### H
rxn 

### was used to investigate favored reaction pathways. However, the similarity in energies of the peroxy radicals formed from the O 2 

### 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 O 3 

### 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 th rough 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 O 3 

### 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 O 3 

### formation, it is not expected to be large.



## AX2.2.9 Importance of Oxygenated VOCs
The role of oxygenated VOCs in driving O 3 

### production has generated increasing interest over the past decade. These VOCs include carbonyl s, 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 O 3 

### 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 O 3 

### 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 O 3 

### . The peroxyacetyl radical CH 3 

### C(O)OO can also react with NO 2 

### to produce PAN, as discussed in Section AX2.2.4. Photolysis of acetone are a minor but important source of HO 2 

### 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 

### cm 2 

### /cm 3 

### for clean continental conditions to

1.1 × 10

! 5 

### cm 2 

### /cm 3 

### 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 O 3 

### 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 O 3 

### 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 signi ficant 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 H 2 

### SO 4 

### 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):

. 

### HO

x 

### Chemistry
(1) Catalytic O 3 

### loss via reaction of O 2 ! 

### + O 3(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 HO 2 

### by cloud droplets is significant and can be acceptably parameterized with a reaction probability of ( HO 2 

### = 0.2, range 0.1 to 1, for HO 2 

### 6 

### 0.5 H 2 

### O 2 

### . However, this approach may overestimate HO 2 

### uptake because the influence of HO 2(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 CH 3 

### C(O)OO in aqueous aerosols may be important at night in the presence of high PAN and aerosol surface area; ( CH 3 C(O)OO 

### = 4 × 10

! 3 

### is recommended.

### AX2-47 . 

### NO

x 

### Chemistry
(6) Hydrolysis of N 2 

### O 5 

### to HNO 3 

### in aqueous aerosols is important (Section AX2.2.4) (and can be parameterized with ( HNO 3 

### = 0.01 to 0.1 [Schutze and Herrmann, 2002; Hallquist et al., 2003]).
(7) Although the mechanism is uncertain, heterogeneous conversion of NO 2 

### to HONO on aerosol surfaces should be considered with ( NO 2 

### = 10

! 4 

### (range 10

! 6 

### to 10

! 3 

### ) for NO 2 

### ÷ 

### 0.5 HONO + 0.5 HNO 3 

### . (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 HNO 3 

### to NO

x 

### in aerosols.

. 

### Heterogeneous ozone loss

(10) There is no evidence for significant loss of O 3 

### 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 BrO

x 

### and ClO

x 

### 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 HO

x 

### and Aerosols

Field measurements of HO

x 

### 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 HO 2 

### or HO 2 

### + RO 2 

### 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 HO

x 

### and H 2 

### O 2 

### 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 HO

x 

### or H 2 

### O 2 

### . No investigations involving the potential

influences of marine aerosols as sources or sinks for HO

x 

### were considered in the above analysis. Relative to conservative seawater tracers such as Mg 2+ 

### 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) condens ation 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, H 2 

### O 2 

### , 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 H 2 

### O 2 

### from the photolysis of phenolic compounds (Anastas io 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 si gnificant source for OH in acidified sea-salt aerosols considered by many current models. Limited experimental evidence indicates that these pathways are important sources of HO

x 

### and RO

x 

### 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, HO 2 

### , and H 2 

### O 2 

### . 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 tr ansfer 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 HO

x 

### plus RO

x 

### 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 ca nnot 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 di fferences between the diurnal behavior of RO 2 *


### derived from the model and that observed possibly attributable to multiphase chemistry. The

measured HCHO concentrations differed from th e model results and were best explained by reactions involving low levels of Cl. Finally, photolytic NO 3 ! 

### 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 HNO 3 

### phase partitioning, most total nitrate (HNO 3 

### + particulate NO 3 ! 

### ) in marine air is associated with sea salt (e.g., Hu ebert et al., 1996; Erickson et al., 1999). At high

mM concentrations of NO 3 ! 

### in sea-salt aerosols under moderately polluted conditions (e.g., Keene et al., 2002) and with quantum yields fo r 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 disso lved 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 O 3 

### cycling in marine air are probably significant. At minimum, the substantial

inferred concentrations of HO 2 

### in aerosol solutions would diminish and perhaps reverse HO 2 

### scavenging by marine aerosols and thereby increase O 3 

### production relative to models based on Jacob’s (2000) recommended reaction probability.

AX2.2.10.2 NO

x 

### Chemistry Jacob (2000) recommended as a best estimate, ( N 2 O 5 

### = 0.1 for the reaction probability

of N 2 

### O 5 

### on aqueous aerosol surfaces with conversion to HNO 3 

### . 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 NO

x 

### concentrations over the Arctic in winter. A decrease in N 2 

### O 5 

### slows down the removal of NO

x 

### and thus increases O 3 

### production. Based on the consistency between measurements of NO y 

### partitioning and gas-phase models, Jacob (2000) considers it unlikely that significant HNO 3 

### is recycled to NO

x 

### 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 HNO 3 

### 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 NO 3 

### (HNO 3 

### + NO 3 ! 

### ) and large fractions of NO y 

### in marine air (e.g., Huebert et al., 1996). Consequently, some caution is warranted when interpreting constituent ratios and NO y 

### budgets

based on such data. Recent work in the Arctic has quantified significant photochemical recycling of NO 3 !



### to NO

x 

### 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 NO 3 ! 

### is

### AX2-51 photolytically reduced to NO 2 ! 

### (Zafariou and True, 1979) in acidic sea-salt solutions (Anastasio et al., 1999). Further photolytic reduction of NO 2 - 

### to NO (Zafariou and True, 1979) could provide a possible mechanism for HNO 3 

### recycling. Early experiments reported production

of NO

x 

### during the irradiation of artificial seawater concentrates containing NO 3 ! 

### (Petriconi and Papee, 1972). Based on the above, we believe that HNO 3 

### recycling in sea-salt aerosols is potentially important and warrants further investigation. Other possible recycling pathways involving highly acidic aerosol solutions a nd soot are reviewed by Jacob (2000). Ammann et al. (1998) reported the efficient conversion of NO 2 

### to HONO on fresh soot particles in the presence of water. They suggest that interaction between NO 2 

### and soot particles may account for high mixing ratios of HONO observed in urban environments. Conversion

of NO 2 

### to HONO and subsequent photolysis to NO + OH would constitute an NO

x 

### -catalyzed O 3 

### 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 NO 2 

### 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 HNO 3 

### decomposed to NO 2 

### and H 2 

### O at higher nitric acid surface coverages, i.e., P(HNO 3 

### ) > = 10

! 4 

### Torr. None of the soot models used were reactive at low nitric acid coverages, at P(HNO 3 

### ) = 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 HNO 3 

### . Heterogeneous production on soot at night is believed to be the mechanism by which

HONO accumulates to provide an early morning source of HO

x 

### in high NO

x 

### 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 NO 2 

### . They estimate that this reaction may account for some part of the unexplained high levels of HONO obs erved 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 NO 2 

### 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 NO 2 

### , HNO 3 

### , NO 3 

### /N 2 

### O 5 

### , HO 2 

### /HO 2 

### NO 2 

### 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 NO 2 

### , NO 3 

### , HO 2 

### and HO 2 

### NO 2 

### deposition to soot, HNO 3 

### reduction

to NO 2 

### , and N 2 

### O 5 

### 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 O 3 

### 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 HNO 3 

### 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 NO 2 

### from black soot. They conclude that these reactions would only have relevance in special situations in urban settings where soot and HNO 3 

### 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 O 3 

### destruction. More recent work suggests that halogen radical reactions may influence O 3 

### chemistry in mid latitudes as well. The weight of available evidence supports the hypothesis that halogen radical chemistry significantly influences O 3 

### 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 proce sses 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 Br 2 

### 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 O 3 

### , 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 O 3 

### in two ways (e.g., Pszenny et al., 1993). Some atomic Cl in marine air reacts directly with O 3 

### 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 O 3 

### production in the presence of sufficient NO

x 

### . Thus, Cl chemistry represents a modest net sink for O 3 

### when NO

x 

### is less than 20 pptv and a net source at higher NO

x 

### . Although available evidence suggest that significant Cl-radical chemistry occurs in
clean marine air, its net influence on O 3 

### 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 O 3 

### 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 O 3 

### to form IO. Most IO photodissociates in sunlight to generate I and atomic O, which rapidly recombines with O 2 

### to form O 3 

### . Consequently, this cycle has no net effect on O 3 

### (Stutz et al., 1999). However, alternative reaction pathways analogous to reactions AX2- 42 through AX2-44 above lead to catalytic O 3 

### 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 O 3 

### destruction (Cox et al., 1999; Ashworth et al., 2002). IO also reacts with NO 2 

### to form INO 3 

### , which can be scavenged by aqueous aerosols. This pathway has been suggested as a potentially important sink for NO

x 

### in the remote MBL and would, thus, contribute indirectly to net O 3 

### destruction (McFiggans et al., 2000). Various lines of observational evidence support aspects of the above scenarios. Mostmeasurements 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 ai r 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 O 3 

### 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 O 3 

### 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 vol atile 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 O 3 

### measured over the remote subtropical Atlantic and Indian Oceans (Dickerson et al., 1999; Burkert et al ., 2003) and early morning depletions of O 3 

### observed in the remote temperate MBL (Galbally et al., 2000) indicate that only about half of the

inferred O 3 

### destruction in the MBL can be explained by conventional HO

x 

### /NO

x 

### chemistry. Model calculations suggest that Br

! 

### and I

! 

### radical chemistry could account for a “missing” O 3 

### 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 O 3 

### destruction given by R AX2-39 to R AX2-41, in areas with high concentrations of halogen radicals the following generic loss pathways for O 3 

### 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 m onoatomic halogen radicals. In contrast to the
situation in marine air, where DOAS measuremen ts 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 O 3 

### but much

smaller values of r between ClO and O 3 

### . 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

10 5 

### /cm 3 

### , or about a factor of 100 higher than found in the marine boundary layer by Rudolph et al. (1997) indicating that, under these cond itions, the Cl initiated oxidation of hydrocarbons

could be substantial. Most of the well-established multiphase reactions tend to reduce the rate of O 3 

### formation in the polluted troposphere. Direct reactions of O 3 

### and atmospheric particles appears to be too slow to reduce smog significantly. Removal of HO 2 

### onto hydrated particles will decrease the production of O 3 

### by the reaction of HO 2 

### with NO. The uptake of NO 2 

### and HNO 3 

### will also result in the production of less O 3 

### . Conditions leading to high concentrations of Br, Cl, and I radicals

can lead to O 3 

### loss. The oxidation of hydrocarbons (especially alkanes) by Cl radicals, in contrast, may lead to the rapid formati on 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 O 3 

### 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 O 3 

### on untreated mineral surfaces (Hanisch and Crowley, 2003; Michel et al., 2002, 2003) have shown that O 3 

### 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 " 

### -Al 2 

### O 3 

### and 5 ± 1 × 10

! 5 

### for reactive uptake on SiO 2 

### surfaces. Usher et al. (2003) found mixed behavior

for O 3 

### 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 " 

### -Al 2 

### O 3 

### surfaces are coated with NO 3 

### derived

from HNO 3 

### , whereas they found that ( 

### increases to 1.6 ± 0.2 × 10

! 4 

### after these surfaces have been pretreated with SO 2 

### . Usher et al. also pretreated surfaces of SiO 2 

### 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 O 3 

### less than dust particles that have accumulated coatings of sulfite or alkenes. These studi es 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 O 3 

### depletions observed in dust clouds transiting the Pacific Ocean. Underwood et al. (2001) studied the uptake of NO 2 

### and HNO 3 

### 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 ( 

### (NO 2 

### ) were found, ranging from < 4 × 10 -10 

### for SiO 2 

### 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 NO 2 

### proceeds on the surfaces that reduction to NO occurs. They recommended a value of ( 

### for HNO 3 

### 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 NO 2 

### was likely to be only of marginal importance but that uptake of HNO 3 

### 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 SiO 2 

### 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 O 3 

### 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 H 2 

### SO 4 

### Solutions The most recent evaluation of Photochemical and Chemical Data by the Jet Propulsion Laboratory (Jet Propulsion Laboratory, 2003) incl udes recommendations for uptake coefficients of various substances on a variety of surfaces including aqueous H 2 

### SO 4 

### 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 N 2 

### O 5 

### on the surface of aqueous H 2 

### SO 4 

### 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 NO 2 

### are much lower (5 × 10 -7 

### to within a factor of three) and thus the uptake of NO 2 

### on the surface of aqueous H 2 

### SO 4 

### solutions is unlikely to be of importance for oxidant cycles. The ava ilable data indicate that uptake of OH and HO 2 

### 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 HO 2 

### .

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 H 2 

### O 2 

### and hydroxymethylhydroperoxide (HOCH 2 

### OOH) 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 (W exler 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 i ons 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 O 3 

### 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 H 2 

### O 2 

### (Venkatachari et al., 2005a,b). The ROS were found in particles of all sizes, with particul arly 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 O 3 

### , 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 O 2 ! 

### ) 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 O 3 

### (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 O 3 

### . Analysis of the SOA formed in their environmental chamber indicated the SOA was mainly organic hydroperoxides. In particular, they obtained yi elds 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 oxidati on 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 O 3 

### . 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 al so 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 O 3 

### 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; We schler and Shields, 1997; Rohr et al., 2002; Nøjgaard et al., 2005). Primary reaction products are Criegee biradicals, nitrate radicals, and peroxyacetyl radicals. Secondary reac tion 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 O 3 

### 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 O 3 

### , will be discussed in this section. Major episodes of high O 3 

### concentrations in the eastern United States and in Europe are associated with slow moving, high pressure syst ems. 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations over the metropolitan areas increase with wind speed indicating that transport of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### maxima in the early morning (Corsmeier et al., 1997). Base d on analysis of the output of model studies conducted by Kasibhatla and Chameides (2000), Hanna et al. (2001) concluded that O 3 

### can be transported over thousands of kilometers in th e upper boundary layer of the eastern half of the United States during specific O 3 

### episodes. Stratospheric-tropospheric exchange (STE) will be discussed in Section AX2.3.1. The

vertical redistribution of O 3 

### and other pollutants by deep, or penetrating convection is discussed in Section AX2.3.2. The potential importance of transport of O 3 

### and precursors by low-level jets is the topic of Section AX2.3.3. Issues related to the transport of O 3 

### from North America are presented in Section AX2.3.4. Relations of O 3 

### to solar ultraviolet radiation and temperature will

then be discussed in Section AX2.3.5.



## AX2.3.1 Stratospheric-Troposph eric Ozone Exchange (STE)
In the stratosphere, O 3 

### formation is initiated by the photodissociation of molecular oxygen (O 2 

### ) 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 O 3 

### in the stratosphere is transported downward into the troposphere. The potential importance of this source of tropospheric O 3 

### has been recognized since the early work of Regener (1941), as cited by Junge (1963). Stratospheric-tropospheric exchange (STE) of O 3 

### 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 O 3 

### 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 O 3 

### 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 tropos phere. These indicators include high potential vorticity, low water vapor mixing ratios, high potential temperature, enhancements in the ratio

of 7 

### Be to 10 

### Be in tropospheric aerosols, as well as enhancements in O 3 

### 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-base d lidars and both geostationary and polar (low earth orbiting) space platforms. The exchange of O 3 

### 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 Mohne n, 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 O 3 

### 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 O 3

### 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 O 3 

### over the poles. The concentrations of O 3 

### (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 O 3 

### 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) pr ovide evidence that stratospheric intrusions

contribute to the O 3 

### 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 O 3 

### in the free troposphere or even the amount of O 3 

### 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 7 

### Be to 10 

### Be 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 O 3 

### . 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 th e 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 stratosphe ric air reaching the surface. Appenzeller et al. (1996) found that maps of PV coupled with sate llite images of humidity can provide indications of the intrusion of stratospheric air into the troposphere, however, they had no measurements of

O 3 

### . Even if measurements of O 3 

### 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 O 3 

### and PV. Recent flights of the NCAR C130 during the TOPSE campaign measured in situ O 3 

### , and curtains of O 3 

### above and below the aircraft observed with a lidar and clearly showed a correspondence between high PV and stratospheric levels of O 3 

### 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,

O 3 

### 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 O 3 

### . 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 O 3 

### 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 airstream s, or dry intrusions (DA or DI) always advect stratospheric O 3 

### into the middle and upper troposphere (Cooper et al, 2001; Cooper et al., 2002a), however the seasonal cycle of O 3 

### in the lowermost stratosphere allows greater quantities

of O 3 

### to enter the troposphere during spring (Cooper et al., 2002b). Other work has focused on the signatures of PV to show specific instan ces 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 O 3 

### 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 O 3 

### 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 O 3 

### . 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 y ear 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 La brador 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 environm ent, 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 O 3 

### 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 O 3 

### into the troposphere is related to the depletion of O 3 

### within the wintertime stratospheric polar vortices. The magnitude of this depletion and the transport of O 3 

### 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 O 3 

### 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 O 3 

### 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 immediatel y 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 O 3 

### in the lower stratosphere and the availability of free radicals to initiate the photochemical processes forming O 3 

### in the boundary layer. Dickerson et al. (1995) pointed out that springtime maxima in O 3 

### observed in Bermuda correlate well with
maxima in carbon monoxide. Carbon monoxide, O 3 

### 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 O 3 

### . However, as NO

x 

### and its reservoirs are transported sourthward they can initiate O 3 

### formation through reactions described in Section AX2.2 (see also Stroud et al., 2003).

### AX2-71 Figure AX2-8. Schematic diagram of a me teorological mechanism involved in high concentrations of O 3 

### 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 O 3 

### 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 Convectio n 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 H 2 

### O, O 3 

### 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 O 3 

### production in the free troposphere. Therefore, convection aids in the transformation of local pollution into a contribu tion 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 O 3 

### and NO

x 

### 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 O 3 

### 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 O 3 

### into the boundary layer (where it is destroyed) is the dominant global effect of d eep convection. Some indications of downward transport of O 3 

### 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 O 3 

### in the upper troposphere caused by deep convection have important radiative forcing implications for climate.

### AX2-73 Other effects of deep convection include pert urbations 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 O 3 

### in a relatively large cumulus cloud. An extension of this work was reported by Greenhut (1986) in which data fromover 100 aircraft penetrations of isolated nonprecipitating cumulus clouds over rural and suburban areas were obtained. Ching and Alkezweeny (1986) reported tracer (SF 6 

### ) 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 O 3 

### over North Carolina in a study of cumulus venting reported by Ching et al. (1988). Data collected on evening fli ghts showed regions of cloud debris containing

aerosol and O 3 

### in the lower free troposphere in excess of background, suggesting that significant vertical exchange had taken place during afte rnoon 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, O 3 

### , NO, NO

x 

### , NO y 

### , and hydrocarbons in the vicinity of an active mesoscale convective system near the Oklahoma/Arkansas border during the 1985 PRE-ST ORM 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 O 3 

### 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 O 3 

### 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-O 3 

### stratospheric air mixed into the anvil. The large amount of vertical trace gas trans port noted by Dickerson et al. (1987) cannot, however, be extrapolated to all convective ce lls. 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, O 3 

### , and NO y 

### into the upper troposphere with the midtroposphere remaining relatively clean. Duri ng 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., NO

x 

### , CO, VOCs), precursors of HO

x 

### are also transported to the upper troposphere by deep convection. Precursors of most importance are water vapor, formaldehyde, hydrogen peroxide, methylhydroperoxide, and acetone. HO

x 

### is critical for oxidizing NO to NO 2 

### in the O 3 

### 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 cu mulonimbus 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 O 3 

### (ppbv).

Source: Dickerson et al. (1987).

### AX2-76 Over remote marine areas the effects of d eep 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-T roposphere Exchange Project (STEP) off the

northern coast of Australia show the influen ce 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 NO y 

### , and O 3 

### (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 NO y 

### and O 3 

### in this remote region were apparently transported upward in the convection. A similar result was noted in CEPEX (Central E quatorial Pacific Experiment; Kley et al., 1996) where a series of ozonesonde ascents showed very low upper tropospheric O 3 

### following deep convection. It is likely that similar transport of low-O 3 

### 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 O 3 

### . This low-O 3 

### convective outflow will likely descend in the subsidence region of the eastern Pacific, leading to some of the cl eanest 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 Stench ikov 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 a nd 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 O 3 

### precursors, a 1-D photochemical model was employed to estimate O 3 

### 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, NO

x 

### , O 3 

### , 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 O 3 

### 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 O 3 

### production there. Downward transport of

O 3 

### 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 × 10 5 

### kg-CO/month) and the shallow convective flux (~16 × 10 5 

### 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 × 10 5


### kg-CO/month), the oxidation of hydrocarbons (~8 × 10 5 

### kg-CO/month) and anthropogenic and

### AX2-78 biogenic emissions (~8 + ~1 × 10 5 

### 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 O 3 

### production, acid deposition, and fine particulate matter. Walcek et al. (1990) included a parameterization of cloud-scale aque ous 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 O 3 

### 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 O 3 

### episodes implying that they may play an important role in the formation of severe O 3 

### 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 pres ent. 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 w ith 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 th e 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 concentrat e 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 O 3 

### 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 O 3 

### maximum but at times could be as much as 80% of the maximum (Corsmeier et al., 1997). The secondary O 3 

### 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 O 3 

### 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 O 3 

### transport by low-level jets was twofold: O 3 

### 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 O 3 

### maxima (in the Lower Fraser Valley, British Columbia) associated with low-level jets that occasionally exceeded half the previous day’s maximum O 3 

### concentration. The largest increases in surface

O 3 

### concentration occurred when boundary layer turbulence coincided with O 3 

### 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 O 3 

### maxima associated with low-level jet evolution in an urban area in Germany. The notion that O 3 

### 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 O 3 

### and the development of secondary O 3 

### maxima resulting from downward transport from the residual layer when a low-level jet is present.

Source: Adapted from Reitbuch et al. (2000); Cors meier 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, NO 2 

### and CO in the residual layer during secondary O 3 

### maxima. Unlike

O 3 

### in the residual layer, concentrations of NO, NO 2 

### , 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 O 3 

### observed at a costal site in Nova Scotia described how temperature and differen ces 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 O 3 

### and its precursors, quantitative statements about the significance of the LLJ in affecting local and regional O 3 

### 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 O 3 

### budget and oxidizing capacity of the troposphere over the North Atlantic Ocean. Early results using isentropic back trajectories suggested that periodic pulses of O 3 

### 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 O 3 

### 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 SO 4 2- 

### , NO 3 ! 

### , 210 

### Pb, etc. suggesting a component originating in North America. In a s ubsequent analysis of data from one year (1992)
when CO observations were available, Dicker son et al. (1995) concluded that anthropogenic sources made a significant contribution to surface O 3 

### , 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 O 3 

### mixing ratios observed on Bermuda after the passage of cold fronts, and to identify the major processes controlling the highly variable O 3 

### 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 O 3 

### (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 O 3 

### on a flight west of Bermuda April 28 (alt. 4100m), indi cating air had been lofted from the continental boundary layer. Meteorological evidence, supported by ozonesonde observations and earlier King Air flights, indicated that stratosphere/tr oposphere exchange associated with an upstream frontal system had injected and advected dry, O 3 

### -rich air into the mid-troposhere region over the continent. This subsiding air mass provided deep layers of enhanced O 3 

### in the offshore,

### AX2-85 postfrontal area. Convection from a devel oping (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 O 3 

### . Ozone mixing ratios exceeded those attributable to boundary layer venting or in-transit photochemical production. These meteorological processes led to pollution and stratospherically

enhanced O 3 

### 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 Nort h 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 O 3 

### due to stratospheric exchange. The ozonesonde climatology of AEROCE clearly established that O 3 

### mixing ratios were always enhanced and increased with height in postfrontal air masses. Postfrontal O 3 

### in the lower troposphere over Bermuda originates in the postfrontal midtroposphere over the continent, supporting the hypothesis that naturally occurring stratospheric O 3 

### 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 O 3 

### can be seen in Figure AX2-8 from Prados (2000). Cold fronts over North Am erica 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 O 3 

### , may be lofted into the mid-to-upper troposphere where they have the potential to mix with layers of air descending

from O 3 

### -rich but relatively unpolluted upper troposphere and lower stratosphere. Through this complex mechanism, both stratospheric and photochemically produced O 3 

### 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 O 3 

### and O 3 

### 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

O 3 

### budget of the North Atlantic region. Previous observations indicated that the O 3 

### produced from anthropogenic sources is greater than that reaching the lower troposphere from the stratosphere and that O 3 

### 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 O 3 

### levels over the North Atlantic. Buhr et al. (1996) measured O 3 

### , CO, NO, and NO y 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### often had mixed boundary layer and upper atmosphere source regions. When a moist and dry air mass with the same photochemical age and O 3 

### concentration were compared, the dry air mass had lower

### AX2-87 concentrations of NO y 

### 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 transpor t 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, NO

x 

### conversion to its oxidation products exceeded 85%, and high hydrogen peroxide concentrations were observed (median 3.6 ppbv, maximum 11 ppbv). CO and O 3 

### concentrations were well correlated (R 2 

### = 0.64) with a slope (0.26) similar to previous measurements in photochemically aged air (Parrish et al., 1998). Ozone depended nonlinearly

on the NO

x 

### oxidation product concentration, but there was a correlation (r 2 

### = 0.73) found

between O 3 

### and the concentration of radical sink species as represented by the quantity ((NO y 

### – NO

x 

### ) + 2H 2 

### O 2 

### ). Banic et al. (1996) determined that the average mass of O 3 

### 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 O 3 

### 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, O 3 

### 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 O 3 

### of stratospheric origin were observed, similar to those reported by Prados et al. (1999). In air masses with differing amounts of anthropogenic pollution, O 3 

### was negatively correlated with CO, which indicates that

### AX2-88 emissions from surface anthropogenic sources had reduced O 3 

### , 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 offour 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 O 3 

### values were associated with airstreams originating in Canada or the Atlantic Ocean marine boundary layer; the highest O 3 

### values were associated with airstreams of recent stratospheric origin. The highest NO y 

### values were seen in polluted outflow from New England in the lower troposphere. A steep and positive O 3 

### /NO y 

### 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 O 3 

### /CO slope as an indicator of photochemical O 3 

### production, O 3 

### 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 O 3 

### production for airstreams at any level, and negative slopes in the dry air airstream indicate STE causes the

O 3 

### increase in the mid- and upper troposphere. Stohl et al. (2002) analyzed total odd nitrogen (NO y 

### ) and CO data taken during NARE in spring 1996 and fall 1997. They studied the removal timescales of NO y 

### originating from surface

emissions of NO

x 

### and what fraction reached the free troposphere. NO

x 

### limits O 3 

### production in the free troposphere and can be regenerated from NO y 

### after the primary NOx has been

exhausted. It was determined that < 50% of the NO y 

### 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 identif ied 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 O 3 

### , on average. Episodic events, such as forest

fires in North America have also been found to result in elevated CO and O 3 

### levels and visible haze layers in Europe (Volz-Thomas, et al., 2003). The O 3 

### is either transported from North America or formed during transport across the North Atlantic Ocean, perhaps as the result of interactions between the photochemical degrada tion products of acetone with emissions of NO

x 

### 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, Phila delphia, New York and Boston), Chicago, Houston, and Los Angeles in which high O 3 

### 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 O 3 

### 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 O 3 

### concentrations are lacking.



## AX2.3.6 The Relation of Ozone to Sola r 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 la titude, 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 O 3 

### 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 O 3 

### levels.

In urban environments the rate of O 3 

### formation is sensitive to the rate of photolysis of several species including H 2 

### CO, H 2 

### O 2 

### , O 3 

### , and especially NO 2 

### . Monte Carlo calculations suggest that model calculations of photochemical O 3 

### production are most sensitive to uncertainty in the photolysis rate coefficient for NO 2 

### (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 O 3 

### to O( 1 

### D) and NO 2 

### , referred to as j(O 3 

### ) and j(NO 2 

### ).

### 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(NO 2 

### ) at the Earth’s surface is known to better th an 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(NO 2 

### ). Many numerical models agreed among themselves and with direct measurements (actinometers) and semi-direct measurements (radiometers) when using ATLAS extraterrestrial flux from Gr oebner 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 O 3 

### 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 O 3 

### 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/m 2 

### and stabilized the atmosphere suppressing convection. This suggests two

### AX2-92 possible feedbacks mechanisms between aerosols and O 3 

### -reduced vertical mixing would tend to increase the severity of O 3 

### episodes, while reduced surface temperatures would decrease it.

AX2.3.6.3 Temperature and Ozone

An association between surface O 3 

### 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 O 3 

### years (Clark and Karl, 1982; Kelly et al., 1986). The relation of daily maximum 8-h average O 3 

### 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 O 3 

### 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 O 3 

### concentrations. The relation of daily maximum 8-h average O 3 

### 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 O 3 

### days (cf., Figure AX3-32). As can be seen from a comparison of Figures AX2-14 and AX2-16, O 3 

### 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 O 3 

### concentrations that increases with temperature. Likewise, Figure AX2-16 shows that a similar qualitative relationship exists

between O 3 

### and temperature even at a number of nonurban locations. The notable trend in these plots is the apparent upper-bound to O 3 

### concentrations as a function of temperature. It is clear that, at a gi ven temperature, there is a wide range of possible

O 3 

### concentrations because other factors (e.g., cloudiness, precipitation, wind speed) can reduce

O 3 

### production rates. The upper edge of the curves may represent a practical upper bound on the

maximum O 3 

### concentration achieved under the most favorable conditions. Relationships between peak O 3 

### and temperature also have been recorded by Wunderli and Gehrig (1991) for three locations in Switzerland. At two sites near Zurich, peak O 3 

### increased 3 to 5 ppb/°C for diurnal average temperatures between 10 and 25 °C, and little change in peak O 3 

### occurred for temperatures below 10 °C. At the third site, a high-altitude location removed from anthropogenic influence, a much smaller variation of O 3 

### with temperature was observed.

### AX2-93 Figure AX2-14. A scatter plot of daily maximum 8-h O 3 

### concentration versus daily maximum temperature in the Baltimo re, MD Air Quality Forecast Area.

Source: Piety (2005)



### Figure AX2-15. A scatter plot of daily maximum 1-h average O 3 

### 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 O 3 

### concentrations versus daily maximum temperature downwind of Phoenix, AZ.

Source: Piety (2005)



### Some possible explanations for the correlation of O 3 

### with temperature include:

(1) Increased photolysis rates under meterological conditions associated with higher temperatures;

(2) Increased H 2 

### O 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 NO

x 

### at higher temperatures;

(4) Increase of anthropogenic hydrocarbon (e.g., evaporative losses) emissions or NO

x 

### , 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 O 3 

### .

### 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

O 3 

### -temperature relationship. When temperatures are low, PAN is relatively stable. Formation of PAN represents a significant sink for NO

x 

### (in low NO

x 

### rural areas) and radicals (in high NO

x 

### urban areas). This has the effect of slowing the rate of O 3 

### production. Sillman and Samson found that the impact of the PAN decomposition rate could explain roughly half of the observed

correlation between O 3 

### 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 me teorological stagnation also explained roughly

half of the observed O 3 

### -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 O 3 

### with temperature does not necessarily imply a causal relation. Extreme episodes of high temperatures (a heat wave) are often multiday events, high O 3 

### 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 O 3 

### associated with higher temperatures, there is also much greater variance in the range of O 3 

### 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 NO

x 

### concentrations found in most environments, ranging from remote continental areas to rural and suburban areas downwind of urban centers the net production of O 3 

### increases with increasing NO

x 

### . At the high NO

x 

### concentrations found in downtown metropolitan areas, especially near busy streets and roadways, and in power plant plumes there is net destruction (titration) of O 3 

### by reaction with NO. In between these two regimes there is a

### AX2-96 transition stage in which O 3 

### shows only a weak dependence on NO

x 

### concentrations. In the high

NO

x 

### regime, NO 2 

### scavenges OH radicals which would otherwise oxidize VOCs to produce peroxy radicals, which in turn would oxidize NO to NO 2 

### . In the low NO

x 

### regime, the oxidation of VOCs generates, or at least does not consume, free radicals and O 3 

### production varies directly

with NO

x 

### . Sometimes the terms VOC limited and NO

x 

### 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 ra dicals without invoking VOCs. The terms NO

x 

### -limited

and NO

x 

### -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 O 3 

### with respect to NO

x 

### concentrations (Hameed et al., 1979; Pinto et al., 1993; Poppe et al., 1993; Zimmerm an and Poppe, 1993). These considerations introduce a high degree of uncertainty into attempts to relate changes in O 3 

### concentrations to emissions of precursors. Various analytical techniques have been proposed that use ambient NO

x 

### and VOC

measurements to derive information about O 3 

### production and O 3 

### -NO

x 

### -VOC sensitivity. It has been suggested that O 3 

### formation in individual urban areas could be understood in terms of

measurements of ambient NO

x 

### 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 NO

x 

### is used to determine whether conditions were NO

x 

### -sensitive or VOC sensitive. This procedure is inadequate because it omits many factors that are recognized as important for O 3 

### 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 O 3 

### 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 O 3 

### changed from NO

x 

### -limited to NO

x 

### -saturated as the season changed from summer to fall at a monitoring site in Shenandoah National Park, VA.

### AX2-97 Photochemical production of O 3 

### generally occurs simultaneously with the production of various other species: nitric acid (HNO 3 

### ), organic nitrates, and hydrogen peroxide. The relative rate of production of O 3 

### and other species varies depending on photochemical conditions, and can be used to provide information about O 3 

### -precursor sensitivity. There are no hard and fast rules governing the levels of NO

x 

### at which the transition from

NO

x 

### -limited to NO

x 

### -saturated conditions occurs. The transition between these two regimes is highly spatially and temporally dependent. Similar responses to NO

x 

### additions from commercial aircraft have also been found for the upper tropos phere (Bruhl et al., 2000). Bruhl et al. (2000)

found that the NO

x 

### levels for O 3 

### production versus loss are highly sensitive to the radical sources included in model calculations. They found that the inclusion of only CH 4 

### and CO oxidation

leads to a decrease in net O 3 

### 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

O 3 

### production to higher NO

x 

### mixing ratios, thereby reducing or eliminating areas in which there

is a decrease in O 3 

### production rates due to aircraft emissions. Trainer et al. (1993) suggested that the slope of the regression line between O 3 

### and

summed NO

x 

### oxidation products (NO

z 

### , equal to the difference between measured total reactive nitrogen, NO y 

### , and NO

x 

### ) can be used to estimate the rate of O 3 

### production per NO

x 

### (also known

as the O 3 

### production efficiency, or OPE). Ry erson et al. (1998, 2001) used measured

correlations between O 3 

### and NO

z 

### to identify different rates of O 3 

### 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 NO

x 

### -limited conditions and NO

x 

### -saturated conditions. The most important correlations are for O 3 

### versus NO y 

### , O 3 

### versus NO

z 

### , O 3 

### versus HNO 3 

### , and

H 2 

### O 2 

### versus HNO 3 

### . The correlations between O 3 

### and NO y 

### , and O 3 

### and NO

z 

### are especially important because measurements of NO y 

### and NO

x 

### are widely available. Measured O 3 

### versus
NO

z 

### (Figure AX2-17) shows distinctly different patte rns in different locations. In rural areas and
in urban areas such as Nashville, TN, O 3 

### shows a strong correlation with NO

z 

### and a relatively steep slope to the regression line. By contrast, in Los Angeles O 3 

### also increases with NO

z 

### , but

the rate of increase of O 3 

### with NO

z 

### is lower and the O 3 

### concentrations for a given NO

z 

### value are generally lower.

### AX2-98 Figure AX2-17. Measured values of O 3 

### and NO

z 

### (NO y 

### –NO

x 

### ) 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 NO

x 

### -limited and NO

x 

### -saturated regimes is also reflected in measurements of hydrogen peroxide (H 2 

### O 2 

### ). Hydrogen peroxide production is highly sensitive

to the abundance of free radicals and is thus favored in the NO

x 

### -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 H 2 

### O 2 

### concentrations between likely NO

x 

### -limited and NO

x 

### -saturated

locations. The discussion in Section AX2.4.1 centers mainly on the relations among O 3 

### , NO

x 

### and its oxidation products, represented as NO

z 

### (NO y 

### –NO

x 

### ) 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 Re lations 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 O 3 

### and its precursors in the southeastern United States during the summer season (Hübler et al., 1998; Meagher et al., 1998; Gold an et al., 2000). Specific issues that were addressed included: (1) the role of biogenic VOC and NO

x 

### emissions on local and regional O 3 

### production, (2) the effect of urban-rural exchange/interchange on local and regional O 3 

### production, (3) sub-grid-scale photochemical and meteorological processes, and (4) the provision of a high-quality chemical and meteorologi cal 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 NO

x 

### -limited and NO

x 

### -saturated regimes. (2) The number of

molecules of O 3 

### produced per molecule of NO

x 

### oxidized in power plant plumes, or the O 3 

### production efficiency (OPE) was found to be inversely proportional to the NO

x 

### emission rate, with the plants having the highest NO

x 

### 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 O 3 

### 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 O 3 

### per molecule

of NO

x 

### . Berkowitz and Shaw (1997) measured O 3 

### 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 O 3 

### aloft revealed values near 70 ppb, while those measured at the surface were closer to 25 ppb. As the daytime mixed layer deepened, surface O 3 

### 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 O 3 

### as a function of NO y 

### 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 O 3 

### precursors aloft is dependent on the occurrence of turbulence, and turbulent mixing could explain the evolution of O 3 

### 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 inst rumented 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 O 3 

### and NO

z 

### 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 O 3 

### nonattainment area (Gallatin). For a rura l coal-fired power plant in an isoprenerich forested area about 100 km west of Nashville (Cumberland), plume chemical maturity and peak O 3 

### and NO

z 

### production were realized within approximately 100 km and 6 hours of CBL transport time. Their findings included approximately 3 molecules of O 3 

### and more than

0.6 molecules of NO

z 

### may be produced in large isolated rural power plant plumes (PPPs) per

molecule of NO

x 

### release; the corresponding peak yields of O 3 

### and NO

z 

### may be significantly greater in urban PPPs. Both power plants can contribute as much as 50 ppb of excess O 3 

### 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 O 3 

### production efficiency in the Cumberland and Paradise PPPs (located in rural Tennessee) were 1 and

2 molecules of O 3 

### produced per molecule of NO

x 

### emitted. The estimated lower and upper limits

to O 3 

### production efficiency in the Johnsonville PPP (also located in rural Tennessee) were higher, at 3 and 7.

The NOAA airborne O 3 

### lidar provided detailed, three-dimensional lower tropospheric O 3 

### 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 O 3 

### 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 NO

x 

### titration close to the power plant, while farther downwind,

### AX2-101 O 3 

### was produced at rates between 1.5 and 4 ppbv h

! 1 

### . The lidar O 3 

### measurements compared reasonably well with in situ values, with the aver age magnitude of the offsets over all the flights at 4.3 ppbv (7%). The highest O 3 

### 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 O 3 

### were studied by Banta et al. (1998) using an airborne differential absorption lidar (DIAL) system. Vertical cross

sections showed O 3 

### concentrations exceeding 120 ppb extending to nearly 2 km above ground
level, but that O 3 

### 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 O 3 

### 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 NO

x 

### 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 O 3 

### concentrations. Thus, monitoring networks, especially in medium-sized urban areas under slow transport conditions, may underestimate the magnitude and frequency of urban O 3 

### 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 10 7 

### cm -3 

### that consumed 50% of the NO

x 

### within approximately 2 hours, at an OPE of 2.5 to 4 molecules for each molecule of NO

x 

### . Anthropogenic hydrocarbons provided approximately 44% of the fuel for O 3 

### production by the urban plume.

Surface and aircraft observations of O 3 

### and O 3 

### 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 O 3 

### measurements was excellent in the well-developed mixed layer

### AX2-102 (r 2 

### = 0.96), especially in rural-regional background air and under stagnant conditions, where surface concentrations change only slowly. Verti cal 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 concentra tions (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). Tw elve crosswind air-sampling traverses weremade 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 O 3 

### production was limited to the edges of the plume. Excess O 3 

### 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 O 3 

### (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 O 3 

### up to 120 ppbv 15 to 25 km downwind of Nashville. Nunnermacker et al. (2000) used data from th e 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 NO

x 

### (2.8 and 4.2 hours)

and NO y 

### (7.0 and 7.7 hours) were determined in the Gallatin and Paradise plumes, respectively.

These NO

x 

### and NO y 

### lifetimes imply rapid loss of NO

z 

### (assumed to be primarily HNO 3 

### ), 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-NO

x 

### chemistry and is an indicator of recent

O 3 

### production from isoprene and therefore biogenic hydrocarbons (BHC). They also measured peroxyacetic nitric anhydride (PAN), peroxypropionic nitric anhydride (PPN), and O 3 

### to estimate the contributions of anthropogenic hydrocarbons (AHC) and BHC to regional tropospheric O 3 

### production.
Airborne measurements of MPAN, PAN, PPN, and O 3 

### were made during the 1994 and

1995 Nashville intensive studies of SOS to determine the fraction of O 3 

### formed from anthropogenic NO

x 

### and BHC (Roberts et al., 1998). It was found that PAN, a general product of hydrocarbon-NO

x 

### photochemistry, could be well represented as a simple linear combination of

contributions from BHC and AHC as indi cated 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 O 3 

### production. It was estimated that substantial O 3 

### (50 to 60 ppbv) was produced from BHC when high NO

x 

### from power plants was present in areas of high BHC emission.

AX2.4.1.3 Results of Studies on Ozone Pr oduction in Mississippi and Alabama Aircraft flights made in June 1990 characterized the variability of O 3 

### and reactive nitrogen in the lower atmosphere over Mississippi and Alabama. The variety and proximity of sources and the photochemical production and loss of O 3 

### were found to be contributing factors (Ridley et al., 1998). Urban, biomass burning, electrical pow er 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 O 3 

### per ppbv of NO

x 

### . Emissions measured from biomass burning had lower efficiencies of 2 to 4 ppbv O 3 

### per ppbv of NO

x 

### , but the average rate of production of O 3 

### 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 O 3 

### titration, while far-field observations of power plant plumes showed net O 3 

### production. Early morning observations below a nocturnal inversion provided evidence for the nighttime oxidation of NO

x 

### to reservoir species.

### AX2-104 Aircraft measurements of O 3 

### and oxides of nitrogen were made downwind of Birmingham, AL to estimate the OPE in the urban plume (Trainer et al., 1995). NO

x 

### emission rates were

estimated at 0.6 x 10 25 

### molecules s

! 1 

### with an uncertainty of a factor of 2. During the summertime it was determined that approximately seven O 3 

### molecules could be formed for every molecule of NO

x 

### emitted by the urban and proximately located power plant plumes. The regional O 3 

### , the photochemical production of O 3 

### during the oxidation of the urban emissions, and wind speed and direction all combined to dictate the magnitude and location of the peak O 3 

### concentrations observed in the vicinity of the Birmingham metropolitan area.

Aircraft observations of rural U.S. coal-fir ed power plant plumes in the middle Mississippi and Tennessee Valleys were used to quantify the nonlinear dependence of tropospheric O 3 

### formation on plume NO

x 

### concentration, determined by plant NO

x 

### emission rate and atmospheric dispersion (Ryerson et al., 2001). The ambient availability of reactive VOCs, primarily biogenic isoprene, was also found to affect O 3 

### production rate and yield in these rural plumes. Plume O 3 

### production rates and yields as a function of NO

x 

### and VOC concentrations differed by a factor of 2 or more. These large differences indicate that power plant NO

x 

### emission rates and geographic locations play a large role in tropospheric O 3 

### production.

AX2.4.1.4 The Nocturnal Urban Plume over Portland, Oregon Aircraft observations of aerosol surface area, O 3 

### , NO y 

### and moisture were made at night in the Portland, Oregon urban plume (Berkowitz et al., 2001). Shortly after sunset, O 3 

### , relative humidity, NO y 

### and aerosol number density were all positively correlated. However, just before
dawn, O 3 

### mixing ratios were highly anti-correlated with aerosol number density, NO y 

### 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 O 3 

### 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 O 3 

### and O 3 

### precursors over Houston, TX, Nashville, TN; New York, NY; Phoenix, AZ, and Philadelphia, PA showed that despite similar NO

x 

### concentrations,

### AX2-105 high concentrations of VOCs in the lower atmosphere over Houston led to calculated O 3 

### production rates that were 2 to 5 times higher than in the other 4 cities (Kleinman et al., 2002).

Concentrations of VOCs and O 3 

### 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 O 3 

### concentrations in the United States within the last 5 years (in excess of 250 ppb).

AX2.4.1.6 Chemical and Meteorological Influen ces 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 th e afternoon from the south and southwest through most of the boundary layer, advecting the urban O 3 

### 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 O 3 

### did not appear to contribute significantly to O 3 

### levels. Sensitivity simulations estimated that 20% to 40% of the afternoon surface O 3 

### mixing ratios (corresponding to 15 to 35 ppb) was due to the entrainment of O 3 

### reservoirs into the growing convective boundary layer. The model results also indicated that O 3 

### production in this arid region is NO

x 

### -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 O 3 

### 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 O 3 

### aloft were associated with local

concentration maxima of SO 2 

### and NO y 

### , but not CO or NO

x 

### . 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 O 3 

### and O 3 

### precursors that had been transported from

### AX2-106 the west and northwest mixed with the local emissions and O 3 

### in excess of 125 ppbv was

measured at the surface. During the blackout of August 14, 2003 Marufu et al. (2004) measured profiles of O 3 

### , SO 2 

### and CO over areas in western Pennsylvania, Maryland and Virginia. They found notable

decreases in O 3 

### , SO 2 

### , and NO

x 

### , over areas affected by the blackout but not over those that were not affected. They also found that CO concentr ations 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 O 3 

### levels in the northeastern United States (Kleinman et al., 2000). Ozone, O 3 

### precursors, and other photochemically active trace gases were measured upwind and downwind of New York City to characterize the O 3 

### formation process and its dependence on NO

x 

### and VOCs. During two flights, the wind was south southwesterly and O 3 

### levels reached 110 ppb. On two other flights, the wind was from the

north-northwest and O 3 

### levels were not as high. When the G-1 observed O 3 

### around 110 ppb, the

NO

x 

### /NO y 

### 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 O 3 

### 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 O 3 

### above the convective boundary layer. The model accounted for these layers through upwind vertical mixing the previous day, subseque nt horizontal transport aloft, and NO titration

of O 3 

### within the stable boundary layer at night. Entrainment of the O 3 

### aloft into the growing

### AX2-107 convective boundary contributed to surface O 3 

### concentrations. During the study period, most of

the O 3 

### appeared to result from local emissions in the vicinity of Philadelphia and the Chesapeake Bay area, but during high O 3 

### episodes, up to 30 to 40% of the O 3 

### 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 O 3 

### 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 SO 2 

### , but not O 3 

### , and contained greater numbers of externally mixed primary sulfate and black carbon (BC) particles. Correlations among O 3 

### , air parcel altitude, particle size, and relative humidity suggest that greater O 3 

### 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 O 3 

### , its precursors, and other oxidation products. Other techniques, involving

statistical relations between O 3 

### and other variables have also been used. Chemistry-transport models (CTM) are driven by emissions inventories for O 3 

### 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 O 3 

### 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 PM 2.5 

### 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 PM 2.5 

### size range) and more O 3 

### 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

O 3 

### and particles generated by the model. A brief overview of atmospheric chemistry-tr ansport models is given in Section AX2.5.1. A discussion of emissions inventories of precurs ors 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 O 3 

### and other air pollutants; to understand the relations between O 3 

### concentrations and concentrations of its precursors such as NO

x 

### and VOCs; and to understand relations among the concentration patterns

of O 3 

### 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 O 3 

### 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 O 3 

### in a particular time period, questions about whether NO

x 

### or VOCs were more important, the influence of meteorology and of emissions fr om 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 O 3 

### precursors. However, this application has met with varying degrees of success because of the highly nonlinear relations

between O 3 

### 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 pr ocesses, 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, Odma n 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 gi ven in Arnold et al. (2003) and Fuentes and Raftery (2005). The domains of MAQSIP and CM AQ 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 O 3 

### 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 factorie s, 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 emissi ons, 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 focu sed on simulations of several days duration (a typical time scale for individual O 3 

### episodes), but there have been several attempts at modeling longer periods. For example, Kasibhatla and Ch ameides (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 O 3 

### . With the shift toward modeling an entire year being driven by the desire to understand observa tions 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 O 3 

### 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 br ief 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 O 3 

### and NO over the daylight period was less than 20%,

and 10% for NO 2 

### for all mechanisms. However, much larger deviations were found for HNO 3 

### , PAN, HO 2 

### , H 2 

### O 2 

### , C 2 

### H 4 

### and C 5 

### H 8 

### (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 NO

x 

### 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 NO 2 

### 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. Emi ssions inventories have been compiled on grids of varying resolution for many hydrocarbons, aldehydes, ketones, CO, NH 3 

### , and NO

x 

### . 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 O 3 

### -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 vari ous 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 measur ements of the amounts of specific trace gases scavenged in observed storms are sparse. Picker ing 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 distributi on 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 O 3 

### 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 v d 

### = (r

a 

### + r b 

### + r c 

### )

! 1 

### where r

a 

### , r b 

### , and r

c 

### 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 r b 

### and r

c 

### 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. Am ong those shortcomings are difficulties in representing dry deposition over varying terrain where horizontal advection plays a significant role in determining the magnitude of r

a 

### 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 simu lation 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 prof iles of most species of interest are sparse. Ozonesonde data have been used to specify O 3 

### 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

O 3 

### profiles (e.g., 35 ppb) at their lateral and upper boundaries; ozonesonde data, however, indicate that the mixing ratio of O 3 

### 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 O 3 

### profiles strongly reduces the potential effects of vertical mixing of O 3 

### from above the planetary boundary layer (via mechanisms outlined in Section AX2.3) on surface O 3 

### levels.

The use of an O 3 

### 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 O 3 

### formation because it is highly nonlinear with respect to NO

x 

### concentrations. Thus, the volume of the grid cell into which emissions are injected is important because the nature of O 3 

### chemistry (i.e., O 3 

### 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 O 3 

### titration to be more clearly separated from regions of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### and its contribution to regional O 3 

### 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, O 3 

### -NO

x 

### -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 km 2 

### 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 210 

### Pb 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### (O 3 

### ) and carbon monoxide (CO) simulated by the various models was evaluated with O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### , 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 O 3 

### 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 (MOZAI C) 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 O 3 

### 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 O 3 

### 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 O 3 

### over the United States is modulated by synoptic meteorology (e.g., Loga n, 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 an alysis on observed and simulated fields over

### AX2-122 Table AX2-4. Chemistry-Transport Models (CTM) Contributing to the Oxcomp

Evaluation of Predicting Tropospheric O 3 

### 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 O 3 

### as well as its precursors in surface air over the United States in summer, including formaldehyde concentrations and

### AX2-123 correlations between O 3 

### and the oxidation products of nitrogen oxides (O 3 

### : NO y 

### -NO

x 

### ), 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 NH 3 

### 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 da ta 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. Sawy er et al. (2000) have reviewed the factors

associated with NO

x 

### emissions by mobile sources. Estimates of NO

x 

### 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

NO

x 

### , mainly in the form of NO. Emission rates depend mainly on fertilization levels and soil temperature. About 60% of the total NO

x 

### emitted by soils occurs in the central corn belt of the

United States. The oxidation of NH 3, 

### 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 O 3 

### 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 Emissions 1 

### (10 12 

### 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 sources 2 

### 3.1 Lightning (50%); soils(50%).

Total 26

1 Emissions are expressed in terms of NO 2 . 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 NO

x 

### from fertilized fields show great variability. Soil NO emissions can be estimated from the fraction of the applied fertilizer nitrogen emitted as NO

x 

### , 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 (10 12 

### g/y) Notes

On-road vehicles 4.8 Exhaust and eva porative losses from gasoline (95%) and diesel (5%) vehicles.

Non-road vehicles 2.9 Exhaust and eva porative 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 burni ng (63%); waste water (23%); landfills (6%); non-biomass incineration (8%).
Biogenic sources 1 

### 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 gi ven in Guenther et al. (2000).

Source: U.S. Environmental Protection Agency (2001).

### AX2-126 Table AX2-7. Emissions of Ammonia by Vari ous Sources in the United States in 1999

Source Emissions (10 12 

### 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 O 3 

### , emissions of NO from soils peak in summer

when O 3 

### formation is at a maximum. A recent NRC report outlined the role of agricultural in emissions of air pollutants including NO and NH 3 

### (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 (10 12 

### 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 emissions 1 

### 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., S tith 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 O 3 

### production by lightning NO is thought to be small. However, lightning NO production can contribute substantially to O 3 

### production in the middle and upper troposphere. DeCaria et al. (2000) estimated that up to 7 ppbv of O 3 

### 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 th ese methods against observed flash rates from
satellite, and examined the effects on O 3 

### 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 famil y, 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 Waldru ff (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 st andard 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 em issions 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 O 3 

### formation in areas far removed from where they were emitted. The oxidation of isoprene can also contribut e 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 strongl y on the stage of combustion. Smoldering combustion, especially involving forest ecosystems favors the production of CH 4 

### , NMHC and CO at the expense of CO 2 

### , whereas active combustion produces more CO 2 

### relative to the other compounds mentioned above. Typical emissions ratios (defined as moles of compound per

### AX2-130 moles of emitted CO 2 

### expressed as a percentage) range from 6 to 14% for CO, 0.6 to 1.6% for

CH 4 

### , 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 O 3 

### -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 O 3 

### -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 O 3 

### 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 O 3 

### is primarily sensitive to NO

x 

### 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 NO

x 

### data can be used to identify the instantaneous production rate for O 3 

### and how the production rate varies with concentrations of

NO

x 

### and VOCs. The instantaneous production rate for O 3 

### is only one of the factors that affect

the total O 3 

### concentration, because O 3 

### 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 em issions 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 NO

x 

### and VOC measurements. Kleinman

### AX2-131 et al. (1997, 2000, 2001) and Tonnesen and Dennis ( 2000a) both derived simple expressions that

relate the NO

x 

### -VOC sensitivity of instantaneous O 3 

### production to ambient VOC and NO

x 

### . These expressions usually involve summed VOC weighted by reactivity. Cardelino et al. (1995, 2000) developed a method that seeks to identify O 3 

### -NO

x 

### -VOC sensitivity based on ambient NO

x 

### 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 O 3 

### 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 O 3 

### formation at the urban/regional scale have traditionally been evaluated based on their ability to correctly simulate O 3 

### . A series of performance statistics that measure the success of individual model simulations to represent the observed distribution

of ambient O 3 

### , 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 O 3 

### 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, A

u 

### ;

Normalized bias, D ;

Gross error, E d 

### (for hourly observed values of O 3 

### >60 ppb)

The following performance criteria for regulatory models were recommended in U.S. Environmental Protection Agency (1991): unpaired peak O 3 

### to within ±15% or ±20%; normalized bias within ±5% to ±15%; and normalized gross error less than 30% to 35%, but only when O 3 

### >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 O 3 

### -precursor relations predicted by the model. The process of O 3 

### formation is sufficiently complex that models can predict O 3 

### correctly without necessarily representing the O 3 

### formation process properly. If the O 3 

### 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

O 3 

### -precursor sensitivity, but without significant differences in the predicted O 3 

### fields. Figures AX2-21a,b provide an example. Referring to the O 3 

### -NO

x 

### -VOC isopleth plot (Figure AX2-22), it can be seen that similar O 3 

### concentrations can be found for photochemical conditions that have very different sensitivity to NO

x 

### 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 O 3 

### (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 (NO

x 

### , CO, and selected VOCs) and an array of secondary species (HNO 3 

### , PAN, H 2 

### O 2 

### ) that are often formed concurrently with O 3 

### . Models for urban/regional O 3 

### 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 f og episodes in winter when vertical mixing , is suppressed. By contrast, secondary species such as O 3 

### 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, NO

x 

### and ethane)and secondary species (O 3 

### , PAN and HCHO) is evident in Figure AX2-23b. Models for urban/regional O 3 

### 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 i nventories 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 O 3 

### for two days (August 10[a] and 11[b], 1992) in Atlanta, GA. The figures show the predicted reduction in peak O 3 

### resulting from 35% reductions in anthropogenic VOC emissions (crosses) and from 35% reductions in NO

x 

### (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 va lues published in Sillman et al. (1995, 1997).

### AX2-135 Figure AX2-22. Ozone isopleths (ppb) as a function of the average emission rate for NO

x 

### and VOC (10 12 

### 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 O 3 

### . The ridge line (shown by solid circles) lies in the transition from NO

x 

### -saturated to NO

x 

### -limited conditions.

The evaluation of urban/regional models is also limited by the availability of data.

Measured NO

x 

### 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 O 3 

### formation, including
VOCs, NO

x 

### , PAN, nitric acid (HNO 3 

### ) and hydrogen peroxide (H 2 

### O 2 

### ) 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 O 3 

### and NO

x 

### 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 prediction s (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; Fe hsenfeld 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 O 3 

### can be misleading because of compensating errors, although this possibility is diminishedwhen 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 O 3 

### and NO

z 

### 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 O 3 

### to NO

x 

### and VOCs. Primarily NO

x 

### -sensitive ( NO

x 

### -limited) areas in models show a strong correlation

between O 3 

### and NO

z 

### with a relatively steep slope, while primarily VOC-sensitive (NO

x 

### saturated) areas in models show lower O 3 

### for a given NO

z 

### and a lower O 3 

### -NO

z 

### 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 O 3 

### versus NO

z 

### between summer and autumn (Jacob et al., 1995;

### AX2-139 Figure AX2-24. Correlations for O 3 

### versus NO

z 

### (NO y 

### –NO

x 

### ) 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 NO

x 

### -limited or NO

x 

### -sensitive (circles), NO

x 

### -saturated or VOC-sensitive (crosses), mixed or with near-zero sensitivity (squares), and dominated by NO

x 

### titration (asterisks) based on the model response to reduced NO

x 

### and VOC.

Source: Sillman and He (2002).



### Hirsch et al., 1996), corresponding to the transition from NO

x 

### -limited to NO

x 

### -saturated patterns, a feature which is also matched by chemistry-transport models. The difference in correlations between secondary species in NO

x 

### -limited to NO

x 

### -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

NO y 

### and O 3 

### formation apparently suppressed by high NO y 

### . Measurements show much lower

### AX2-140 Figure AX2-25a,b. Evaluation of model versus measured O 3 

### versus NO y 

### for two model scenarios for Atlanta. The model values are classified as NO

x 

### limited (circles), NO

x 

### -saturated (crosses), or mixed or with low sensitivity to NO

x 

### (squares). Diamonds represent aircraft measurements.

Source: Sillman et al. (1997).

### AX2-141 NO y 

### in the Atlanta plume. This error was especially significant because the model locations with high NO y 

### were not sensitive to NO

x 

### , while locations with lower NO y 

### were primarily

sensitive to NO

x 

### . The second model scenario (with primarily NO

x 

### -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 s ite located about 50 km NW of Berlin. (This

location was chosen as O 3 

### episodes in central Europe are often associated with SE winds.) Concentrations of major compounds such as O 3 

### , 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 RO 2 

### (organic peroxy), HO 2 

### (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 O 3 

### calculated using radical concentrations predicted by the mechanisms and those obtained by
measurements, and measurements of NO

x 

### 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 NO

x 

### (>10 ppb). However, at

lower NO

x 

### concentrations, both mechanisms substantially overestimate OH concentrations and moderately overestimate HO 2 

### 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 HO 2 

### to OH and RO 2 

### to OH ratios better than the individual measurements. The production of O 3 

### was found to increase linearly with NO (for NO <0.3 ppb) and to decrease with NO (for NO >0.5 ppb).

OH and HO 2 

### concentrations measured during the PM 2.5 

### 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 O 3 

### versus NO

z 

### and (b) O 3 

### versus the sum 2H 2 

### O 2 

### + NO

z 

### for Nashville, TN. The model values are classified as NO

x 

### -limited (gray circles), NO

x 

### -saturated (×s), mixed or with near-zero sensitivity (squares), or dominated by NO

x 

### titration (filled circles). Diamonds represent aircraft measurements.

Source: Sillman et al. (1998).

### AX2-143 Figure AX2-27. Time series of concentrations of RO 2 

### , HO 2 

### , and OH radicals, local O 3 

### photochemical production rate and concentrations of NO

x 

### 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 HO 2 

### 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 NO

x 

### and

NMOC to NO

x 

### during the early 1990s in tunnels and ambient air (summarized in Air Quality Criteria for Carbon Monoxide [U.S. Environmen tal 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 NO

x 

### emissions are predicted correctly by

emissions factor models. Road side remote se nsing 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 wh en 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 NO

x 

### emissions decreased by almost a factor of three over 12 yr (s uch 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 NO

x 

### emissions from mobile sources may be

### AX2-145 underestimated and/or increasing. The authors conclude that O 3 

### photochemistry in U.S. urban areas may have become more NO

x 

### -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, SO 2 

### and NO y 

### at an East Coast site. By taking advantage of the nature of mobile sources (they emit NO

x 

### and CO but little

SO 2 

### ) and power plants (they emit NO

x 

### and SO 2 

### 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 NO

x 

### emissions in agreement with emissions inventories (U.S. Environmental Protection Agency, 1997). Parrish et al. (1998) and Parrish and Fehs enfeld (2000) proposed methods to derive emission rates by examining measured ambient ratios among individual VOC, NO

x 

### and NO y 

### . 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 NO y 

### (e.g., Parrish et al., 1991), between individual VOC species

and NO y 

### (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 i nventories 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

NO

x 

### 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 NO

x 

### . However, Cardelino and Chameides (2000) reported that measured NO duri ng 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). NO

x 

### measurements are made with commercial chemilluminescent detectors with molybdenum converters. However these measurements typically include some organic nitrates in addition to NO

x 

### , and cannot be interpreted as a “pure”

NO

x 

### measurement (see summary in Parrish and Fehsenfeld, 2000). Total reactive nitrogen (NO y 

### ) is included in the PAMS network only at a few sites. The possible expansion of PAMS to include more widespread NO y 

### measurements has been suggested (McClenny, 2000). A major issue concerning measured NO y 

### is the possibility that HNO 3 

### , a major component of NO y 

### , 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 NO y 

### is used to identify NO

x 

### -limited versus NO

x 

### -saturated conditions. The correlation between O 3 

### and NO y 

### differs for NO

x 

### -limited versus NO

x 

### -saturated locations, but this difference is driven primarily by

differences in the ratio of O 3 

### to HNO 3 

### . If HNO 3 

### were omitted from the NO y 

### 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 O 3 

### in the ambient atmosphere at ground level. As noted above, sparse surface networks tend to

underestimate maximum O 3 

### 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 O 3 

### measurements were summarized in AQCD 96, so this section will focus on the current state of

ambient O 3 

### measurement, tests for artifacts, and on new developments. Several reports in the reviewed scientific literature have investigated interferences in O 3 

### 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 NO

x 

### , 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 th ese filters to avoid artifacts associated with particle loading on the filters. The possibility for substantive interferences in O 3 

### detection exists, but such interferences have not been observed even in urban plumes. Ryerson et al. (1998) measured O 3 

### 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 year s, 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 O 3 

### (relative to the CL technique) in Mexico City and in a smog chamber study. They suggested that O 3 

### 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 produci ng 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 pa rts 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 O 3 

### . 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 O 3 

### (and SO 2 

### ) 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 O 3 

### for a chemical zero (Penrose et al., 1995).

Interferences from other oxidants such as NO 2 

### 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 O 3 

### . 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 NO 2 

### and back again, thus these two species are often referred to together as NO

x 

### (NO + NO 2 

### ). The photochemical interconversion of NO and NO 2 

### leads to O 3 

### formation. Because NO 2 

### is a health hazard at sufficiently high concentrations, it is itself a criteria pollutant. In EPA documents,

### AX2-150 emissions of NO

x 

### are expressed in units of mass of NO 2 

### per unit time, i.e., the total mass of NO

x 

### that would be emitted if all the NO were converted to NO 2 

### . Ambient air monitors have been required to demonstrate compliance with the standard for NO 2 

### and thus have focused on measuring this gas or determining an upper limit for its concentration.

NO

x 

### can be oxidized to species such as nitrous acid (HNO 2 

### ), nitric acid (HNO 3 

### ), aerosol nitrate (NO 3 ! 

### ), and organo-nitrates such as alkyl nitrates (RONO 2 

### ) and peroxy acetyl nitrate, PAN, (CH 3 

### C(O)O 2 

### NO 2 

### ). The sum of these species (explicitly excluding N 2 

### , N 2 

### O, and reduced N

such as NH 3 

### and HCN) is called NO y 

### . Nitrates play important roles in acid rain, and nutrient cycling including over nitrification of surface ecosyst ems and in the formation of fine particulate matter, but are generally inactive photochemically. Some studies refer specifically to the oxidized or processed NO y 

### species, NO y 

### -NO

x 

### , as NO

z 

### because this quantity is related to the degree of photochemical aging in the atmosphere. Several NO

z 

### species such as PAN and HONO can be readily photolyzed or thermally dissociated to NO or NO 2 

### and thus act as reservoirs for

NO

x 

### . This discussion focuses on current met hods 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 us e. 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 N 2 

### (in the concentrations indicated above) are obtainable from specialty gas companies. Information as to whether a company supplies such mixtures is obtainable from th e 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 (Gue nther et al., 1996). Additional details can be found in the previous AQCD for O 3 

### (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 O 3 

### at low pressure. Modern commercial

NO

x 

### 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 O 3 

### 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 N 2 

### . Standard additions of NO at the inlet will account for NO loss or

conversion to NO 2 

### 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 measur ed 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 previ ous 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; Gregor y 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 O 3 

### 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 NO 2 

### . Garnica et al. (2000) describe a technique involving selective excitation at one wavelength followe d 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 de veloped. Ryerson et al. (2000) developed a photolytic converter based on a Hg lamp with increased radiant intensity in the region of peak

NO 2 

### photolysis (350 to 400 nm) and producing convers ion efficiencies of 70% or more in less than 1 s. Because the converter produces little radiation at wavelengths less than 350 nm,

interferences from HNO 3 

### 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 HO 2 

### NO 2 

### for example,

dissociate to NO 2 

### at higher temperatures.

### AX2-153 Laser induced fluorescence for NO 2 

### detection involves excitation of atmospheric NO 2 

### 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 NO 2 

### , 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 us es 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 ratiosup to 1.0 ppb. This high-sensitivity laser-induced fluorescence system has yet to undergo longterm field tests.

NO 2 

### can be detected by differential optical absorption spectroscopy (DOAS) in an open, long-path system (Kim and Kim, 2001). Va ndaele et al. (2002) reported that the DOAS technique measured higher NO 2 

### 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 NO 2 

### with DOAS and photolysis followed by
chemiluminescence. The found differences of as much as 110% in clean air from the west, but

for NO 2 

### 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 NO 2 

### Compliance Versus Monitoring for Ozone Formation

Observations of NO 2 

### have been focused on demonstrating compliance with the NAAQS for

NO 2 

### . Today, few locations violate that standard, but NO 2 

### and related NO y 

### compounds remain among the most important atmospheric trace gases to measure and understand. Commercial

instruments for NO/NO

x 

### detection are generally constructed with an internal converter for

reduction of NO 2 

### to NO, and generate a signal referred to as NO

x 

### . These converters, generally constructed of molybdenum oxides (MoOx), reduce not only NO 2 

### but also most other NO y

### AX2-154 species (Fehsenfeld et al., 1987; Crosley, 1996; Nunnermacker et al., 1998). Thus the NO

x 

### signal is more accurately referred to as NO y 

### . Unfortunately with an internal converter, the instruments may not give a faithful indication of NO y 

### either — reactive species such as HNO 3 

### will adhere to the walls of the inlet system. Most recently, commercial vendors such as Thermo Environmental (Franklin, MA) have offered NO/NO y 

### 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 NO y 

### , suitable for evaluation of photochemical models. States should be encouraged to make these NO y 

### measurements where ever possible.



## AX2.6.3 Measurements of Nitric Acid Vapor, HNO 3 

### Accurate measurement of nitric acid vapor, HNO 3 

### , 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 HNO 3 

### partitioning between the gas and deliquesced-particulate phases in ambient air. In equation form,

where K H 

### is the Henry’s Law constant in M atm-1 and Ka is the acid dissociation constant in M. Thus, the primary controls on HNO 3 

### phase partitioning are its thermodynamic properties (K H 

### , K
a 

### , 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), HNO 3 

### 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 contro lled by atmospheric concentrations of HNO 3 

### vapor and particulate NO 3 ! 

### 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). Consequen tly, smaller aerosol size fractions are typically close to thermodynamic equilibrium with respect to HNO 3 

### 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 HNO 3 

### (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 NO 3 ! 

### is associated. This change in pH may cause the bulk mix to be supersaturated with respect to HNO 3 

### leading to volatilization and, thus, positive measurement bias in HNO 3 

### sampled downstream. Alternatively, when undersaturated super-um size fractions (e.g., sea salt) accumulate on a bulk filter and chemically interacts over time with HNO 3 

### in the sample air stream, scavenging may lead to negative bias in HNO 3 

### sampled downsteam. Because the magnitude of both effects will vary as functi ons 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 HNO 3 

### measured downstream. Widely used methods for measuring HNO 3 

### 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 HNO 3 

### 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; Neum an et al., 2002). CIMS relies on selective

formation of ions such as SiF 5 - 

### A 

### HNO 3 

### or HSO 4 - 

### A 

### HNO 3 

### 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 HNO 3 

### 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

NO 3 ! 

### corresponded to relatively greater fractions of total NO 3 !



### .



## 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 C 2 

### to C 10 

### 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 C 2 

### to C 16 

### –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 O 3 

### 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, biom ass 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. Substantia l 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 (CH 3 

### CN), methanol (CH 3 

### OH), acetone (CH 3 

### COCH 3 

### ), acetaldehyde (CH 3 

### CHO), benzene (C 6 

### H 6 

### ) and toluene (C 6 

### H 5 

### CH 3 

### ) (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 H 3 

### O + 

### primary ions and volatile trace gases with a proton affinity higher than that of water. In to a flow drift tube continuously flushed with
ambient air, H 3 

### O + 

### ions (from a hollow cathode ion source) are injected. On collisions between

H 3 

### O + 

### 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 Chem ical Ionization Mass Spectrometer (AP-CIMS) (Crutzen et al., 2000; Sprung et al., 2001). Su fficient 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 (O 3 

### ), the uses of these data in assessing the exposure of vegetation to O 3 

### , concentrations

of O 3 

### 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 O 3 

### 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 O 3 

### AQCD (U.S. Environmental Protection Agency, 1996a), O 3 

### is the only photochemical oxidant other than nitrogen dioxide (NO 2 

### ) that is routinely monitored and for which a comprehensive database exists. Data for peroxyacetyl nitrate (PAN), hydrogen peroxide (H 2 

### O 2 

### ), 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-O 3 

### oxidants; nor are extensive data available on the relationships of levels and patterns of these oxidants to those of O 3 

### . 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 O 3 

### . 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 f unction 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 O 3 

### concentrations for different locations within the United States and U.S. territories (CFR, 2000). Table AX3-1 shows the O 3 

### seasons during which continuous, hourly averaged O 3 

### concentrations must be monitored. Note that O 3 

### monitoring is optional outside of the “ozone season” and is monitored in many locations throughout the year.
In Section AX3.2, surface O 3 

### concentrations are characterized and the difficulties of characterizing background O 3 

### 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 th is 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 O 3 

### with NO 2 

### , sulfur dioxide (SO 2 

### ), and 24-h PM 2.5 

### . Indoor O 3 

### concentrations, including sources and factors affecting indoor O 3 

### 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 Texas 1 January — December
Kentucky March — October Texas 1 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations that are used for two main purposes: (1) performing experiments relating the effects of exposure to O 3 

### on humans, animals, and vegetation; and (2) assessing the health benefits associated with setting different levels of the NAAQS for O 3 

### . 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 concentr ations that would be observed in the United States if anthropogenic sources of O 3 

### precursors were turned off in continental North America (the United States, Canada and Mexico), i.e., the definition includes O 3 

### formed from natural sources everywhere in the world and from anthropogenic O 3 

### precursors outside of North

America. The 1996 O 3 

### AQCD considered two possible methods for quantifying background O 3 

### concentrations for the two purposes mentioned above. The first method relied on mathematical

models and historical data. The second met hod used the distribution of hourly average O 3 

### 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 O 3 

### AQCD, simulations of mathematical models were limited; therefore, the second method was employed to quantify background O 3 

### concentrations.

Sections AX3.2.1 and AX3.2.2 review data for O 3 

### concentrations in urban and nonurban (but influenced by urban emissions) environm ents. 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 O 3 

### concentrations at

these sites. The characterization of PRB O 3 

### 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 O 3 

### concentrations and Figure AX3-2 shows the 95th percentile values of the daily maximum 8-h O 3 

### 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 O 3 

### concentrations, are shown in Figure AX3-3. The period from May to September was chosen because, although O 3 

### was monitored for different lengths of time across the country, all O 3 

### 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 i ndicate 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations in Houston, TX were below the nationwide median, its 95th percentile value ranks in the highest 5% nationwide. Conversely, mean O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### among
monitors within counties. Box plots showing the percentile distribution of nationwide O 3 

### 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 numer ical values are given in Table AX3-2. The differences between the 50th and 95th percentile values indicate the range of O 3 

### levels between “typical” O 3 

### days and “high” O 3 

### days. These differences are approximately 40, 30, and 25 ppb Figure AX3-2. Countywide 95th percentile value of daily maximum 8-h O 3 

### 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 O 3 

### concentrations. As might be expected, the daily maximum 1-h and 8-h O 3 

### concentrations are highly correlated. Lehman et al. (2004) have shown that the eas tern United States can be divided into five regions, each of which exhibit spatial, relatively coherent spatial patterns of O 3 

### 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 O 3 

### 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 Figur e AX3-7, are characterized by different patterns

of O 3 

### properties such as temporal persistence and seasonal variability. Figure AX3-7 shows nonurban, monthly average, daily maximum 8-h O 3 

### 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 O 3 

### 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 O 3 

### 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 appare nt. 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 PooledAcross Monitoring Sites for May to September 2000-2004Concentrations are in ppb.PercentilesPooled Group/Avg. TimeNumberof Values Mean 1 5 10 25 30 50 70 75 90 95 99Daily 1-h Maximum ConcentrationsMonitors inCSAs367,121 58 20 29 34 44 46 56 66 70 84 94 116Monitors notin CSAs323,891 55 20 28 33 43 45 54 64 67 79 87 1048-h Daily Maximum ConcentrationsMonitors inCSAs367,029 50 16 23 28 37 40 49 58 61 73 81 98Monitors notin CSAs323,815 49 16 23 28 37 39 48 57 59 70 77 9124-h Average ConcentrationsMonitors inCSAs367,121 33 10 15 18 24 26 32 39 41 50 56 68Monitors notin CSAs323,891 34 10 15 18 25 27 33 39 41 50 56 68



### AX3-11

### AX3-12 Figure AX3-7. Box plots showing O 3 

### 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 O 3 

### 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 O 3 

### produced from emissions in urban areas is transported to more rural downwind
locations, elevated O 3 

### concentrations can occur at considerable distances from urban centers. In addition, major sources of O 3 

### precursors such as power plants and highways are located in nonurban areas and also produce O 3 

### in these areas. Due to lower rates of chemical scavenging in Figure AX3-8. Hourly average O 3 

### 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, O 3 

### 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 O 3 

### concentrations at RRMS so that assessments of the possible effects of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### before being admitted into the exposure chambers. As a result, O 3 

### 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 O 3 

### concentrations at four relatively remote monitoring sites (RRMS), show that annual mean values of the daily 8-h maximum O 3 

### 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 O 3 

### 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 O 3 

### 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 do ts 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 O 3 

### 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 O 3 

### AQCD (U.S. Environmental Protection Agency, 1996a) concluded that the annual average “background” concentration of O 3 

### 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 O 3 

### AQCD also included O 3 

### 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 Cu ster NF (MT) during the months of April to October. There were eight occurrences of hourly average O 3 

### 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 O 3 

### 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

### AX3-18Table AX3-3. Seasonal (April to October) Percentile Distribution of Hourly Ozone Concentrations (ppm), Number ofHourly Mean Ozone Occurrences$0.08 and$0.10, Seasonal 7-h Average Concentrations, SUM06, and W126 Values for SitesExperiencing Low Maximum Hourly Average Concentrations with Data Capture of$75%SitePercentilesMax.No. ofObs.HoursSeasonal7-hSUM06(ppm-h)W126(ppm-h)Year Min. 10 30 50 70 90 95 99$0.08$0.10Redwood NP060150002(California)235 m1988 0.002 0.011 0.018 0.023 0.029 0.038 0.041 0.046 0.06 4825 0 0 0.026 1.8 0.11989 0.000 0.010 0.017 0.022 0.027 0.034 0.038 0.042 0.047 4624 0 0 0.024 1.0 0.01990 0.000 0.011 0.018 0.023 0.028 0.035 0.038 0.043 0.053 4742 0 0 0.025 1.2 0.01991 0.001 0.012 0.019 0.025 0.031 0.038 0.041 0.045 0.054 4666 0 0 0.027 1.7 0.01992 0.000 0.010 0.017 0.021 0.026 0.035 0.039 0.045 0.055 4679 0 0 0.023 1.1 0.01993 0.000 0.010 0.017 0.022 0.027 0.035 0.038 0.042 0.054 4666 0 0 0.025 1.1 0.01994 0.001 0.011 0.018 0.024 0.028 0.035 0.038 0.043 0.050 4846 0 0 0.026 0.0 1.2Olympic NP(Washington)530090012125 m1989 0.000 0.003 0.010 0.015 0.022 0.030 0.035 0.046 0.065 4220 0 0 0.021 0.7 0.11990 0.000 0.005 0.012 0.018 0.023 0.030 0.034 0.043 0.064 4584 0 0 0.022 0.8 0.31991 0.000 0.006 0.014 0.019 0.024 0.033 0.036 0.044 0.056 4677 0 0 0.025 0.9 0.01993 0.000 0.004 0.010 0.016 0.021 0.029 0.034 0.041 0.064 4595 0 0 0.022 0.7 0.31994 0.000 0.006 0.013 0.019 0.025 0.033 0.038 0.043 0.062 4044 0 0 0.025 0.2 0.81995 0.000 0.006 0.014 0.020 0.027 0.037 0.040 0.048 0.077 4667 0 0 0.027 0.8 1.91996 0.000 0.006 0.013 0.019 0.025 0.034 0.038 0.043 0.058 4811 0 0 0.025 0.0 1.01997 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 0.024 0.3 1.11999 0.000 0.006 0.014 0.019 0.026 0.036 0.039 0.044 0.050 4656 0 0 0.024 0.0 1.12000 0.000 0.006 0.013 0.019 0.025 0.035 0.039 0.045 0.061 4676 0 0 0.024 0.1 1.22001 0.002 0.009 0.017 0.023 0.028 0.036 0.041 0.046 0.055 4643 0 0 0.027 0.0 1.4

### AX3-19Table AX3-3 (cont’d). Seasonal (April to October) PercentileDistribution of Hourly Ozone Concentrations (ppm), Numberof Hourly Mean Ozone Occurrences$0.08 and$0.10, Seasonal 7-h Average Concentrations, SUM06, and W126 Values forSites Experiencing Low Maximum Hourly Average Concentrations with Data Capture of$75%SitePercentilesMax.No. ofObs.HoursSeasonal7-hSUM06(ppm-h)W126(ppm-h)Year Min. 10 30 50 70 90 95 99$0.08$0.10Glacier NP300298001(Montana)963 m1989 0.000 0.003 0.015 0.026 0.036 0.046 0.050 0.058 0.067 4770 0 0 0.036 5.9 1.81990 0.000 0.003 0.014 0.026 0.035 0.044 0.047 0.052 0.066 5092 0 0 0.036 4.1 1.31991 0.000 0.001 0.014 0.027 0.036 0.046 0.049 0.056 0.062 5060 0 0 0.036 5.3 0.71992 0.000 0.001 0.013 0.025 0.033 0.043 0.048 0.055 0.077 4909 0 0 0.033 4.1 11993 0.000 0.000 0.010 0.020 0.029 0.040 0.044 0.050 0.058 5071 0 0 0.029 0.0 2.31994 0.000 0.001 0.014 0.026 0.036 0.046 0.050 0.056 0.061 5072 0 0 0.036 0.1 5.41995 0.000 0.000 0.010 0.022 0.031 0.041 0.045 0.051 0.066 4744 0 0 0.023 0.3 2.31996 0.000 0.002 0.013 0.025 0.035 0.046 0.051 0.058 0.065 4666 0 0 0.035 1.9 5.41997 0.000 0.000 0.008 0.017 0.026 0.041 0.045 0.053 0.058 4378 0 0 0.027 0.0 2.31998 0.000 0.003 0.013 0.025 0.035 0.047 0.051 0.058 0.064 4649 0 0 0.036 1.4 5.61999 0.000 0.002 0.015 0.026 0.035 0.046 0.051 0.058 0.068 4540 0 0 0.035 1.3 5.42000 0.000 0.001 0.011 0.023 0.033 0.044 0.048 0.055 0.062 4551 0 0 0.033 0.7 3.82001 0.000 0.000 0.013 0.025 0.033 0.042 0.044 0.049 0.057 4643 0 0 0.033 0.0 2.7Yellowstone NP(Wyoming)5603910102484 m1988 0.002 0.020 0.029 0.037 0.044 0.054 0.058 0.070 0.098 4257 17 0 0.043 14.0 8.91989 0.002 0.018 0.027 0.036 0.044 0.052 0.057 0.063 0.071 4079 0 0 0.042 11.0 6.71990 0.000 0.015 0.023 0.029 0.036 0.043 0.046 0.053 0.061 4663 0 0 0.034 3.8 0.51991 0.004 0.020 0.030 0.037 0.042 0.048 0.051 0.057 0.064 4453 0 0 0.042 7.7 1.21992 0.001 0.018 0.029 0.036 0.042 0.051 0.056 0.064 0.075 4384 0 0 0.042 10.7 6.31993 0.000 0.018 0.028 0.036 0.042 0.047 0.050 0.054 0.060 4399 0 0 0.041 6.5 0.21994 0.003 0.022 0.033 0.040 0.046 0.053 0.056 0.062 0.072 4825 0 0 0.046 6.0 15.21995 0.004 0.022 0.033 0.040 0.045 0.052 0.055 0.059 0.065 4650 0 0 0.045 2.8 12.5

### AX3-20Table AX3-3 (cont’d). Seasonal (April to October) PercentileDistribution of Hourly Ozone Concentrations (ppm), Numberof Hourly Mean Ozone Occurrences$0.08 and$0.10, Seasonal 7-h Average Concentrations, SUM06, and W126 Values forSites Experiencing Low Maximum Hourly Average Concentrations with Data Capture of$75%SitePercentilesMax.No. ofObs.HoursSeasonal7-hSUM06(ppm-h)W126(ppm-h)Year Min. 10 30 50 70 90 95 99$0.08$0.10Yellowstone NP(Wyoming)5603910112468 m1997 0.005 0.026 0.035 0.040 0.045 0.051 0.054 0.060 0.068 4626 0 0 0.043 3.3 12.41998 0.004 0.029 0.038 0.043 0.048 0.055 0.058 0.064 0.073 4827 0 0 0.046 9.9 20.01999 0.012 0.033 0.040 0.046 0.051 0.059 0.062 0.069 0.079 4733 0 0 0.049 27.1 29.82000 0.009 0.031 0.039 0.045 0.050 0.057 0.060 0.065 0.074 4678 0 0 0.047 17.0 23.42001 0.012 0.034 0.041 0.046 0.050 0.057 0.060 0.065 0.078 4869 0 0 0.048 16.9 25.6Denali NP(Alaska)022900003640 m1988 0.003 0.018 0.024 0.028 0.033 0.044 0.050 0.053 0.056 4726 0 0 0.031 0.0 4.01990 0.003 0.017 0.024 0.029 0.034 0.040 0.043 0.048 0.050 3978 0 0 0.030 2.1 0.01991 0.005 0.018 0.024 0.028 0.034 0.041 0.043 0.047 0.057 4809 0 0 0.030 2.7 0.01992 0.003 0.016 0.023 0.028 0.034 0.044 0.047 0.050 0.054 4800 0 0 0.031 3.7 0.01993 0.002 0.017 0.023 0.028 0.033 0.041 0.043 0.048 0.055 4773 0 0 0.030 2.6 0.01994 0.003 0.017 0.022 0.027 0.033 0.042 0.045 0.049 0.053 4807 0 0 0.030 0.0 2.91995 0.001 0.013 0.019 0.025 0.032 0.042 0.044 0.052 0.059 4825 0 0 0.028 0.0 3.01996 0.002 0.015 0.022 0.028 0.035 0.044 0.047 0.052 0.063 4831 0 0 0.031 0.1 4.11997 0.001 0.015 0.023 0.030 0.038 0.045 0.048 0.051 0.084 4053 1 0 0.032 0.2 4.01998 0.004 0.018 0.023 0.030 0.036 0.048 0.050 0.055 0.058 4782 0 0 0.032 0.0 6.01999 0.002 0.016 0.024 0.029 0.036 0.045 0.048 0.054 0.058 4868 0 0 0.032 0.0 4.72000 0.003 0.014 0.019 0.025 0.029 0.034 0.036 0.038 0.049 4641 0 0 0.025 0.0 1.02001 0.002 0.016 0.023 0.029 0.036 0.048 0.051 0.055 0.068 4868 0 0 0.032 0.7 11.1Badlands NP460711001(South Dakota)730 m1989 0.006 0.020 0.027 0.034 0.041 0.049 0.053 0.060 0.071 4840 0 0 0.040 9.2 3.11990 0.006 0.019 0.027 0.032 0.037 0.044 0.048 0.054 0.063 4783 0 0 0.037 4.8 0.81991 0.005 0.020 0.028 0.033 0.040 0.047 0.050 0.056 0.066 4584 0 0 0.038 6.2 0.7

### AX3-21Table AX3-3 (cont’d). Seasonal (April to October) PercentileDistribution of Hourly Ozone Concentrations (ppm), Numberof Hourly Mean Ozone Occurrences$0.08 and$0.10, Seasonal 7-h Average Concentrations, SUM06, and W126 Values forSites Experiencing Low Maximum Hourly Average Concentrations with Data Capture of$75%SitePercentilesMax.No. ofObs.HoursSeasonal7-hSUM06(ppm-h)W126(ppm-h)Year Min. 10 30 50 70 90 95 99$0.08$0.10Theod. Roos.NP380530002(North Dakota)730 m1984 0.000 0.017 0.025 0.032 0.039 0.047 0.050 0.059 0.068 4923 0 0 0.038 7.0 2.81985 0.000 0.019 0.026 0.032 0.038 0.046 0.049 0.054 0.061 4211 0 0 0.038 5.0 0.11986 0.004 0.017 0.027 0.033 0.039 0.047 0.050 0.056 0.062 4332 0 0 0.039 5.5 0.41989 0.004 0.023 0.032 0.039 0.045 0.054 0.058 0.065 0.073 4206 0 0 0.046 14.2 11.01992 0.005 0.019 0.027 0.033 0.039 0.047 0.050 0.056 0.063 4332 0 0 0.040 6.1 0.81993 0.004 0.018 0.025 0.031 0.037 0.045 0.048 0.055 0.064 4281 0 0 0.038 4.6 0.71994 0.000 0.018 0.028 0.035 0.041 0.049 0.052 0.058 0.079 4644 0 0 0.041 1.1 8.41995 0.000 0.018 0.028 0.035 0.041 0.050 0.053 0.058 0.064 4242 0 0 0.042 1.2 7.71996 0.003 0.022 0.031 0.037 0.043 0.051 0.054 0.059 0.064 3651 0 0 0.044 1.8 8.51997 0.000 0.016 0.029 0.037 0.044 0.053 0.058 0.069 0.082 4344 8 0 0.046 11.8 14.6Theod. Roos.NP380070002(North Dakota)808 m1999 0.007 0.024 0.031 0.037 0.042 0.049 0.052 0.058 0.070 5105 0 0 0.041 1.6 102000 0.002 0.021 0.031 0.036 0.043 0.050 0.053 0.058 0.066 5105 0 0 0.041 2.3 10.52001 0.002 0.023 0.031 0.036 0.042 0.049 0.052 0.058 0.064 5099 0 0 0.041 1.9 9.2Custer NF, MT300870101(Montana)1006 m1978 0.000 0.010 0.020 0.035 0.040 0.050 0.055 0.060 0.070 4759 0 0 0.033 3.0 8.31979 0.010 0.025 0.035 0.040 0.045 0.050 0.055 0.060 0.075 5014 0 0 0.043 7.3 13.21980 0.010 0.025 0.035 0.040 0.050 0.055 0.060 0.065 0.070 4574 0 0 0.043 22.4 19.71983 0.010 0.025 0.035 0.040 0.045 0.05 0.055 0.060 0.065 4835 0 0 0.042 4.2 10.7

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations at fairly clean sites in the United States are higher than the 0.038 and 0.039 ppm

values cited in the 1996 O 3 

### AQCD, and these updated values should be used to characterize O 3 

### at

these sites.

As described in the 1996 O 3 

### AQCD, the O 3 

### 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 O 3 

### 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 O 3 

### 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.

### AX3-23Table AX3-4. The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Experiencing Low MaximumHourly Average Concentrations with Data Capture of$75%Site Year 1 2 3 4 5 6 7 8 9 10Redwood NP060150002(California)235 m1988 0.061 0.058 0.053 0.052 0.0490.047 0.046 0.046 0.045 0.0451989 0.044 0.043 0.043 0.043 0.0420.042 0.042 0.042 0.041 0.0411990 0.051 0.048 0.048 0.047 0.0470.046 0.045 0.044 0.043 0.0431991 0.048 0.047 0.046 0.045 0.0450.045 0.044 0.044 0.043 0.0431992 0.060 0.053 0.045 0.045 0.0450.044 0.044 0.043 0.043 0.0421993 0.049 0.046 0.043 0.043 0.0430.042 0.042 0.042 0.041 0.0411994 0.048 0.048 0.046 0.046 0.0450.044 0.044 0.043 0.043 0.043Olympic NP530090012(Washington)125 m1989 0.054 0.052 0.047 0.044 0.0440.044 0.042 0.042 0.038 0.0381990 0.056 0.048 0.046 0.046 0.0430.040 0.040 0.039 0.038 0.0381991 0.050 0.048 0.045 0.043 0.0420.041 0.041 0.041 0.041 0.0411993 0.055 0.052 0.044 0.042 0.0400.039 0.038 0.038 0.037 0.0371994 0.050 0.046 0.042 0.042 0.0420.042 0.041 0.041 0.040 0.0401995 0.064 0.063 0.050 0.049 0.0450.045 0.044 0.044 0.044 0.0441996 0.046 0.046 0.046 0.046 0.0430.042 0.041 0.041 0.041 0.0401997 0.052 0.051 0.046 0.045 0.0450.045 0.044 0.043 0.042 0.0421998 0.051 0.050 0.049 0.046 0.0440.043 0.042 0.041 0.041 0.0411999 0.045 0.044 0.044 0.043 0.0430.042 0.042 0.042 0.042 0.0412000 0.051 0.051 0.048 0.047 0.0450.044 0.043 0.042 0.042 0.0422001 0.051 0.050 0.047 0.045 0.0450.044 0.044 0.044 0.043 0.043

### AX3-24Table AX3-4 (cont’d). The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Experiencing LowMaximum Hourly Average Concentrations with Data Capture of$75%Site Year 1 2 3 4 5 6 7 8 9 10Glacier NP300298001(Montana)963 m1989 0.062 0.061 0.060 0.059 0.0580.057 0.056 0.056 0.056 0.0561990 0.058 0.057 0.055 0.054 0.0530.053 0.052 0.052 0.052 0.0521991 0.060 0.057 0.057 0.057 0.0560.055 0.055 0.054 0.054 0.0531992 0.062 0.056 0.055 0.054 0.0540.054 0.053 0.053 0.053 0.0531993 0.055 0.052 0.051 0.051 0.0500.050 0.049 0.049 0.049 0.0481994 0.057 0.057 0.056 0.056 0.0550.055 0.055 0.055 0.054 0.0531995 0.061 0.055 0.053 0.052 0.0520.052 0.051 0.051 0.051 0.0501996 0.059 0.059 0.058 0.058 0.0570.057 0.055 0.056 0.055 0.0551997 0.056 0.054 0.052 0.052 0.0520.051 0.050 0.050 0.050 0.0501998 0.060 0.059 0.058 0.058 0.0560.056 0.055 0.055 0.055 0.0541999 0.065 0.065 0.060 0.058 0.0560.055 0.055 0.055 0.055 0.0542000 0.059 0.058 0.058 0.056 0.0540.052 0.051 0.050 0.050 0.0502001 0.054 0.052 0.049 0.049 0.0490.048 0.047 0.047 0.047 0.047Yellowstone NP560391010(Wyoming)2484 m1988 0.068 0.068 0.067 0.066 0.0660.066 0.064 0.064 0.063 0.0611989 0.067 0.065 0.064 0.063 0.0630.061 0.061 0.061 0.061 0.0601990 0.057 0.056 0.054 0.054 0.0530.052 0.050 0.050 0.049 0.0481991 0.059 0.058 0.058 0.057 0.0560.056 0.056 0.055 0.055 0.0551992 0.066 0.064 0.064 0.063 0.0630.061 0.061 0.059 0.059 0.0581993 0.057 0.054 0.054 0.054 0.0530.053 0.053 0.052 0.052 0.0521994 0.067 0.063 0.063 0.061 0.0610.061 0.061 0.061 0.059 0.0591995 0.064 0.062 0.061 0.060 0.0590.059 0.059 0.059 0.059 0.058

### AX3-25Table AX3-4 (cont’d). The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Experiencing LowMaximum Hourly Average Concentrations with Data Capture of$75%Site Year 1 2 3 4 5 6 7 8 9 10Yellowstone NP560391011(Wyoming)2468 m1997 0.065 0.065 0.062 0.061 0.0610.060 0.057 0.056 0.056 0.0561998 0.069 0.068 0.066 0.066 0.0630.063 0.061 0.061 0.061 0.0601999 0.078 0.074 0.073 0.071 0.0700.070 0.070 0.069 0.068 0.0672000 0.070 0.069 0.067 0.065 0.0650.065 0.064 0.064 0.063 0.0632001 0.068 0.068 0.066 0.066 0.0650.064 0.064 0.064 0.064 0.063Denali NP022900003(Alaska)640 m1988 0.055 0.054 0.054 0.053 0.0530.053 0.052 0.052 0.052 0.0521990 0.049 0.048 0.048 0.048 0.0480.047 0.047 0.046 0.046 0.0461991 0.054 0.054 0.050 0.050 0.0470.046 0.046 0.046 0.045 0.0441992 0.053 0.052 0.052 0.051 0.0500.050 0.049 0.049 0.049 0.0491993 0.053 0.053 0.051 0.048 0.0480.047 0.047 0.046 0.046 0.0461994 0.053 0.051 0.049 0.049 0.0490.048 0.048 0.048 0.048 0.0481995 0.058 0.056 0.056 0.054 0.0510.050 0.049 0.046 0.046 0.0461996 0.058 0.053 0.053 0.053 0.0520.052 0.052 0.052 0.051 0.0511997 0.054 0.053 0.052 0.051 0.0510.050 0.050 0.049 0.049 0.0491998 0.057 0.056 0.056 0.055 0.0540.054 0.054 0.054 0.053 0.0531999 0.056 0.056 0.054 0.054 0.0540.053 0.053 0.053 0.052 0.0512000 0.046 0.046 0.044 0.044 0.0440.043 0.043 0.042 0.042 0.0422001 0.061 0.058 0.057 0.055 0.0550.055 0.053 0.053 0.053 0.053Badlands NP460711001(South Dakota)730 m1989 0.069 0.066 0.064 0.063 0.0600.058 0.057 0.057 0.057 0.0571990 0.061 0.059 0.055 0.055 0.0540.052 0.052 0.051 0.051 0.0501991 0.058 0.058 0.056 0.056 0.0560.055 0.055 0.054 0.054 0.053

### AX3-26Table AX3-4 (cont’d). The Top 10 Daily Maximum 8-h Average Concentrations (ppm) for Sites Experiencing LowMaximum Hourly Average Concentrations with Data Capture of$75%Site Year 1 2 3 4 5 6 7 8 9 10Theod. Roos. NP380530002(North Dakota)730 m1984 0.064 0.062 0.062 0.062 0.0590.058 0.057 0.057 0.057 0.0571985 0.058 0.055 0.055 0.054 0.0540.054 0.053 0.053 0.053 0.0521986 0.059 0.058 0.057 0.056 0.0550.055 0.054 0.053 0.053 0.0521989 0.073 0.069 0.066 0.065 0.0650.064 0.063 0.063 0.063 0.0631992 0.060 0.059 0.058 0.058 0.0560.056 0.056 0.054 0.054 0.0541993 0.062 0.059 0.056 0.056 0.0550.053 0.052 0.052 0.052 0.0521994 0.066 0.064 0.058 0.058 0.0570.056 0.056 0.056 0.056 0.0551995 0.060 0.059 0.058 0.058 0.0580.058 0.057 0.057 0.056 0.0551996 0.060 0.059 0.059 0.059 0.0580.058 0.057 0.057 0.057 0.0561997 0.080 0.073 0.072 0.071 0.0690.068 0.066 0.066 0.063 0.063Theod. Roos. NP380070002(North Dakota)808 m1999 0.063 0.060 0.059 0.058 0.0570.057 0.057 0.056 0.056 0.0562000 0.062 0.061 0.060 0.059 0.0590.057 0.057 0.057 0.057 0.0572001 0.060 0.059 0.059 0.058 0.0580.057 0.057 0.056 0.055 0.055Custer NF, MT300870101(Montana)1006 m1978 0.069 0.065 0.063 0.062 0.0610.061 0.060 0.060 0.060 0.0581979 0.073 0.066 0.066 0.065 0.0630.060 0.060 0.060 0.059 0.0591980 0.069 0.069 0.069 0.068 0.0670.067 0.066 0.066 0.064 0.0641983 0.064 0.061 0.060 0.060 0.0590.058 0.058 0.058 0.056 0.056

### 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 Me trics for Characterizing Exposures of Vegetation to Ozone
The previous O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 interpola tion 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 O 3 

### 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 O 3 

### 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 NO

x 

### 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 Septemb er) 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 O 3 

### 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 O 3 

### exposure on vegetation and for establishing the spatial variations in O 3 

### concentrations as they are used in epidemiologic studies. Intracity variations in O 3 

### concentrations are described in Section

AX3.3.1. Small scale horizontal and vertical variations in O 3 

### concentrations are discussed in Section AX3.3.2. Ozone concentrations at high el evations are characterized in Section AX3.3.3.



## AX3.3.1 Spatial Variability of Ozon e Concentrations in Urban Areas
Many processes contribute to spatial variability in O 3 

### concentrations in urban areas. Ozone formation occurs more or less continuously downwind of sources of precursors, producing a gradient in O 3 

### concentrations. Ozone “titration” by reaction with NO can deplete O 3 

### 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 Septemb er) 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 Septemb er) 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 O 3 

### . Mixing of O 3 

### from aloft can also lead to local increases in O 3 

### concentration. The spatial variability in O 3 

### 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 O 3 

### over different regions of the country, and also to provide insight into the spatial distribution of O 3 

### 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 O 3 

### 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 O 3 

### 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 x ij and x ik represent the 24-h average PM 2.5 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 O 3 

### 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 O 3 

### 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 de nsities 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 (P 90 

### ) of the absolute difference in concentrations, and coefficients of divergence (COD) 1 

### . These methods of analysis follow those used for characterizing PM 2.5 

### and PM 10-2.5 

### concentrations in Pinto et al. (2004) and in the latest edition of the PM AQCD (U.S. Environmental Protection Ag ency, 2004a). Data were aggregated over

local O 3 

### 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 O 3 

### concentrations

over the local O 3 

### season from 1999 to 2001, the range of intersite correlation coefficients, the range of P 90 

### differences in O 3 

### 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 wereTable AX3-5. Summary Statistics for Ozone (in ppm)Spatial Variability in Selected U.S. Urban AreasUrban AreaNumber ofSitesMinimumMean Conc.MaximumMean Conc.MinimumCorr. Coeff.MaximumCorr. Coeff.MinimumP90aMaximumP90MinimumCODbMaximumCODBoston, MA 18 0.021 0.033 0.46 0.93 0.012 0.041 0.17 0.45New York, NY 29 0.015 0.041 0.45 0.96 0.0080 0.044 0.17 0.55Philadelphia, PA 12 0.020 0.0410.79 0.95 0.011 0.036 0.23 0.46Washington, DC 20 0.022 0.0410.72 0.97 0.010 0.032 0.17 0.45Charlotte, NC 8 0.031 0.043 0.48 0.95 0.012 0.038 0.17 0.32Atlanta, GA 12 0.023 0.047 0.63 0.94 0.013 0.045 0.24 0.55Tampa, FL 9 0.024 0.035 0.74 0.94 0.011 0.025 0.20 0.35Detroit, MI 7 0.022 0.037 0.74 0.96 0.0090 0.027 0.19 0.36Chicago, IL 24 0.015 0.039 0.38 0.96 0.0080 0.043 0.16 0.50Milwaukee, WI 9 0.027 0.0380.73 0.96 0.0090 0.025 0.18 0.33St. Louis, MO 17 0.022 0.0380.78 0.96 0.0090 0.031 0.15 0.41Baton Rouge, LA 7 0.018 0.0310.81 0.95 0.0090 0.029 0.23 0.41Dallas, TX 10 0.028 0.043 0.67 0.95 0.011 0.033 0.16 0.36Houston, TX 13 0.016 0.036 0.73 0.96 0.0090 0.027 0.20 0.38Denver, CO 8 0.022 0.044 0.60 0.92 0.013 0.044 0.16 0.46El Paso, TX 4 0.022 0.032 0.81 0.94 0.012 0.023 0.24 0.31Salt Lake City, UT 8 0.029 0.048 0.52 0.92 0.012 0.043 0.13 0.51Phoenix, AZ 15 0.021 0.058 0.29 0.95 0.011 0.057 0.15 0.61Seattle, WA 5 0.015 0.038 0.63 0.94 0.0080 0.024 0.16 0.46Portland, OR 5 0.015 0.036 0.73 0.91 0.011 0.025 0.20 0.50Fresno, CA 6 0.030 0.047 0.90 0.97 0.0090 0.027 0.17 0.40Bakersfield, CA 8 0.028 0.0470.23 0.96 0.013 0.052 0.20 0.58Los Angeles, CA 14 0.010 0.0420.42 0.95 0.010 0.053 0.22 0.59Riverside, CA 18 0.018 0.0540.38 0.95 0.013 0.057 0.15 0.64aP90 = 90th percentile absolutedifference 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 O 3 

### concentrations vary

within individual urban areas from factors of 1.4 to 4.0. The highest annual mean O 3 

### 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 O 3 

### concentration (0.010 ppm) was found in Lynwood in the urban core of the Los Angeles MSA. CO and NO

x 

### monitors at this site recorded the highest concentrations in California, indicating that titration of O 3 

### by NO freshly emitted from tail pipes of motor vehicles is responsible for the low O 3 

### values that are found. Ratios of highest to lowest mean O 3 

### 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 O 3 

### titration to varying degrees in their urban centers; and with maximum O 3 

### 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, P 90 

### 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 P 90 

### equaled or exceeded

seasonal mean O 3 

### concentrations. This was reflected in both values for P 90 

### and for the COD. It is instructive to compare the metrics for spatial variability shown in Table AX3-5 to

those calculated for PM 2.5 

### and PM 10-2.5 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Baton Rouge, LA MSA. The mean hourly measured O 3 

### 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 O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Detroit-Ann Arbor-Flint, MI CMSA. The mean hourly measured O 3 

### 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 O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the St. Louis, MO-IL MSA. The mean hourly measured O 3 

### 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 O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Phoenix-Mesa, AZ MSA. The mean hourly measured O 3 

### concentration at each site is given above its letter code. For each data pair, the Pearson correlation coefficient, 90th percentile difference in absolute co ncentrations, the coefficient of divergence, and number of observations are given.

### AX3-50 Figure AX3-33. Locations of O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Fresno, CA MSA. The mean hourly measured O 3 

### 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 O 3 

### concentrations is larger than for PM 2.5 

### concentrations and comparable to that obtained for PM 10-2.5 

### . Intersite correlation coefficients in some areas (e.g., Philadelphia, PA; Atlanta, GA; Portland, OR) can be very similar for both PM 2.5 

### and for O 3 

### . However, there is much greater variability in the concentration fields of O 3 

### as evidenced by the much higher COD values. Indeed, COD values are higher for O 3 

### than for PM 2.5 

### in each of the

urban areas examined. In all of the urban areas examined for O 3 

### some site pairs are always very highly correlated with each other (i.e., r > 0.9) as seen for PM 2.5 

### . These sites also show less

### AX3-51 Figure AX3-34. Locations of O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Bakersfield, CA MSA. The mean hourly measured O 3 

### 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 O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Los Angeles-Orange County, CA CMSA. The mean hourly measured O 3 

### 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 O 3 

### sampling sites (a) by AQS ID# (b) and intersite correlation statistics (c) for the Riverside-Orange County, CA CMSA. The mean hourly measured O 3 

### 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 O 3 

### 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 O 3 

### . These sources are not confined to urban areas. Sources

of emissions that react with O 3 

### such as highways and power plants are also found in rural areas. Johnson (1995) described the results of studies examining O 3 

### upwind and downwind of roadways in Cincinnati, OH. In these studies, O 3 

### 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 O 3 

### profile varied inversely with that of NO, as mi ght be expected. For peak NO concentrations of 30 ppb, the O 3 

### mixing ratio was about 36 ppb, or about 70% of the upwind value. The magnitude of the downwind depletion of O 3 

### depends on the emissions of NO, the rate of mixing of NO from the roadway and ambient temperatures. So depletions of O 3 

### downwind of roadways are expected, but with variable magnitude, although scavenging of O 3 

### by NO near roadways was more pronounced before the implementation of stringent NOx emissions controls. Guidance for the placement of O 3 

### 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 O 3 

### 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, O 3 

### levels are lower at sites located near traffic than those located some distance away and the scavenging of O 3 

### by emissions of NO from roadways is a major source of spatial variability in O 3 

### concentrations.

Vertical Variations in Ozone Concentrations In addition to horizontal variability in O 3 

### concentrations, consideration must also be given to variations in the vertical profile of O 3 

### 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 O 3 

### , 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 O 3 

### occurs throughout the planetary boundary layer. However, O 3 

### is also destroyed on the surfaces of buildings, vegetation, etc. On most
surfaces, O 3 

### is destroyed with every collision. In addition, O 3 

### is scavenged by NO emitted by motor vehicles and soils. These losses imply that the vertical gradient of O 3 

### 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 O 3 

### near the surface has been performed in nonurban areas with the aim of calculating fluxes of O 3 

### 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 O 3 

### 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 O 3 

### decreased by only about 7% during unstable conditions. The average decrease was about 10% for all measurements. As might be expected, O 3 

### 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 O 3 

### obtained in a spruce forest in northwestern Hungary in late summer 1991 (Horvath et al., 2003). The fall off in O 3 

### 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 concentra tions experienced at high-elevation cities are similar to those experienced in low-elevation cities. For example, the distribution of hourly average concentrations for several O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentration weighted by stability class was 33.1 ppb at 4 m.

Source. Horvath et al. (1995).

### AX3-59 Concentrations of O 3 

### vary with altitude and latitude. Although a number of reports contain

data on O 3 

### concentrations at high altitudes (e.g., Co ffey 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 O 3 

### exposure differences at different elevations. When applying different exposure indi ces to the MCCP data, there appears to be no consistency in the relationship between O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 SitesSite Elevation (m) Latitude LongitudeHowland Forest (HF1), ME 65 458° 11' 68° 46'Mt. Moosilauke (MS1), NH 1000 438° 59' 18" 71° 48' 28"Whiteface Mountain (WF1), NY 1483 448° 23' 26" 73° 51' 34"Shenandoah NP (SH1), VA 1015 38° 37' 12" 78° 20' 48"Shenandoah NP (SH2), VA 716 38° 37' 30" 78° 21' 13"Shenandoah NP (SH3), VA 524 38° 37' 45" 78° 21' 28"Whitetop Mountain (WT1), VA 1689 36° 38' 20" 81° 36' 21"Mt. Mitchell (MM1), NC 2006 35° 44' 15" 82° 17' 15"Mt. Mitchell (MM2), NC 1760 35° 45' 82° 15'



### AX3-60Table AX3-7. Seasonal (April-October) Percentiles,SUM06, SUM08, and W126 Values for the MCCP SitesSite Year Min. 10 30 5070(ppm) 90 95 99 Max.No.Obs. SUM06SUM08(ppm-h) W126Howland Forest, ME(HF1)1987 0.000 0.013 0.021 0.028 0.035 0.0460.052 0.065 0.076 4766 5.9 0.0 7.71988 0.000 0.012 0.021 0.028 0.036 0.0470.054 0.076 0.106 4786 10.9 2.9 11.6Mt. Moosilauke, NH(MS1)1987 0.006 0.027 0.036 0.045 0.053 0.0650.074 0.086 0.102 4077 45.0 9.5 40.11988 0.010 0.026 0.033 0.043 0.055 0.0760.087 0.113 0.127 2835 51.9 21.2 43.4Whiteface Mountain,NY (WF1)(36-031-0002)1987 0.011 0.029 0.037 0.046 0.053 0.0670.074 0.087 0.104 4703 63.5 12.2 50.51988 0.014 0.025 0.033 0.043 0.056 0.0780.089 0.110 0.135 4675 94.4 40.8 78.3Whiteface Mountain,NY (WF3)1987 0.010 0.025 0.033 0.039 0.047 0.0640.075 0.091 0.117 4755 45.4 14.4 40.3Whiteface Mountain,NY (WF4)1987 0.000 0.011 0.023 0.031 0.041 0.0560.065 0.081 0.117 4463 23.8 5.1 21.3Mt. Mitchell, NC(MM1)1987 0.008 0.034 0.044 0.051 0.058 0.0670.074 0.085 0.105 3539 59.4 7.8 46.51988 0.011 0.038 0.054 0.065 0.075 0.0950.106 0.126 0.145 2989 145.1 69.7 116.61989 0.010 0.038 0.047 0.054 0.059 0.0680.072 0.081 0.147 2788 54.8 3.5 40.71992 0.005 0.036 0.043 0.048 0.053 0.0630.069 0.081 0.096 3971 37.8 4.4 36.7Mt. Mitchell, NC(MM2)1987 0.017 0.032 0.042 0.049 0.056 0.0670.073 0.083 0.096 3118 47.0 5.1 37.41988 0.009 0.029 0.041 0.050 0.060 0.0800.092 0.110 0.162 2992 68.7 28.1 57.7Shenandoah Park,VA (SH1)1987 0.000 0.023 0.036 0.044 0.054 0.0690.076 0.085 0.135 3636 54.2 8.5 42.01988 0.006 0.024 0.036 0.047 0.058 0.0770.087 0.103 0.140 3959 80.9 29.6 67.2Shenandoah Park,VA (SH2)1987* 0.003 0.027 0.040 0.049 0.059 0.071 0.077 0.086 0.145 2908 55.7 7.8 41.81988 0.006 0.029 0.042 0.054 0.064 0.0830.095 0.108 0.145 4661 133.8 55.8 109.4



### AX3-61Table AX3-7 (cont’d). Seasonal (April-October) Percentiles, SUM06, SUM08, and W126 Values for the MCCP SitesSite Year Min. 10 30 5070(ppm) 90 95 99 Max.No.Obs. SUM06SUM08(ppm-h) W126Shenandoah Park,VA (SH3)1987 0.000 0.018 0.029 0.037 0.047 0.061 0.068 0.080 0.108 3030 23.1 2.6 19.21988 0.000 0.020 0.031 0.040 0.051 0.067 0.076 0.097 0.135 4278 52.3 15.6 44.2Whitetop Mountain,VA (WT1)1987 0.01 0.038 0.051 0.059 0.066 0.078 0.085 0.096 0.111 4326 147.7 32.4 105.71988 0.000 0.030 0.046 0.058 0.068 0.084 0.094 0.119 0.163 3788 133.8 51.0 102.8*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 O 3 

### 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 O 3 

### sites. Among the MCCP Shenandoah National Park sites, marginally higher O 3 

### 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 O 3 

### 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 O 3 

### 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 forest s they monitored experienced differences in O 3 

### 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 O 3 

### 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 O 3 

### concentration. In most cases, mixing ratios or mole fractions are used to describe O 3 

### concentrations. Lefohn et al. (1990b) pointed out that the manner in which concentration is reported may be importantwhen 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 O 3 

### 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 Sites a

Site Year Quarter 24-h 12-h 7-h 1-h Max. SUM06 10 3 ppb-h SUM08 10 3 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 Sites a

Site Year Quarter 24-h 12-h 7-h 1-h Max. SUM06 10 3 ppb-h SUM08 10 3 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 O 3 

### 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 linkexperimental data obtained at low-elevation sites with air quality data monitored at the highelevation stations. This topic is further disc ussed in Annex AX9 when considering effective dose considerations for predicting vegetation effects associated with O 3 

### .



## AX3.4 DIURNAL PATTERNS IN OZONE CONCENTRATION

AX3.4.1 Introduction

Diurnal variations in O 3 

### 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 effect s 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 O 3 

### 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 O 3 

### scavengers is generally lower, so O 3 

### concentrations remain fairly constant (Wolff et al., 1987) . A flat diurnal pattern is usually interpreted as indicating a lack of efficient scavenging of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### for April through October 2000 to 2004 are shown in Figure AX3-41. As can be seen from Figure AX3-41, daily 1-h O 3 

### maxima tend to occur in mid-afternoon and daily 1-h O 3 

### 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 O 3 

### data are shown in Figure AX3-42. As can be seen from Figure AX3-42, daily maximum eight hour O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### maxima at night. The diurnal variability of O 3 

### averaged over 8 hours in the same twelve urban areas is shown in Figures AX3-44a-l. The diurnal patterns of 1-h O 3 

### 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 Bo ston 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### levels. This pattern is more typical for the Los Angeles-Long Beach-Riverside, CA area even for high O 3 

### days. The same general timing patterns are found for 1-h daily maximum O 3 

### concentrations as for the daily maximum 8-h average O 3 

### concentration. As mentioned above, the daily maximum

8-h O 3 

### 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 O 3 

### concentration is highly correlated with the daily maximum 1-h average O 3 

### concentration, there are situations where the daily maximum 8-h average O 3 

### concentration may be driven by very high values in the daily maximum 1-h average O 3 

### concentration as illustrated in Figure AX3-43j. In cases such as these, the predicted 8-h average might overestimate the

short-term O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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, O 3 

### concentrations differ from weekdays to weekends. Heuss et al. (2003) described the results of a nationwide analysis of weekday/weekend differences that demonstrated significant variati on in these differences across the United States.

Weekend 1-h or 8-h maximum O 3 

### concentrations varied from 15% lower to 30% higher than weekday levels across the U.S. The weekend O 3 

### 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 O 3 

### concentrations also had higher O 3 

### on weekends even though the traffic and O 3 

### precursor levels were substantially reduced on weekends. The authors reported that detailed studies of this phenomenon indicated that the primary cause of the higher O 3 

### on weekends was the reduction in oxides of nitrogen emissions on weekends in a volatile organic compound (VOC)-limited (NO

x 

### -saturated) chemical regime (cf., Chapter 2). Heuss et al. (2003) hypothesized that the lower O 3 

### on weekends in other locations may result

from NO

x 

### reductions in a NO

x 

### -limited regime (cf., Chapter 2). Pun et al. (2003) described the day-of-week behavior for O 3 

### in Chicago, Philadelphia, and Atlanta. In Chicago and Philadelphia, maximum 1-h average O 3 

### increases on weekends. In
Atlanta, O 3 

### builds up from Mondays to Fridays and declines during the weekends. Fujita et al. (2003) pointed out that since the mid-1970s, O 3 

### 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 O 3 

### precursors are lower on weekends. Blanchard and Tanebaum (2003) noted that despite significantly lower O 3 

### precursor levels on weekends, 20 of 28 South Coast Air Basin sites showed statistically significant higher mean O 3 

### levels on Sundays than on weekdays. Chinkin et al. (2003) noted that ambient O 3 

### 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 O 3 

### 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 O 3 

### 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/week end differences for the 8-h averages. As can

### AX3-80 be seen from the figures, the lowest O 3 

### 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 Fi gure 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### by NO from local sources. Figure AX3-49a shows the diurnal pattern of 1-h average O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### to very low levels at night as shown. A relatively high peak 1-h O 3 

### concentrations is reached at 2 to 3 p.m. Figure AX3-51b shows the diurnal pattern

of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### will follow these basic patterns. Similar relations are found for the 8-h average O 3 

### concentrations.



## AX3.4.3 Diurnal Patterns in Nonurban Areas
Composite diurnal patterns of O 3 

### are shown in Figure AX3-55 for hourly averaged O 3 

### and in Figure AX3-56 for 8 hour average O 3 

### 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 O 3 

### are smoother and shallower at the rural sites than at the urban sites. Maxima in hourly averaged O 3 

### concentrations also tend to occur in afternoon. However, highest concentrations observed during any particular hour at ni ght 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 O 3 

### Figure AX3-51b. Diurnal variations in hourly averaged O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations are higher at the CASTNET sites than at the

urban sites. The diurnal variability of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### during the night and by photochemical reactions that form O 3 

### during the day. These sources are lacking in the vicinity of the North Dakota site, and O 3 

### observed there arrives mainly from transport from distant source regions. Logan (1989) described the diurnal variability of O 3 

### 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 O 3 

### in the United States during the past few decades can be found in the previous AQCD for O 3 

### . 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 O 3 

### exposures than other

sites. Variation in O 3 

### 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 J ones, 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 O 3 

### 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 O 3 

### 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 Progr am (MCCP) sites, noted the presence of the flat diurnal pattern typical of high-elevation s ites 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 O 3 

### 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 O 3 

### monitoring sites experience differing types of diurnal patterns, as shown in this section. The difference in diurnal patterns may influence the potential for O 3 

### 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 O 3 

### concentrations by month for selected urban sites for 2002. As can be seen from the figure, maximum 1-h O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### levels are confined to the summer. Highest average O 3 

### 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 O 3 

### varies across the 12 cities and high O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### averaged over November through March for EPA’s 12 cities.



## AX3.5.2 Seasonal Variations in Nonurban Areas
In assessing the effects of O 3 

### on vegetation, it is important to characterize the seasons in which the highest O 3 

### concentrations would be expected to occur in nonurban areas. It should not be assumed that highest O 3 

### concentrations occur at all locations during the summer. For example, places where highest average O 3 

### concentrations are observed during the spring (i.e., the months of April or May) versus the summer (E vans 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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, O 3 

### concentrations in rural areas of the eastern United States are affected differently by anthropogenic and natural emissions of NO

x 

### and hydrocarbons. These differences can affect the timing of occurrence of local peak O 3 

### concentrations (Logan, 1989).

O 3 

### episodes occur when the weather is particularly conducive to photochemical formation of O 3 

### . Taylor et al. (1992) reported that the temporal patterns of O 3 

### 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 reporte d. Meagher et al. (1987) reported that for

rural O 3 

### 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 freque ncy 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 O 3 

### 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 O 3 

### 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 O 3 

### episodes

occurred in the eastern United States. Lefohn et al. (1990a) characterized the O 3 

### concentrations for several sites in the United States exhibiting low maximum hourly average c oncentrations. 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 O 3 

### 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 O 3

### 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 O 3 

### . 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 O 3 

### 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 O 3 

### occurred during the period from fall to spring did not always have the lowest exposures to O 3 

### .



## AX3.6 TRENDS IN OZONE CONCENTRATIONS

Evidence for Trends in Ozone Concentratio ns at Rural Sites in the United States Year-to-year variability in the nationwide May to September, mean daily maximum 8-h O 3 

### 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 O 3 

### concentrations are shown in Figure AX3-65. Sites considered in this analysis are shown in the map in Figure AX3-3. Mean O 3 

### 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 O 3 

### during these 2 years. Trends in compliance metrics such as the fourth

### AX3-105 highest daily maximum 8-h average O 3 

### 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 O 3 

### concentrations observed at selected national park sites across th e United States. Figures AX3-67a-h show yearto-year variability in the 95th percentile value of daily maximum 8-h O 3 

### 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 O 3 

### 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 O 3 

### concentrations have resulted. As a result, trends are not shown for these sites. As noted in The Ozone Report—Measuri ng Progress through 2003 (U.S. Environmental Protection Agency, 2004b), O 3 

### trends in national parks in the South and the East are similar to nearby urban areas and reflect the regional nature of O 3 

### pollution. For example, O 3 

### trends in Charleston, SC and Charlotte, NC track those in nearby Cowpens NP and Cape Romaine NP in
South Carolina; O 3 

### in Knoxville and Nashville, TN tracks O 3 

### in Great Smoky NP; O 3 

### in Philadelphia, PA and Baltimore, MD tracks Brigantine NP in New Jersey; and New York, NY
and Hartford, CT track O 3 

### 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 O 3 

### 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 insi de 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### from Lassen Figure AX3-67q-v. Year-to-year variability in 95th percentile of daily maximum 8-h O 3 

### 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 O3Concentrations at National Parksin the United States (1990 to 2004). Trends are given as ppb yr!1.Mean P 95 P 98Site trend p–value trend p–value trend p–valueAcadia NP (ME) 0.04010.037 1.010.037!0.2 0.349Brigantine NWR (NJ)!0.8020.014!1.720.004!1.920.003Cape Cod NS (MA) 0 0.423 0 0.349!0.5 0.19Cape Romain NWR (SC) 0.710.046 1.010.01 1.0 0.07Chiricahua NM (AZ) 0.2210.046 0.2 0.084 0.15 0.218Cowpens NB (SC) 0 0.423 0.1 0.349 0.4 0.349Denali NP (AK) 0.17 0.12 0.610.01 0.610.002Glacier NP (MT) 0 0.5 0.1 0.349 0.27 0.19Grand Canyon NP (AZ) 0.25 0.07 0 0.5 0.13 0.218Great Smoky Mountains NP (NC-TN) 0.29 0.248 0.9 0.19 0.4 0.423Joshua Tree NP (CA)3— — — — ——Lassen Volcanic NP (CA) 0.25 0.141 0.2 0.19 0 0.5Mammoth Cave NP (KY)3— — — — ——Olympic NP (WA) 0.14 0.141 0.310.037 0.2 0.19Pinnacles NM (CA)!0.1 0.218!0.5 0.07!0.56 0.057Rocky Mountain NP (CO) 0.9110.004 1.010.014 0.88 0.07Saguaro NM (AZ)!0.2 0.279!0.3 0.19!0.38 0.141Sequoia/Kings Canyon NP (CA) 0.38 0.218 0 0.461 0 0.539Shenandoah NP (VA) 0 0.461!0.2 0.385 0.33 0.279Theodore Roosevelt NP (ND) 0.3810.023 0.2 0.19 0.2 0.141Voyageurs NP (MN)3— — — — ——Yellowstone NP (WY)3— — — — ——1Upward trend, significant at p = 0.05 level.2Downward trend, significant at p = 0.05 level.3Site 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 fr om five U.S. West Coast, marine boundary layer sites, Jaffe et al. (2003) reported that O 3 

### 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 O 3 

### precursors in Asia. They found positive trends in O 3 

### in all seasons. They also noted that diurnal variations during summer were about 21 ppb, but only about 6 ppb during spring. Although Lassen Volcan ic National Park site is not close to any major emission sources or urban centers, the site experiences maximum hourly average O 3 

### 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 O 3 

### 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, CH 3 

### CH 2 

### C(O)OONO 2 

### ) concentrations were given in the 1996 O 3 

### 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 H 2 

### O 2 

### were also presented in the 1996 O 3 

### AQCD. Data for these species are obtained as part of specialized fiel d 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 O 3 

### , 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 O 3 

### 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., O 3 

### and organic nitrates) are closely related photochemically and correlate with each other strongly. Others (e.g., O 3 

### and H 2 

### O 2 

### ) show a more complex correlation pattern. Although NO 2 

### is produced mainly by the reaction of directly emitted NO with O 3 

### with some contributions from direct emissions, in practice, it behaves like a primary species. The

timescale for conversion of NO to NO 2 

### is fast (5 min or less), so NO and NO 2 

### ambient concentrations rapidly approach values determined by the photochemical steady state. The sum

NO + NO 2 

### (NO

x 

### ) behaves like a typical primary species, while NO and NO 2 

### reflect some additional complexity based on photochemical interconversion. As a primary species, NO 2 

### generally does not correlate with O 3 

### in urban environments. In addition, chemical interactions among O 3 

### , NO and NO 2 

### have the effect of converting O 3 

### to NO 2 

### and vice versa, which can result in a significant anti-correlation between O 3 

### and NO 2 

### . 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 O 3 

### . Photochemical production is initiated by the reaction of primary and secondary VOCs with OH radicals, the resulting organic radicals subsequently react with NO 2 

### (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 O 3 

### . 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 O 3 

### (Sillman et al., 1990). Ozone and PAN may

### AX3-116 show different seasonal cycles, because they are affected differently by temperature. Ambient

O 3 

### 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, O 3 

### /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 O 3 

### and PAN, and between O 3 

### and other organic nitrates (Pippin et al., 2001; Roberts et al., 1998). Moreover, the uncertainty in the relationship between O 3 

### and PAN grows as the level of PAN increases. Individual primary VOCs are generally highly correlated with each other and with NO

x 

### (Figure AX3-69). A summary of the results of a number of field studies of the concentrations of precursors including NO

x 

### and nonmethane organic compounds (NMOCs) are summarized in the

1996 O 3 

### AQCD.

Formation of H 2 

### O 2 

### takes place by self-reaction of photochemically generated HO 2 

### radicals, so that there is large seasonal variation of H 2 

### O 2 

### concentrations and values in excess of 1 ppb are mainly limited to the summer months (Kleinman, 1991). Although H 2 

### O 2 

### is produced from photochemistry that is closely related to O 3 

### , it does not show a consistent pattern of correlation

with O 3 

### . Hydrogen peroxide is produced in abundance along with O 3 

### only when O 3 

### is produced

under NO

x 

### -limited conditions. When the photochemistry is NO

x 

### -saturated much less H 2 

### O 2 

### is produced. In addition, increasing NO

x 

### tends to slow the formation of H 2 

### O 2 

### under NO

x 

### -limited

conditions. Measurements of gas phase peroxides in the atmosphere were reviewed by Lee et al. (2000). Ground level measurements of H 2 

### O 2 

### 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 J une 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 f ound 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 O 3 

### (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 hydr operoxides 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 H 2 

### O 2 

### over the eastern United States were reported by Heikes et al. (1987). More recent aircraft measurements of hydroperoxide (H 2 

### O 2 

### , CH 3 

### OOH and

HOCH 2 

### OOH) 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 NO y 

### at a measurement site in Boulder, CO. Instances with SO 2 

### >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% contributi on from organic hydroperoxides. Median O 3 

### was about 70 ppbv at the same time. The concentra tions 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 O 3 

### is generally accompanied by elevated HNO 3 

### , although the correlation is not as strong as between O 3 

### and organic nitrates. Ozone often correlates with HNO 3 

### , because they have the same precursor (NO

x 

### ). However, HNO 3 

### can be produced in significant quantities in winter,

even when O 3 

### is low. The ratio between O 3 

### and HNO 3 

### also shows great variation in air pollution
events, with NO

x 

### -saturated environments having much lower ratios of O 3 

### to HNO 3 

### (Ryerson et al., 2001). Aerosol nitrate is formed primarily by the combination of nitrate (supplied by HNO 3 

### ) with ammonia, and may be limited by the availability of either nitrate or ammonia.

### AX3-119 Nitrate is expected to correlate loosely with O 3 

### (see above), whereas ammonia is not expected to

correlate with O 3 

### . In addition to nitrate, other oxidants are pres ent 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 H 2 

### O 2 

### concentrations. Unlike O 3 

### and gas phase H 2 

### O 2 

### 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 NO 3 

### radicals. The concentration of ROS, expressed as equivalent H 2 

### O 2 

### (5.2 to 6.1 × 10 -7 

### M/m 3 

### , ranged from 20% to 100% that of O 3 

### (diurnal average: 30%), with highest values at night. The ratio was likely higher at the early morning minimum

for O 3 

### . 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/m 3



### . However, O 3 

### levels were also substantially lower leading to ROS concentrations about 20%

those of O 3 

### . It is of interest to note that gas phase OH concentrations measured at the same time ranged from about 7.5 × 10 4 

### /cm 3 

### to about 1.8 × 10 6 

### /cm 3 

### , 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 NO

x 

### . 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 (H orowitz 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 st udy 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 concentrati ons 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 Paci fic 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 O 3 

### production, enhancing the O 3 

### background (Kotchenruther et al., 2001b; Hudman et al., 2004). Relations between primary and secondary components discussed above are illustrated by considering data for O 3 

### and PM 2.5 

### . Ozone and PM 2.5 

### 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, PM 2.5 

### , regarded as a function

of O 3 

### , increases to the left of the inflection point (at about 30 ppbv O 3 

### ) and also increases

with O 3 

### to the right of the inflection point. Data to the left of the minimum in PM 2.5 

### 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 PM 2.5 

### contains a large secondary component during the summer and has a larger primary component during winter. During the winter, O 3 

### 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 PM 2.5 

### and O 3 

### 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 PM 10 

### and O 3 

### on a seasonal basis in several urban areas (cf., Figure 7-24). Although PM 10 

### contains proportionately more primary material than does PM 2.5 

### , relations similar to those shown in Figure AX3-70 are found, re flecting the dominant contribution from PM 2.5 

### to PM 10 

### .

### 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 PM 2.5 

### concentrations versus binned mean O 3 

### 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 atdifferent hours during the period, the co-occurrence pattern was defined as “complexsequential.” For characterizing the different types of co-occurrence patterns for O 3 

### /NO 2 

### , O 3 

### /SO 2 

### , and NO 2 

### /SO 2 

### , 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 minimumconcentration 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 NO 2 

### /O 3 

### and SO 2 

### /O 3 

### 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-t o-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 PM 2.5 

### . Because of the availability of the PM 2.5 

### data, daily

co-occurrence of PM 2.5 

### and O 3 

### over a 24-h period was characterized. Because PM 2.5 

### data are mostly summarized as 24-h average concentrations in the AQS data base, a daily co-occurrence

of O 3 

### and PM 2.5 

### was subjectively defined as when an hourly average O 3 

### concentration $ 

### 0.05 ppm

and a PM 2.5 

### 24-h concentration $ 

### 40 μg/m 3 

### occurred over the same 24-h period. For exploring the co-occurrence of O 3 

### 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 estimat e 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 O 3 

### and NO 2 

### were defined by the presence or absence

of NO 2 

### . 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 O 3 

### , the number of

co-occurrences with NO 2 

### was small.

### AX3-124 Figure AX3-71. The co-occurrence pattern for O 3 

### and NO 2 

### .

Source: Lefohn and Tingey (1984).



### Using 2001 data from the U.S. EPA AQS database, patterns that showed air pollutant pairs

of O 3 

### /NO 2 

### 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 O 3 

### season (Table AX3-1). In 2001, there were 341 monitoring sites that co-monitored O 3 

### and NO 2 

### . 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 O 3 

### and NO 2 

### using 2001 data from the AQS.



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

Because elevated SO 2 

### 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 SO 2 

### and O 3 

### . Lefohn et al. (1987) reported that even with a threshold of 0.03 ppm O 3 

### , the number of co-occurrences with SO 2 

### 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 O 3 

### episodes at specific rural locations appeared to be associated with elevated SO 2 

### levels. The investigators defined the

co-occurrence of O 3 

### and SO 2 

### 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 O 3 

### , nitrogen, and sulfur in forested areas using cumulative exposures of O 3 

### with data on dry deposition of sulfur and nitrogen. The authors concluded in

### AX3-126 Figure AX3-73. The co-occurrence pattern for O 3 

### and SO 2 

### .

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 O 3 

### 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 O 3 

### and SO 2 

### or of O 3 

### and NO 2 

### . Using 2001 data from the EPA AQS database, patterns that showed air pollutant pairs

of O 3 

### /SO 2 

### 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 O 3 

### and SO 2 

### . 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 O 3 

### and SO 2 

### 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 O 3 

### and SO 2 

### . Similar to the analysis summarized by Lefohn and Tingey (1984), most of thecollocated 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 PM 2.5 

### Using 2001 data from the EPA AQS, the daily co-occurrence of PM 2.5 

### and O 3 

### over a 24-h period was characterized. There were 362 sites where PM 2.5 

### and O 3 

### monitors were collocated. As described in the introduction selection of this annex, a daily co-occurrence of O 3 

### and PM 2.5 

### is subjectively defined as an hourly average O 3 

### concentration $ 

### 0.05 ppm and a PM 2.5 

### 24-h

concentration $ 

### 40 μg/m 3 

### 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 PM 2.5 

### and O 3 

### was infrequent.

### AX3-128 Figure AX3-75. The co-occurrence pattern for O 3 

### and PM 2.5 

### using 2001 data from AQS.



## AX3.8.5 Co-Occurrence of Oz one with Acid Precipitation
Concern has been expressed about the possible effects on vegetation from co-occurring exposures of O 3 

### 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 O 3 

### and acidic deposition (i.e., H + 

### ). Lefohn and Benedict (1983) reviewed the EPA SAROAD monitoring data for 1977 through 1980 and, using National Atmos pheric Deposition Program (NADP) and EPRI wet deposition data, evaluated the frequency dist ribution of pH events for 34 NADP and 8 EPRI chemistry monitoring sites located across the United States. Unfortunately, there were few sites

where O 3 

### and acidic deposition were co-monitored. As a result, Lefohn and Benedict (1983) focused their attention on O 3 

### 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 O 3 

### monitoring data and weekly and event acidic deposition data from the NADP and EPRI databases, the authors identified specific locations where the hourly mean O 3 

### concentrations were $ 

### 0.1 ppm and 20% of the wetfall daily or weekly samples were below pH

4.0. Elevated levels of O 3 

### 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 O 3 

### 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 O 3 

### and H + 

### concentrations. The authors stated that they believed, based on the available data, the greatest potential for interaction between acid rain and O 3 

### 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., O 3 

### and acidic deposition) could be used

because O 3 

### exposures are regional in nature. However, work by Lefohn et al. (1988) has shown that hourly mean O 3 

### 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 O 3 

### concentrations from known locations to other areas within a region may provide only qualitative indications of actual O 3 

### exposure patterns. In the late 1970s and the 1980s, both the private sector and the government funded researchefforts 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 O 3 

### 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 O 3 

### and cloud deposition will be different from those patterns associated with O 3 

### and deposition by precipitation.

### AX3-130 Smith and Lefohn (1991) explored the relationship between O 3 

### and H + 

### in precipitation, using data from sites that monitored both O 3 

### 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 O 3 

### exposure were at least moderately high (i.e., annual H + 

### deposition $ 

### 0.5 kg ha

! 1 

### and an annual O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### level and pH (or H + 

### deposition) were weak to nonexistent. Sites most subject to relatively high levels of both H + 

### and O 3 

### 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 O 3 

### and acid precipitation, results have been reported on

the co-occurrence of O 3 

### and acidic cloudwater in high-elevation forests. Vong and Guttorp (1991) characterized the frequent O 3 

### -only and pH-only, single-pollutant episodes, as well as the simultaneous and sequential co-occurrences of O 3 

### 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 O 3 

### average concentrations

$ 

### 0.07 ppm and cloudwater events with pH # 

### 3.2. The authors reported that simultaneous

occurrences of O 3 

### 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 O 3 

### -only episode. As would be expected,

O 3 

### -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 O 3 

### concentrations used for NAAQS-setting purposes are referred to as Policy Relevant Background (PRB) O 3 

### 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 O 3 

### NAAQS, EPA assesses risks to human health and environmental

effects to O 3 

### levels in excess of PRB concentrations. Issues concerning the methodology for estimating PRB O 3 

### concentrations are described in detail in Annex AX3, Section AX3.9.

Contributions to PRB O 3 

### include: photochemical interactions involving natural emissions
of VOCs, NO

x 

### , and CO; the long-range transport of O 3 

### and its precursors from outside North America; and stratospheric-tropospheric excha nge (STE). Processes involved in STE are

described in detail in Annex AX2.3. Natural sources of O 3 

### precursors include biogenic emissions, wildfires, and lightning. Biogenic emissions from agricultural activities are not

considered in the formation of PRB O 3 

### . Most of the issues concerning the calculation of PRB O 3 

### center on the origin of springtime

maxima in surface O 3 

### concentrations observed at monitoring sites in relatively unpolluted areasof 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 O 3 

### values, especially those averaged over 1-h to

8-h observed at O 3 

### monitoring sites during late winter through spring (i.e., February to June). The issues raised do not affect interpretations of the causes of summertime O 3 

### episodes as strongly. Summertime O 3 

### 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 O 3 

### 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 O 3 

### 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 st udies (Lelieveld and Dentener, 2000; Browell et al., 2003) attribute the springtime maximum in tropospheric O 3 

### concentrations to tropospheric production rather than transport from the stratosphere. It should be noted here that O 3 

### 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 14 

### C, 137 

### Cs and 90 

### Sr. Springtime O 3 

### 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 Grubiši ƒ 

### , 1991). Of the numerous measurements of tropospheric O 3 

### made in the 19th century, only the iodine catalyzed oxidation

of arsenite has been verified with modern labor atory 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 O 3 

### mixing ratios ranged from 5 to 16 ppb with uncertainty of ±2 ppb. Interferences from SO 2 

### were avoided as the Montsouris data were
selected to exclude air from Paris, th e only source of high concentrations of SO 2 

### 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 O 3 

### concentrations at Yellowstone National Park, Wyoming in 1998, 1999, 2000, and 2001.

Figure AX3-76b. Hourly average O 3 

### concentrations at Yellowstone National Park, Wyoming for the period January to December 2001.

Source: U.S. Environmental Protection Agency (2003).

### AX3-134 surface O 3 

### 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 O 3 

### profiles at a large number of sites indicate a positive gradient in O 3 

### mixing ratios with increasing altitude in the troposphere and a springtime maximum in O 3 

### 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 re gions 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, O 3 

### formed by lightning-generated NO

x 

### also contributes to

the vertical O 3 

### gradient (Lelieveld and Dentener, 2000). This O 3 

### could be either background or not, depending on the sources of radical precursors. Another contributing factor is the increase

of O 3 

### lifetime with altitude (Wang et al., 1998). Free-tropospheric O 3 

### 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 fold s 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 th rough 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 cu mulonimbus 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 O 3 

### (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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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, Spitsbergen a 475 1989-1993 28-33 b

Mauna Loa, Hawaii c 3397 1992-2001 37-46 d

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 Backgro und 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 37-45 a 68-79 a
Rocky Mountain NP, Colorado 2743 1994-2001 40-47 a 68-102 a
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 38-43 a 81-109 a
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 Cana dian Background Stations (CAPMoN a 

### , 2003)

Location Elevation (m) Period of Record Range of Annual Medians Range of Annual Maxima

Kejimkujik, Nova Scotia b 127 1989-2001 25-34 76-116
Montmorency, Quebec 640 1989-1996 28-32 73-99
Algoma, Ontario a 411 1988-2001 27-33 76-108
Chalk River, Ontario 184 1988-1996 25-31 79-107
Egbert, Ontario a 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 tr ansport 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 (NO y 

### ) (defined in AX2.2.2) and VOCs to Arctic regions can occur from midlatitude-source regions. In addition, O 3 

### 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 O 3 

### 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 O 3 

### and NO 2 

### in the Arctic spring. Jaffe et al. (1991) found NO y 

### concentrations approaching 1 ppb in Barrow, Alaska, in the spring and attributed them to long-range transport.

### AX3-139Table AX3-13. Number of Hours$0.05 ppm for Selected Rural O3Monitoring in the United Statesby Month for the Period 1988 to 2001Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001Denali National Park, Alaska February 0 0 0 0 0 0 0 0 0 0 0 0 14Denali National Park, Alaska March 0 0 0 0 0 0 0 0 52 0 122 17 0 24Denali National Park, Alaska April 217 0 2 0 64 10 31 21 12 51 236 119 0 302Denali National Park, Alaska May 26 1 0 24 10 17 1 54 97 35 79 29 0 98Denali National Park, Alaska June 0 0 0 0 0 0 0 0 27 0 0 22 0 6Yellowstone National Park,WyomingFebruary 0 0 11 3 0 21 6 0 1 5 252 23 77Yellowstone National Park,WyomingMarch 194 2 4 95 26 285 14 7 98 150 509 286 307Yellowstone National Park,WyomingApril 228 17 16 217 62 311 185 65 163 385 517 242 461Yellowstone National Park,WyomingMay 225 2 10 196 47 180 193 212 216 289 458 240 350Yellowstone National Park,WyomingJune 58 67 139 33 28 116 81 94 149 78 212 181 172

### AX3-140Table AX3-13 (cont’d). Number of Hours$0.05 ppm for Selected Rural O3Monitoring in the United States by Monthfor the Period 1988 to 2001Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001Glacier National Park,MontanaFebruary 0 0 0 0 0 8 0 0 0 0 0 0Glacier National Park,MontanaMarch 49 9 24 10 23 40 35 9 6 17 5 4Glacier National Park,MontanaApril 31 64 29 5 45 16 46 52 49 128 16 0Glacier National Park,MontanaMay 20 81 67 41 66 51 51 4 122 103 63 23Glacier National Park,MontanaJune 24 37 31 5 29 13 119 0 3 0 6 0Voyageurs National Park,MinnesotaFebruary 3 0 0 0 0 43 22 0 0 23 0 6 32 0Voyageurs National Park,MinnesotaMarch 6 2 0 0 1 94 10 39 49 220 40 215 60 0Voyageurs National Park,MinnesotaApril 48 0 31 22 27 56 65 30 64 128 254 221 175 0Voyageurs National Park,MinnesotaMay 183 33 14 10 174 78 96 107 111 146 191 247 143 62Voyageurs National Park,MinnesotaJune 92 2 0 55 50 66 190 37 221 25 23 28 95

### AX3-141Table AX3-14. Number of Hours$0.06 ppm for Selected Rural O3Monitoring Sites in the United States by Monthfor the Period of 1988 to 2001Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001Denali National Park,AlaskaFebruary 0 0 0 0 0 0 0 0 0 0 0 0 0Denali National Park,AlaskaMarch 0 0 0 0 0 0 0 0 0 0 0 0 0 0Denali National Park,AlaskaApril 0 0 0 0 0 0 0 0 0 0 0 0 0 0Denali National Park,AlaskaMay 0 0 0 0 0 0 0 0 2 0 0 0 0 9Denali National Park,AlaskaJune 0 0 0 0 0 0 0 0 0 0 0 0 0 2Yellowstone NationalPark, WyomingFebruary 0 0 0 0 0 0 0 0 0 0 6 0 0Yellowstone NationalPark, WyomingMarch 37 0 0 0 0 0 0 0 1 0 120 1 4Yellowstone NationalPark, WyomingApril 59 0 0 29 0 20 4 0 0 64 158 11 77Yellowstone NationalPark, WyomingMay 20 0 0 61 3 42 24 38 26 54 169 49 139Yellowstone NationalPark, WyomingJune 8 7 18 2 1 13 0 0 22 4 27 43 18Glacier National Park,MontanaFebruary 0 0 0 0 0 0 0 0 0 0 0 0Glacier National Park,MontanaMarch 1 0 0 0 0 0 0 0 0 0 0 0

### AX3-142Table AX3-14 (cont'd). Number of Hours$0.06 ppm for Selected Rural O3Monitoring Sites in the United States by Monthfor the Period of 1988 of 2001Site Name Month 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001Glacier National Park,MontanaApril 0 0 1 0 0 0 0 0 2 1 0 0Glacier National Park,MontanaMay 2 7 13 0 0 4 5 0 16 19 8 0Glacier National Park,MontanaJune 0 3 1 0 1 0 16 0 0 0 0 0Voyageurs NationalPark, MinnesotaFebruary 1 0 0 0 0 1 8 0 0 0 0 0 0 0Voyageurs NationalPark, MinnesotaMarch 0 0 0 0 0 34 0 5 2 15 0 9 4 0Voyageurs NationalPark, MinnesotaApril 9 0 1 0 0 5 8 0 17 2 57 24 41 0Voyageurs NationalPark, MinnesotaMay 77 6 0 0 40 9 40 2 27 46 53 139 43 6Voyageurs NationalPark, MinnesotaJune 30 0 0 28 17 5 113 12 115 0 5 0 32

### AX3-143 Figure AX3-78. Maximum hourly average O 3 

### 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 O 3 

### , PAN, and NO

x 

### in Alaska and Svalbard, Norway and concluded that PAN decomposition can lead to photochemical O 3 

### production. At Poker Flat, Alaska, O 3 

### production was directly observable. Herring et al. (1997) tracked springtime O 3 

### maxima in Denali National Park, Alaska, an area one might presume to be pristine. They measured NO

x 

### and hydrocarbons and concluded that, in the spring, O 3 

### was produced predominantly by photochemistry at a calculated rate of 1 to 4 ppb/day, implying that

the O 3 

### observed could be produced on timescales ranging from about a week to a month. Solberg et al. (1997) tracked the major components of NO y 

### in remote Spitsbergen, Norway for the first half of the year 1994. They observed high concentrations of PAN (800 ppt) peaking simultaneously with O 3 

### (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 O 3 

### precursors in the winter and substantial quantities of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### has been performed as part of the AEROCE and NARE studies (cf., Sections AX2.3.4a,b) and TOPSE (Browell et al., 2003). Thes e first two studies found that elevated or

surface O 3 

### > 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 Figur e 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 O 3 

### 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 O 3 

### observed at the surface, since the subsiding conditions are also associated with strong inversions and clear skies that promote O 3 

### production within the boundary layer. Thus, it would be highly problematic to use observations alone as estimates of PRB O 3 

### 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 O 3 

### budget. Estimates of O 3 

### STE of O 3 

### 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 O 3 

### 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 O 3 

### 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 me teorological mechanism involved in high concentrations of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 Atmosphere1Reference ModelStratosphereTroposphereExchange(STE)ChemicalProduction2ChemicalLoss2DryDepositionBurden(Tg)Lifetime(days)3TAR411 models 770 ± 400 3420 ± 770 3470 ± 520 770 ± 180 300 ± 30 24 ± 2Lelieveld andDentener (2000)570 3310 3170 710 350 33Bey et al. (2001a)5GEOS-CHEM 470 4900 4300 1070 320 22Horowitz et al.(2003)MOZART-2 340 5260 4750 860 360 23Von Kuhlmannet al. (2003)MATCH-MPIC 540 4560 4290 820 290 21Shindell et al. (2003) GISS 417 NR6NR 1470 349 NRPark et al. (2004) UMD-CTM 480 NR NR 1290 340 NRRotman et al. (2004) IMPACT 660 NR NR 830 NR NRWong et al. (2004) SUNYA/UiO GCCM 600 NR NR 1100 376 NR1From global CTM simulations describing the atmosphere of the last decade of the 20th century.2Chemical production and loss rates are calculated for the odd oxygen family, usually defined as Ox= O3+ O + NO2+ 2NO3+ 3N2O5+ HNO4+peroxyacylnitrates (and sometimes HNO3), to avoid accounting for rapid cycling of O3with short-lived species that have little implication for its budget.Chemical production is mainly contributed by reactions of NO with peroxy radicals, while chemical loss is mainly contributedby the O(1D) + H2O reactionand by the reactions of O3with HO2C,COH, and alkenes. Several models in this table do not report production and loss separately (“NR” entry in the table),reporting instead net production. However, net production isnot a useful quantity for budget purposes, because (1) it represents a small residual betweenlarge production and loss, (2) it represents the balance between STE and dry deposition, both of which are usually parameterized as a flux boundarycondition.3Calculated as the ratio of the burden tothe sum of chemical and deposition losses4Means and standard deviations from an ensemble of 11 CTM budgetsreported in the IPCC TAR. The mean budget does not balance exactly becauseonly 9 CTMs reported chemical production and loss statistics.5The Martin et al. (2003) more recent version ofGEOS-CHEM gives identical rates and burdens.6Not reported.



### AX3-146

### AX3-147 Even if the magnitude of cross-tropopause O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### vertical profile that was recorded at Boulder, CO on May 6, 1999, at 1802 UTC (1102 hours LST). The ragged vertical profile of O 3 

### 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 O 3 

### , 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 (Fi gure 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 O 3 

### 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 Mode ls to Simulate Tropospheric Ozone
The current generation of global CTMs includes detailed representation of tropospheric

O 3 

### -NO

x 

### -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 O 3 

### 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 O 3 

### . Stratosphere-troposphere exchange of O 3 

### in global models is generally parameterized. The parameterizations are typically constrained to match the global mean O 3 

### cross-tropopause flux, which is in turn constrained by a number of observational proxies (550 ± 140 Tg O 3 

### 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 O 3 

### (Logan, 1999). Such evaluations show that the parameterized cross-tropopause O 3 

### flux in global models results in a good simulation of tropospheric O 3 

### , 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 O 3 

### concentrations across the United States. A net global O 3 

### flux of 490 Tg O 3


### year ! 1 

### from the stratosphere to the troposphere is imposed in the GEOS-CHEM model, consistent with the range constrained by observati ons (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 210 

### Pb- 7 

### Be-O 3 

### relationships observed

in three aircraft missions over the western Pacific indicates that the model does not underestimate the stratospheric source of O 3 

### (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 O 3 

### 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 O 3 

### under-prediction in regions of preferred stratospheric downwelling. Fiore et al. (2002a, 2003b) presented a detailed evaluation of the model simulation for O 3 

### 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 O 3 

### frequency distributions at sites in the eastern United States (although sub-grid-scale local peaks are underestimated), the O 3 

### to (NO y 

### - NO

x 

### ) relationships, and that the highest O 3 

### 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 O 3 

### over the eastern United States are also well reproduced, indicating that GEOS-CHEM captures the synoptic-scale transport processes modulating surface O 3 

### 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 O 3 

### 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 km 2 

### horizontal resolution showed that the models exhibit similar skill at capturing the observed variance in O 3 

### concentrations with comparable model biases (Fiore et al., 2003b).

Simulations to Quantify Background Ozone Over the United States The sources contributing to the O 3 

### 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 NO

x 

### , NMVOC, and CO emissions are set to zero, and (3) a natural O 3 

### simulation in which global anthropogenic NO

x 

### , NMVOC and CO emissions are set to zero and the CH 4 

### concentration is set to its 700 ppbv pre-industrial value. Anthropogenic emissions of NO

x 

### , nonmethane volatile organic compounds (NMVOCs), and CO include c ontributions from fuel use, industry, and fertilizer application. The difference between the standard and background simulations represents regional pollution, i.e., the O 3 

### enhancement from North American anthropogenic emissions. The difference between the background and natural simulations represents hemispheric pollution, i.e., the O 3 

### enhancement from anthropogenic emissions outside North

America. Methane and NO

x 

### contribute most to hemispheric pollution (Fiore et al., 2002b). A tagged O 3 

### 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 O 3 

### 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 O 3 

### simulation where surface concentrations were controlled by large-scale processes.



## AX3.9.3 Mean Background Concentratio ns: Spatial and Seasonal Variation
The analysis of Fiore et al. (2003a) focuse d on the 2001 observations from the Clean Air Status and Trends Network (CASTNet) of rura l 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 NO

x , NMVOC, and CO emissions
set to zero 2 / × 2.5 /

Natural Global anthropogenic NO

x , NMVOC, and CO emissions set to zero and CH 4 concentration set to its 700 ppbv preindustrial value 4 / × 5 /

Stratospheric Tagged O 3 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) O 3 

### concentrations averaged over the CASTNet stations in each U.S. quadrant.

Measured O 3 

### 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 anth ropogenic emissions in North America; see Table AX3-16) are shown as diamonds in Figure AX3-82. Mean afternoon background O 3 

### 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 O 3 

### 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 O 3 

### (Wang et al., 1998).

Results from the natural O 3 

### simulation (no anthropogenic emissions anywhere; Table AX3-16) are shown as crosses in Figure AX3-82. Natural O 3 

### concentrations are also highest in the West and in spring when the influence of stratospheric O 3 

### on the troposphere peaks (e.g., Holton et al., 1995). Monthly mean natural O 3 

### 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 O 3 

### 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 (O 3 

### 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 O 3 

### 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-Ozo ne Occurrences at Remote Sites
Lefohn et al. (2001) pointed out the frequent occurrence of high-O 3 

### 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 O 3 

### 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 O 3 

### are shown. The U.S. quadrants are centered at 98.75 B 

### W and 37 B 

### 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 O 3 

### 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 indi cate that 2001 had fewer than average incidences of high-O 3 

### events. At Voyageurs National Park in Minnesota, March and April 2001 had lower-than-average frequencies of high-O 3 

### events, but May and June were more typical. Overall, 2001 was considered to be a suitable year for analysis of high-O 3 

### 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 O 3 

### 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. Fior e et al. (2003a) tested whether an analysis restricted to these mean 1300 to 1700 LT surface concentrations captures the same frequency

of O 3 

### >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 O 3 

### >50 and 60 ppbv at the CASTNet sites is always greater than the percentage of all hourly occurrences above these thresholds, indicating

that elevated O 3 

### concentrations preferentially occur in the afternoon. Furthermore, Table AX3-17 shows that the frequency of observation of high-O 3 

### 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-O 3 

### 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) O 3 

### concentrations in surface air at the CASTNet sites for March through October 2001. Model distributions for background, natural, and stratospheric

O 3 

### (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 O 3 

### concentrations in surface air are usually below 40 ppbv. The background O 3 

### 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 O 3 

### versus NO y 

### - NO

x 

### correlation is affected by different

relative removal rates of O 3 

### and NO y 

### (Trainer et al., 1993). Natural O 3 

### 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 O 3 

### 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-O 3 

### 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, O 3 

### 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) O 3 

### 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 O 3 

### (Table AX3-23).

Source: Fiore et al. (2003a).



### Figure AX3-84. Daily mean afternoon (13 to 17 LT) O 3 

### 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) O 3 

### 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-O 3 

### events. The simulated background contribution (diamonds) ranges from 15 to 36 ppbv with a 25 ppbv mean. The natural O 3 

### 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-O 3 

### 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-O 3 

### events, ppbv. In 2001, monthly mean observed and simulated O 3 

### 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 O 3 

### and the

lack of O 3 

### >60 ppbv in July and August reflects a stronger Bermuda high-pressure system sweeping pollution from southern regions eastw ard before it could reach Voyageurs National

Park. Frequently observed concentrations of O 3 

### between 60 to 80 ppbv at Yellowstone NP in spring (Figures AX3-76a,b) have been attribut ed by Lefohn et al. (2001) to natural sources, because they occur before local park traffic star ts and back-trajectories do not suggest influence from long-range transport of anthropogenic sources. More hours with O 3 

### >60 ppbv occur in April and May of 2001 (Table AX3-17) than in th e 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations are rarely above 60 ppbv. While variations in the background play a role in governing the observed total O 3 

### 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 O 3 

### 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) O 3 

### 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) O 3 

### are also shown.

Source: Fiore et al. (2003a).

### AX3-161 high temperatures and anticyclonic circulation, conditions conducive to photochemical O 3 

### production. Peak O 3 

### 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 O 3 

### 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 O 3 

### and related photochemical

oxidants are based on the measured O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### AQCD (U.S. Environmental Protection Agency, 1996a), based on then currently available information, indicated that less emphasis should be placed on O 3 

### 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 O 3 

### 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 O 3 

### were significantly different

from ambient O 3 

### concentrations. Ambient O 3 

### varied from O 3 

### concentrations measured at fixedsite monitors. Very limited personal exposure measurements were available at the time the

1996 O 3 

### AQCD was published, so estimates of O 3 

### exposure or evaluated models were not provided. The two available personal exposure st udies 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 O 3 

### exposure modeling primarily addressed work reported by McCurdy (1994) on population-based models (PBMs). Literature published since publication of the 1996 O 3 

### 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 O 3 

### source-to-exposure events and to evaluate their usefulness in providing population-based estimates.



## AX3.10.3 Concepts of Human Exposure

Human exposure to O 3 

### 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 O 3 

### , is the contact of that chemical with the exchange boundary (U.S. Environmental Protection Agency, 1992)

. Therefore, inhalation exposure to O 3 

### is based on measurements of the O 3 

### 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 ai r 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 O 3 

### 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

t 1 

### and t 2 

### the starting and ending time of the exposure, respectively.



## AX3.10.5 Methods to Estimate Personal Exposure
There are two approaches for measuring pers onal exposure; direct and indirect methods (Ott, 1982, 1985; Navidi et al., 1999). Direct appr oaches 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 O 3 

### exposure. The difficulty in developing a passive O 3 

### monitor is in identifying a chemical or trapping reagent that

can react with O 3 

### . 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 O 3 

### -trapping reagents. Only sodium nitrite and MBTH gave sensitive, linear responses at environmentally relevant concentrations. However, MBTH overestimated the O 3 

### concentrations significantly, suggesting an interfer ence 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 O 3 

### . 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 of1.3 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-pyr idyl)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 coefficien t of 5% for field-tested paired samples. The imprecision was estimated to be 1.0 ppb.

A series of studies have been conducted us ing 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 studi es in southern California (Avol et al., 1998a; Geyh et al., 1999, 2000; Delfino et al., 1996), Baltim ore, 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 “c ontrol 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 , c i 

### is the concentration in the i th
microenvironment, and ) 

### t i 

### is the duration spent in the i th 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 mi croenvironments 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) sugge sted 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 O 3 

### exposures include indoor residences, other indoor locations, outdoors near roadways, other outdoor locations, and in-vehicles. Outdoor locations near roadways are segreg ated from other outdoor locations because N 2 

### O

emissions from automobiles alter O 3 

### and related photochemical oxidant concentrations compared to concurrent typical ambient levels. Indoor re sidences 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 O 3 

### and related

### AX3-167 photochemical oxidants is their diurnal weekly (weekday-weekend) and seasonal variability.

Few indoor O 3 

### sources exist, but include electronic equipment, O 3 

### generators, and copying machines. Some secondary reactions of O 3 

### take place indoors that produce related photochemical oxidants that could extend the exposures to those species above the estimates

obtained from O 3 

### alone. (See discussion on O 3 

### 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 O 3 

### through mechanistic models is complicated by the fact that O 3 

### (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 NO

x 

### that are emitted by a wide variety of both anthropogenic and natural (biogenic) emission sources. This makes O 3 

### a secondary pollutant with complex nonlinear and multiscale dynamics in time and space. Concentration levels experienced by individuals and populations exposed to O 3 

### are therefore affected by (1) emission levels and spatiotemporal patterns of the gaseous precursors: VOCs and NO

x 

### , 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 O 3 

### , 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 O 3 

### production or health

effects that result from O 3 

### 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 O 3 

### exposure and observed health and other effects.

Health effects associated with O 3 

### have mostly been considered effects of acute exposures.

Peak O 3 

### and related photochemical oxidants concentrations typically occur towards later in the day during the summer months. Elevated concentrations can last for several hours.
Furthermore, O 3 

### participates in multiphase (gas/aerosol) chemical reactions in various

microenvironments. Several recent studies show that O 3 

### reacts indoors with VOCs and NO

x 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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, O 3 

### -exposure modeling is very often identified explicitly with populationbased modeling, while models describing the specific mechanisms affecting the exposure of an

individual to O 3 

### , 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-ba sed exposure modeling research has shifted from

O 3 

### 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 O 3 

### 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 (geographi cal) domain for Population Based Modeling are defined. The temporal framework of the analysis (period, resolution) and the comprehensive modeling of individual/population exposure to O 3 

### (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; Geor gopoulos 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 O 3 

### through space-time analysis of fixed monitor data, or emissions-based, photochemical, air quality modeling; (2) estimation of

### AX3-170Figure AX3-87a. Detailed diagram illustrating components of an exposure model.Source: ICF Consulting and ManTechEnvironmental Technology, Inc. (2003)

### AX3-171Figure AX3-87b. Detailed diagram illustrating components of an exposure model.Source: ICF Consulting and ManTechEnvironmental Technology, Inc. (2003)

### AX3-172 levels and temporal profiles of O 3 

### in various outdoor and indoor microenvironments such as street canyons, residences, offices, restaurant s, 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 attribut es 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, reflecti ng/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, O 3 

### 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 O 3 

### 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 O 3 

### exposures include the AirPEx (Air Pollution Exposure) model (Freijer et al., 1998), which basically replicates the pNEM approach, and the AirQUIS (Air Quality Inform ation 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 O 3 

### dose over any averaging period of concern

from 1 h to an entire O 3 

### 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 O 3 

### 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

### AX3-174Table AX3-18. Activity Pattern Studies Included inthe Consolidated Human Activity Database (CHAD)Study NameCalendar TimePeriodof the Study Age1Days2DiaryRate5Documentation orReference NotesType3Time4Baltimore Jan-Feb 1997Jul-Aug 199865+ 391 Diary; 15-minblocks24-h Standard No Williams et al. (2000a,b) Multiple days, varying from 5-15;part of a PM2.5PEM studyCARB: Adolescents and Adults Oct1987-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 Aug19850-86 2614 Diary 24 h; nominal7 pm-7 amYes Johnson (1989) 3 consecutive days; 186 P-Dremoved7Denver (EPA) Nov 1982-Feb 1983 18-70 805 Diary 24 h; nominal7 pm-7 amNo Akland et al. (1985)Johnson (1984)Part of CO PEM6study; 2 consec.days; 55 P-D removed7Los Angeles: Elem. SchoolChildrenOct 1989 10-12 51 Diary 24-h Standard Yes Spier et al. (1992) 7 P-D removed7Los Angeles: High SchoolAdoles.Sept-Oct 1990 13-17 43 Diary 24-h StandardYes Spier et al. (1992) 23 P-D removed7National: NHAPS-A8Sept 1992-Oct 1994 0-93 4723 Retrospective 24-h Standard No9Klepeis et al. (1995)Tsang and Klepeis (1996)A national random-probabilitysurveyNational: NHAPS-B8As above 0-93 4663 Retrospective 24-h Standard No9As above As aboveUniversity ofMichigan:ChildrenFeb-Dec 1997 0-13 5616 Retrospective 24-h Standard No Institute for SocialResearch (1997)2 days of data: one is a weekenddayValdez, AK Nov 1990-Oct 1991 11-71 401 Retrospective Varying 24-hperiodNo Goldstein et al. (1992) 4 P-D removed7Washington, DC (EPA) Nov 1982-Feb 1983 18-98 699 Diary 24 h; nominal7 pm-7 amNo Akland et al. (1985)Hartwell et al. (1984)Part of a CO PEM6study; 6 P-Dremoved71All studies included both genders. The agerange depicted is for the subjects actually included; in most cases, there was notan upper limit for the adult studies.Ages are inclusive. Age 0 =babies < 1 year old.2The 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.3Retrospective: 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 went through the day.4Standard = midnight to midnight.5Was activity-specific breathing rate data collected?6PEM = a personal monitoring study. In addition to the diary, a subject carried a small CO or PM2.5monitor throughout the sampling period.7P-D removed = The number of person-days of activity pattern data removed from consolidated CHAD because of missing activityandlocation information; completeness criteria are listed inthe text.8National Human Activity Pattern Study; A = the air version; B = the water version. The activity data obtained on the two versions are identical.9A question was asked regarding which activities (within each 6-htime 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 facilita te 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 

## V E



# ⋅

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 . 

## V E



# ⋅

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/O 3 

### in the 1980s used a reduced form of a mass balance equation to

estimate indoor O 3 

### concentrations from outdoor concentrations. The second generation of pNEM/O 3 

### was developed in 1992 and used a simple mass balance model to estimate indoor O 3 

### concentrations. Subsequent enhancements to pNEM/O 3 

### 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 O 3 

### levels to simulate attainment of proposed NAAQS. During the mid-1990s, the EPA applied updated versions of pNEM/O 3 

### to three different population groups in ni ne selected urban areas (Chicago, Denver, Houston, Los Angeles, Miami, New York, Philade lphia, 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/O 3 

### and summarize the results of the application of the model to the nine urban areas. These versions of pNEM/O 3 

### used a revised probabilistic mass balance model to determine

O 3 

### concentrations over 1-h periods in indoor and in-vehicle microenvironments (Johnson, 2003).

The model assumed that there are no indoor sources of O 3 

### , that the outdoor O 3 

### concentration and AER during the clock hour is constant at a specified value, and that O 3 

### decays at a rate proportional to the outdoor O 3 

### concentration and the indoor O 3 

### 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 populati on. 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 database s 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 PM 10 

### . 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 O 3 

### 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 a nd 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- to

### work 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 microenvironmen ts (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 O 3 

### exposure models and approaches are summarized in

Table AX3-19.Table AX3-19. Personal and Population Exposure Models for OzoneModel Name Model Type Microenvironments or Predictors Notes ReferencepNEM Probabilistic General population, outdoor workers,outdoor childrenProvides estimates of exposure within a definedpopulation for a specified period of time.Uses activity records from CHAD and CADSJohnson et al.(1996a,b,c)APEX PC-based Outdoors, indoor residence,in-vehicleSimulates movement through time and space.Estimates hourly exposures and doses.Uncertainties in predicted distributions have notbeen addressed.ICF Consulting andManTechEnvironmentalTechnology, Inc.(2003)Mentor/SHEDS Probabilistic General population, outdoors, indoors,in-vehicleEmployees detailed person oriented exposureapproach that includes personal activity data,physiology, and microenvironmental conditions.Allows calculation of exposure and dose foreach activity event.Georgopoulos et al.(2005)REHEX General population Provides estimates of exposure for 1-day to3 yrs. Can represent variability in activities ofthe population to capture extremes in exposuredistributions.Lurmann and Colome(1991)



### AX3-179

### 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 PM 10 

### 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 s outhern 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 exposurein 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 O 3 

### 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 O 3 

### 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 O 3 

### AQCD (U.S. Environmental Protection Agency, 1996a) focused on the pNEM/O 3 

### 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/O 3 

### - derived models (the Systems Applications In ternational 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 pr ecursor 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 O 3 

### 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 con centration 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 O 3 

### concentrations were <120 ppb, however, the situation was reversed when O 3 

### concentrations exceeded 120 ppb. The authors concluded that kriging O 3 

### 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 O 3 

### levels with the capacity to predict O 3 

### concentrations at anylocation 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 O 3 

### declined by approximately 20% over the analysis period. The authors also suggested that the O 3 

### 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 O 3 

### (Guttorp et al., 1997; Cressie, 1997; Stein and Fang, 1997). Spatiotemporal distributions of O 3 

### 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 interpola tion 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 O 3 

### 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 O 3 

### 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

O 3 

### and PM 10 

### 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 O 3 

### concentration patterns have been derived, microenvironments that can represent either out door 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

### AX3-183 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 (l ocal 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 O 3 

### concentrations indoors (Nazaroff and Cass, 1986; Hayes, 1989, 1991). An example of a mass balance indoor air model for O 3 

### and benzene can be found in the work of Freijer and Bloemen (2000). They used outdoor O 3 

### measurements to parameterize a simplified linearized formulation of transport, transformation, and sources and sinks in the

indoor microenvironment. The pNEM/O 3 

### 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 dC IN



### is the indoor pollutant concentration (mass/volume), t is time in hours, v is the air exchange rate, C OUT 

### 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 O 3 

### I/O ratios as influenced by time patterns in outdoor concentrations,
ventilation rate, and indoor emissions. The microenvironment was 250 m 3 

### . 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 O 3 

### sources are not common. The time series

for outdoor O 3 

### concentrations consisted of 100-day periods during the summer, with hourly measured concentrations. The following assumptions were made: (1) O 3 

### 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 O 3 

### concentration that leaves the microenvironment equals

the O 3 

### 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 O 3 

### in the microenvironment also may occur through independent sources and sinks. Figure AX3-88 represents the measured outdoor O 3 

### concentrations and modeled indoor O 3 

### concentrations. The indoor modeled O 3 

### 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 qualit y, 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### . 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 O 3 

### 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 O 3 

### -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 O 3 

### concentrations (thin line) and modeled indoor concentrations (bold line).

Source: Adapted from Freijer and Bloemen (2000).

### AX3-186 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-O 3 

### 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 O 3 

### 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 O 3 

### 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/O 3 

### -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 O 3 

### 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 O 3 

### monitors have been used in several field studies to determine average daily O 3 

### exposure as well as in scripted studies to evaluate O 3 

### exposures over one to several-hour time periods. Table AX3-20 lists the results of O 3 

### exposure studies. Delfino et al. (1996) measured 12-h personal daytime O 3 

### 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 O 3 

### 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 O 3 

### levels. The lower

### AX3-187 Table AX3-20. Personal Exposure Measurements

Location, Population, Sample Duration n Personal Exposure Mean a (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, Hourly b 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations during either the winter or summer. Only a single individual (n = 14 summer and 13 winter) had a significant correlation with outdoor concentrati ons. Geyh et al. (2000) measured indoor and outdoor concentration and personal O 3 

### 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 O 3 

### 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 O 3 

### exposures were lower than the levels measured at the nearest monitor stations retrieved from the AQS. There was no significant difference in the O 3 

### exposure for both groups during the non-O 3 

### 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 O 3 

### season (18.8 and 25.4 ppb for Upland and the mountain communities) (two-tailed t -test, p < 0.01). During the O 3 

### season, differences were found in indoor concentrations and personal O 3 

### 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 O 3 

### exposure (mean personal exposure to outdoor concentration ratio = 0.18 and 0.35, respectively) compared to

### AX3-189 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 O 3 

### air concentrations (estimated at 35%), local variability in O 3 

### 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

O 3 

### concentrations or to an interference affecting the personal O 3 

### samplers, particularly at the lower concentration range, leading to a small positive error. Temporal plots of O 3 

### 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

O 3 

### concentrations had consistent patterns, suggesting that the ambient air was the primary source

for O 3 

### 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 O 3 

### concentrations measured in the personal air space were always considerably lower than the ambient concentrations. Bernard et al. (1999) assessed O 3 

### 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, O 3 

### concentrations were higher during the warmer months. Mean

O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### .

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 O 3 

### 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 O 3 

### and its precursors. Finally, the 1-h daily maximum and 8-h average O 3 

### concentrations can have different spatial patterns with elevated daily 8-h O 3 

### concentrations typically being over a wider spatial area.

### AX3-191 Therefore, O 3 

### 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 O 3 

### inlet probe should be placed at a height and location that best approximates where people ar e 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 O 3 

### 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 O 3 

### levels tend to be much lower than outdoor ambient levels, the use of ambient monitoring data to determine exposure generally overestimates true personal O 3 

### exposure, resulting in exposure estimates

biased towards the null. Information on monitored ambient concentrations of O 3 

### and other photochemical oxidants appears earlier in this chapter.

AX3.10.7.3 Ozone Concentrations in Microenvironments

The 1996 O 3 

### AQCD for Ozone (U.S. Environmental Protection Agency, 1996a) reported

O 3 

### I/O ratios for a variety of indoor environm ents 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 O 3 

### ratios were generally noted in indoor environments with high AERs or 100% outside air intake. Studies published since completion of the 1996 O 3 

### AQCD are discussed in this section. The findings of the more recent

studies on O 3 

### I/O ratios are included in Table AX3-21. Northeast States for Coordinated Air Use Management (NESCAUM, 2002) monitored

levels of O 3 

### inside and outside of nine schools located in the New England states. The schools

### AX3-192Table AX3-21. Indoor/Outdoor Ozone RatiosLocation and VentilationConditionsIndoor/Outdoor RatioMean (range) Comments ReferenceToronto, Canada, HomesWinter – 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 homes.Air conditioners were present in about 80% of the homes, most werecentral units that used recycled air. Air conditioners used in only 13 ofthe 40 homes on a daily basis. Measurements were made both insideand outside of the homes for 5 consecutive 24-h periods. Homes withelectrostatic air cleaners had higher I/O ratios during the winter months.The mean average weekly AER for all homes during the winter monthswas 0.69 ± 0.88 h!1with 50% of the homes with an AER of less than0.41 h!1. For the summer months, the mean average AER was 1.04 ±1.28 h!1with 50% of the homes with an AER of less than 0.52 h.Liu et al.(1995)Boston, MA, Homes (26)Winter – continuously 24 hSummer – continuously 24 h0.30 ± 0.42 (ND - 1.31)0.22 ± 0.25 (ND - 0.88)Study examined the potential for O3to react with VOCs to form acidaerosols. Carbonyls were formed. No clear trend of O3with AERs.The average AER was 0.9 h!1during the winter and 2.6 h!1during thesummer. Four residences in winter and nine in summer with 24 haverage concentrations. Air concentrations varied from 0-34.2 ppbindoors and 4.4-40.5 ppb outdoors.Reiss et al.(1995)Mexico City, SchoolWindows/Doors Open (27)Windows/Doors Closed,cleaner off (41)Windows/Doors Closed,cleaner on (47)0.73 ± 0.040.17 ± 0.020.15 ± 0.02Study conducted over 4-day period during winter months. Two-minaveraged measurements were taken both inside and outside of theschool every 30 min from 10 a.m. to 4 p.m. Estimated air exchange rateswere 1.1, 2.1, and 2.5 h!1for low, medium, and high flow rates. Ozoneconcentrations decreased with increasing relative humidity.Gold et al.(1996)Los Angeles, CAHomes (95)Other locations (57)0.280.18Study conducted in September. Monitored O3concentrations consistedof twenty-one 24-h periods beginning at 7 p.m. and ending at 7 p.m. onthe following day. Ozone concentrations were higher at the fixedmonitoring sites during the afternoon. The weather was sunny and thetemperature was high. I/O ratio was lower when windows were closed.The effect of air conditioning on the I/O was varied.Johnson(1997)

### AX3-193Table AX3-21 (cont’d). Indoor/Outdoor Ozone RatiosLocation and VentilationConditionsIndoor/Outdoor RatioMean (range) Comments ReferenceMexico CityHomes (237)Schools (59)0.20 ± 0.18 (0.04 - 0.99)0.1 - 0.30.3 - 0.4Ozone monitoring occurred between September and July. Studyincluded 3 schools and 145 homes. Most of the homes were large anddid not have air conditioning. Ninety-two percent of the homes hadcarpeting, 13% used air filters, and 84% used humidifiers. Thirty-fivepercent opened windows frequently, 43% sometimes, and 22% neverbetween 10 a.m. and 4 p.m. Ozone was monitored at the schools sitesfrom 8 a.m. to 1 p.m. daily for 14 consecutive days. Homeswere monitored for continuous 24-h periods for 14 consecutive days.I/O based on 1-h average concentrations.Romieuet al. (1998)Los Angeles, Homes (239)SummerWinter0.37 ± 0.25 (0.06 - 1.5)0.43 ± 0.290.32 ± 0.21Four hundred and eighty-one samplescollected inside and immediatelyoutside of home from February to December. Ratios based on 24-haverage O3concentrations indoors and outdoors. Low outdoorconcentrations resulted in low indoor concentrations. However, highoutdoor concentrations resulted in a range of indoor concentrationsand ratios. I/O ratios were highest during the summer months.Avol et al.(1998a)CaliforniaHomesno 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 operatedthe air conditioning. I/O ratios based on 24-h continuous ambientconcentrations and 0.5-1 h average indoor concentrations.Lee et al.(1999)Munich GermanyOfficeGymnasiumClassroomResidenceBedroomLivingroomHotel roomCar0.4 - 0.90.49 - 0.920.54 - 0.770.47 - 1.00.74 - 1.00.020.4 - 0.6Indoor concentrations were dependent on the type of ventilation. Jakobi andFabian(1997)La Rochelle, France 0 - 0.45 I/O ratio determinedfor 8 schools. Monitoring conducted for a 2-wkperiod. Schools located in various areas with different ambient O3concentrations, types of ventilation systems, and the presumedair-tightness of building envelop. Building air-tightness and ambient O3concentration influenced indoor O3I/O.Blondeauet al. (2005)

### AX3-194Table AX3-21 (cont’d). Indoor/Outdoor Ozone RatiosLocation and VentilationConditionsIndoor/Outdoor RatioMean (range) Comments ReferenceMontpellier, France, Homes (110) 0.41 Ozone measurementswere made over 5-day periods in and outside of 21homes during the summer and winter months. The winter I/O ratio was0.31 compared to 0.46 during the summer months.Bernardet al. (1999)Southern CA, HomesUpland Mountains0.68 ± 0.18(windows open)0.07 - 0.11(AC used)Ozone measurements were taken at 119 homes (57 in Upland and 62 intowns located in the mountains) during April and May. I/O ratios werebased on average monthly outdoor concentrations and average weeklyindoor concentrations. I/O ratio was associated with the home location,number of bedrooms, and the presence of an air conditioner. I/O ratiosbased on subset of the homes.Geyh et al.(2000);Lee et al.(2002)Krakow, PolandMuseums (5)0.13 - 0.42 Ozone continuously monitoredat five museums and cultural centers.Monitoring conducted during the summer months for 21-46 h or 28-33days at each of the sites. The I/O was found to be dependent on theventilation rate, i.e., when the ventilation rate was high, the I/O ratioapproached unity, while in rooms sequestered from the outdoor air orwhere air was predominantly recycled through charcoal filters, the O3levels indoors were greatly reduced resulting in low I/O ratios.Salmon et al.(2000)Buildings, GreeceThessalonikiAthens0.24 ± 0.18 (0.01 to 0.75) There was no heating/air conditioning system in the building atThessaloniki. Windows were kept closed during the entire monitoringperiod. Complete air exchange took place every 3 h. I/O ratio rangedfrom 0.5-0.90, due to low deposition velocity on indoor surfaces. The airconditioning system in continuous use at the Athens site recirculatedthe air. Complete air exchange was estimated to be 1 h. Monitoringlasted for 30 days at each site, but only the 7 most representative dayswere used for calculation of the I/O ratio.Drakou et al.(1998)Southern California, Museum 0.19 ± 0.05 Measurementsmade over a 2-wk period (24-h avg). Ratio forconcentrations at the buffer zone with the roll-up door closed.Hisham andGrosjean(1991)ND = not detectable.

### AX3-195 represented a variety of environmental conditions in terms of ambient O 3 

### concentration, sources, geographic location, population density, traffic patterns, and building types. Schools were monitored during the summer months to establish baseline O 3 

### 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 O 3 

### . As expected, outdoor concentrations of O 3 

### were higher than those found indoors. Averaged O 3 

### 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 O 3 

### concentrations in classrooms in Mexico City under three different ventilation conditions: windows/doors open, air cleaner off;
windows/doors closed, air cleaner off; and wi ndows/doors closed, air cleaner on. Two-minute averaged outdoor O 3 

### levels varied between 64 and 361 ppb, while indoor O 3 

### concentrations ranged from 0 to 247 ppb. The highest indoor O 3 

### 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. Th e authors indicated that the indoor levels, and

therefore O 3 

### exposure to students in schools, can be reduced to < 80 ppb by closing windows and

doors even when ambient O 3 

### levels reach 300 ppb. In a second Mexico City study, Romieu et al. (1998) measured O 3 

### 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 O 3 

### concentrations during 5-h measurements at the schools were 22 ppb and 56 to 73 ppb, respectively. The mean indoor and

outdoor O 3 

### 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 O 3 

### concentrations for residences in the
Boston, MA area. Four residences were monitore d 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 O 3 

### . Indoor O 3 

### concentrations were higher during the summer months, with concentrations reaching 34.2 ppb. Indoor O 3 

### concentrations reached as high as 3.3 ppb during the winter monitoring period. In one instance, O 3 

### concentrations were higher indoors than outdoors. The authors attributed that finding to analytical difficulties. Outdoor O 3 

### concentrations were generally higher during the summer monitoring period, with concentrations reaching 51.8 ppb. Indoor concentrations were dependent on the outdoor O 3 

### concentrations and AER. Indoor and

outdoor O 3 

### 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 O 3 

### concentrations were present during the

non-O 3 

### seasons. Indoor O 3 

### concentrations were always below outdoor O 3 

### concentrations. The

mean indoor and outdoor O 3 

### concentrations over the sampling period were 13 ± 12 ppb and 37 ± 19 ppb, respectively. There was a correlation between indoor O 3 

### concentration and ambient temperatures. The effect was magnified when the windows were open. When a central refrigerant recirculating air conditioner was used, indoor O 3 

### concentrations declined. The authors were able to predict indoor O 3 

### 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 differe nt locations with different housing stock or at different times of the year. Lee et al. (2002) reported indoor and outdoor O 3 

### 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 O 3 

### concentrations were based on

### AX3-197 Table AX3-22. Indoor and Outdoor O 3 

### 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 differe nt locations with different housing stock or at different times of the year. Lee et al. (2002) reported indoor and outdoor O 3 

### 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 O 3 

### concentrations were based on monthly and weekly averages, respectively. Housing characteristics were not found to affect

indoor O 3 

### concentrations. Indoor O 3 

### concentrations were significantly lower than outdoor O 3 

### concentrations. Average indoor and outdoor O 3 

### concentrations were 14.9 and 56.5 ppb. Homes with air conditioning had lower O 3 

### concentrations, suggesting decreased ventilation or greater

O 3 

### removal. Chao (2001) evaluated the relationship between indoor and outdoor levels of various air pollutants, including O 3 

### , 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 we re off during the working hours. Indoor O 3 

### concentrations were low in all of the monitored apartments, ranging from 0 to 4.9 ppb with an average of 2.65 ppb. Outdoor O 3 

### concentrations ranged from 1.96 to 15.68 ppb. Table AX3-23 provides information on the indoor and outdoor O 3 

### concentrations and the apartment

characteristics. Drakou et al. (1995) demonstrated the complexity of the indoor environment. Measurements of several pollutants, including O 3 

### , were made inside and outside of two nonresidential buildings in Thessaloniki and Athe ns, Greece. The building in Thessaloniki was a

58-m 3 

### 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-m 3 

### 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 O 3 

### concentrations closely followed the outdoor concentrations at the Thessaloniki building. The averaged 7-day indoor and outdoor O 3 

### concentrations were 9.39 and

### AX3-199 Table AX3-23. Indoor and Outdoor O 3 

### Concentrations in Hong Kong

Apartment No. Floor Area Floor No. Window Opening Frequency AER (h

! 1 ) Indoor O 3 Conc. Outdoor O 3 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 O 3 

### 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 O 3 

### concentrations noted at this site. The averaged 7-day indoor and outdoor O 3 

### concentrations were 8.14 and 21.66 ppb, respectively. Weschler et al. (1994) reported that indoor O 3 

### concentrations closely tracked outdoor O 3 

### 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 m 2 

### with a volume of 5095 m 3 

### . Indoor O 3 

### 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 fi rst 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 O 3 

### at the switching station was transport from outdoors. Indoor O 3 

### concentrations closely tracked outdoor concentr ations, measuring from 30 to 70% of the outdoor

concentrations. Indoor O 3 

### 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

O 3 

### 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 NO

x 

### . Figures AX3-89 and AX3-90 compare the outdoor and indoor O 3 

### concentrations, including the AER, for two 1-week periods during the study.

The relationships between indoor and outdoor O 3 

### 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 O 3 

### concentrations were noted at the Figure AX3-89. Air exchange rates and outdoor and indoor O 3 

### 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 O 3 

### and PAN concentrations in a private residence in Germany. All measurements were made in naturally ventilated rooms. Johnson (1997) conducted a scripted study usi ng four trained technicians to measure hourly average O 3 

### 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 O 3 

### levels $ 

### 20 ppb were as follows: indoor residence, 0.28; other
locations indoors, 0.18; outdoor near roadwa ys, 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 ro adways, probably reflect the reaction of O 3 

### with NO emitted by automobiles. Figure AX3-90. Air exchange rates and outdoor and indoor O 3 

### 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 O 3 (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 42 a

Wawel Castle, Room 15 31 8

Wawel Castle, Senator’s Hall 31.8 7

Matejko Museum, outdoors 26.9 21 b

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 O 3 

### concentrations found that concentrations increased with increasing elevation. The ratio of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 conditi oned 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 O 3 

### 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 O 3 

### (r = 0.34 in summer, r = 0.46 in winter), however, the aut hors indicated that this finding was unclear due to the low personal/ambient ratios. The personal O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### measurements at the fixed station in northern Raleigh. The average O 3 

### concentration inside the cars was 11.7 ppb, approximately one-third of the ambient air concentration. Jakobi and Fabian (1997) found that O 3 

### 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, O 3 

### concentrations outdoors greatly exceeded concentrations inside the car (see Figure AX3-92). Few studies have been conducted in indoor environments containing O 3 

### sources. Black et al. (2000) measured O 3 

### concentrations in a photocopy room at the University of California during one business day. The room volume was 40 m 3 

### . 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations in an office associated with the use of a photocopier and a laser printer. They noted a 3.0 ppb increase in O 3 

### 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 O 3 

### concentrations from the use of the laser printer. The U.S. Environmental Protection Agency (Steiber, 1995) measured O 3 

### concentrations

from the use of three home/office O 3 

### generators. The O 3 

### generators were placed in a 27 m 3 

### room with doors and windows closed and the heating, ve ntilating 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 (ave raged output). At the high output setting, averaged output O 3 

### 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, O 3 

### 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 O 3 

### concentration in moving cars.

Source: Jaboki and Fabian (1997).

### AX3-206 temperature and humidity. Indoor concentrations generally closely track outdoor O 3 

### concentrations. Limited information on PAN c oncentrations indoors also indicate that indoor

PAN concentrations track outdoor concentra tions (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 O 3 

### 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 O 3 

### 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; Weschl er 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 Compa ny, 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 alumi num siding covering the wood outer walls. The

house had one exterior door located in the front a nd 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 scen arios 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 desi gned 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 a nd 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 Californiawhere 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 O 3 

### 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 O 3 

### faster. Fleecy materials, such as carpets, have larger A/V ratios and remove O 3 

### faster than smooth surfaces (Weschler, 2000). O 3 

### can react with carpet, decreasing O 3 

### concentrations and increasing

### AX3-210 emissions of formaldehyde, acetaldehyde, and other C 5 

### –C 10 

### aldehydes. Off-gassing of 4-phenylcyclohexene, 4-vinylcyclohexene, and styr ene was reduced (Weschler et al., 1992). The

rate of O 3 

### reaction with carpet diminishes with cumulative O 3 

### 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 O 3 

### reactions with latex paint. The emission rate also was relative humidity-dependent, increasing with higher relative humidity. Klenø et al. (2001)

evaluated O 3 

### 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, O 3 

### 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, O 3 

### removal leveled off to a moderate rate. Morrison et al. (1998) reported that small amounts of O 3 

### (~9%) are removed by lined ductwork of ventilation systems. The removal efficiency decreases with continued exposure to O 3 

### . Unlined ductwork is less efficient in removing O 3 

### . Ozone is scavenged by fiberglass insulation (Liu and Nazaroff, 2001). More O 3 

### was scavenged (60 to 90%) by fiberglass that had not been previously exposed.

Table AX3-25 lists the removal rates for O 3 

### in different indoor environments. Jaboki and Fabian (1997) found the O 3 

### 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 O 3 

### and PAN decay in several closed rooms and in a car after a period of intensive ventilation. Figure AX3-94 plots the O 3 

### and PAN decay rates in these environments. Several studies have examined factors within homes that may scavenge O 3 

### and lead to

decreased O 3 

### concentrations (Lee et al., 1999; Wainman et al., 2000; Weschler and Shields, 1997). These reactions produce related oxidant species while reducing indoor O 3 

### levels. Lee et al. (1999) studied 43 homes in Upland, CA in the Los Angeles metropolitan region and reported that O 3 

### 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 O 3 

### 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, k d 

### (A/V), h –1 

### Reference

Aluminum Room (11.9 m 3 ) Stainless Steel Room (14.9 m 3 ) Bedroom (40.8 m 3 ) Office (55.2 m 3 )

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 m 3 ) Office (20.7 m 3 )

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

3.6 a 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

! 1.0 b

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 O 3 

### 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 O 3 

### chemistry is greater (Weschler and Shields, 2000, 2003). Since O 3 

### is primarily an outdoor pollutant, the air exchange rate will influence the

amount of O 3 

### 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 O 3 

### 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, alkyl peroxy, hydroperoxy, and alkoxy radicals. The

reaction of O 3 

### with alkenes can produce aldehydes, ketones, and organic acids (Weschler and Shields, 2000; Weschler et al., 1992). The indoor chemistry of O 3 

### 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 O 3 

### with VOCs are lost to further reaction

with VOCs. For each molecule of O 3 

### 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 O 3 

### 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 O 3 

### was reported to be almost exclusively the result of oxidation by hydroxy radicals. Fan et al. (2003) attributed the formation of so me secondary organic aerosols from the reaction

of O 3 

### 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 O 3 

### and OH radicals is found in Weschler (2000) and Nazaroff and Weschler (2004).

The reaction between O 3 

### 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 O 3 

### and " 

### -pinene reactions. When O 3 

### was introduced into the test chamber, particle concentrations increased to >10 7 

### particles/cm 3 

### . Clausen found that the reaction of limonene vapor with O 3 

### increased the particle concentration to 3 × 10 5 

### from a background

concentration of <10 3 

### particles/cm 3 

### . Poupard et al. (2005) and Blondeau et al. (2005) found a negative correlation between O 3 

### and particle concentration in eight school buildings in France. The researchers assumed that the increased particle concentration and decreased O 3 

### concentration was likely the result of homogeneous processes involving O 3 

### . 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 O 3 

### and NO 2 

### in the indoor environment may be a significant source of HNO 3 

### . When there are elevated concentrations of

both O 3 

### and NO 2 

### 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 NO 2 

### (See equation AX3-10). Decomposition and formation of PAN in the indoor environment is influenced by NO 2 

### and NO.

When the concentration ratio of NO/NO 2 

### 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 O 3 

### levels are low and when motor vehicle emissions are large or there

is an indoor source of NO

x 

### (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 O 3 

### are office equipment (photocopiers, facsimile machines, and laser printers) and air cleaners (electrostatic air filters and precipitators and O 3 

### generators). Generally O 3 

### emissions from photocopiers and laser printers are limited due to installed filtering systems (Black and Wortha n, 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 O 3 

### by catalytically reducing the O 3 

### to oxygen (Aldrich et al., 1995). Leovic et al. (1996, 1998) measured O 3 

### emissions from four dry-process photocopi ers. Ozone emissions ranged from 1300 to 7900 μg/h. Most electrostatic air filters and precipitators are designed to minimize the production

of O 3 

### . However, if excessive arcing occurs, the units can emit a significant amount of O 3 

### into the indoor environment (Weschler, 2000). Niu et al. (2001) measured O 3 

### emissions from 27 air cleaners that used ionization processes to remove particulates. The test were conducted in a

2 × 2 × 1.60 m 3 

### stainless steel environmental chamber. The tests were terminated after 1.5 h

if no increase in O 3 

### concentration was noted. If an increase in O 3 

### 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 O 3 

### or only

small amounts. Five units were found to emit O 3 

### ranging from 56 to 2757 μg/h. There are many brands and models of O 3 

### generators commercially available. The amount

of O 3 

### 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 O 3 

### output may not be proportional to the control setting. Some units are equipped with a sensor that automatically controls O 3 

### 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 NO 2 

### 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 NO 3 

### with acetaldehyde to form the acetyl radical, CH 3 

### CO. The acetyl radical then reacts with oxygen to form and acetylperoxy radical which reacts with NO 2 

### 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

O 3 

### concentrations to directly document trends over time or location. However, since O 3 

### (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 O 3 

### 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 O 3 

### concentrations appear to have occurred in urban centers than in rural regions. The decline in daily and weekly average O 3 

### concentrations from 1989 to 1995 in rural regions was 5% and 7%, re spectively (Wolff et al., 2001; Lin et al., 2001; Holland et al., 1999). A detailed discussion of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 estim ate 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 me thod certainly lacks precision and, in most cases, the analyses that use it will underestimate the eff ect 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 exposuremeasures. 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 PM 2.5 

### and several gaseous air pollutant (O 3 

### , SO 2 

### , NO 2 

### , CO, and exhaust-related VOCs) exposures were not ge nerally 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 mont hs. Ambient pollutant concentrations were not associated with corresponding personal exposures, except for PM 2.5 

### . The gaseous pollutants were found to be surrogates of PM 2.5 

### and were generally not correlated. The authors concluded that multipollutant models in epidemiologic studies of PM 2.5 

### may not be suitable, and health effects attributed to the gaseous pollutants may be the result of PM 2.5 

### exposure. It should be noted that the 95th percentile O 3 

### concentrations in the study was lower than 60 ppb, an O 3 

### concentration at which respiratory effects are not ed. It would be important to examine whether

O 3 

### is a surrogate for personal PM 2.5 

### at high O 3 

### levels when attributing adverse health effects to

O 3 

### or PM 2.5 

### . Künzli et al. (1996) assessed potential lifetime exposure to O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### .

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 O 3 

### 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 indi vidual. Few studies have been conducted using multipollutants or photochemical agents other than O 3 

### , to better represent “real-world” exposures with the exception of NO 2 

### . Studies by Hazucha et al. (1992), Adams (2003), and Adams and Ollison (1997) examined the effect of varying O 3 

### 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 O 3 

### monitoring stations. Photochemical agents produced in the ambient air can penetrate indoors and react with other pollutants to produce other potentially irritating compounds. Rei ss et al. (1995) reported that organic acids, aldehydes and ketones were produced indoors by reactions of O 3 

### with VOCs. The produced compounds included oxidants that can be respirator y irritants. The indoor concentrations were

### AX3-220 dependent upon the O 3 

### concentrations indoors and the AER within the building. Weschler and Shields (1997) summarized indoor air chemical reac tions that depend directly or indirectly on the presence of O 3 

### . They indicated that O 3 

### 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 O 3 

### concentration and the presence of the other necessary precursors, VOCs, and NO 2 

### , along with an optimal AER. A variety of the photochemical oxidants related to O 3 

### 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 NO 2 

### through thermal decay. PAN removal increases with increasing temperature, and at a given temperature, with increasing

NO/NO 2 

### concentration ratio (Grosjean et al., 2001). Other free radicals that can form indoors

include HO C 

### and HO 2 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 methodologi es 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 O 3 

### 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 O 3 

### 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 O 3 

### , at higher concentrations than present in ambient air, even as the O 3 

### 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 aler ts are issued in California on days when O 3 

### 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 O 3 

### concentrations. Ozone exposure modeling has been conducted for the general population and sensitive subgroups. The pNEM/O 3 

### model takes into consideration the temporal and spatial distribution of people and O 3 

### throughout the area of consideration, variations in O 3 

### concentrations within microenvironments, and the effects of exertion/exercise (increased ventilation) on O 3 

### uptake. The pNEM/O 3 

### model consists of two principal parts: the cohort exposure program and the exposure extrapolation program. The methodology in corporated much of the general framework described earlier in this section on assessing O 3 

### exposure and consists of five steps: (1) define the study area, population of interest, subdivi sions 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/O 3 

### 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; Hartwe ll 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 O 3 

### decay rate is assumed to be proportional to the indoor O 3 

### 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 O 3 

### 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 outdoormicroenvironments. 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. Mode l 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 O 3 

### above the NAAQS than those living in higher income districts. The author indicated that O 3 

### 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.

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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 Extra polation. It includes tables that summarize
new literature published since the 1996 Ozone Air Quality Criteria Document or O 3 

### 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 direc tly responsible for toxic effects may be the
inhaled gas, ozone (O 3 

### ), 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 O 3 

### as a reactive gas and discussed the characterization of dose measurement by parameters,
including: (1) inhaled O 3 

### concentration; (2) amount of O 3 

### inhaled as determined by minute
volume, vapor concentration, and exposure duration; (3) uptake or the amount of O 3 

### retained
(i.e., not exhaled); (4) O 3 

### or its active metabolites delivered to target cells or tissues; (5) O 3 

### or its
reactive metabolites delivered to target biomolecules or organelles; and (6) O 3 

### 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 O 3 

### that
participates in the effects of cellular perturbation and/or injury.
Understanding dosimetry as it relates to O 3 

### -induced injury is complex due to the fact

that O 3 

### 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 O 3 

### 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 O 3 

### dose. Since the

1996 O 3 

### AQCD (U.S. Environmental Protection Ag ency, 1996), most new experiments have

been carried out in humans to obtain direct measurements of absorbed O 3 

### 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 O 3 

### occur. Nevertheless,
experimentation is important for determining dose, making dose comparisons between
subpopulations and between different species, a ssessing 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 transpor t 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 O 3 

### in the liquid lining layer and in tissues is quasi first-order

### AX4-3 with respect to O 3 

### concentration. There is considerable discrepancy between rate constants used
in models. Both the uptake of O 3 

### at the gas-liquid interface and the fraction of O 3 

### (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 O 3 

### model predictions.
A review (Miller, 1995) of the factors influencing RT uptake of O 3 

### 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 O 3 

### 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 O 3 

### dosimetry that better enable
quantitative extrapolation from laboratory animal data. The next two sections review the
available new experimental studies on O 3 

### 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 O 3 

### 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 O 3 

### by human beings.
Asplund et al. (1996) studied the effects of continuous O 3 

### inhalation on O 3 

### bolus uptake,
and Rigas et al. (1997) investigated the potential effects of continuous coexposure to O 3 

### , nitrogen dioxide (NO 2 

### ), or sulfur dioxide (SO 2 

### ) on O 3 

### absorption. In both of these studies,

### AX4-4Table AX4-1. New Experimental Human Studies on Ozone DosimetryaPurpose/ObjectiveSubjectCharacteristicsRegion ofInterestBreathingPatterns/Exposure Results ReferenceDetermine the effectof continuous O3inhalation on O3uptake8 male,3 female,22-31 years old,166-186 cm,64-93 kgCentralconductingairways(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 fourmeasurement intervals, the absorbed fraction(AF) changed +0.045,!0.005, and!0.03 forthe 0, 0.12, and 0.36 ppm continuousexposures, respectively. These changes areapproximately +6,!1, and!4 % based on anaverage AF value of 0.7 in the range of 70 to120 mL.bBoth nonzero exposures weresignificantly different than the air exposure.Asplund et al.(1996)Evaluate theinfluence of VDonintersubject variationof O3dose.10 male,22-30 years old,163-186 cm,64-92 kg;10 female,22-35 years old,149-177 cm,48-81 kgConductingairwaysBolus-response test (VT= 500mL at 250 mL/sec constantflow rate). Fowler singlebreath N2washout method todetermine VD.On average, for the same VP, women had alarger AF than men; women had a smaller VDthan men. However, for the same value ofVP/VD, AF for men and women wereindistinguishable. Further analysis indicated“that previously reported gender differencesmay be due to a failure in properly accountingfor tissue surface within the conductingairways.”Bush et al.(1996a)Investigate theeffect of continuousexposure to O3,nitrogen dioxide andsulfur dioxide on O3absorption.6 male, 21-29 yearsold, 165-185 cm,60-92 kg;6 female,19-33 years old,152-173 cm,48-61 kgLowerconductingairways(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 gender, allexposures except O3resulted in an increase ofAF. Based on an AF reference valueb, thechange in AF ranged from!3 to +7 %.Only the O3and the NO2(0.36 ppm)exposures were significantly different fromthe air exposures.Rigas et al.(1997)

### AX4-5Table AX4-1 (cont’d). New Experimental Human Studies on Ozone DosimetryaPurpose/ObjectiveSubjectCharacteristicsRegion ofInterestBreathingPatterns/Exposure Results ReferenceCompare 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 kgcConductingairways.Nasal andoral routesBolus-response technique;VT= 500 mL; 3 constant flowrates: 150, 250, and1000 mL/sec.Ozone dose to the URT was sensitive to themode of breathing and to the respiratory rate.With increased airflow rate, O3retained by theupper airways decreased from 95 to 50%.TB region dose ranged from 0 to 35%.Mass transfer theory indicated that thediffusion resistance of the tissue phase isimportant for O3. The gas phase resistanceswere the same for O3and Cl2.Nodelmanand Ultman(1999a)cTo determine O3uptake relative toinhaled O3dose.5 male,5 female,18-35 years old,175 ± 13 (SD) cm,72 ± 13 (SD) kgRespiratorytract; oralbreathingBreath-by-breath calculationof O3retention based on datafrom fast response analyzersfor O3and airflow rates.Oral breathing: 0.2 or0.4 ppm O3at VEofapproximately 20 L/minfor 60 min or 40 L/min for30 min.The FA for all breaths was 0.86.Concentration, minute volume, and time havesmall but statistically significant effects on AFwhen compared to intersubject variability.The investigators concluded: for a givensubject, constant O3exposure, a given exerciselevel, and time <2 h, inhaled dose is areasonable surrogate for the actual uptakeof O3. However, the actual doses may varyconsiderably among individuals who areexposed to similar inhaled doses.Rigas et al.(2000)

### AX4-6Table AX4-1 (cont’d). New Experimental Human Studies on Ozone DosimetryaPurpose/ObjectiveSubjectCharacteristicsRegion ofInterestBreathingPatterns/Exposure Results ReferenceStudy the effect ofgas flow rate and O3concentration on O3uptake in the nose.7 male, 3 female,26 ± years,170 ± 11 (SD) cm,75 ± 20 (SD) kgNasalcavitiesFor 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) O3exposureconcentration = 0.4 ppm; flowrates = 3, 5, 8, and 15 L/min.(2) O3exposure = 0.1, 0.2,and 0.4 ppm; flow rate =15 L/min.(3) O3exposure= 0.4 ppm, flow rate= 15 L/min; AF was measuredevery 5 min for 1 h.(1) With the exposure concentration at0.4 ppm O3, AF decreased from 0.80 to0.33 when the flow rate was increased from3 to 15 L/min. (2) At a flow rate of 15 L/min,the AF changed from 0.36 to 0.32 when theexposure concentration increased from 0.1 to0.4 ppm O3. (3) Statistical analysis indicatedthat the AF was not associated with the time atwhich the measurement was taken.Santiagoet al. (2001)Evaluate intersubjectvariability in O3uptake; correlatedifferences inbreathing pattern andlung anatomy with O3uptakenonsmokers,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 kgRespiratorytract; oralbreathingContinuous: 1 h exposure to0.25 ppm, exercising at30L/min.Bolus: breath-by-breathcalculation of O3retention.Timing of bolus varied tocreate penetration volumes of10 to 250 mL. Peak inhaledbolus of ~1 ppm.Continuous: Fractional O3uptake efficiencyranged from 0.70 to 0.98 (mean 0.89 ± 0.06).Inverse correlation between uptake andbreathing frequency. Direct correlationbetween uptake and tidal volume. Intersubjectdifferences in forced respiratory responses notdue to differences in O3uptake.Bolus: The penetration volume at which 50%of the bolus was taken up was 90.4 mL infemales and 107 mL in males. Distribution ofO3shifts distally as the size of the airwayincreases.Ultman et al.(2004)aSee Appendix A for abbreviations and acronyms.bFig. 4, Hu et al. (1994), for the 250 mL/s curve and penetration volume range of 70 to 120 mL; the average AF is approximately0.7.cSubject 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 O 3 

### . Depending on the
gas and concentration, changes in absorbed fraction ranged from

! 

### 3 to +7 % (see Table AX4-1).

Continuous O 3 

### exposure lowered the uptake of O 3 

### , whereas NO 2 

### and SO 2 

### increased the uptake

of O 3 

### . The investigators concluded that in the tested airways, NO 2 

### and SO 2 

### increased the
capacity to absorb O 3 

### because more of the compounds oxidized by O 3 

### were made available.
On the other hand, they conjectured that continuous O 3 

### exposure depleted these compounds,
thereby reducing O 3 

### uptake.
Bush et al. (1996a) investigated the effect of lung anatomy and gender on O 3 

### 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), to tal lung capacity (TLC), and dead space (V D 

### ). 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 V D 

### , but not with
height, weight, age, gender, FVC, or TLC. Th at is, in all subjects, whether men or women,
dosimetry differences could be explained by differences in V D 

### . Combining their data with those
of Hu et al. (1994), where absorbed fraction was de termined for several flow rates, Bush et al.
(1996a) inferred that Ka was proportional to flow rate/V D 

### . 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 V D 

### 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 O 3 

### and chlorine gas (Cl 2 

### ) 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, O 3 

### 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 O 3 

### 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 O 3 

### in ELF would cause concomitant changes in

the O 3 

### 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 O 3 

### uptake in lungs are responsible for variation in O 3 

### -induced
changes in lung function parameters and that differences in O 3 

### 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 O 3 

### reached areas where gas exchange takes place. To quantify
intersubject differences in O 3 

### bolus uptake, they measured the penetration volume at which 50%

of the O 3 

### 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 O 3 

### uptake and cause reduced
penetration of O 3 

### into the distal lung. Data from the continuous exposure sessions indicated that

overall O 3 

### uptake was related to breathing pattern but was not correlated with V D 

### . Thus, these
findings indicate that overall O 3 

### uptake is not related to airway size, but that the distribution

of O 3 

### 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 stea dy-state mass transfer by convection (but no

### AX4-9 dispersion) and the mass transfer of O 3 

### 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 convecti on-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 O 3 

### uptake to the
quantity of O 3 

### inhaled (fractional absorption, FA). Five men and five women were exposed
orally to 0.2 or 0.4 ppm O 3 

### while exercising at a minute volume of approximately 20 L/min for

60 min or 40 L/min for 30 min. Ozone reten tion was calculated from breath-by-breath data
taken from fast response analyzers of O 3 

### 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 O 3 

### retained by the RT is equal to FA times the quantity of O 3 

### inhaled; thus, relatively
large changes in concentration, minute volume, or exposure time may result in relatively large

### AX4-10 changes in the amount of O 3 

### 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 O 3 

### concentration on O 3 

### 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 O 3 

### was

restricted to the nasal cavities. The fraction of O 3 

### absorbed was calculated using the inlet and

outlet concentrations. Inlet concentration and airflow rate were varied in order to determine their

effect on O 3 

### 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 subj ect 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 O 3 

### 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 O 3 

### , 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 O 3 

### uptake
in lungs are responsible for variation in O 3 

### -induced changes in lung function parameters and that

differences in O 3 

### 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 O 3 

### 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 O 3 

### uptake measuring dead
space volume, cross-sectional area of peripheral lung (A p 

### ) for CO 2 

### diffusion, FEV 1 

### , FVC,

and FEF 25%-75% 

### . The fractional O 3 

### 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 %A p 

### , but did not correlate with individual %FEV 1 

### . Neither of these parameters correlated with the penetration volume determined in the bolus

studies mentioned above. The authors conclude d that the intersubject differences in forced
respiratory responses were not due to differences in O 3 

### 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 O 3 

### uptake.
Plopper et al. (1998) examined the relationship between O 3 

### dose and epithelial injury in
Rhesus monkeys. Using 18 

### O content in lung tissues, the respiratory bronchioles were confirmed
as the site receiving the greatest O 3 

### dose (mass 18 

### O per dry lung weight). Furthermore, the
greatest cellular injury occurred in the vicinity of the respiratory bronchioles and was dependent

on the delivered O 3 

### dose to these tissues. After a 2 h exposure, the antioxidant glutathione
(GSH) was increased in the proximal intrapulmonary bronchus after 0.4 ppm O 3 

### and decreased
in the respiratory bronchiole after 1.0 ppm O 3 

### . Perhaps an adaptive response, chronic O 3 

### 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 O 3 

### -induced tissue injury (Duan et al ., 1993, 1996). Plopper et al
. (1998) concluded that, in monkeys, there was a close association between site-specific O 3 

### dose,
the degree of epithelial injury, and reduced-glutathione depletion. Within a species, antioxidant
defenses against O 3 

### 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 O 3 

### 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 O 3 

### for 8 h. Interestingly, in rats with
a C-fiber conduction block to prevent O 3 

### -induced rapid shallow breathing, it was the long path
terminal bronchioles that received the greatest epithelial injury. Overall, O 3 

### -induced rapid
shallow breathing appears to protect the large conducting airways while producing a more even
distribution of injury to the terminal bronchiol es (Joad et al ., 2000; Schelegle et al ., 2001).
Postlethwait et al . (2000) have also identified the conducting airways as a primary site of

acute O 3 

### -induced cell injury. Such data must be considered when developing models that
attempt to predict site-specific locations of O 3 

### -induced injury. The early models computed
relationships between delivered regional dose and response with the assumption that O 3 

### 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 O 3 

### (further discussed
in Section 5.3.1). Thus, models must consider O 3 

### reaction/diffusion in the ELF and ELF-derived
reactions products.
Table AX4-2 presents a summary of new theoretical studies on the uptake of O 3 

### by the RTs
(or regions) of humans and laboratory animals that have become available since the 1996 O 3 

### 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 singl e-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 O 3 

### 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 O 3 

### 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 O 3 

### -induced rapid shallow breathing, it was the long path terminal bronchioles that
received the greatest epithelial injury.

### AX4-13Table AX4-2. New Ozone Dosimetry Model InvestigationsaPurpose/ObjectiveType of mass transportmodel/Anatomical modelbSpecies/RT region ofinterest/Regionalanatomical modelsVentilation andExposure Results ReferenceTo 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 general shapeof the dose versus generation plot along any path fromthe trachea to a sac is independent of path: generallythe tissue dose decreases with increasing generationindex. In the TB region, the coefficient of variation fordose ranges from 0 to 34 %,depending on generation.The maximum ratio of the largest to smallest dose inthe same generation is 7; the average ratio being 3.In the first PUL region model segment, the coefficientof variation for the dose is 29 %. (2) The average doseto the first PUL region model segment increases withincreasing VT.Overton andGraham(1995)To incorporate intothe CFD model ofKimbell et al. (1993)resistance to masstransfer in the nasallining and toinvestigate theeffects of this liningon O3uptake.Three dimensional steadystate Navier-Stokes equationsfor solving air velocity flowfield. Three dimensionalsteady-state convectiondiffusion equation for O3transport.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 the range ofmeasured uptake. Results suggest that mucus resistanceis important for describing O3dosimetry and thisthickness may play a role for determining patternsof O3-induced lesions in the rat nasal passage.CohenHubal et al.(1996)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 airway volumebut are relative insensitiveto characteristics of therespiratory airspace. Although the gas-phase resistanceto lateral diffusion limits O3absorption during quietbreathing, diffusion through mucus may becomeimportant at the large respiratory flows that arenormally associated with exercise. The single-pathconvection-diffusion model was a reasonable approach/to simulate the bolus-response data.Bush et al.(1996b)

### AX4-14Table AX4-2 (cont’d). New Ozone Dosimetry Model InvestigationsaPurpose/ObjectiveType of mass transportmodel/Anatomical modelbSpecies/RT region ofinterest/Regionalanatomical modelsVentilation andExposure Results ReferenceTo 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 Pulmonaryventilation rangedfrom 34 mL/s(in 1-month-old)to 190 mL/s(in 15-year-old).VTvaried with age.Regional extraction is insensitive to age. Extraction perunit surface area is 2- to 8-fold higher in infantscompared to adults. PU and ET regions have a largeincrease in unit extraction with increasing age. Earlypostnatal period is time oflargest differences in PK,due to immaturity of metabolic enzymes.Sarangapaniet al. (2003)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 characterization of therole of TB region expansion (mainly the rat) andvolume is important foran improved understanding ofrespiratory-tract dosimetry modeling of reactive gases.(2) Extrapolations based on dose in the PAR can differsignificantly from those based on exposureconcentration or total uptake.(3) Human subjects who appear similar outwardly mayhave very different PAR doses and potentially differentresponses to the same exposure.(Uptake by the URTwas not considered.)Overtonet al. (1996)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 O3only) (1) Using parametervalues from the literature and assuming that absorptionwas gas-phase controlled, the simulations of O3datawere realistic at flow rate = 250 mL/s, but not realisticat 1000 mL/s. (2) Accurate simulations at 250 mL/srequired modification of mass transfer coefficientsreported in the literature for the conducting airways.(3) It was necessary to include a diffusion resistance forthe ELF based on an assumed O3reaction rate constantthat was much greater than in in vitro estimates.(4) Partial validation of the final parameters(determined at 250 mL/s) was obtained by simulationsof bolus-response data at flow rates of 150 and 1000mL/s. Validation was obtained also by simulatinginternal measurements of O3in subjects exposed duringquiet breathing.Bush et al.(2001)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 dimensions appropriate to thedosimetry investigation; or the original structure may be simplified, keeping or scaling the original dimensions.

### AX4-15 Rat effects data (from the PAR) are availabl e that are identified with the lobe and the
generation in the lobe from which tissue sa mples 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), C ohen-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 O 3 

### 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 O 3 

### flux was correlated with measured cell
proliferation for the CFD simulation that incorpor ated 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 regi on (PAR) dose, and PAR dose ratio to TB region
volume (V TB 

### ) 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 O 3 

### . For each species, three literature values of V TB 

### 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 V TB 

### depends on species, ventilation, TB region
overall mass transfer coefficient (k TB 

### ), and expansion. For k TB 

### = 0.26 cm/s and quiet breathing,
AF was predicted to vary by less than 3% for the ±2 SD range of V TB 

### . In contrast, the PAR
dose predicted for the smallest V TB 

### is five times larger than the PAR dose predicted with the

### AX4-16 largest V TB 

### . The effect of V TB 

### 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 V TB 

### 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 V TB 

### was used. For various values of f, V T 

### , k TB 

### , and expansion, the PAR
dose ratios at upper and lower values of V TB 

### deviated in absolute values from the PAR dose ratio

calculated at the mean values of V TB 

### by as little as 10% to as large as 310%. The smallest
deviation occurred at the largest V T 

### and smallest k TB 

### for both species; whereas, the largest

deviation occurred at the smallest V T 

### and largest k TB 

### for both species.
Bush et al. (2001) modified the single-path mode l of Bush et al. (1996b) in order to be able

to simulate absorbed fraction data for O 3 

### (and Cl 2 

### , 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 O 3 

### 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 O 3 

### 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 O 3 

### in humans. This model indicated that regional extraction of O 3 

### 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 O 3 

### from the RT.
Mudway and Kelly (2004) attempted to model O 3 

### dose-inflammatory response using a
meta-analysis of 23 exposures in published human chamber studies. The O 3 

### 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 O 3 

### dose and neutrophilia in bronchoalveolar lavage
fluid (BALF). Linear relationships were also observed between O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### . 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 O 3 

### 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 O 3 

### 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 O 3 

### -induced airway effects due to the similarities in pulmonary structure between primates

and ferrets.

### AX4-19 The rat is a key species used in O 3 

### 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 O 3 

### at exposure to 0.1, 0.3, and 0.5 ppm O 3 

### 8 h/day for 4 consecutive days. A dose-dependent disruption of HR and T

co 

### 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 O 3 

### and observed this hypothermic response which included
lowered HR, lowered T

co 

### , and increased inflammatory components in BALF. The authors
suggest that the response is an inherent reflexive pattern that can possibly attenuate O 3 

### toxicity in
rodents. They discuss the cascade of effects created by decreases in T

co 

### , 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 O 3 

### 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 O 3 

### exposures.

### AX4-20 

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### AX4-21 Olson, D. E.; Sudlow, M. F.; Horsfield, K.; Filley, G. F. (1973) Convective patte rns of flow during inspiration. Arch. Intern. Med. 131: 51-57. Overton, J. H.; Graham, R. C. (1995) Simulation of the upt ake of a reactive gas in a rat respiratory tract model with an asymmetric tracheobronchial region patterned on co mplete conducting airway cast data. Comput. Biomed. Res. 28: 171-190. Overton, J. H.; Graham, R. C.; Menach e, M. G.; Mercer, R. R.; Miller, F. J. (1996) Influence of tracheobronchial region expansion and volume on reactive gas uptake and in terspecies dose extrapolations. Inhalation Toxicol. 8: 723-745. Patra, A. L.; Ménache, M. G.; Shaka, N. B.; Gooya, A. (1987) A morphometric study of nasal-pharyngeal growth for particle deposition in the rat. Am. Ind. Hyg. Assoc. J. 48: 556-562. Pinkerton, K. E.; Menache, M. G.; Pl opper, C. G. (1995) Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part IX. Changes in the tracheobronchial epithelium, pulmonary acinus, and lung antioxidant enzyme activity. Cambridge, MA: Health Effects Institute; pp. 41-98; research report no. 65. Available from: NTIS, Springfield, VA; PB95-261996. Pinkerton, K. E.; Weller, B. L.; Men ache, M. G.; Plopper, C. G. (1998) C onsequences of prolonged inhalation of

ozone on F344 /N rats: collaborative studies. Part XIII. A comparison of changes in the tracheobronchial epithelium and pulmonary acinus in male rats at 3 a nd 20 months. Cambridge, MA: Health Effects Institute; research report no. 65. Postlethwait, E. M.; Joad, J. P.; Hyde, D. M.; Schelegle, E. S.; Bric, J. M.; We ir, A. J.; Putney, L. F.; Wong, V. J.; Velsor, L. W.; Plopper, C. G. (2000) Three-dimens ional mapping of ozone-induced acute cytotoxicity in tracheobronchial airways of isolated perfused ra t lung. Am. J. Respir. Cell Mol. Biol. 22: 191-199. Raabe, O. G.; Yeh, H. C.; Schum, G. M.; Phalen, R. F. (1976) Tracheobronchial geometry: human, dog, rat, hamster. Albuquerque, NM: Lovelace Foundation; report no. LF-53. Rigas, M. L.; Ben-Jebria, A.; Ultman, J. S. (1997) Longit udinal distribution of ozone absorption in the lung: effects of nitrogen dioxide, sulfur dioxide, and ozone exposures. Arch. Environ. Health 52: 173-178. Rigas, M. L.; Catlin, S. N.; Ben-Jebria, A.; Ultman, J. S. (2000) Ozone uptake in the intact human respiratory tract: relationship between inhaled dose and act ual dose. J. Appl. Physiol. 88: 2015-2022. Santiago, L. Y.; Hann, M. C.; Ben-Jebria, A.; Ultman, J. S. (2001) Ozone adsorption in the human nose during unidirectional airflow. J. Appl. Physiol. 91: 725-732. Sarangapani, R.; Gentry, P. R.; Covington, T. R.; Teeguarden, J. G.; Clewell, H. J., III. (2003) Evaluation of the potential impact of age- and gender-specific lung mor phology and ventilation rate on the dosimetry of vapors. Inhalation Toxicol. 15: 987-1016. Schelegle, E. S.; Alfaro, M. F.; Putn ey, L.; Stovall, M.; Tyler, N.; Hyde, D. M. (2001) Effect of C-fiber-mediated, ozone-induced rapid shallow breathing on airway epithe lial injury in rats. J. Appl. Physiol. 91: 1611-1618. Sterner-Kock, A.; Kock, M.; Braun, R.; Hyde, D. M. (2000) Ozone-induced epithelial injury in the ferret is similar to nonhuman primates. Am. J. Respir. Crit. Care Med. 162: 1152-1156. Ultman, J. S.; Ben-Jebria, A.; Arnold, S. F. (2004) Up take distribution of ozone in human lungs: intersubject variability in physiologic response. Boston, MA: Health Effects Institute; research report no. 125. Available: http://www.healtheffects.org/Pubs/Ultman.pdf [29 July, 2005]. U.S. Environmental Protection Agency. (1996) Air quality criteria for ozone and related photochemical oxidants. Research Triangle Park, NC: Office of Research and Development; report nos. EPA/600/AP-93/004aF-cF. 3v. Available from: NTIS, Springfield, VA; PB96-185582, PB96-185590, and PB96-185608. Available online at: www.epa.gov/ncea/ozone.htm. Watkinson, W. P.; Gordon, C. J. (1993) Caveats regard ing the use of the laboratory rat as a model for acute toxicological studies: modulation of the toxic res ponse via physiological and behavioral mechanisms. Toxicology 81: 15-31. Watkinson, W. P.; Campen, M. J.; Wichers, L. B.; Nolan, J. P.; Costa, D. L. (2003) Cardiac and thermoregulatory responses to inhaled pollutants in healthy and co mpromised rodents: modulation via interaction with environmental factors. Environ. Res. 92: 35-47. Weibel, E. R. (1963) Morphometry of the hum an lung. New York, NY: Academic Press Inc. Yeh, H. C.; Schum, G. M.; Duggan, M. T. (1979) Anatom ic models of the tracheobronchial and pulmonary regions of the rat. Anat. Rec. 195: 483-492.

### AX5-1 

# AX5. ANNEX TO CHAPTER 5 OF OZONE AQCDTable AX5-1. Cellular Targets of Ozone InteractionConcentrationppm Duration Species Effects Reference0.22 4 h withexerciseRat, male, SD, 90 daysold, 300-330 g,n = 6/groupDemonstrated the ozonation of PUFA to form nonanal and hexanal in rat BALF.Increases in nonanal not accompanied by significant changes in lung function,epithelial permeability, or airway inflammation. Hexanal levels did not increasesignificantly. Levels of both aldehydes returned to baseline by 18 h PE.Framptonet al. (1999)0.5-10 bothwith andwithout 5% CO21 h Rat, male, SD, 90 daysold, 300-330 g,n = 6-14/groupO3plus CO2increased the VTand the yield of aldehydes with a maximalaldehyde yield at 2.5 ppm for 1 h. 0.5 ppm O3with 5% CO2, levels of hexanaland nonanal increased at 30 min, decreased slightly from that level at 60 min,was maximal at 90 min and then dropped to 60 min levels at 120 min. Levels ofheptanal did not change appreciablyduring this time course. Suggests thatlevels of these aldehydes were dependent on a dynamic relationship betweentheir production and the disappearance from the ELF.Pryor et al.(1996)0.25-1.0 30-60 min Rat, male, SD,250-275 g,n = 3-5/group3 modelsystems:isolatedepithelial lining fluid,intact lung, andliposome suspensionsPUFAs directly react with O3. The amount of bioactive lipids produced isinversely related to AA availability.Postlethwaitet al. (1998)0.3-1.1 Chemicalsystems:15-10 min.Cell: 1-2 hInterfacial films(dipalmitoylglycero-3-phosphocholine(DPPC));Rat, SDBALF; human lungfibroblast cell lineDPPC films: reduced O3reactive absorption by antioxidants. Human lungfibroblast cell line: AA produced cell injury; high levels of O3and AA wereneeded to induce cell injury; the DPPC films reduced the amount of cell injury.Suggests that O3reactions with ELF substrates cause cell injury; that films ofactive, saturated phospholipids reduce the local dose of O3-derived reactionproducts; and that these interfacial phospholipids modulate the distribution ofinhaled O3and the extent of site-specific cell injury.Connoret al. (2004)0.4 1 h withexerciseHuman AM Ozone exposure caused apoptosis, anincrease in a 32-kDa protein adduct, andan increase in ferritin and a 72-kDa heatshock protein. Exposure of AM toHNE replicated these effects suggestingthat creation of protein adducts andapoptotic cell death are cellular toxic effects of acute O3exposure and that theyare mediated, at least in part by HNE.Hamiltonet al. (1998)



### AX5-2Table AX5-2. Effects of Ozone on Lung MonooxygenasesConcentrationppm Duration Species Effects Reference1.01.08 h90 daysRat, male, SD,350-600 g,n = 3-6/groupIncreases CYP2E1 activity in lobar-bronchi and major daughter airwaywith 8 h exposure. Decreased CYP2E1 activities in both major and minordaughter airways with 90-day exposure. O3does not result in consistentdramatic alterations in CYP2E1 activities.Watt et al.(1998)0.8 8 h/day for90 daysRat, male, SD,275-300 gCYP2B activity increased. Linked to Clara cells in distal lung only—not intrachea or proximal airway.Paige et al.(2000a)1 2 h Mice, male, 2-3 monthsold, Clara Cell SecretoryProtein deficient,WT strain 129n = 3/groupCCSP-/-mice had increases in IL-6 andMT mRNA that preceded decreasesin Clara cell CYP2F2 mRNA. WT mice had levels change, but to a lesserdegree.Mango et al.(1998)NA Rat, male, SD, adultmonkey, Rhesus, 0.75 to9.7 years oldMicrodissection 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 activitieswere high, and conversely, low intrachea. Monkeys: did not exhibit site-selective differences in CYP2B1,CYP1A1, or P450 reductase; however, they had high CYP2E1 activityin parenchyma and distal bronchioles.Lee et al.(1998)CYP = Cytochrome P450WT = wild-typeMT = metallothioneinCCSP = Clara Cell Secretory Protein



### AX5-3Table AX5-3. Antioxidants, Antioxidant Metabolism, and Mitochondrial Oxygen ConsumptionConcentrationppm Duration Species Effects Reference1.0 6 h/day,5 days/weekfor 2 or3 monthsRat, male Fischer F344,30-32 days old, n = 4Immunohistochemistry and immunogold labeling studies. In epithelialcells in airways and parenchyma: reduced Cu-Zn SOD labeling withO3-exposure. In the CAR regions, in both AMs and Type II epithelialcells: significantly increased levels ofMn SOD. Mn SOD levels were notincreased in Type I epithelial cells,fibroblasts, or Clara cells. Suggeststhat the increased levels of Mn SOD in Type II cells in the proximalalveolar duct confer tolerance and protection from further O3-inducedinjury.Weller et al.(1997)0.2 6 h Dog, male, mongrel,~/9 kg, n = 6/groupBlocking antioxidant transport with probenecid caused heterogeneouslydistributed increases in peripheral airway resistance and reactivity.Probenecid inhibited O3-induced neutrophilic inflammation, which isevidence of a dissociation between airway function and inflammation.Probenecid caused a 50-60% decreasein plasma urate, a decrease inascorbate, and a decrease in BALFprotein. Suggests probenecid haseither a direct or indirect effect on either cytokine or leukotriene transport.Freed et al.(1999)0, 0.1, 0.25,0.5, 1.0 or 1.530-720 min Model of continuallymixed, interfacial exposureModeled the interactions of O3with three ELF antioxidants, AA, UA andGSH. Ranking of reactivity with O3was UA > AA > GSH. Antioxidantscaused no changes in sample pH and protein carbonyl formations.Consumption of the antioxidants occurred in a linear fashion with timeand a positive relationship to O3concentration. Suggests that GSH isnot an important substrate for O3; UA appeared to be the most importantsubstrate.Mudway andKelly (1998)Cu = CopperZn = ZincMn = ManganeseSOD = Superoxide DismutaseAM = Alveolar MacrophageBALF = Bronchoalveolar Lavage FluidAA = Ascorbic AcidUA = Uric AcidGSH = Reduced Glutathione



### AX5-4Table AX5-4. Lipid Metabolism and Content of the LungConcentrationppm Duration Species/Cell Line Effects ReferenceNA 60 min Cultured human epithelialcells (BEAS-2B)Incubation with 10 μM lipid oxidation products caused significantrelease of arachidonic acid. Suggests that lipid oxidation products causeactivation of specific lipases, which then trigger the activation of secondmessenger pathways (e.g., phospholipase A2or phospholipase C).Pryor et al.(1995)NA Cultured human bronchialepithelial cells (NHBE)and BEAS-2B cellsIncubation with lipid ozonation product1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PC-ALF)and 1-hydroxy-1-hydroperoxynonane (HHP-C9). PC-ALF elicitedrelease of (PAF) and prostaglandin E2, but not IL-6. HHP-C9 causedrelease of PAF and IL-6 in these cells, but not prostaglandin E2.Suggests that O3-induced production of lipid ozonation productscauses release of proinflammatorymediators that then generate anearly inflammatory response.Kafoury et al.(1999)0.06, 0.125, and0.25 ppm2 to 48 h Lung (calf surfactant) Dose- and time-dependent increase in the formation of1-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) inducedapoptosis in pulmonary epithelial-like A549 cells at 100-200 μM,and (3) elicited release of IL-8 from A549 cells at 50-100 μM.Uhlson et al.(2002)0.8 30 min Human red blood cell(RBC) modelHuman RBCs intermittently covered by an aqueous film consisting ofrat BALF or BALF plus added reagents that included AA, UA, GSH,Trolox (a vitamin E analog), SOD, catalase, desferrioxamine,deithylenetriaminepentaacectic acid, mannitol or BSA. Oxidation oflipids in BALF or on membranes was assayed by measuring TBARSaccumulation and loss of acetylcholinesterase activity. AA and GSHinduced dose-dependent oxidative damage to the cell membrane proteinsand lipids via secondary oxidant formation. Conclusion: early in O3exposure, ELF antioxidants are high enough to drive reactive absorptionof O3into the ELF and to concurrently quench secondary reactionproducts, thus limiting cell injury. With continued exposure, O3fluxwould decrease, cellular injury would increase due to depletedantioxidants levels. They hypothesizethat especially in areas whereO3deposition is high, unreacted O3and cytotoxic products can diffuseto the cell membranes, causing injury.Ballinger et al.(2005)



### AX5-5Table AX5-4 (cont’d). Lipid Metabolism and Content of the LungConcentrationppm Duration Species/Cell Line Effects Reference2.00.2, 0.5, or 1.04 h1 hRat BALF exposed to O3in 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$-hydroxy-5oxo-5,6-seco-cholestan-6-al.Extracted lipid reaction productseither immediately or 24 h PE.Higher levels of 5$,6$-epoxycholesterol were recovered in the extractimmediately PE. Both 5$,6$-epoxycholesterol and its most abundantmetabolite, cholestan-6-oxo-3$,5"-diol, were cytotoxic to 16-HBE cellsat physiologically relevant concentrations. Both reaction products werealso shown to be potent inhibitors of cholesterol synthesis.Pulfer andMurphy(2004)0.5, 1.0, 2.0,or 3.03 h Mice, C57BL/6J,8-12 weeks old female.n = 4In BALF, lavaged cells, and whole lung homogenate there was adose-dependent increase in formation cholestan-6-oxo-3$,5"-diol atexposure levels of 0.5, 1.0 and 2.0 ppm O3, respectively. In BALFand lavaged cells O3induced increases in 5$,6$-epoxycholesterol atexposure levels of 0.5 and 1.0, respectively.Pulfer et al.(2005)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



### AX5-6Table AX5-5. Effects of Ozone on Protein SynthesisConcentrationppm Duration Species Effects Reference0.4 1,3,7,28, or56 daysRat, male, Wistar,200 g,n = 5/groupCentriacinar thickening of septa after 7 days of exposure, whichprogressed at 28 and 56 days of exposure. After 28 days of O3, theincrease in collagen content in ductular septa was apparent and itincreased progressively until the 56-day time point. Collagen contentdecreased with PE recovery, the structural fibrotic changes in ductularsepta did not return to control levels. Respiratory bronchioles werepresent at an increasing degree, which persisted after an 80-d recoveryperiod. Suggests that subchronic O3exposures in rats creates aprogression of structural lung injury that can evolve into a more chronicform, which included fibrosis.van Bree et al.(2001)Table AX5-6. Effects of Ozone on Differential Gene ExpressionConcentrationppm Duration Species Effects Reference1 8 h for threeconsecutivenightsMice, C57BL/6,20-25 g,n = 5-6/groupOzone exposure induced changes in expression of 260 genes ( 80%repressed and 20% induced). Cell cycle genes upregulated:S-adenosylmethionine decarboxylase 3, ribonucleotide reductase, and clusterin.NF-6B-induced genes upregulated: serum amyloid protein, topoisomeraseII", monocyte chemoattractant protein,platelet-derived growth factor,and inhibitor of apoptosis. Downregulation of transcripts for isoformsof myosins and actins. CYP family genes downregulated: 2a4, and 2e1,and 2f2, as were aryl-hydrocarbon receptor and several glutathionetransferases. Metallothionein 1 and 2 and lactotransferrin upregulated.Major histocompatibility complex genes and lymphocyte specificproteins downregulated.Gohil et al.(2003)



### AX5-7Table AX5-7. Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceMicrobiologic Endpoints0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 gNo effect on cumulative mortality from subsequent lung infectionwith 4-8 × 106Listeria monocytogenes, but concentration-relatedeffects on morbidity onset and persistence. One-week exposed rats:listeric burdens trended higher than incontrols; 0.3 ppm rats displayedcontinual burden increases and no onset of resolution; in situ IL-1",TNF-", and IFN-(levels 48 and 96 h post-infection (4 × 106level)higher than controls. Three-week exposed rats: no O3-related changein bacterial clearance; IL-1", TNF-", and IFN-(levels higher thancontrol only at 48 h post-infection (4 × 106) and only with 0.3 ppm rats.Cohen et al.(2001, 2002)0.8 3 h Rat, male, Fischer F344,8 weeks old,n = 4-10/groupSingle exposure toS. zooepidemicusled to differential clearancepatterns in exposed rats maintained onad libitumor O3-mitigatingcalorie-restricted diets.Dong et al.(1998)Clearance Endpoints (Non-Microbial)0.01 -1.0 10 min Rat, SD Single 10 min exposure of tracheal explants, followed by 1 h incubationwith particles, led to dose-related increases in uptake of amositeasbestos and titanium dioxide particles. Effect inhibited by addedcatalase or desferoxamine, butnot by superoxide dismutase.Churg et al.(1996)0.4 6 h Dog, male, mixed breed,1-3 years old,n = 7/groupIncreased tracheal permeability to99mTc-DTPA after direct sublobarexposure to O3. Clearance halftimes remained significantly lower for1-7 days PE, but recovered by 14 days PE.Foster andFreed (1999)Alveolar Macrophage Endpoints (General)0.8 3 h Rat, male, SD,250-275 g,n = 5-6/groupIncreased ex vivo AM adherence to epithelial cultures mitigated bycell pretreatment with anti-CD11b or anti-ICAM-1 antibodies.Bhalla (1996)0.8 3 h Rat, male, SD,250-300 g,n = 5/groupIncreased ex vivo AM adherence to epithelial cell cultures mitigatedby cell pretreatment with anti-TNF-"/IL-1"antibodies.Pearson andBhalla (1997)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.Cohen et al.(1996)



### AX5-8Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceAlveolar Macrophage Endpoints (Functional)0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 gSuperoxide anion: increased AM production (1 week; 0.1, 0.3 ppm);no intergroup differences noted after IFN-(stimulation.H2O2: reduced production (1 week; 0.1, 0.3 ppm); further reducedproduction after treatment with IFN-((0.1, 0.3 ppm, 1 and 3 weeks).Cohen et al.(2001)0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 gIncreased AM superoxide anion production (1 week; 0.1, 0.3 ppm),Lower H2O2production (1 week; 0.1, 0.3 ppm). Reduced productionafter treatment with IFN-(- superoxide (0.3 ppm, 1 week) and H2O2(0.1 ppm, 1 week) - relative to cells without IFN-(treatment.No effects from 3-week exposures.Cohen et al.(2002)0.3 5 h/day,5 days/week,4 weeksRat, male, Fischer F344,200-250 g,n = 10/groupNo effect on AM endotoxin-stimulated IL-1", IL-6, or TNF-"production. Decrease in stimulated, but not spontaneous, superoxideformation; variable effects on H2O2formation. No effect on AMspontaneous, endotoxin-, or IFN-(-stimulated, NO formation.Cohen et al.(1998)0.8 3 h Rat, male, SD, 250-275 g, n = 5-6/groupIncreased AM motility in response to chemotaxin; effect mitigatedby cell pretreatment with anti-CD11b or anti-ICAM-1 antibodies.Bhalla (1996)0.8 3 h Rat, male, Fischer F344,8 weeks old,n = 4-10/groupDecrease in AM phagocytic activity. Dong et al.(1998)0.8 3 h Mice, female,(B6J129SV)(C57BL/6X 129 NOS-/-),8-16 weeks old,n = 3-12/groupIncreased AM spontaneous and IFN-(+ LPS-induced NOS expressionand NO production and PGE2release. Initial decrease in ROIproduction, with eventual rebound. Knockout (NOS-/-) mice AMincapable of similar response to O3– no inducible NO or PGE2above control levels and consistent decreased ROI production.Fakhrzadehet al. (2002)1.0 24 h/day,3 daysRat, male, Wistar,8-12 weeks,BALF from exposed rats subsequently inhibited IFN-(-inducedAM NO production.Koike et al.(1998, 1999)



### AX5-9Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceCytokines, Chemokines: Production, Binding, and Inducible Endpoints0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 g,Superoxide anion: no intergroup differences noted after IFN-(stimulation. H2O2: reduced production after treatment with IFN-(.Cohen et al.(2001)0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 g,n = 3-5/groupDecreased expression of CD3 among lung lymphocytes (0.1 ppm only;3 weeks); effect exacerbated by stimulation with IFN-"(but not withIL-1"). Decreased expression of CD25 (IL-2R) on CD3+lymphocytes(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 withIFN-(; superoxide anion (0.3 ppm, 1 week) and H2O2(0.1 ppm, 1 week)- relative to untreated cells.Cohen et al.(2002)0.3 5 h/day,5 days/week,4 weeksRat, male, Fischer F344,200-250 g,n = 10/groupNo effect on AM endotoxin-stimulated IL-1", IL-6, or TNF-"production.Cohen et al.(1998)0.31.02.524 or 96 h1, 2, or 4 h,or 24 hMice, male, C57BL/6J,adult, n = 3/group0.3 ppm: Increased lung: MIP-2, MCP-1, and eotaxin mRNAexpression.1.0 ppm: After 4 h, increased lung: MIP-2, MCP-1, eotaxin, andIL-6 mRNA expression.2.5 ppm: After 2 h, increased lung: MIP-2, MCP-1, eotaxin, andIL-6 mRNA expression.No exposure-related increases in lung IL-1", IL-1$, IL-1R", IL-10,IL-12, or IFN-(mRNA expression.Johnston et al.(1999a)1.0 4 h Mice cell line(WEH1-3)Decreased binding of IFN-(by WEHI-3 cells. Decreased superoxideanion production by IFN-(-treated cells; no similar effect on H2O2production. Decreased IFN-(-stimulated phagocytic activity. No effecton IFN-(-inducible Ia (MHC Class II) antigen expression.Cohen et al.(1996)1.0 6 h Rat, male, SD,200-250 g,n = 3-6/groupIncreased AM MIP-1", CINC, TNF-", and IL-1$mRNA expression.Induced increase in MIP-1"and CINC mRNA temporally inhibitedby cell treatment with anti-TNF-"/IL-1$antibodies.Ishii et al.(1997)



### AX5-10Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceCytokines, Chemokines: Production, Binding, and Inducible Endpoints(cont’d)1.0 24 h/day,3 daysRat, male, Wistar,8-12 weeks oldBALF from exposed rats subsequently inhibited: ConA-stimulatedlymphocyte IFN-(production, but had no effect on IL-2 production;IL-2-induced lymphoproliferation; and, IFN-(-induced AM NOproduction.Koike et al.(1998, 1999)1.0 24 h Mice, male, C57BL/6J,8 weeks old, n = 3/groupIncreased lung: MIP-2 (4 h PE) and MCP-1 (4 and 24 h PE) mRNAexpression.Johnston et al.(2001)1.0 24 h Mice, male, C57BL/6J,8 weeks old, n = 3/groupIncreased lung MIP-2 and MCP-1 mRNA expression (4 and 24 h PE);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 recoveryperiod. Enhanced expressions ofsome cytokines/chemokines weremaintained longer than normal by coexposure to endotoxin.Johnston et al.(2002)1.0 8 h/day,3 daysMice (C57BL/6)(C57BL/6Ai-NOS-/-)n = 3-10/groupKnockout (NOS-/-) mice have more lavageable MIP-2 after exposurethan wild-type; both greater than control.Kenyon et al.(2002)1.0, 2.5 4 or 24 h Mice, male, C57BL/6J,adult, n = 3/groupDose-related increases in cytokine/chemokine induction. Increasedlung MIP-1", MIP-2, eotaxin (4 and 24 h), IL-6 (4 h only), and iNOSmRNA expression.Johnston et al.(2000a)0.6, 2.0 3 h Mice, C57BL/6, Rat,Wistar, 14-16 weeksold, n = 4-6/groupIncreased 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.Zhao et al.(1998)0.8 3 h Rat, male, SD,250-300 g, n = 5/groupIncreased ex vivo AM adherence to epithelial cells mitigated by celltreatment with anti-TNF-"or IL-1"antibodies.Pearson andBhalla (1997)0.8 3 h Mice, female,B6J129SV,C57BL/6X 129 NOS-/,8-16 weeks,n = 3-12/groupIncreased AM IFN-(+ LPS-induced NOS expression and NOproduction, as well as induced PGE2release. Knockout (NOS-/-)mice AM incapable of similar response to O3- no inducible NO orPGE2above control levels.Fakhrzadehet al. (2002)



### AX5-11Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceCytokines, 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/groupIncreased AM IFN-(+ LPS-induced NOS expression and NOproduction.Laskin et al.(2002)2.0 3 h Rat, female, SD,200-225 g,n = 4-6/groupIncreased AM spontaneous and IFN-(+ LPS-induced NOS expressionand NO production. AM from exposed rats showed rapidonset/prolonged activation of NF6B.Laskin et al.(1998a)0.08-0.25 and 1%OVA4 h,3 times/week,4 weeksMice, female, BALB/c,C57BL/6,6-8 weeks old,n = 4-12/groupO3- dose-dependent increases in IgE, IL-4, IL-5; recruitment ofeosinophils and lymphocytes in BALB/c; O3+ OVA - increased IgG,antibody titers, leukotrienes, airway responsiveness, immediatecutaneous hypersensitivity reactions in BALB/c. In C57BL/6 onlyO3+ OVA caused cutaneous hypersensitivity and altered IgG responses.NeuhausSteinmetzet al. (2000)Alveolar Macrophage/Lung NO- and iNOS-Related Endpoints0.3 5 h/day,5days/week,4 weeksRat, male, Fischer F344,200-250 g,n = 10/groupNo effect on AM spontaneous, endotoxin-, or IFN-(-stimulated,NO formation.Cohen et al.(1998)0.8 3 h Mice, female,B6J129SV,C57BL/6X 129 NOS-/-,8-16 weeks,n = 3-12/groupIncreased AM IFN-(+ LPS-induced NOS expression and NOproduction and PGE2release. Knockout (NOS-/-) mice AM incapable ofsimilar response to O3- no inducible NO or PGE2above control levels.Fakhrzadehet al. (2002)0.8 3 h Mice, female,B6J129SV,C57BL/6X 129 NOS-/-,8-16 weeks,n = 3-4/groupIncreased AM spontaneous and IFN-(+ LPS-induced NOS expressionand NO production. AM from exposed mice showed rapid andprolonged activation of NF6B, STAT-1 (expression, activity),phosphoinositide 3-kinase, and protein kinase B.Laskin et al.(2002)



### AX5-12Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceAlveolar Macrophage/Lung NO- and iNOS-Related Endpoints(cont’d)1.0 8 h/day,3 daysMice, C57BL/6,C57BL/6Ai-NOS-/-,n = 3-10/groupKnockout (NOS-/-) mice have more lavageable PMN, MIP-2,and protein in lungs after exposure than wild-type.Kenyon et al.(2002)1.0 24 h/day,3 daysRat, male, Wistar,8-12 weeks, n = 2/groupBALF from exposed rats subsequently inhibited IFN-(-inducedAM NO production.Koike et al.(1998, 1999)1.0, 2.5 4 or 24 h Mice, male, C57BL/6J,adult, n = 3/groupDose-related increase in lung iNOS mRNA expression. Johnston et al.(2000a)2.0 3 h Rat, female, SD,200-250 g,n = 1-3/groupIncreased AM spontaneous, IFN-(, and LPS-induced NO production,as well as spontaneous and LPS-induced NOS expression. Effectsomewhat ameliorated by pretreatment with bacterial endotoxin.Pendino et al.(1996)2.0 3 h Rat, female, SD,200-225 g,n = 3-6/groupIncreased AM spontaneous and IFN-(+ LPS-induced NOSexpression and NO production. AM from exposed rats showedrapid onset/prolonged activation of NF6B.Laskin et al.(1998b)3.0 6 h Rat, female, BrownNorway, 250-300 g,n = 4-8/groupIncreased lung iNOS mRNA expression. Effect blocked bypretreatment with dexamethasone.Haddad et al.(1995)0.12, 0.5, or 2 3 h Mice, female, BALB/c,5-6 weeksDose-dependent increases in nitrate and Penh; increases in nNOS, butnot iNOS or eNOS.Jang et al.(2002)Surface Marker-Related Endpoints0.8 3 h Rat, male, SD,250-275 g,n = 5-6/groupIncreased expression of AM CD11b, but no effect on ICAM-1. Bhalla (1996)1.0 4 h Mice cell line(WEH1-3)No effect on IFN-(-inducible Ia (MHC Class II) antigen expressionon WEHI-3 cells.Cohen et al.(1996)1.0 2 h Rat, female, SD,170-210 g,n = 8-12/groupDecreased expression of integrins CD18 on AM and CD11b on PMN.No effect on PMN CD62L selection.Hoffer et al.(1999)



### AX5-13Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceSurface Marker-Related Endpoints(cont’d)1.0 3 days Rat, male, Wistar andFischer F344,8-10 weeks, n = 3/groupIncreased expression of surface markers associated with antigenpresentation: Ia (MHC Class II) antigen, B7.1, B7.2, and CD11b/con BAL cells. Effect attributed to influx of monocytes.Koike et al.(2001)0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 gDecreased expression of CD3 among lung lymphocytes (0.1 ppm only;3 weeks); effect exacerbated by stimulation of cells with IFN-"(but notwith IL-1"). Decreased expression of CD25 (IL-2R) on CD3+lymphocytes (0.3 ppm only; 3 weeks); effect worsened by treatmentof cells with IL-1"(0.1 and 0.3 ppm; 3 weeks).Cohen et al.(2002)NK- and Lymphocyte-Related Endpoints0.1, 0.3 4 h/day,5 days/week,1 or 3 weeksRat, male, Fischer F344,200-250 gDecreased expression of CD3 among lung lymphocytes (0.1 ppm only;3 weeks); effect exacerbated by stimulation of cells with IFN-"(but not with IL-1"). Decreased expression of CD25 (IL-2R) onCD3+lymphocytes (0.3 ppm only; 3 weeks); effect worsened bytreatment of cells with IL-1"(0.1 and 0.3 ppm; 3 weeks).Lymphoproliferation: no effect on spontaneous or IL-2-inducibleforms; 0.1 ppm increased response to ConA mitogen (1 week only);0.3 ppm - decreased response to ConA (1 week only).Cohen et al.(2002)0.4, 0.8, 1.6 12 h Mice, male, BALB/c,6-8 weeks old,n = 5-8/groupDecreased pulmonary delayed-type hypersensitivity reactions to lowMW agents, likely via activation of TH2-dependent pathways.Garssen et al.(1997)1.0 24 h/day,3 daysRat, male, Wistar,8-12 weeks oldLavage fluid from exposed rats subsequently inhibited ConA-stimulatedlymphocyte IFN-(production, but had no effect on IL-2 production;material also inhibited IL-2-induced lymphoproliferation.Koike et al.(1999)



### AX5-14Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceSusceptibility Factors0.3 24 to 72 h MiceC57BL/6JC3H/HeJC3H/HeOuJ, 6-8 weeksold, n = 4-8/groupLavageable protein concentration lowered by inhibition of iNOS and bytargeted disruption ofNos2; reducedNos2andTlr4mRNA levels in theO3-resistant C3H/HeJ mice.Kleebergeret al. (2001b)1 4 h CHO-K1 cell line SP-A Differences exist biochemically and functionally in SP-A variants.O3exposure affects the ability of variants to stimulate TNF-"and IL-8.Wang et al.(2002)0.3 24-72 h Mice, male, C57BL/6J,C3H/HeJ, C3H/HeOuJ,6-8 weeks old,n = 5-16/groupIdentified a candidate gene on chromosome 4, Toll-like receptor 4(Tlr4), a gene implicated in endotoxin susceptibility and innateimmunity. O3-resistant strain C3H/HeJ and C3H/HeOuJ (differing fromthe O3-resistant strain by a polymorphism in the coding region ofTlr4)were exposed, greater protein concentrations were demonstrated in theOuJ strain. Differential expression ofTlr4mRNA with O3exposure.Suggests quantitative trait locus on chromosome 4 is responsible for asignificant portion of the genetic variance in O3-induced lunghyperpermeability; potential interaction between the innate and acquiredimmune system.Kleebergeret al. (2000)0.1 2 h Mice, male, C57BL/6,6-8 weeks oldSensitized the mice to OVA by intratracheal instillation of OVA-pulseddendritic cells (the principal antigen-presenting cells in airways).Created Th2 lymphocyte-dependent eosinophilic airway inflammation.Groups of mice exposed to O3during sensitization by OVA-pulseddendritic cells showed no modification of the allergic sensitizationprocess, whereas, previously sensitized mice exposed to O3,demonstrated increases in allergen-induced airway inflammation.Suggests that dendritic cells are an important component of O3-inducedeosinophilic airway inflammation.Depuydt et al.(2002)



### AX5-15Table AX5-7 (cont’d). Effects of Ozone on Lung Host DefensesConcentrationppm Duration Species Effects ReferenceSusceptibility Factors(cont’d)0.1, 0.5, and 1.0 2 h Human lymphocytes Subsequent to O3exposure, when lymphocytes were stimulatedwith pokeweed mitogen (PWM, a T-cell-dependent stimulus)orStaphylococcus aureusCowan 1 strain (SAC, a T-cell-independentstimulus), 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 O3may have direct effects onIgG-producing cells and concurrently an effect that is mediatedby altered production of T cell immunoregulatory molecules.Becker et al.(1991)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 bya mechanism that does not involve metal chelation or oxidativemodification of the proteins.Bridges et al.(2000)AM = Alveolar macrophage; PE = Postexposure (i.e., time after O3exposure 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 A;OVA = Ovalbumin; SP-A = Surfactant Protein A; SP-D = Surfactant Protein D



### AX5-16Table AX5-8. Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference0.10.20.50.5 h, in vitro Rat, SD, primary alveolarType II cellsDecreased transepithelial resistance (Rt) after 0.5 ppm from 2 to 24 hPE and at 48 h in monolayers subjected to PMNs. Significantly lowerRtafter PMN treatment at 0.2 and 0.5 ppm.Cheek et al.(1995)0.10.20.41.01 h, in vitro Guinea pig, male andfemale, Hartley, and humanalveolar macrophagesExposure of guinea pig alveolar macrophages to 0.4 ppm for 60 minproduced a significant increase in IL-6 and TNF-", and an exposure ofhuman alveolar macrophages to identical O3concentration increasedTNF-", IL-1$, IL-6 and IL-8 protein and mRNA expression.Arsalane et al.(1995)0.20.40.823 h/day for 1 week Guinea pigs, female(Hartley), 260-330 gn = 4-10/groupIncrease in BALF protein and albumin immediately after0.8 ppm exposure, with no effect of ascorbate deficiency in diet.O3-induced increase in BALF PMN number was only slightlyaugmented by ascorbate deficiency.Kodavanti et al.(1995)0.26 8 h/day, 5 days/weekfor 1-90 daysMice, male (mastcell-deficient and-sufficient), 6-8 weeks oldn = 4-8/groupGreater increases in lavageable macrophages, epithelial cells andPMNs in mast cell -sufficient and mast cell-deficient mice repleted ofmast cells than in mast cell-deficient mice. O3-induced permeabilityincrease was not different in genotypic groups.Kleebergeret al. (2001b)0.3 48 h and 72 h.Exposures repeatedafter 14 daysMice, male, C57BL/6J andC3H/HeJ, 6-8 weeks oldGreater BALF protein, inflammatory cell and LDH response inC57BL/6J than in C3H/HeJ after initial exposure. Repeated exposurecaused a smaller increase in BALF protein and numberof macrophages, lymphocytes and epithelial cells in both strains,but PMN number was greater in both strains of mice compared toinitial exposure.Paquette et al.(1994)0.10.31.060 min Rat basophilic leukemia cellline (RBL-2H3)O3inhibited IgE- and A23187 - indued degranulation. Spontaneousrelease of serotonin and modest generation of PGD2 occurred onlyunder conditions that caused cytotoxicity.Peden andDailey (1995)0.32.072 h3 hMice, male and female,C57BL/6J and C3H/HeJGreater PMN response in C57BL/6Jthan in C3H/HeJ after acute andsubacute exposures. Responses ofrecombinant mice were discordantand suggested two distinct genes controlling acute and subacuteresponses. Genes termed Inf-1 and Inf-2.Tankersley andKleeberger,(1994)0.3 48 h Mice, C57BL/6J andC3H/HeJ, 6-8 weeks oldSusceptibility to O3is linked to a quantitative trait locus, and TNF-"is identified as a candidate gene.Kleebergeret al. (1997)



### AX5-17Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference0.31.02.524 or 48 h1, 2 or 4 h2, 4 or 24 hMice, male, C57BL/6J,8 weeks oldn = 3/group0.3 ppm for 24 h caused increase in mRNA for eotaxin, MIP-1a andMIP-2.1 ppm for 4 h caused increase in mRNA for eotaxin, MIP-1a, MIP-2,and IL-6.2.5 ppm for 2 and 4 h caused increase in mRNA for MIP-1a, MIP-2and IL-6 and metallothionein. Greater increases and lethality after 24h.Johnston et al.(1999a)0.3 72 h Mice, male {HeJ, OuJ,Nos2 (+/+) [C57BL/6JNos2 (+/+)], and Nos2(!/!) [C57BL/6J-Nos2(!/!)]}, 6-8 weeks oldO3induced permeability was decreased by pretreatment with a nitricoxide synthase inhibitor and in animals with iNOS gene knocked out.Kleebergeret al. (2001a)0.4 5 weeks Guinea pigs, male,(Hartley), 5 weeks old (350-450 g)n = 7-8/groupOvalbumin instillation in the nose caused an increase in O3-inducedinfiltration of eosinophils in nasal epithelium.Iijima et al.(2001)0.15, 0.3,or 0.53 h Rat, male, SD6-8 weeks old,n = 2-6/groupTime-related increase in permeability and inflammation, with a peakat 8 h PE, after 0.5 ppm. No change following exposure to 0.15 or 3ppm.Bhalla andHoffman(1997)0.5 4 h, 12-4 PM fordaytime and 7-11PM for nighttimeexposures. Exposuresrepeated 16 h later.Rat, male, Wistar,60-90 days oldn = 5-15/groupSignificantly greater increase in IL-6, but not inflammation, followinga nighttime exposure compared to daytime exposure. An initialnighttime exposure resulted in lesser inflammation following asubsequent exposure. Pretreatment with IL-6 receptor antibodyabolished cellular adaptive response without affecting inflammatoryresponse induced by initial nighttime exposure.McKinney et al.(1998)0.51.02.0Rat, male, Fisher,90 days oldn = 6-12/groupIncrease in BALF protein and albumin occurred immediatelyafter 2 ppm exposure, and at 18 h after 1 ppm. No increase after0.5 ppm. The movement of water and protein into airspace were notcoupled.Cheng et al.(1995)



### AX5-18Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference1.0-2.0 3 h Mice, C57BL/6, 6-8 weeksold and rats, Wistar,14-16 weeks oldn = 4-6/groupSteady state MCP-1 mRNA increase after 0.6 ppm, with maximalincrease after 2 ppm. After 2 ppm, MIP-2 mRNA peaked at 4 h PEand MCP-1 mRNA peaked at 24 h PE. BALF neutrophils andmonocytes peaked at 24 and 72 h PE, respectively. BALF MCP-1activity induced by O3was inhibited by an anti-MCP-1 antibody.Zhao et al.(1998)0.5 24 h following a 3-d (6h/day) exposure tocigarette smokeMice, male, B6C3F1,25 ± 2 g, 10 weeks old,n = 6/groupBALF protein, neutrophils and lymphocytes were increased in animalsexposed to smoke and then to O3. Macrophages from this group alsoresponded with greater release of TNF-"upon LPS stimulation.Yu et al. (2002)0.5 8 h during nighttime Rat, male, Wistar, SD andFischer F344, 90 days oldn = 3-8/groupExposure resulted in a significantly greater injury, inflammation andBALF levels of IL-6 in Wistar than in SD or F344 rats.Dye et al.(1999)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/groupComparable effect on the leakage of alveolar protein in ratsof different age groups, but a greater increase occurred in interleukin-6and N-acetyl-beta-D-glucosaminidase in senescent animals than injuvenile and adult rats.Vincent et al.(1996).0.8 3 h Rat, male, SD,6-8 weeks old,n = 5/groupIncreased adhesion of macrophages from exposed animals torat alveolar type II epithelial cells in culture. Treatment withanti-TNF-"+ anti-IL-1"antibody decreased adhesion in vitro, but notpermeability in vivo.Pearson andBhalla (1997)0.8 3 h Rat, male, SD6-8 weeks old,n = 5/groupIncrease in fibronectin protein in BALF and lung tissue, andfibronectin mRNA in lung tissue. The increase produced by O3wasamplified in animals pre-treated intra-tracheally with rabbit serum toinduce inflammation.Gupta et al.(1998)0.8 3 h Rat, male, SD,200-225 g,n = 2-9/groupTreatment of animals with IL-10 prior to O3exposure caused areduction in O3induced BALF protein, albumin and fibronectin andtissue fibronectin mRNA.Reinhart et al.(1999)



### AX5-19Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference0.8 8 h Monkey, male, Rhesus,3 years 8 months-3 years10 months oldn = 2-6/groupPretreatment of monkeys with a monoclonal anti-CD18 antibodyresulted in a significant inhibition of O3-induced neutrophil emigrationand accumulation of necrotic airway epithelial cells.Hyde et al.(1999)0.81.0-2.048 h3 hRat, male, SD,6-8 weeks old,200-225 g,n = 3-8/groupCyclophosphamide treatment ameliorated O3-induced BALFneutrophils and albumin after shortterm and 1-day exposure. Antineutrophil serum reduced lavageable neutrophils but did not affectpermeability.Bassett et al.(2001)0.8 8 h Monkeys, male, Rhesus,3 years 8 months-3 years10 months old (5.1-7.6 kg)n = 2-6/groupTracheal epithelium of exposed animals expressed b6 integrin. Theintegrin expression was reduced or undetectable in animals treatedwith CD-18 antibody.Miller et al.(2001)0.8 3 h Mice, female,C57BL/6X 129 NOS-/-knockout and wild-typeB6J129SV F2,8-16 weeks old,n = 3-12/groupAlveolar macrophages from O3exposed wild-type mice producedincreased amounts of NO, peroxynitrite, superoxide anion, and PGE2.Nitrogen intermediates were not produced and PGE2 was at controllevel in exposed NOSII knockout mice. These mice were alsoprotected from O3-induced inflammation and injury.Fakhrzadehet al. (2002)1.0 5 min exposure ofairway segmentsfollowingbronchoscopyDogs, male, Mongrel,Adult,n = 1-4/groupMast cells from O3-exposed airways of ascarissensitive dogs releasedsignificantly less histamine and PGD2 following in vitro challengewith ascaris antigen or calcium ionophore.Spannhake(1996)1.00.20.51.08 h, assayed 1 and2 h PEIn vitro at liquid/airinterfaceMonkeys (Rhesus)Primary TBE, BEAS-2b Sand HBE1Increase in steady state IL-8 mRNA in airway epithelium. Increase inIL-8 protein staining declined at 24 h after exposure.Dose related increase in IL-8 release in the conditioned media. Ozoneproduced greater toxicity in cell lines than in primary cultures.Chang et al.(1998)1.0 3 h Rat, male, SD,6-8 weeks old,n = 4-5/groupTime-related increase in BALF protein, fibronectin (Fn), and alkalinephosphatase (AP) activity. Fn mRNA detected in macrophages, andAP in Type II cells and in BALFPMNs from exposed animals only.Bhalla et al.(1999)



### AX5-20Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference1 2 h Rats, female, SD,170-210 gn = 8-12/groupThe expression of CD18 on alveolar macrophages and CD11b onblood PMNs was lowered by exposure, but CD62L expression onblood PMNs was not affected.Hoffer et al.(1999)1 3 h Rat, male, SD,6-8 weeks old,n = 5/groupTime-related increase in BALF albumin, PMNs, MIP-2 and ICAM-1,and increase in MIP-2 mRNA only at early time point in BALFmacrophages. MIP-2 mRNA not detected in lung tissue.Bhalla andGupta (2000)1 3 h Rat, male, SD,250-275 g,n = 6/groupOzone induced increase in BALF albumin, fibronectin and PMNnumber was associated with an increase in expression of TNF-", IL1", IL-6 and IL-10 mRNA. Pretreatment with anti-TNF-"antibodycaused downregulation of gene expression and reduction of BALFalbumin and PMN number, but not fibronectin.Bhalla et al.(2002)1 6 h Rat, male, SD,200-250 g,n = 3-6/groupIncrease in number of macrophages with mRNA transcripts andimmunocytochemical staining of IL-1, TNF-", MIP-2 and cytokineinduced neutrophil chemoattractact (CINC). Chemokine activitieswere reduced by treatment of macrophages with anti-IL-1$and antiTNF-"antibodies.Ishii et al.(1997)0.51.02.54 h Mice, male(129 wild-type or Clara CellSecretory Protein-/-),2-5 months old,n = 3/groupIncreases in IL-6 and metallothionein mRNA by 2 h after exposure to1 ppm. mRNA increases were further enhanced in CCSP-/-mice.Mango et al.(1998)1.0 8 h/night for threenightsMice, (C57BL/6 wild-typeand iNOS knockout)n = 3-10/groupO3exposure produced greater injury, as determined by measurementof MIP-2, matrix metalloproteinases, total protein, cell content andtyrosine nitration of whole lung protein, in iNOS knockout mice thanin wild-type mice.Kenyon et al.(2002)1.0 4 h Mice, male (129 strain,wild-type and Clara CellSecretory Protein-deficient),2-3 months old,n = 3/groupIncreases in abundance of mRNAs encoding eotaxin, MIP-1aand MIP-2 in CCSP-/-, but no change in wild-type mice.Johnston et al.(1999b)



### AX5-21Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference1.2 6 h Rat, male, Brown Norway,200-250 g,n = 4/groupEotaxin mRNA expression in the lungs increased 1.6-fold immediatelyafter and 4-fold at 20 h. Number of lavageable eosinophils increased3- and 15-fold respectively at these time points. Alveolarmacrophages and bronchial epithelial cells stained positively foreotaxin.Ishii et al.(1998)2.0 3 h Mice, male, C57BL/6J,6-8 weeks old,n = 5-10/groupO3-induced increase in protein and PMNs in BALF, and pulmonaryepithelial cell proliferation were significantly reduced in animals pretreated with UK-74505, a platelet activating factor-receptor antagonist.Longphre et al.(1999)2.0 3 h Rat, female, SD,6-8 weeks oldBALF cells from exposed animals released 2 to 3 times greater IL-1and TNF-", and greater fibronectin. Immunocytochemistry showedgreater staining of these mediators in lung tissue from exposed rats.Pendino et al.(1994)1.1 8 h Rat, Wistar, -depleted ofneutrophils, 43 days old,n = 9-10/groupEpithelial necrosis in the nasal cavity, bronchi, and distal airways.Proliferation of terminal bronchiolar epithelial cells also decreasedby O3exposure, suggesting a role for neutrophils in the repair process.Vesely et al.(1999)0.32 48 h(subacute)3 h(acute)Mice, male, C57BL/6J,WTTNRF1KOTNRF2KO6-8 weeks old,n = 3-12/groupTNFR1 and TNFR2 KOs less sensitive to subacute O3exposure thanWT. With acute exposures, airway hyperreactivity was diminished inKO mice compared to WT mice, but lung inflammation andpermeability were increased.Cho et al.(2001)0.3 24 to 72 h MiceC57BL/6JC3H/HeJC3H/HeOuJ6-8 weeks old,n = 5-16/groupDifferential expression ofTlr4mRNA. Kleebergeret al. (2000)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/groupTwo strains consistently O3-resistant: C3H/HeJ and A/J. Two strainsconsistently O3-vulnerable: C57BL/6J and 129/SvIm. Five strainswith inconsistent phenotypes withintermediate responses: CAST/Ei,BTBR, DBA/2J, FVB/NJ, and BALB/cJ.Savov et al.(2004)



### AX5-22Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference113 h- examined at 3 h PE1 h examined 24 h PEGuinea pigs, male,Dunkin-Hartley,OVA-sensitizedPMN levels significantly increased, without any change in BALprotein levels, suggesting a lack of correlation between the twoendpoints. Increased AHR.Increase in PMN, no increase in BAL protein levels. No increasedAHR, suggesting a dissociation between PMN levels and AHR.Sun et al.(1997)0.4 1 or 5 days/ 12 h/day,recovery period in freshair of 5, 10, 15, or 20days after the 5-dpreexposureRat, Wistar, male,7 weeks old,n = 5/groupExposure for 5 days caused lower BALF proteins, fibronectin, IL-6,and inflammatory cells than animals exposed for 1 day. Postexposurechallenge with single O3exposures at different time points showedthat a recovery of susceptibility to O3(as measured by BALF levels ofalbumin, IL-6, and the number of macrophages and neutrophils)occurred at ~15-20 days, but total protein and fibronectin levelsremained attenuated even at 20 days post-5-day exposure. Therecovery with regards to BrdU labeling occurred in 5-10 days after the5-day exposure.Van Breeet al. (2002)2 2 h, examined 2, 12,and 48 h PERat, female, SD,200-250 gn = 4-7/groupAdherence of neutrophils to pulmonary vascular endothelium wasmaximal within 2 h after exposure and returned to control levels by 12h PE.Lavnikova et al.(1998)1.0 or 2.5 4, 20, or 24 h,examined immediatelyPE10 minMice, C57BL/6J, 36 h and 8weeks oldEndotoxin (10 ng)n = 3/groupRPA for IL-12, IL-10, IL-1", IL-1$, IL-1Ra, MIF, IFN-(, MIP-1",MIP-2,IL-6, and Mt. Newborn mice: increased Mt mRNA only.8-week-old mice: increased MIP-1", MIP-2, IL-6, and Mt mRNA.Both age groups had similar cytokine/chemokine profiles withendotoxin exposure, suggesting thatthe responses to endotoxin, whichdoes not cause epithelial injury, and the responses to O3, which does,demonstrate that differences in inflammatory control betweennewborn and adult mice is secondary to epithelial injury.Johnston et al.(2000b)0.8 3 days, continuous Rat, male, SD,30 days old,n = 6/groupGeneral dietary restriction to 20% of the freely-fed diet for60 days caused an extreme reduction in body weight and highersurvivability. Levels of antioxidants and detoxifying enzymesincreased less than in freely fed animals.Elsayed (2001)



### AX5-23Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference1.80.113 h24 h/day for up to3 days, assaysimmediately or at 16 hPEMice, female, C57BL/6JCBA C3H/HeJ AKR/JSJL/J, 6-8 weeks old,n = 4-7/groupBoth exposure levels caused a transient increase in CC16 inserum that correlated with BALF changes in protein, LDH, andinflammatory cells. Inverse relationship between preexposure levelsof CC16 in BALF and epithelial damage based on serum CC16 levelsand BALF markers of inflammation. Inverse relationship betweenpreexposure levels of albumin in BALF and lung epithelium damage.Suggests that a major determinant of susceptibility to O3is basal lungepithelial permeability. C57BL/6Jmice had lower levels of CC16a(the more acidic form) than C3H/HeJ. Both the strains had similarlevels of CC16b. Suggests that basal lung epithelial permeability is amajor determinant of susceptibility; greater epithelial permeabilityobserved in C57BL/6J may be due to difference in the expression ofCC16a and possibly other antioxidant/inflammatory proteins.Broeckaertet al. (2003)1 or 3 2-6 h, assayed at 2,8 and 24 h PERat, female, BrownNorway, 250-300 g,n = 4-8/groupMIP-2 peaked at 2 h and rapidly declined. PMNs in BALF increasedat 2, 8 and 24 h. No significant increase in AMs, eosinophils,lymphocytes or epithelial cells. MIP expression preceded increase inPMN. Both responses suppressedby dexamethasone, which suggestsa mechanism of glucocorticoid regulation of inflammation.Haddad et al.(1995)1 or 3 3 h Rat, male, Brown Norway,200-250 g,n = 3/groupIncrease in lung CINC mRNA within 2 h PE exposure.Significant increase in PMNs in BALF 24 h PE. Anti-CINC antibody(1 mg, i.v.) suppressed neutrophilia but not the increase in AHRto acetylcholine. Anti-CINC antibody inhibited BALF neutrophiliainduced at 3 ppm AHR. Results suggest that CINC causes O3-inducedneutrophil chemoattraction, but is not involved in the induction ofozone-induced AHR.Koto et al.(1997)0.1-223 h, assayed 6 h PE(exposure-response)3 h, assayed 0, 2, 6, or24 h PE (time-course)Mice,C57BL/6,n = 2-4/groupO3$1 ppm increased MIP-2 mRNA and recruitment of neutrophils.MIP-2 increase was immediate and decreased to control by 24 h PE.Driscoll et al.(1993)



### AX5-24Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference0.12,0.24,0.53 h, NF-6B assayed 0 hPE, TNF-"assayed 0,1, 2, 4, 16, 20 or 22 hPECultures of human nasalepithelial (HNE) cellsElectron spin resonance signal suggested free radical production.Small dose-response activation of NF-6B coincided with O3-inducedfree radical production. TNF-"increased with exposures to 0.24 and0.5 ppm at 16 h PE. Results suggest that the human airway epitheliumplays a role in directing the inflammatory response to inhaled O3viafree radical-mediated NF-6B.Nichols et al.(2001)0.8 3 h Rats, SD, 200-250 g,n = 5-6/groupAMs from O3-exposed rats exhibited greater motility and greateradhesion in cultures of epithelial cells (ARL-14). O3-induced motilityand adhesion were attenuated with AMs incubated in the presence ofMabs to leukocyte adhesion molecules, CD11b, or epithelial celladhesion molecules, ICAM-1. Increased surface expression of CD11bbut no change in ICAM-1 expression in AMs from O3-exposed rats.Demonstration of alteration of AM functions following O3exposure.Possible dependence of these functions on the biologic characteristics,rather than the absolute expression, of cell adhesion molecules.Bhalla (1996)2 3 h Mice, male and female,C57BL/6J, assayedimmediately or 3, 6, 9, or 21h PEIncrease in tissue expression of ICAM-1 3 -9 h PE, remaining until 21h PE. Bronchioles and terminal bronchiole/alveolar duct regions:Enhanced ICAM-1-IR 0 - 3 h PE, returning to baseline by 21 and 9 h,respectively. Lung parenchyma: maximal ICAM-1 expression andPMN influx concurrent 3 h, followed by transepithelial migration ofPMNs to the airway lumen. Suggests regional variations in airwayinflammatory activity; upregulation of ICAM-1 may play a role inlocal regulation of PMN influx to the airways after acute exposure.Takahashi et al.(1995a)2 4 h Rat, SD, male, 225-250 g,treated with 10 mg/kgebselen every 12 h from 1 hbefore O3exposure,n = 4/groupEbselen significantly decreased pulmonary inflammation (albumin andPMN in BALF) 18 h PE without altering AM expression of iNOS.Ebselen inhibited the nitration reaction of tyrosine residues andenhanced expression of Cu-, Zn-,and Mn SOD. Suggests that ebselenscavenges peroxynitrite during O3-induced inflammation and mayprotect against acute lung injuries by modulating the oxidant-relatedinflammatory process.Ishii et al.(2000a)



### AX5-25Table AX5-8 (cont’d). Effects of Ozone on Lung Permeability and InflammationConcentrationppm Duration Species Effects Reference3 2 h Human transformedbronchial epithelial cells(16-HBE)Guinea pigs, Hartley, male,450-550 g,n = 3-5/groupNO donors increased IL-8 production dose-dependently. TNF-"plusIL-1$plus INF(increased IL-8 in culture supernatant of epithelialcells. NOS inhibitors (aminoguanidine plus NG-nitro-L-argininemethyl ester) attenuated the cytokine-induced IL-8 production.O3induced AHR to acetylcholine and increased PMN in BALF.Persisting for 5 h. Pretreatment with NOS inhibitors did not affectAHR 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.Inoue et al.(2000)0.12,0.5,1, or23 h Mice, female, BALB/c, 5-6weeks oldO3exposure caused dose-dependent increases in nitrate (indicative ofin vivo NO generation). Increases in enhanced pause (Penh) were alsodose-dependent. Increases in NOS-1, but not in NOS-3 or iNOSisoforms. Suggest that NOS-1 may induce airway responsiveness byneutrophilic airway inflammation.Jang et al.(2002)PMN = Polymorphonuclear leukocytePE = Postexposure (time after O3exposure ceased)BAL = Bronchoalveolar lavageBALF = Bronchoalveolar lavage fluid



### AX5-26Table AX5-9. Effects of Ozone on Lung Structure: Acute and Subchronic ExposuresConcentrationppm Duration Species Effects Reference0.10.51.08 h/day × 1 day8 h/day × 1 day8 h/day × 1, 10,75, and 90 daysRat; male, SD,350-600 g,n = 3-6/groupNo dose-related response on CYP2E1, one of six P450 enzymes identifiedin respiratory tissue. CYP2E1 activity was elevated (250% and 280%)in the lobar bronchi/major daughters airways immediately after 1.0 ppm O3exposure for 1 day and 10 days, respectively, but not in the trachea or distalbronchioles; CYPE1 activity was unchanged and decreased after 1.0 ppmO3exposure for 75 and 90 days, respectively.Watt et al.(1998)0.20.43, 7, 28, and56 days; 3-, 7-,and 28-dayrecovery from28 days ofexposureMice, male, NIH,Rat, male, WistarRIV:ToxGuinea pig,male, HartleyCrl:(HA)BR,7 weeks old,n = 3-9/groupConcentration-related centriacinar inflammation, with a maximum after3 days of exposure; number of alveolar macrophages and pulmonary celldensity increased progressively until 56 days of exposure, with the guineapig the most sensitive species. Concentration and exposure-time dependenthypertrophy of bronchiolar epithelium in mouse only. Exposure to 0.2 ppmfor 3 and 7 days caused significant histological and morphometric changesin all 3 species; exposure for 56 days caused alveolar duct fibrosis in ratand guinea pigs. Total recovery in rats after 28-d exposure, but not inguinea pigs or mice.Dormanset al. (1999)0.20.40.823 h/day for7 daysGuinea pig, female,Hartley; ±AH2dietTreatment-related lesions were observed after exposure to 0.4 and 0.8 ppmO3; lesions were primarily seen in the terminal bronchioles and consistedof mononuclear cell and neutrophilic infiltrate and thickening of theperibronchiolar interstitium. Effects were only marginally exacerbatedby the AH2(ascorbic acid) deficient diet and lesions were resolved after1 week in FA.Kodavantiet al. (1995)0.4 12 h/day;1- or 7-dayexposureRat, WistarRiV:TOX,male and female,1, 3, 9, and 18 monthsof age,n = 5-6/groupCentriacinar inflammation (increased alveolar macrophages and PMNs;increased proximal and ductular septal density) was greatest in young rats(1 month and 3 months for 1-and 7-day exposures, respectively) anddecreased with age. No major gender differences were noted.Dormanset al. (1996)



### AX5-27Table AX5-9 (cont’d). Effects of Ozone on LungStructure: Acute and Subchronic ExposuresConcentrationppm Duration Species Effects Reference0.41.02 h Monkey;adult male RhesusReduced glutathione (GSH) increased in the proximal intrapulmonarybronchus after 0.4 ppm O3and decreased in the respiratory bronchiole after1.0 ppm O3. Local O3dose (measured as excess18O) varied by as much as afactor of three in different airways of monkeys exposed to 1.0 ppm, withrespiratory bronchioles having the highest concentration and the parenchymathe lowest concentration. After exposure to 0.4 ppm, the O3dose was 60%to 70% less and epithelial injury was minimal, except in the respiratorybronchiole, where cell loss and necrosis occurred, but was 50% less thanfound at 1.0 ppm.Plopper et al.(1998)0.5 8 h+ BrdU to labelepithelial cellsRat, male, FischerF344, 13 weeks old,n = 6/groupO3exposure induced a transient influx ofneutrophils and a significant (17%)loss of NTE cells 2-4 h after exposure. Increased epithelial DNA synthesiswas first detected 12 h PE. LI and ULLI indices of epithelial cell DNAsynthesis were greatest 20-24 h and still elevated 36 h PE; numeric densityof NTE cells returned to control levels 20-24 h PE.Hotchkisset al. (1997)0.5 8 h/day,3 or 5 days;+ fluticasonepropionate (FP)intranasallyRat, male, FischerF344, 203-232 g,n = 6/groupNo significant difference of fluticasone propionate on morphometry of themaxilloturbinates; O3exposure caused neutrophilic rhinitis with 3.3- and1.6-fold more intraepithelial neutrophils (3-day and 5-day exposure,respectively) and marked mucous cell metaplasia (5-day exposure only)with numerous mucous cells and approximately 60 times moreintraepithelial mucosubstances in the nasal transitional epithelium;FP-treated rats exposed to O3had minimal nasal inflammation and mucouscell metaplasia.Hotchkisset al. (1998)0.5 8 h/day,3 days+ endotoxin(100 μg/mL)intranasallyRat, male, FischerF344/N Hsd, 12weeks old,n = 6/groupEndotoxin-induced neutrophilia in nasal mucosa with NTE; mucous cellmetaplasia was not detected in air/endotoxin-exposed rats, was observedin O3/saline-exposed rats, and was most severe in O3/endotoxin-exposedrats.Fanucchiet al. (1998)



### AX5-28Table AX5-9 (cont’d). Effects of Ozone on LungStructure: Acute and Subchronic ExposuresConcentrationppm Duration Species Effects Reference0.5 8 h/day,1, 2, or 3 days+ BrdU to labelepithelial cells+ antiratneutrophilantiserumRat, male, FischerF344/N, 10-12 weeksold, n = 6-8/groupAcute O3exposure induced a rapid increase in rMuc-5AC mRNA levelsprior to the onset of mucous cell metaplasia; neutrophilic inflammationcoincided 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 secretorycells, amount of stored intraepithelial mucosubstances, and steady-staterMUC-5AC mRNA levels. Four days after a 3-d exposure,antiserum-treated, O3-exposed rats had 66% less stored intraepithelialmucosubstances and 58% fewer mucous cells in their NTE than did controls.Antiserum treatment had no effects on O3-induced epithelial cellproliferation or mucin mRNA upregulation.Cho et al.(1999a, 2000)0.5 8 h/day,3 days+ endotoxinRat, male, FischerF-344, 10-12 weeksold, n = 6/groupEnhanced epithelial lesions in the NTE and respiratory epithelium of thenose and conducting airways by endotoxin and O3exposures, respectively;synergistic effects of coexposuremediated 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.Wagner et al.(2001a,b)0.5 8 h/day,1 and 3 days+ OVA(1%, 50 μL/nasalpassage)Rat, male, BrownNorway, 10-12 weeksold, n = 6/groupO3enhanced the appearance of eosinophils in the maxilloturbinates ofOVA-challenged rats but did not increase inflammation in other nasaltissues; O3/OVA coexposures for 3 days increased the number of epithelialcells as well as the appearance of mucus-containing cells in the NTE liningthe maxilloturbinates.Wagner et al.(2002)1 8 h Rat, male, SD,10 weeks old,Ferret, male, 18months old,Monkey, male,Rhesus, 4 years old,n = 4-8/groupSevere, acute infiltration of neutrophils along with necrotic bronchiolarepithelium in all lung regions, especially in the centriacinar region; necrosisand inflammation was more severe in ferrets and monkeys than in rats.Sterner-Kocket al. (2000)



### AX5-29Table AX5-9 (cont’d). Effects of Ozone on LungStructure: Acute and Subchronic ExposuresConcentrationppm Duration Species Effects Reference0.5 8 h/day for 3 days,assayed 2 h or4 days PERat, male, FischerF344/N, with orwithout priorexposure to100 μg/dayendotoxin,10-12 weeks old,n = 8/group2 h PE: Endotoxin/O3rats had 48 and 3 times more PMNs in the NTE thandid saline/air- and saline/O3-exposed rats, respectively at 2 h PE. O3-onlyrats had 35% more NTE cells and 2-fold more mucin mRNA than didsaline/air-exposed rats.4 days PE: Endotoxin/O3rats had 5 and 2 times more IM and mucous cells,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-inducedmucous cell metaplasia.Cho et al.(1999b)0.8 8 h/day for90 daysRats, SD, male,275-300 g, treatedi.p. with1-nitronaphthalene(0, 50, or 100 mg/kg)1-nitronaphthalene (a pulmonary toxicant requiring metabolic activation)-treated rats exposed to O3showed greater histopathologic and morphometriceffects in the centriacinar region ofthe lung. Caused denudation of thebasement membrane and necrosis of remaining epithelial cells. Increasedseverity of ciliated cell toxicity in O3-exposed rats. No differences in theintrapulmonary airways or trachea in sensitivity to 1-nitronaphthalene,suggesting a site-selective synergy between O3and 1-nitronaphthalene.Paige et al.(2000b)AM = Alveolar macrophagePE = Postexposure (i.e., time after O3exposure ceased)LM = Light microscopyEM = Electron microscopyRB = Respiratory bronchioleTB = Terminal bronchioleIAS = Interalveolar septumPMN = Polymorphonuclear leukocyte



### AX5-30Table AX5-10. Effects of Ozone on Lung Structure: Subchronic and Chronic ExposuresConcentrationppm Duration Species Effects ReferenceMexico CityAmbient:0.018($0.12 for18 1-hintervals)23 h/day for7 weeksRat, male andfemale, FischerF344,8 weeks oldNo inflammatory or epithelial lesions in nasal airways or respiratory tract. Moss et al.(2001)0.120.51.06 h/day,5 days/weekfor 20 monthsRat, male,Fischer F344,6-8 weeks oldLM morphometry of CAR remodeling. Thickened tips of alveolar septalining ADs (alveolar entrance rings) 0.2mm from TB in rats exposed to 0.12 ppmand to 0.6 mm in rats exposed to 1.0 ppm. At 0.5 and 1.0 ppm, atrophy of nasalturbinates, mucous cell metaplasia in NTE, increased volume of interstitium andepithelium along ADs due to epithelial metaplasia, and bronchiolar epithelialhyperplasia. At 1.0 ppm, increased AMs and mild fibrotic response (increase ininterstitial matrix and cellular interstitium;the latter due to increase in volumein 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).Catalano et al.(1995a,b);Chang et al.(1995);Harkema et al.(1994, 1997a,b)Pinkerton et al.(1995);Plopper et al.(1994);Stockstill et al.(1995)0.120.501.06 h/day,5 days/weekfor 24 and30 monthsMice, male andfemale, B6C3F1,6-7 weeks old,n = 50/groupEffects in the nose and centriacinar region of the lung at 0.5 and 1.0 ppm.Nasal lesions were mild: hyalinedegeneration, hyperplasia, squamousmetaplasia, 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 inmice exposed to 1.0 ppm O3, but there was minimal interstitial fibrosis.Herbert et al.(1996)0.121.06 h/day,5 days/week,for 2 or3 monthsRat, male,Fischer F344/N,4-5 weeks old,n = 4/groupMorphometric changes (epithelial thickening, bronchiolarization) occurred after2 or 3 months exposure to 1.0 ppm O3; effects were similar to those found with20 months exposure (see Pinkerton et al., 1995)Pinkerton et al.(1998)



### AX5-31Table AX5-10 (cont’d). Effects of Ozone on LungStructure: Subchronic and Chronic ExposuresConcentrationppm Duration Species Effects Reference0.011 6 months Rat, male,Wistar, 2 monthsCO = 1.25 ppm; PM = 35.18 μg/m3; SO2= 29.05 μg/m3. Induction of secretoryhypertrophy, acidic mucous secretion, and ciliary damage.Lemos et al.(1994)0.250.58 h/day,7 days/weekfor 13 weeksRat, male,Fischer F344/NHSD,10-14 weeks oldn = 5-6/groupMucous cell hyperplasia in nasal epithelium after exposure to 0.25 and 0.5 ppmO3; still evident after 13 weeks recovery from 0.5 ppm O3exposure. Mucous cellmetaplasia found only after 0.5 ppm O3, but still detectable 13 weeks PE.Harkema et al.(1999)0.4 23.5 h/dayfor 1, 3, 7, 28,or 56 daysRat, Wistar,7 weeks old,n = 5/groupAcute 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 today 56, and slowly returned to nearcontrol levels with PE recovery. Histological examination and morphometryof the lungs revealed CAR inflammatory responses throughout O3exposure;thickening of septa was observed at day 7.Ductular septa thickened progressivelyat day 7, 28, and 56 of exposure; showed increased collagen at day 28, which wasfurther enhanced at day 56. Increased RBs with continuous exposure. Collagenand bronchiolization remained present after a recovery period.Van Bree et al.(2002)0.5 8 h/day for1, 3, and6 monthsRat, male,Fischer F344/NIncreased Bcl-2, a regulator of apoptosis, after 1 month, decreasing somewhatthereafter, returning to baseline by 13 weeks PE; increased number of metaplasticmucous cells in NTE after 3 and 6 months.Tesfaigzi et al.(1998)0.5 8 h/day for5 days,every 5 daysfor a total of11 episodesMonkey;Rhesus,30-day-olds,n = 6/groupIncreased density and distribution ofgoblet cells in RB whole mounts stainedwith AB/PAS; extensive remodeling of distal airway with O3and O3+ HDMAchallenge; increased airways resistance and reactivity, and respiratory motoradaptation also occurred. Authors conclude that periodic cycles of acute injuryand repair associated with the episodic nature of environmental patterns of O3exposure alters postnatal morphogenesisand epithelial differentiation in thedistal lung of infant primates.Schelegle et al.(2003);Chen et al.(2003);Plopper andFanucchi (2000)



### AX5-32Table AX5-10 (cont’d). Effects of Ozone on LungStructure: Subchronic and Chronic ExposuresConcentrationppm Duration Species Effects Reference0.8 8 h/day for90 days+ 1-NN(100 mg/kg)Rat, male, SD,275-301 gIncreased O3-induced centriacinar toxicity (histopathology, TEM, morphometry)of 1-Nitronaphthalene (1-NN), a pulmonary cytotoxicant requiring metabolicactivation, especially to ciliated cells.Paige et al.(2000b)0.5 11 episodes of5 days each,8 h/dayfollowed by9 days ofrecoveryMonkey,Macaca mulatta,30 days oldIn small conducting airways O3caused decrements in density of airway epithelialnerves. Reduction greater with HDMA + O3. O3or HDMA + O3caused increasein number of PGP 9.5 (pan-neuronal marker) in airway. CGRP-IR nerves werein close contact with the PGP9.5 positive cells. Appearance of clusters ofPGP9.5+/CGRP!cells. Suggests episodic O3alters developmental pattern ofneural innervation of epithelial compartment.Larson et al.(2004)0.5 11 episodes of5 days each,8 h/dayfollowed by9 days ofrecoveryMonkey,Rhesus,30 days old,n = 6/groupAbnormalities in the BMZ included: (1) irregular and thin collagen throughoutthe BMZ; (2) perclecan depeleted or severely reduced; (3) FGFR-1immunoreactivity was reduced; (4) FGF-2 immunoreactivity was absent inperlecan-deficient BMZ, but was presentin the lateral intercelluar space (LIS),in basal cells, and in attenuated fibroblasts; (5) syndecan-4 immunoreactivitywas increased in basal cells.Evans et al.(2003)TB = Terminal bronchiolePE = Postexposure (i.e., time after O3exposure ceased)AM = Alveolar macrophageLM = Light microscopyTEM = Transmission Electron MicroscopyBMZ = Basement Membrane ZoneEM = Electron microscopyRB = Respiratory bronchioleIAS = Interalveolar septumC × T = Product of concentration and time



### AX5-33Table AX5-11. Effects of Ozone on Pulmonary FunctionConcentrationppm Duration Species Effects Reference0.5 6 or 23 h/dayover 5 daysRats, male,Fischer 344,90 days old,n = 28-36/group,ambient temperature10, 22, or 34 °CToxicity increased with decreases intemperature. At 10 °C: decreased bodyweight, total lung capacity, BALF protein, alkaline phosphatase activity,% PMN, and lysozyme. Ozone-induced changes in lung volume wereattenuated during the 5 exposure days and returned to control levels after7 days recovery. The responses to repeated O3exposure in rats wereexacerbated by reduced ambient temperature, presumably as a result ofincreased metabolic activity.Wiester et al.(1996)2 3 h, assayed 1and 24 h PEMice, male,C57BL/6J C3H/HeJ,53 days old,n = 5-7/groupchallenged by CO2(5 or 8%)C57BL/6J mice: CO2-induced changes in VEwere attenuated 1 h after O3exposure; VTwas reduced 1 h after O3exposure; the diminished VT1 hafter O3was coincident with reducedf, mean inspiratory flow, and slope ofVE-to-%CO2relationship compared with FA.; VEpartially reversed 24 h afterO3relative to FA.C3H/HeJ: VTwas reduced 1 h after O3exposure; increasedfto sustain thehypercapnic VE response similar to air exposure.Suggests that control of ventilation during response to CO2is governed,in part, by genetic factors in these two strains of mice, implying differentialO3susceptibility.Tankersleyet al. (1993)0.3 48 and 72 h, withre-exposure after14 days ofrecoveryMice,C57BL/6J,C3H/HeJ,6-8 weeks oldVEandfwere measured before and immediately after exposure. NormocapnicVEwas greater following subacute O3exposure in C57BL/6J mice than inC3H/HeJ mice, due to increasedfand reduced VT, respectively. Ventilatoryresponses to both normocapnia and hypercapnia were similar after O3reexposure in both strains. Suggests that: increased VTin C57BL/6J micemay contribute to the increased susceptibility to lung injury due to a greaterdose of O3reaching the lower lung; mechanistic separation of airwayinflammation and ventilation.Paquetteet al. (1994)2 2-3 h, assayed0 h PEMice, male,C57BL/6J,C3H/HeJ,4 or 11-12 weeks old,n = 4-6/groupUsing18O-labeled O3. C3H/HeJ mice had 46% less18O in lungs and 61% lessin trachea, than C57BL/6J. C3H/HeJ mice had a greater body temperaturedecrease following O3exposure than C57BL/6J mice. Suggests that thedifferences in susceptibility to O3are due to differences the ability to decreasebody temperature and, consequently decrease the dose of O3to the lung.Slade et al.(1997)



### AX5-34Table AX5-11 (cont’d). Effects of Ozone on Pulmonary FunctionConcentrationppm Duration Species Effects Reference2 3 h, assayed 6 hafter exposureMice, male andfemale, AKR/J,C3H/HeJ, CBA/J,129/J, NJ, C57BL/6J,C3HeB/FeJ, SJL/JMeasured tracheal transepithelial potential in the six strains and in progeny ofB6 and C3 strain mice. Fl mice and second generation backcrosses with theresistant parent were O3resistant. Ratios of 1:1 (resistant:susceptible) wereobtained with second generation backcrosses with the susceptible parent,suggesting 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 thatthe responses are controlled by disparate genetic factors.Takahashiet al. (1995b)2 3 h Mice, C3H/HeJ, A/J,C57BL/6J, 129/SvIm,CAST/Ei, BTBR,DBA/2J, FVB/NJ,BALB/cJ,n = 6-24/groupUsed 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 Penhto MCh at 6 and 24 h after exposureto O3.DBA/2J, A/J, FVB/NJ, CAST/Ei, C3H/HeJ: increases in sensitivity to MChat 6 h after exposure, return to near baseline by 24 h after exposure to O3.Savov et al.(2004)VE= Minute ventilationVT= Tidal volumef= Frequency of breathingFA = Filtered airMCh = Methacholine



### AX5-35Table AX5-12. Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference0.10.34 h/day,4 days/weekfor 24 weeksGuinea pig, male andfemale, Hartley,200-250 g,n = 10-20/groupO3exposure did not produce airway hyperresponsiveness to ACh innonsensitized animals; in OVA-sensitized animals, there was increasedresponsiveness to both nonspecific (ACh) and specific (OVA) airwaychallenge that persisted for 4 weeks after exposure 0.1 and 0.3 ppm O3.Effects were not gender specific and were not associated with BALFinflammatory indicators, but were associated with antigen-specificantibodies in blood.Schlesingeret al.(2002a,b)0.150.300.601.24 h Guinea pig, maleHartley,500-600 g,n = 5-8/groupIncreased airway responsiveness to Hist, but not ACh, 16-18 h after1.2 ppm O3exposure only. Increased responsiveness to SP occurred afterexposure to$0.3 ppm O3.Segura et al.(1997)0.3 4 h/day for 1,3, 6, 12, 24,or 38 daysGuinea pig, maleHartley,500-600 g,n = 6-7/groupIncreased airway responsiveness to SP occurred 16-18 h after exposureto 0.3 ppm O3for 1, 3, 6, 12, and 24 days; but not after 48 days. Highlysignificant correlation between airway responsiveness and BALF totalcells, AMs, neutrophils, and eosinophils, suggesting that airwayinflammation is involved.Vargas et al.(1998)0.5 8 h/day for 5 days,repeated every14 days for6 monthsRhesus monkey,male, 30 days old,n = 6/groupIncreased airway responsiveness to Hist after 10 episodes of exposure toO3+ HDMA in sensitized infant monkeys.Schelegleet al. (2003)1 1 h Guinea pig, male,Dunkin-Hartley,250-300 g,n = 6-7/groupIncreased bronchial responsiveness at 3 h, but not 24 h after O3; OVA hadno effect on baseline, but enhanced airway responsiveness 24 h after O3.Sun et al.(1997)1 1 h Mice, male,C57BL/6,6 weeks old,n = 10-31/groupOzone caused increased Cdynand VE, and decreased PaO2in OVAsensitized mice.Yamauchiet al. (2002)2 2 h Rat, male, FischerF344,14 months old,n = 6/groupIncreased airway responsiveness to MCh 2 h PE. Dye et al.(1999)



### AX5-36Table AX5-12 (cont’d). Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference0.3-3.0 3 h Mice, AJ, male andfemale,aged 2, 4, 8, or12 weeks,n = 42-50/groupNose-only exposure plethysmographs. VEdecreased with increasing age.O3caused concentration-related decrease in VEat all ages, but with lessresponse in the 2-weeks old. Younger mice with less decrease inO3-induced VE demonstrated 3- to4-times greater inhaled dose whennormalized for body weight. The 2- to 4-weeks mice showed no AHR atany dose, while the 8- and 12-week old mice demonstrated dose-relatedincreases in AHR. Older mice demonstrated increased levels of IL-6 andMIP-2. Suggests that young mice are less sensitive to O3for the endpointsof two cytokine and AHR.Shore et al.(2002)0.3 5 h Mice, BALB/c,3 weeks old,n = 5/groupMice OVA-sensitized day 7-14; exposed day 21-23, assayed day 24 or25 Decrease in Penhin rats exposed to O3, as a function of MChconcentration.Goldsmithet al. (2002)2 3 h Mice, C57BL/6J, andob/ob,8-12 weeks old,n = 6-7/groupCompared C57BL/6J and ob/ob mice ( strain obese due to defect in genecoding for satiety hormone leptin). Intravenous MCh challenge inducedAHR and inflammation in both groups, but was greater in obese mice.Dose per gram of lung tissue was greater in obese mice. Suggests obesemice get greater dose of O3.Shore et al.(2003)2 Rats, male andfemale, SD,2, 4, 6, 8, or 12weeks,n = 4-19/groupNose-only-exposure plethysmographs exposure.8,12 week rats: O3-induced 40-50% decreases in VE(primarily dueto decrease in VT).6 week rats: O3-induced changes in VEwere significantly less.2, 4 week rats: no O3-induced changes in VE.BALF protein and PGE2 were greaterthan in older rats. Suggests higherdelivered dose to younger rats, decreased ventilatory response, andgreater lung injury.Shore et al.(2000)2 2 h Guinea pigs, male,Hartley, 400-600 g,n = 6/groupAHR to MCh peaked 2 h PE; PMN in BALF increased until 6 h PE.Tazanolast (a mast cell stabilizing drug, doses 30, 100, or 300 mg/kg)administered before O3exposure inhibited O3-induced AHR dosedependently. Suggests that mast cells may play in role in thedevelopment of AHR.Igarashi et al.(1998)



### AX5-37Table AX5-12 (cont’d). Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference1 or 3 4 h, assayed 4 to72 PEMice,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/groupDemonstrated O3-induced cutaneous, as well as bronchial, mast celldegranulation. PMN influx observed at 1 ppm only in normal mice.AHR in response to MCh with 1 ppm observed in both. Suggests thatmast cells are involved in O3-induced PMN influx but not AHR.Noviski et al.(1999)2 2 h Cat, 2-3 kg,n = 5/groupCats anesthetized and mechanically ventilated, challenged with ACh.Pretreated with polyethylene glycol-superoxide dismutase (PEG-SOD)or PEG-catalase (PEG-CAT) 5 min before O3exposure. PEG-SODpartially prevented O3-induced AHR, PEG-CAT did not. Suggestssuperoxide involvement in O3-induced AHR.Takahashiet al. (1993)0.75 4 h, MCh challenge6 h PEMiceFVB/N, andFVB/N with$2-AR transgene,10-14 weeks old,n = 10/groupTargeted expression (using CCSP promoter) of$2-adrenergic receptors($2-AR) to airway epithelium to mimic agonist activation. Heterozygousmice from generations 2 to 4 used. MCh challenge dose needed to increasePenhwas greater in CCSP-$2-AR mice. CCSP-$2-AR mice less responsiveto O3. Suggests that$2-ARs regulate airway responsiveness and that$-agonists induce bronchodilation through activation of receptors onsmooth muscle cells and epithelial cells.McGraw et al.(2000)2 2 h, assayed 2 h PE Rat, male, SD,2.5-3.5 months old,n = 5/groupNeonatal rats treated with capsaicin. Challenged with MCh following O3.Capsaicin-treated rats: O3had no effect on pulmonary conductance;decreased dynamic compliance; increase in AHR.During O3exposure: 50% decrease in HR and 2.5 °C decrease in coretemperature in both controls and capsaicin rats.Suggests that C-fibers inhibit O3-induced AHR but do not modulate HRor core temperature.Jimba et al.(1995)



### AX5-38Table AX5-12 (cont’d). Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference1 3 h, assayed 4 h PE Rat, SD, treatedwith capsaicinor tachykininantagonists,n = 6/groupRats treated with CP-99994 (neurokinin-1 receptor antagonist) andSR-48968 (neurokinin-2-receptor antagonist). O3induced greaternumbers of PMN in BALF of treated rats. The antagonists has noeffects on pulmonary mechanics or airway responsiveness.Suggests that tachykinins are involvedin the protective effects of C-fibersagainst O3-induced inflammation.Capsaicin treatment induced increased PMN in BALF. O3exposurereduced VEin both vehicle and capsaicin-treated rats, but the capsaicintreatment caused a greater, more immediate reduction.Suggests that the increase in BALF PMN is not due to a greater inhaleddose of O3reaching the lung.Takebayashiet al. (1998)2 3 h, ACh challenge0 and 24 h PEMice, 8 weeks old,15-25 g.DBA/2J, AKR/J,A/J, C3H/HeJ,C57BL/6J, SJL/H,129/J,n = 6-8/groupDiffering 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 andin C57BL/6J and SJL/J strains at 50 μg/kg.Ozone did not alter reactivity in other strains. MCh or carbachol challengenot affected by O3, suggesting that cholinesterase function is affected byO3. C57BL/6J and A/J mice treated with cyclophosphamide(an immunosuppressant) or anti-PMN caused decreased O3-inducedPMN levels but did not alter AHR, suggesting that O3-induced AChhyperreactivity correlates with susceptibility and that PMN influxis independent of AHR.Zhang et al.(1995)



### AX5-39Table AX5-12 (cont’d). Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference0.05 4 h, challenged withiv 5-HTRats, male, LongEvans, SD, Fisher344, Brown-Norway,BDII, BDE, DA,Lewis and Wistar,6-8 weeks old,n = 10/groupAHR: developed in Lewis, BDII and Long-Evans rats 90 min after O3.Baseline AHR differed among strains; did not correlate with O3-inducedAHR.PMN influx: did not occur in any strain.LE rats: AHR lasted$12 h PE with no change in BALF PMN, LDH,alkaline phosphatase, or protein.Suggests that O3-induced AHR occurs without airway inflammation andthat genetic factors may alter the sensitivity to O3.Depuydt et al.(1999)0.2 7 h, assayed 3 h PE Rabbits, NewZealand white, 5 kg,n = 5-7/groupO3-induced decrease in tracheal transepithelial potential difference, but nochange 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 resistance;enhancement of O3-induced peripheral lung reactivity.Suggests that O3exposure may affect tracheal epithelial function andincrease central airway reactivity, possibly through vagally-mediatedmechanisms.Freed et al.(1996)0.4 4 h, assayed byACh, SP, orhistamine challenge0 or 48 h PERabbits, NewZealand white, maleand female, 2.5-3 kg,n = 4-6/groupUsed isolated perfused lung model allowing partitioning of the totalpressure gradient into arterial, pre- and postcapillary, and venouscomponents. O3-induced inhibition of pulmonary mechanical reactivity toACh, SP, and histamine. No change in baseline pulmonary resistance ordynamic compliance. At 48 h PE O3altered vasoreactivity of the vascularbed.. Ozone-induced modification of the vasoreactivity of the vascular bedat 48 h PE and elevation of arterialsegmental pressure. Suggests that O3can directly induce vascular constriction both immediately and 2 daysfollowing exposure and can inhibit ACh-, SP-, and histamine-inducedchanges in lung mechanics.Delaunoiset al. (1998)



### AX5-40Table AX5-12 (cont’d). Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference0, 0.12, 0.5, or1.06 h/day,5 days/week for20 monthsRat, male andfemale,Fischer 344,6-7 weeks oldIsolated eighth generation airways following O3exposure. Circumferentialtension development was measured in response to bethanechol,acetylcholine, and electrical field stimulation and normalized to smoothmuscle area. 0.5 ppm caused an increase in smooth muscle area.Maximum responses of the small bronchi of male rats were significantlyreduced after exposure to 0.12 and 0.5 ppm O3. Suggests that O3-inducedincreases in airway responsiveness do not persist with near-lifetimeexposure and that chronic exposure alters smooth muscle cell function.Szarek et al.(1995)0.5 8 h/day for 7 days Guinea pig, male,Hartley, 5 weeks oldRepeated exposure increased rapidly adapting receptor activity tosubstance P, methacholine, and hyperinflation; no significant effects onbaseline or substance P- and methacholine-induced changes in lungcompliance and resistance.Suggest that because agonist-inducedchanges in receptor activity precedelung function changes, the responsiveness of rapidly adapting receptorswas enhanced.Joad et al.(1998)0.5 8 h/day for 5 daysfollowed by 9 daysof FA; for11 episodesMonkey, Rhesus,30-d old,n = 6/groupHalf of the monkeys were sensitized to house dust mite allergen (HDMA)at 14 and 28 days of age before exposure. HDMA and histamine aerosolchallenges administered until Rawdoubled. Baseline Rawelevated after10 exposure episodes in the HDMA + O3group compared to the FA,HDMA, and O3exposure groups. Aerosol challenge with HDMA at theend of the 10th episode did not significantly affect Raw, VT,f, or SaO2.AHR appeared to develop following episode 6. Aerosol challenge withHDMA at the end of the 10th episode did not significantly affect Raw, VT,f,or SaO2. HDMA + O3group: had increases in serum IgG, histamine andeosinophils; greater alteration in airway structure and content suggestingthat O3can enhance the structural remodeling and allergic effects ofHDMA sensitization exposure groups.Schelegleet al. (2003)



### AX5-41Table AX5-12 (cont’d). Effects of Ozone on Airway ResponsivenessConcentrationppmExposureDurationSpecies, Sex, Strain,and Age Observed Effect(s) Reference1 8 h Rat, Wistar,some treatedwith capsaicin,n = 6-8/groupVehicle-treated: O3-induced rapid shallow breathing pattern; BrdU labelstarted at the bifurcation of the mainstem bronchi and increased distally.Capsaicin treated: no O3-induced changes in respiratory frequency;reduced BrdU labeling density in the terminal bronchioles supplied byshort airway paths. Suggests that O3-induced rapid shallow breathingis protective of conducting airways and allows distribution of injury tomore distal regions.Schelegleet al. (2001)1 2 h Rat, male, Wistar,100-120 days old,n = 7-10/groupExamined the site-specific deposition of18O at breathing frequencies of 80,120, 16, or 200 bpm at a VTto produce a constant minute ventilation of72.8 ml/min/100 g body weight.All frequencies: parenchymal areas had a lower content of18O than tracheaand bronchi; right caudal parenchymal levels did not change.80 to 160 bpm: deposition reduced in midlevel trachea and increased inboth mainstream bronchi; increased deposition in parenchyma supplied byshort (cranial) airway paths.200 bpm: increased deposition in trachea increased; increased depositionin right cranial and caudal bronchi regions: decreased content in rightcranial parenchymal.Suggests that the effect of rapid,shallow breathing is to create a moreevenly distributed injury pattern with less deposition of O3) in the tracheaand a small effect on deposition in the parenchyma.Alfaro et al.(2004)MCh = Methylcholine, ACh = Acetylcholine, Hist = Histamine,5-HT = 5-Hydroxytryptamine, SP = Substance P, FS = Field Stimulation, CCh = Carbachol,TX = Thromboxane, KCl = Potassium Chloride, Pt = Platinum; Route: iv = intravenous, inh = inhalation., sc = subcutaneous, ip= intraperitoneal,OVA = Ovalbumin, BALF = bronchoalveolar lavage fluid, HDMA = House Dust Mite Allergen, Cdyn= Dynamic Lung Compliance, VE= Minute Ventilation,PaO2= partial pressure of arterial oxygen, AHR = airway hyperreactivity, VT= Tidal Volume, Raw= airway resistance,f= frequency of breathing,SaO2= oxygen saturation of arterial blood.



### AX5-42Table AX5-13. Effects of Ozone on Genotoxicity/CarcinogenicityConcentrationppmExposureDurationSpecies,Sex, Strain,and Age Observed Effect(s)Reference1 0, 12, 24, 48,72, or 96 hGuinea pigs,Dunkin-Hartley,male, 2 mo-old,n = 4/groupFollowing O3exposure, two main bronchi were removed and tracheobronchial cells were isolatedand assayed for DNA strand breaksusing fluormetric analysis.Ozone induced an increase inBALF protein and in DNA strand breaks, but didnot change cell yield or viability. The amountof DNA in alkali lysates was decreased at 72 h,which suggests an increase in strand breaks atthat time point.Ferng et al.(1997)1 or 2290 min90 min/dayfor 5 daysMice, female,BALB/c(20.6 g) orMutaTM(26.0 g)n = 11-21/groupO3-induced increase in strand breaks up to 200 min following exposure. No effects after 200 min.O3did not affect the level of oxidized amino acids in lung or the level of 8-oxo-deoxyguanosinein nuclear DNA. O3-induced induction of IL-6 mRNA following DNA strand breaks, which doesnot support inflammation causing DNA damage.Mutagenic mice had no O3-induced mutations in cII transgene.Bornholdtet al. (2002)0.12, 0.50,and 1.06 h/day,5 days/week forup to 9 monthsMice, female,A/J,n = 29-35/groupAt 5 months, no difference in lung tumor multiplicity or incidence. At 9 months, no differencesin lung tumor multiplicity between control miceand mice exposed to any concentration of O3.The highest, and only statistically significant lung tumor incidence, was found in the mice exposedto 0.5 ppm O3. In the O3-exposed mice allowed to recover in filtered air, only the mice exposed to0.12 ppm O3had increases in lung tumor incidence and multiplicity. Authors consider the resultsto be spurious and of no significance for data interpretation.Witschi et al.(1999)0.5 6 h/day,5 days/week for12 weeksMice, male andfemale, B6C3F1,5-6 weeks old,n = 20 M and 20FSporadic differences in mean body weight between O3-exposed mice and air-exposed controls,as well as significant differences in the meanabsolute and relative weights of liver, spleen,kidney, testes, and ovary. No O3-related increased incidence of neoplasms in lung tissue.Oviductal carcinomas observed upon histopathologic examination in 30% of O3-exposedfemale mice.Kim et al.(2001)0, 0.12, 0.5, or1.06 hr/day,5 days/week,to ppm 2-yrand lifetimeRats, male andfemale, FischerF-344/N,n = 5 M + 5 F(acute)n = 50 m + 50F/groupCocarcinogenicity study with subcutaneous administration of 0, 0.1, or 1.0 mg/kg body weightof 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and inhalation of 0 or 0.5 ppmO3to male rats.O3caused dose-related increase in inflammation inCAR; increased fibrosis; extension of thebronchiolar epithelium to the proximalalveoli; but no increase in neoplasms.NNK (1.0 mg/kg) alone causes increased bronchiolar/alveolar neoplasms.NNK + O3: no enhancement of neoplasms.Suggests that O3is not carcinogenic; does not enhance neoplasms growth; and creates mildsite-specific lesions which persist with continued exposure.Boormanet al. (1994)



### AX5-43Table AX5-14. Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceNEUROBEHAVIORAL EFFECTS0.10.20.51.04 h Rat, male, Wistar,47-50 days old,n = 25/groupRats exposed for 4 h to 0.2, 0.5, and 1 ppm O3showed long-term memorydeterioration and decreased motor activity, which was reversed 24 h later.Brain and pulmonary Cu/Zn SOD levels were increased in animals exposedto 0.1, 0.2, and 0.5 ppm O3, but decreased in animals exposed to 1 ppm O3.Rivas-Arancibiaet al. (1998)0.10.40.71.11.54 h Rat, male, Wistar,300-350 g,n = 10/groupO3caused memory impairment at$0.7 ppm (one trial passive avoidance test),decreased motor activity at$1.1 ppm, and increased lipid peroxidation at$0.4 ppm. Lipid perioxidation levels from the frontal cortex, hippocampus,striatum and cerebellum increased with increasing O3concentration.Dorado-Martinezet al. (2001)0.30.630 days Mice, CD-1M, F, 28-33 g,n = 6-7/groupO3exposure slightly but selectively affected neurobehavioral performance inmale mice assessed with a 5-min open-field test on exposure day 4 and 19 andon day 3 after the end of the exposure. O3exposure, however, did not grosslyaffect neurobehavioral development.Reversal learning in the Morris watermaze 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 wererecorded in O3prenatally exposed mice. Except for the first open-field test,altered responses were observed only in animals exposed to 0.3 ppm O3.Sorace et al.(2001)0.350.751.512 h Rat, male, Wistar,270 g,n = 10/groupO3exposure decreased paradoxical sleepafter 2 h of exposure, and increasedslow wave sleep after 12 h of exposure at all O3concentrations; 5-HTconcentrations in the pons increased with increasing O3concentration.Paz and HuitrónReséndiz (1996)0.7 4 h Rat, male, Wistar,47-50 days old,n = 6-10/groupVitamin E administered before or after O3exposure blocked memorydeterioration (passive avoidance)andincreases in lipid peroxidation levelsin the striatum, hippocampus and frontalcortex that were associated withoxidative stress.Guerrero et al.(1999)0.7 4 h Rat, male, Wistar,27 months old,n = 3-4/groupO3exposure increased ultrastructural alterations in the hippocampus andprefrontal cortex in aged rats comparedwith controls. These areas are relatedto learning and memory functions, which are the first degenerative agingchanges observed.Niño-Cabreraet al. (2002)



### AX5-44Table AX5-14 (cont’d). Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceNEUROBEHAVIORAL EFFECTS(cont’d)0.70.84 h Rat, male, Wistar,47, 540, or 900days old,n = 10-30/groupTaurine (43 mg/kg) given before or after O3exposure improved memorydeterioration in an age-specific manner.Old rats showed peroxidation in allcontrol groups and an improvement in memory with taurine. When taurinewas applied before O3, peroxidation levels were high in the frontal cortexof old rats and the hippocampus of young rats; in the striatum, peroxidationcaused by O3was blocked when taurine was applied either before or afterexposure.Rivas-Arancibiaet al. ( 2000)1 12 h/dayduring darkperiodRat, female, adult,n = 6/groupO3exposure during pregnancy affectsthe neural regulation of paradoxicalsleep and circadian rhythm of rat pups 30, 60, and 90 days after birth.Haro and Paz(1993)1 4 h Rat, male, Wistar,n = 24/groupO3caused alterations in long-term memory and a significant reduction ofdendritic spines. Results provide evidence that deterioration in memory isprobably due to the reduction in spine density in the pyramidal neurons of thehippocampus.Avila-Costa et al.(1999)1 3 h Rat, male, Wistar,275 g,n = 10/groupO3or its reaction products affect the metabolism of major neurotransmittersystems as rapidly as after 1 h ofexposure. 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.González-Piñaand Paz (1997)1.5 24 h Rat, male, Wistar,n = 11/groupAdult rats exposed to O3spend decreased time in wakefulness andparadoxical sleep and a significant increase in time in slow-wave sleep.Neurochemical changes include increased metabolism of serotonin inthe medulla oblongata, pons, and midbrain.Huitrón-Reséndizet al. (1994)0.5 20 h/dayfor 5 daysRat, SD,220-240 g,n = 10-20/groupO3produced marked neural disturbances in structures involved in theintegration of chemosensory inputs, arousal, and motor control.O3inhibited tyrosine hydroxylase activity in noradrenergic brainstem cellgroups, including the locus ceruleus (-62%) and the caudal A2 subset (!57%).Catecholamine turnover was decreased by O3in the cortex (!49%) andstriatum (!18%) but not in the hypothalamus.Cottet-Emardet al. (1997)



### AX5-45Table AX5-14 (cont’d). Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceNEUROBEHAVIORAL0.4, 0.8, or 1.2 24 h Cat, male, adult,n = 5/groupEvaluated EEG of sleep-wake organization in cats. 0.4 O3did not change theamount of sleep parameters, did decrease paradoxical sleep during first 8 hof exposure. At 1.2 ppm paradoxical sleep was reduced during O3exposure,followed by a dose-related increase of slow-wave sleep. Suggests O3-inducedchanges in sleep patterns.Paz and BazanPerkins (1992)0.75, 1.5 and 3.0 4 h Rat, male, Wistar,250-300 g,n = 15/groupRecorded evoked potential in visual cortex and lateral geniculate nucleus.P1, N1 and P2 components delayed in the visual cortex and lateral geniculatenucleus at 3.0 ppm O3. N1 component in the visual cortex affected at 1.5 ppmO3. Suggest O3-induced alterations in synaptic excitability and conductionmechanisms in the visual pathway.CustodioRamierez andPaz (1997)1-1.5 4 h Rat, male, Wistar,~250 gn = 5/groupO3-induced loss of dendritic spines on primary and secondary dendrites ofgranule cells; swelling of Golgi apparatus and mitochondrion; dilation cisternsof the rough endoplasmic reticulum; vacuolation of neuronal cytoplasm.Suggests O3-induced oxidative stress creates alterations in the granule layerof the olfactory bulb and possible modifications of function.Colín-Barenqueet al.(1999)NEUROENDOCRINE EFFECTS0.5 to 3.0 3 h Rat, male, SD,44-47 days old,n = 4-6/groupHyperthyroid, T4-treated rats (0.1-1.0 mg/kg/day for 7 days) had increasedpulmonary injury (BALF LDH, albumin, PMNs) at 18 h PE compared tocontrol rats.Huffman et al.(2001)1.0 24 h Rat, male, SD,3-4 months oldHyperthyroid, T3-treated rats had increased metabolic activity and O3-inducedpulmonary injury, but lipid peroxidation, as assessed by alkane generation,was not affected.Sen et al. (1993)



### AX5-46Table AX5-14 (cont’d). Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceCARDIOVASCULAR EFFECTS0.10.30.55 h Rat, Wistaryoung (4-6months) and old(22-24 months)n = 9-14/groupTransient rapid shallow breathing with slightly increased HR appeared1-2 min after the start of O3exposure, possibly due to olfactory sensation;persistent rapid shallow breathing with a progressive decrease in HR occurredwith a latent period of 1-2 h. The last 90-min averaged values for relativeminute ventilation tended to decrease with the increase in the level ofexposure to O3and these values for young rats were significantly lower thanthose for old rats. An exposure of young rats to 0.1 ppm O3for shorter than5 h significantly decreased the tidalvolume and HR and increased breathingfrequency, but no significant changes were observed in old rats. There wereno differences between young and old ratsin non-observable-adverse-effectlevels (NOAELs) for the O3-induced persistent ventilatory and HR responses,when the NOAELs were determined by exposure to 0.3 and 0.5 ppm O3.Arito et al. (1997)0.10.30.58 h/dayfor 4 daysRat, male, Wistar,10 weeks old,n = 9/groupCircadian rhythms of HR and core body temperature were significantlydecreased on the first and second O3exposure days in a concentrationdependent manner, and returned to control levels on the third and fourth days.Iwasaki et al.(1998)0.25 to 2.0 2 h to 5 days Rat, Fischer F344,Mice, C57BL/6J,C3H/HeJ, Guineapig, Hartley,n = 4-10/groupRobust and consistent decreases in HR and core body temperature; smallerdecreases in metabolism, minute ventilation, blood pressure, and cardiacoutput that vary inversely with ambient temperature and body mass.Watkinson et al.(2001)0.5 6 h/day23 h/dayfor 5 daysRat, male, FischerF-344,100-120 days old,n = 4-6/groupMinimal extrapulmonary effects wereobserved at a core body temperature of34 °C; O3exposures at 22 and 10 °C produced significant decreases in heartrate (160 and 210 beats/min, respectively), core body temperature (2.0 and3.5 °C, respectively), and body weight (15 and 40 g, respectively).Decreases in these functional parameters reached their maxima over the first2 exposure days and returned to control levels after the 3rd day of exposure.Watkinson et al.(1995);Highfill andWatkinson (1996)



### AX5-47Table AX5-14 (cont’d). Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceCARDIOVASCULAR EFFECTS(cont’d)0.5 8 h Rat, male, FischerF-344,270-330 g,n = 6/groupO3exposure increased atrial natriureticpeptides in the heart, lung, andcirculation, suggesting they mediate the decreased BP and pulmonaryedema observed with similar O3exposures.Vesely et al.(1994a,b,c)00.50.50.524 h/day6 h/day23 h/dayRat, male, FischerF-344 kept at oneof threetemperatures:10 °C, 22 °C,34 °C at rest,moderate or heavyCO2-stimulatedventilation,100-120 days old,n = 4-8/group0.5 ppm O3for both 6 h/day and 23 h/day caused decreases in heart rate andcore temperature (termed hypothermic response) and increases in BALFinflammatory markers. Exercise in 0 ppm O3caused increases in heart rateand core temperature, 0.5 ppm O3decreases. CO2and O3induced thegreatest deficits. Dose, animal mass,and environmental stress are suggestedto modify the hypothermic response.Watkinson et al.(2003)REPRODUCTIVE AND DEVELOPMENTAL EFFECTS0.20.40.6Continuous upto days 17 ofpregnancyMice, male andfemale, CD-1,25-27 gNo significant effects on either reproductive performance, postnatal somaticand neurobehavioral development (as assessed by a Fox test battery) or adultmotor activity (including within-session habituation); some subtle orborderline behavioral deficits were noted, however.Petruzzi et al.(1995)0.30.60.9Continuous upto postnatal day26Mice, male andfemale, CD-1,27-30 g,n = 11-15/groupO3caused subtle CNS effects,but did not affect the animals' capability tolearn a reflexive response (limb withdrawal); females exposed to 0.6 ppmO3showed a reduced preference for the right paw than both their same-sexcontrols and 0.6 ppm males. The effect was more robust in the case of anorganized avoidance response (wall-rearing).Petruzzi et al.(1999)



### AX5-48Table AX5-14 (cont’d). Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceREPRODUCTIVE AND DEVELOPMENTAL EFFECTS(cont’d)0.30.6Continuousuntil gestationalday 17Mice, male andfemale, CD-1,28-30 g,n = 6-9/groupExposure to O3did 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).Sorace et al.(2001)0.40.81.2Continuousduring gestationday 7-17Mice, CD-1 No effect of O3on reproductive performance; no significant somaticdevelopmental effects in O3-exposed pups except for a delay in eyeopening that was not concentration dependent.Bignami et al.(1994)0.6 Continuousfrom birth toweaningMice, male andfemale, CD-1,25-27 g,n = 13-16/groupExposure to O3did not produce any significant impairment of the acquisitionphase during swimming navigation, a sensitive indicator for hippocampaldamage; however, O3slightly increased the swimming paths during the lastday of the reversal phase. Mice exposed to O3showed a slightly butsignificantly higher swimming speed during all the days, which was unrelatedto differences in body weight and to navigational performances. Moreover,mice exposed to O3(with the exception of one animal) had a strong tendencyto make turns to the left while the controls, independent of sex, preferredclockwise turns.Dell’Omo et al.(1995a,b)1 12 h/day forentire gestation,assayed atpostnatal day 0,12, and 60Rat, male andfemale, Wistar,n = 9-10/groupHistological and planimetric analysis using sagittal sections of the anteriorcerebellar 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 chromatinaround periphery. Suggests that gestational exposure to O3induces permanentcerebellar damage.Rivas-Manzanoand Paz (1999)EFFECTS ON LIVER, SPLEEN, THYMUS1.02.03 h Rat, female, SD,200-225 gHigh O3exposure stimulates hepatocytes to produce increased amountsof nitric oxide as well as protein,possibly mediated by cytokines suchas TNF-"produced by alveolar macrophages. When macrophage functionis blocked, hepatic injury induced by O3is prevented.Laskin et al.(1994, 1996,1998b);Laskin andLaskin (2001)



### AX5-49Table AX5-14 (cont’d). Systemic Effects of OzoneConcentrationppm Duration Species Effects ReferenceEFFECTS ON LIVER, SPLEEN, THYMUS(cont’d)2.0 2 h Rat, male, FischerF-344,2, 9, or 24 monthsold,n = 2/groupUtilizing electron paramagnetic resonance (EPR) spectroscopy of chloroformextracts of liver homogenates, asignificant flux of hydrogen peroxideproduced from the reaction of O3with lipids of the extracellular lining couldbe a source of biologically relevantamounts of hydroxyl radical. EPR signalsfor carbon-centered alkoxyl and alkyl adducts were detected with C-phenylN-tert-butyl nitrone (PBN) in the liver of animals exposed to O3.Vincent et al.(1996)EFFECTS ON CUTANEOUS TISSUE0.5 2 h Mice, hairlessfemale"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.Valacchi et al.(2000)0.8 6 h Mice, SKH-1hairlessIncreased lipid peroxidation in the skin epidermis and dermis activated stressproteins HSP27 and HO-1, and activated a proteolytic enzyme system(MMP-9) related to matrix injury and repair processes.Valacchi et al.(2003)0.81.010.02 h Mice, SKH-1hairlessHigh O3depletes hydrophilic antioxidants in the SC: vit. C decreased to 80%,GSH decreased to 41%, and uric acid decreased to 44% of control levels afterexposure to$1.0 ppm O3.Weber et al.(2000)1.05.010.02 h Mice High O3exerts an oxidizing effect on theoutermost layer of the skin (SC);depletes low-molecular-weight antioxidants ("tocopherol, vit. C, glutathione,uric acid) in a concentration dependent manner; increases malondialdehydelevels associated with lipid peroxidation.Weber et al.(2001)0, 0.8, 1, and 10 2 h Mice, SKH-1hairless1 ppm O3depleted SC levels of vitamin C ( 80%), GSH (41%), and UA(44%). Suggests that hydrophilic antioxidants in the SC modulate the effectsof O3-induced oxidative stress.Weber et al.(1999)RER = Rough endoplasmic reticulum NADPH = Reduced nicotinamide adenine dinucleotide phosphate LPS = LipopolysaccharidePE = Postexposure (i.e., time after O3exposure ceased) NADH = Reduced nicotinamide adenine dinucleotide SRBC = Sheep red blood cellTSH = Thyroid stimulating hormone B[a]P = Benzo[a]pyrene TBA = Thiobarbituric acidT3= Triiodothyronine NK = Natural killer IgE = Immunoglobulin E.T4= Thyroxine PHA = Phytohemagglutin PHA = Phytohemagglutincyt. = Cytochrome ConA = Concanavalin A



### AX5-50Table AX5-15. Interactions of Ozone With Nitrogen DioxideConcentrationppmDuration Species Endpoints Interaction ReferenceO3NO2MORPHOLOGY0.8 14.4 6 h/day,7 days/weekfor 90 daysRat, male, SD,10-12 weeksold,n = 4/groupMorphometry of lungparenchyma; DNA probesfor procollagen; in situmRNA hybridization.Syngeristic; more peripheral centriacinar lesion, but sameafter 7, 78, and 90 days of exposure.Farman et al.(1999)0.3 1.2 Continuousfor 3 daysRat, male, SD,3 months old,n = 4/groupDNA single strand breaks;polyADPR synthetase ofAMs; total cells, protein,and LDH in BALF.None; effect due to O3. Bermúdezet al. (1999);Bermúdez(2001)BIOCHEMISTRY0.8 14.4 6 h/day,7 days/weekfor 9 weeksRat, male, SD,10-12 weeksoldn = 4/groupLung hydroxyproline,hydrooxypyridinium,DNA, and protein contentof whole lung; morphologyand labeling index.Synergistic; fibrosis after 7-8 weeks of exposure;50% mortality at ~10 weeks.Farman et al.(1997)0.4 7 90 days Rat, male, SD,200-225 gPMN, pulmonary edema,fibrosis, MIP-2.1-3 days: enhanced MIP-2, IL-1$, TNF-", thioredoxin,and IL-6 expression; pulmonary edema and PMN influx,which reversed by day 8; activation of NF6B.15-45 days: no tissue responses observed, suggestingadaptation.60 and 90 days: increased lung collagen; increasedexpression of transforming growth factor-13 and TNF-",activation of NF6B.MnSOD and GPX not altered during exposure.Suggests that cytokines play a role in the early responsesto combined O3and NO2and that pulmonary fibrosis ismore dependent on concentration than on cumulative dose.Ishii et al.(2000b)



### AX5-51Table AX5-15 (cont’d). Interactions of Ozone With Nitrogen DioxideConcentrationppmDuration Species Endpoints Interaction ReferenceO3NO2BIOCHEMISTRY(cont’d)0.8 14.4 1, 5, and8 weeksRat, male, SD,10-12 weeksold,n = 4/groupImmunohistochemisty andmorphometric analysis ofTNF-"and MnSOD levelsin alveolar ducts.Triphasic response. 1-3 weeks: initial inflammation;TNF-"increased in proximal area.4-5 weeks: partial resolution.6-8 weeks: rapidly progressive fibrosis; elevated MnSOD;TNF-"increased in proximal area.TNF-"increased in interstitial cells at all time points.Suggests O3-induced increases in MnSOD in areas ofinjury and in more protected areas; O3-induced increasesin TNF-"correlate spatiotemporally with injury.Weller et al.(2000)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-cytochrome c reductase.GDT = GSH-disulfide transhydrogenase. GSH = Glutathione.GSHPX = GSH peroxidase. 6-PG-D = 6-phosphogluconate dehydrogenase.



### AX5-52Table AX5-16. Interactions of Ozone with FormaldehydeO3HCHO Duration Species Endpoints Interaction Reference0.4 3.6 8 h/day for3 daysRat, male,Wistar,n = 20/groupO3or 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.Proliferativeresponse:No interactiveeffectsCassee andFeron (1994)0.6 10 3 h, withexercise at2× restingventilationRat, male,SD, 7 weeksHCHO did not alter O3-induced changes in breathing pattern.Parenchymal injury attributed to O3alone.Additive effectsin transitionalepitheliumand tracheaMautz (2003)0.2-10 0.4-4 30 min Mice,BALB/c,n = 4Continuously measuredf, VT, expiratory flow, Ti, Te, andrespiratory patterns during acute exposures. HCHO: appeared tobe a pure sensory irritant at lower concentrations. O3: inducednon-dose-dependent transient increase in rapid, shallow breathing.No effect level of HCHO was 0.3 ppm, for O31.0 ppm. Suggeststhat O3and HCHO have the same respiratory effects in BALB/cmice and humans, with similar sensitivities.Not additive Nielson et al.(1999)



### AX5-53Table AX5-17. Interactions of Ozone with Tobacco SmokeO3HCHO Duration Species Endpoints Interaction Reference1.5 7 ml breaths at33% challenge1 h Guinea pig,male, Hartley,320-460 g,n = 5 to 9Pulmonary resistance and dynamic lung compliance were comparedpre- and post-O3exposure.Pre-O3: cigarette smoke induced bronchoconstriction after l min.Post-O3: cigarette smoke induced bronchoconstriction more quicklyand for a longer period.Selective antagonism of neurokinin 1 and 2 receptors blocked thenenhanced O3-induced bronchoconstriction, suggesting that endogenoustachykinins modulate O3-induced bronchoconstriction.Synergistic Wu et al.(1997)0.5 ADSS30 mg/m36 h/dayfor 3 days24 hMice, male,B6C3F1,10 weeks old,n = 11Aged and diluted side stream cigarette smoke (ADSS) exposurefollowed by O3.ADSS + O3: greater increase in BALFcells, %PMN, and proteinscompared to alone; 402% increasein proliferating cells in CAR;LPS-stimulated release of IL-6decreased; LPS-stimulated releaseof TNF-"increased.ADSS alone: no change in number of proliferating cells in CAR;LPS-stimulated release of TNF-"increased.O3alone: 280% increase in proliferating cells in CAR;LPS-stimulated release of IL-6 decreased.Suggests that O3-induced lung injury is enhanced by prior ADSSexposure.Synergism Yu et al.(2002)



### AX5-54Table AX5-18. Interactions Of Ozone With ParticlesConcentrationDuration Species Endpoints Interaction ReferenceO3(ppm)PM(mg/m3)SULFURIC ACID0.10.20.02-0.15(0.4-0.8 μm)23.5 h/day orintermittent 12 h/dayfor up to 90 daysRat, male, SD,250-275 g,n = 6/groupMorphologyBiochemistryNo interaction Last andPinkerton(1997)0.10.30.60.50 (0.3 μm)0.125 (0.3 μm)3 h Rabbit NZWmale, 3.5-4.5 kg,n = 5/groupAM intracellularpH homeostasis andH+extrusionAntagonism Chen et al.(1995)0.10.30.60.50 (0.3 μm)0.125 (0.3 μm)3 h Rabbit NZWmale, 3.5-4.5 kg,n = 5/groupAirway responsiveness(in vitro bronchialrings + ACh)Antagonism El-Fawalet al. (1995)0.6 0.5 (0.06 and0.3 μm MMD)4 h/day for 2 days Rat, male, SD,250-300 g,n = 10/groupMorphology: volumepercentage of totalparenchyma containing injuredalveolar septae;bromodeoxyuridine celllabeling index in the periacinarregionSynergism: ultrafine + O3, butnot fineSynergism: fine + O3Kimmel et al.(1997)PARTICLE MIXTURES0.1 Diesel PM (NIST#2975) reacted withO3for 48 h24 h (IT) Rat, male, SD,250-300 g,n = 4-13Inflammation Synergism Madden et al.(2000)0.160.300.590.05-0.22 mg/m3ammonium bisulfate0.03-0.10 mg/m3C0.11-0.39 pm NO20.02-0.11 mg/m3HNO3;(0.3 μm MMAD)4 h/day, 3 days/weekfor 4 weeksRat, male,Fischer F344N,11 weeks old,n = 8-30breathing pattern, morphology,lavagable protein, andclearanceComplex interactions, butpossible loss of typicalattenuation seen with O3onlyexposure, reflectingpersistence of inflammation.Mautz et al.(2001)



### AX5-55Table AX5-18 (cont’d). Interactions Of Ozone With ParticlesConcentrationDuration Species Endpoints Interaction ReferenceO3(ppm)PM(mg/m3)PARTICLE MIXTURES(cont’d)0.2 0.07 and 0.14 mg/m3ammonium bisulfate(0.45 μm MMMD);0.05 and 0.10 mg/m3carbon4 h/day, 3 days/weekfor 4 weeksRat, male,Fischer F344,22-24 monthsold,n = 5-10BAL protein and albumin;plasma hydroxylase andfibronectinQuestionable interaction.No changes in BALF proteinor prolyl 4-hydroxylase inblood. Small decease inplasma fibronectin withcombined exposure.Bolarin et al.(1997)0.2 0.50 mg/m3ammoniumbisulfate (0.45 μmMMMD) and elementalcarbon)4 h/day, 3 days/weekfor 4 weeks; nose onlyRat, FischerF344N-NIA,22-24 months oldDNA labeling of dividing lungepithelial and interstitial cellsby 5-bromo-2-deoxyuridineSynergism. Increased AMphagocytosis and respiratoryburst. Decreased lungcollagen.Kleinmanet al. (2000)0.3 0.063 to 1.57 mg/m3CAPs (Boston) + ipOVA sensitizationSensitized at day 7and 14. Challenged atday 21, 22, and 23.5 h O3exposureMice, BALB/c,n = 5-6/groupAirway function Interaction: increased RLand airway responsiveness innormal and OVA-sensitizedmice.Kobzik et al.(2001)0.4 0.20 and 0.50 mg/m3fine, H2O2-coatedcarbon (0.26 μmMMMD)4 h/day for 1 or 5 days Rat, SD,300 g,n = 10Inflammation Synergism for effect on day 5.Greater response at high dose,contrasts with O3along whereinflammation was greatest at0.4 ppm on day 1.Kleinmanet al. (1999)0.5 Endotoxin (IN)100 μg 24 h and48 h after the 3rdO3exposure8 h/day for 3 days Rat, FischerF344,10-12 weeks old,n = 6/groupNasal morphology Synergism: increasedintraepithelial mucosubstancesand mucous cell metaplasiaFanucchiet al. (1998)Wagner et al.(2001a,b)0.5 OVA (IN)50 μl (1%)8 h/day for 1 day or3 consecutive daysRat, Brown,Norway,10-12 weeks old,n = 6/groupNasal morphology Synergism: increasedintraepithelial mucosubstancesand mucous all metaplasia.Wagner et al.(2002)



### AX5-56Table AX5-18 (cont’d). Interactions Of Ozone With ParticlesConcentrationDuration Species Endpoints Interaction ReferenceO3(ppm)PM(mg/m3)\PARTICLE MIXTURES(cont’d)0.8 0.5 mg, 1.5 mg, or5 mg of PM fromOttawa Canada(EHC-93)2, 4, and 7 days afterIT instillationRat, male,Wistar,200-250 g,n = 5/groupInflammation Interaction: increased TNF-"in BALF.Ulrich et al.(2002)1 0.11 mg/m3ultra finecarbon (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/groupInflammation Interaction: increasedPMNs and ROS release fromBALF cells for old rats andmice primed with endotoxin;depressed in young rats.Elder et al.(2000a,b)1 Endotoxin (37.5 EU)for 10 min4, 20, or 24 h Mice,C57BL/6J, 36 hold, 8 weeks old,n = 12/groupInflammation Synergism: increased BALFprotein and PMNs.Johnstonet al. (2000b,2002)1 Endotoxin (IN) 0, 2,or 20 μg in 120 μL8 h, repeated after24 hRat, male,Fischer F344,10-12 weeks old,n = 6/groupLung morphometric analysisand inflammationSynergism: increasedBALF PMNs and mucinglycoprotein; increasedintraepithelialmucosubstances andmucingene mRNA.Wagner et al.(2003)



### AX5-57Table AX5-18 (cont’d). Interactions Of Ozone With ParticlesConcentrationDuration Species Endpoints Interaction ReferenceO3(ppm)PM(mg/m3)PARTICLE MIXTURES(cont’d)0.8 EHC-93,5 mg/m3or50 mg/m34 h exposure, clean airfor 32 h,3H injectionfollowed by assay at90 minRat, male,Fischer F344,200-250 g,n = 6/groupControl rats:3H labeling(indicative of proliferation)low in bronchioles andparenchyma.ECH-93 alone: no inductionof proliferation.O3alone: increased celllabeling in bronchioles andparenchyma, suggestive ofreparative cell proliferation.ECH-93 + O3: both dosesof EHC-93 potentiatedproliferation, especiallyin epithelia of terminalbronchioles and alveolarducts, but not distalparenchyma. Suggests thatambient PM can enhanceO3-induced proliferationsand exacerbate injury.Synergism of proliferation Vincent et al.(1997)0.8 (EHC93) at 50 mg/m34 h, exposure, cleanair for 32 h,3Hinjection followed byassay at 90 minRat, male,Fischer F344,200-250 g,n = 4/groupO3+ EHC-93: epithelial cellinjury and proliferation(3H-labeling) higher thansingle 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 Adamsonet al. (1999)



### AX5-58Table AX5-18 (cont’d). Interactions Of Ozone With ParticlesConcentrationDuration Species Endpoints Interaction ReferenceO3(ppm)PM(mg/m3)PARTICLE MIXTURES(cont’d)0.15 HNO350 μg/m34 h/day, 3 days/weekfor 40 weeks,nose-only exposureRat, male,Fischer F344/N, 8weeks old,n = 4-5/groupO3alone: 28% increase inlung putrescine.HNO3alone: 21% decrease inlung putrescineO3and O3+ HNO3:56% increase in lungputrescinePulmonary spermidine andspermine did not change withany exposure.Suggests role of putrescine inregulation of inflammation.Synergism Sindhu et al.(1998)0.5 Carbon Black (CB),0.5 or 1.5 mg/ratIntratracheal CBfollowed by 7 daysor 2 months of O3Rat, male, Wistar,7 weeks old,n = 7-8/groupPhagocytotic capacity:decreased in CB-exposedgroup, unchanged in O3group.Formation of superoxide anionradicals and numbers ofingested particles increased at2 months in O3group.Chemotactic migration:decreased in CB-treated group.Suggests that CB impairsphagocytosis and chemotacticmigration in AMs, whereas O3stimulates these functions.Synergism Creutzenberget al. (1995)



### AX5-59Table AX5-18 (cont’d). Interactions Of Ozone With ParticlesConcentrationDuration Species Endpoints Interaction ReferenceO3(ppm)PM(mg/m3)PARTICLE MIXTURES(cont’d)0.018 CH2O 3.3 ppbTSP 0.068 mg/m3PM100.032 mg/m3PM2.50.016 mg/m323 h/day for 7 weeks Rat, male andfemale, FischerF344,9 weeks old,n = 5/groupExposure to filtered andunfiltered Mexico City air.Histopathology revealed nonasal lesions in exposed orcontrol rats; tracheal and lungtissue from both groupsshowed similar levels ofminor abnormalities.Moss et al.(2001)VMD = Volume median diameterFg = Geometric standard deviationMMAD = Mass median aerodynamic diameterCMD = Count median diameterPM = Particulate MatterOVA= OvalbuminRL= Total Pulmonary ResistanceAED = Aerodynamic diameterBAL = Bronchoalveolar lavageAM = Alveolar macrophageIN = IntranasalIT = IntratrachealUnless indicated otherwise, whole-body exposures used



### AX5-60Table AX5-19. Effects of Other Photochemical OxidantsConcentrationppm Duration Species EffectsReferenceH2O2(10, 20, or100 ppb) and/or(NH4)2S04(429 or 215 Ág/m3;0.3-0.4 gm massmedian diameter)2 h,assayed 0or 24 h PERat,female, SD,n = 4-18/groupExposures alone or in combination.H2O2+ (NH4)2S04: no effect on BALF cell number,viability, protein or LDH at eithertime point; increased PMNs adhered to vascular epithelium; increased TNF-"by AMs atboth time points; at 0 h PE, transient increase in superoxide anion by AMs; decreased NOproduction; nitrotyrosine detected; heme oxygenase-1 expression upregulated in AMs;H2O2only: decreased NO production which persisted for 24 h.Suggests that PM-induced effects are augmented by H2O2and that PM-induced tissueinjury may be modulated by cytotoxic mediators produced by AMs.Morio et al.(2001)PAN0.13,0.66,1.310.077,0.192,0.3840, 15, 39, or 78 ppm3 h1 h1 hPBL frommice, male,CD-1, 5 weeksold, n = 25Mice, male,B6C3F1,6 weeks old,n = 4In vitro: Exposed peripheral blood lympocytes (PBL) to PAN; assayed for chromosomeaberrations, sister chromatid exchanges and DNA damage. DNA damage was observedat cytotoxic concentrations of PAN.No effects at noncytotoxic exposures.In vivo: Nose-only exposures. No dose-related effects at any exposure level in anyassay.Suggests that PAN, both in vitro and in vivo, is not a DNA damaging agent or clastogen.Kligermanet al. (1995)3 ppm PAN 1 month Hamster,Chinese,n = 4Measured 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 wasobserved in bone marrow or lung. Suggests no mutagenicity in vivo.Heddle et al.(1993)~300 ppb78 ppm~80 ppm3H-PAN4, 7, 10, or12 h24 h1 hSalmonellaTA100Mice, BigBlue®, male,4 weeks old,n = 15Gas phase exposure PAN-induced mutants: 59% GC6TA; 29% GC6AT;2% GC6CG; 10% multiple mutations — primarily GG6TT tandem-basesubstitutions.Nose-only exposure. Mutagenic at the lacIgene in the lung; no tandem-base mutations.Nasal tissue: 3.9% of the radiolabel.Lung: 0.3 % of radiolabel.Suggests that PAN is weakly mutagenic in Salmonella (with a signature GG6TTtransversion) and in mouse lung.DeMariniet al. (2000)



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### AX6-1 

# ANNEX AX6. CONTROLLED HUMAN EXPOSURE STUDIES OF OZONE AND RELATED PHOTOCHEMICAL OXIDANTS

AX6.1 INTRODUCTION
Results of ozone (O 3 

### ) 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 O 3 

### is obtained.

More direct evidence of human health effects due to O 3 

### exposure can be obtained through controlled human exposure studies of volunteer subjects or through field and epidemiologic studies of populations exposed to ambient O 3 

### . Controlled human exposure studies, discussed in this chapter, typically use fixed concentrations of O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentrations include decreased inspiratory capacity; mild bronchoconstriction; rapid, shallow breathing pattern during exercise; and symptoms of cough and pain on deep inspiration.
In addition, O 3 

### 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 (FEV 1 

### ).

Given that both FEV 1 

### and FVC are subject to decrease with O 3 

### exposures, changes in the ratio (FEV 1 

### /FVC) become difficult to interpret and so are not discussed. The majority of controlled human studies have investigated the effects of exposure to

variable O 3 

### concentrations in healthy subjects performing continuous exercise (CE) or intermittent exercise (IE) for variable periods of time. These studies have several importantlimitations: (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 O 3 

### as function of O 3 

### concentration (C), minute
ventilation ( 

## 0 V E 

### ), and duration or time (T) of exposure. In most of these studies, subjects were
exposed to O 3 

### and to filtered air (FA [reported as 0 ppm O 3 

### ]) as a control. The most salient observations from these studies were: (1) healthy subjects exposed to O 3 

### concentrations

$ 

### 0.08 ppm develop significant reversible, transient decrements in pulmonary function if 

## 0 V E 

### or T are increased sufficiently, (2) there is a large degree of intersubject variability in physiologic and symptomatic responses to O 3 

### and these responses tend to be reproducible within a given individual over a several months period, and (3) subjects exposed repeatedly to O 3 

### 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 O 3 

### exposures of 1- to 8-h in duration on pulmonary function in healthy nonsmoking subjects are examin ed by reviewing studies that investigate: (1) the O 3 

### 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 O 3 

### exposures on sedentary subjects were discussed in the 1986 EPA criteria document (U.S. Environmental Protection Agency, 1986). The lowest O 3 

### concentration at which significant reductions in FVC and FEV 1 

### were reported was 0.5 ppm (Folinsbee et al., 1978; Horvath et al., 1979). Based on the average O 3 

### responses in these two studies (corrected for FA responses), resting young adults (n = 23, age = 22) exposed to 0.5 ppm O 3 

### have a ~4% reduction in FVC and a ~7% reduction

FEV 1 

### . At lower O 3 

### 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 O 3 

### experienced statistically significant decrements in pulmonary function and respiratory symptoms. As an example, 2 hr exposures to 0.12 and 0.18 ppm O 3 

### during heavy IE
(exercise 

## 0 V E 

### = 65 L/min) have resulted in FEV 1 

### 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 O 3 

### 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 O 3 

### dose-response characteristics, many investigators modeled
acute responses as a function of total inhaled O 3 

### dose (C × T × 

## 0 V E 

### ), which was found to be a

### AX6-4 better predictor of response than O 3 

### concentration, 

## 0 V 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 O 3 

### with exercise, Folinsbee et al. (1988) reported a good correlation (r = 0.81) between total inhaled O 3 

### dose and FEV 1 

### decrements. For a given exposure duration, total inhaled O 3 

### dose can be increased by increases

in C and/or 

## 0 V E 

### . In exposures of fixed duration, results of several studies suggested that O 3 

### concentration was a more important predictor of response or explained more of the variability in
response than 

## 0 V 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 FEV 1 

### decrement
occurring at a given C and 

## 0 V E 

### , doubling C (e.g., from 0.1 to 0.2 ppm) would increase the FEV 1 

### decrement by 400%, whereas doubling the 

## 0 V E 

### (e.g., from an exercise 

## 0 V E 

### of 20 to 40 L/min)
which would only increase the FEV 1 

### decrement by 190%. Thus, C appears to have a greater

affect than 

## 0 V E 

### on FEV 1 

### responses even when total inhaled O 3 

### doses are equivalent.
New studies (i.e., not reviewed in th e 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 a ffecting 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 O 3 

### versus FA exposures, many of the newer studies have tested the effects of a placebo versus treatment in modulating responses to O 3 

### 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 O 3 

### concentrations (0.0, 0.12, 0.18, 0.24,
0.30, or 0.40 ppm) at rest or one of two levels of IE ( 

## 0 V E 

### of 25 and 35 L/min/m 2 

### BSA). FEV 1 

### was measured preexposure, after 1 h of exposure, and immediately postexposure. Decrements

in FEV 1 

### were modeled by sigmoid-shaped curve as a function of subject age, O 3 

### concentration,



## 0 V E 

### , and T. The modeled decrements reach a plateau with increasing T and dose rate (C × 

## 0 V E 

### ).

That is, for a given O 3 

### concentration, exercise 

## 0 V E 

### level, and after a certain length of exposure,

the FEV 1 

### response tends not to increase further with increasing duration of exposure. The

modeled FEV 1 

### responses increased with C × 

## 0 V E 

### and T, decreased with subject age, but were onlyAX6-5Table AX6-1. Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours During ExerciseaOzoneConcentrationbExposureDuration andActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.407842 h IE4 × 15 minon bicycle,V.E= 30 L/minNA 5 M, 4 F6 M, 7 FHealthy adults25 ± 2 years oldMild atopicasthmatics22 ± 0.7 years oldO3-induced reductions in FVC (12%, 10%) and FEV1(13%, 11%) for asthmatic and healthy subjects.Significant reductions in mid-flows in both asthmatics andhealthy subjects. Indomethacin pretreatment significantlydecreased FVC and FEV1responses to O3in healthy but notasthmatic subjects. See Section AX6.3.2 and Tables AX6-3and AX6-13.Alexis et al.(2000)0.00.203922 h IE4 × 15 minat V.E= 20L/min/m2BSA20 °C50% RH8 M, 5 F Healthy NSmedian age 23 yearsMedian O3-induced decrements of 70 mL, 190 mL, and400 mL/s in FVC, FEV1, and FEF25-75, respectively.Spirometric responses not predicted of inflammatoryresponses.See Sections AX6.2.5.2, AX6.5.6, and AX6.9.3and Table AX6-12.Blomberget al. (1999)0.00.203922 h IE4 × 15 minat V.E= 20L/min/m2BSA20 °C50% RH10 M, 12 F Healthy NSmean age 24 yearsSignificant O3-induced decrement in FEV1immediatelypostexposure but not significantly different from baseline2 h later. No correlation between Clara cell protein (CC16)and FEV1decrement. CC16 levels, elevated by O3exposure,remained high at 6 h postexposure, but returned to baselineby 18 h postexposure.See Table AX6-13.Blomberget al. (2003)0.00.3306472 h IE4 × 15 minon bicycleergometer(600 kpm/min)NA 9 M Healthy NS26.7 ± 7 years oldO3-induced reductions in FVC (7%). FRC not altered by O3exposure. Post FA, normal gradient in ventilation whichincreased from apex to the base of the lung. Post O3,ventilation shifted away from the lower-lung into middleand upper-lung regions. The post O3increase in ventilationto mid-lung region was correlated with decrease inmidmaximal expiratory flow (r = 0.76, p < 0.05).Foster et al.(1993)0.00.3506902.2 h IE2 × 30 minon treadmill(V.E.50 L/min)Final 10 min rest19-23 °C48-55%RH15 M Healthy NS25.4 ± 2 years oldPre- to post-O3, mean FVC and FEV1decreased by 12 and14%, respectively. Following O3exposure, there was apronounced slow phase evident in multibreath nitrogenwashouts which, on average, represented a 24% decreasein the washout rate relative to pre-O3.Foster et al.(1997)



### AX6-5Table AX6-1 (cont’d). Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours during ExerciseaOzoneConcentrationbExposureDuration andActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.120.180.240.300.4002353534715897842 h rest or IE(4 × 15 minat V.E= 25 or 35L/min/m2BSA)22 °C40% RH485 M (eachsubjectexposed at oneactivity levelto one O3concentration)Healthy NS18 to 36 years oldmean age 24 yearsStatistical analysis of 8 experimental chamber studiesconducted between 1980 and 1993 by the U.S. EPA inChapel Hill, NC. Decrement in FEV1described by sigmoidshaped curve as a function of subject age, O3concentration,V.E, and time. Response decreased with age, was minimallyaffected by body size corrections, and was not moresensitive to O3concentration than V.E.Also see SectionAX6.5.McDonnellet al. (1997)0.4 784 2 h IE20 min mild-mod.exercise,10 min restNA 4 M, 5 F Healthy NS30 ± 3 years oldSubjects previously in Nightingale et al. (2000) study.Placebo-control: Immediately postexposure decrementsin FVC (9%) and FEV1(14%) relative to pre-exposurevalues. FEV1decrement only 9% at 1 hr postexposure.By 3 h postexposure, recovery in FVC to 97% and FEV1to 98% of preexposure values. Significant increases in8-isoprostane at 4 h postexposure. Budesonide for2 wk prior to exposure did not affect responses.Montuschiet al. (2002)0.00.2392 2 h IE4 × 15 minat V.E= 20L/min/m2BSA20 °C50% RH6 M, 9 F9 M, 6 FHealthy adults24 years oldMild asthmatics29 years oldO3-induced FEV1decrement (8%, healthy adults;3% asthmatics) and PMN increase (20.6%, healthy adults;15.2% asthmatics). Primary goal was to investigaterelationship between antioxidant defenses and O3responses in asthmatics and healthy adults.See TablesAX6-3 and AX6-13.Mudwayet al. (2001)Stenforset al. (2002)0.4 784 2 h IE20 min mild-mod.exercise,10 min restNA 6 M, 9 F Healthy NSmean age ~31 yearsPlacebo-control: O3caused significant decrements in FEV1(13.5%) and FVC (10%) immediately following exposure,a small increase in MCh-reactivity, and increased PMNs andmyeloperoxidase in induced sputum at 4 h postexposure.FEV1at 96% and FVC at 97% preexposure values at 3 hpostexposure. Budesonide for 2 wk prior to exposure didnot affect spirometric responses.See Section AX6.2.5 andTable AX6-13.Nightingaleet al. (2000)



### AX6-6Table AX6-1 (cont’d). Controlled Exposure of Healthy Humans to Ozone for 1 to 2 Hours during ExerciseaOzoneConcentrationbExposureDuration andActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.4784 2 h IE4 × 15 min at.VE=18 L/min/m2BSA2 exposures:25% subjectsexposed to air-air,75% to O3-O321 °C40% RHWeakresponders7 M, 13FStrongresponders21 M, 21 FHealthy NS20 to 59 years oldSignificant O3-induced decrements in spirometric lungfunction. Young adults (<35 years) were significantly moreresponsive than older individuals (>35 years). Sufentanil,a narcotic analgesic, largely abolished symptom responsesand improved FEV1in strong responders. Naloxone, anopioid antagonist, did not affect O3effects in weakresponders.See Section AX6.2.5.1.Passannanteet al. (1998)0.00.4784 2 h IE4 × 15 minat V.E= 20L/min/m2BSA20 °C40% RHPlacebo group15 M, 1 FAntioxidantgroup13 M, 2 FHealthy NSmean age 27 yearsPlacebo and antioxidant groups had O3-induced decrementsin FEV1(20 and 14%) and FVC (13 and 10%), respectively.Percent neutrophils and IL-6 levels in BAL fluid obtained1 h postexposure were not different in the two treatmentgroups.See Table AX6-13.Samet et al.(2001)Steck-Scottet al. (2004)0.00.25490 1 h CEV.E= 30 L/minNAFace maskexposure32 M, 28 F Healthy NS22.6 ± 0.6 years oldMean O3-induced FEV1decrements of 15.9% in males and9.4% in females (gender differences not significant). FEV1decrements ranged from!4 to 56%; decrements >15% in20 subjects and >40% in 4 subjects. Uptake of O3greater inmales than females, but uptake not correlated withspirometric responses.Ultman et al.(2004)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.cStudies conducted in exposure chamber unless otherwise indicated.



### AX6-7

### AX6-8 Figure AX6-1. FEV 1 

### decrements as a function of O 3 

### 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 ( 

## 0 V E 

### ) represent average across intervals of rest and exercise.

Source: McDonnell et al. (1997). 

### minimally affected by body size corrections to 

## 0 V E 

### . Fitted and experimental FEV 1 

### decrements

following a 2 h exposure at three nominal levels of 

## 0 V E 

### are illustrated in Figure AX6-1 as a

function of O 3 

### concentration. Their analysis indicated that C was marginally, but not
significantly, more important than 

## 0 V E 

### in predicting FEV 1 

### 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 

## 0 V E 

### in predicting FEV 1 

### responses by considering only the 

## 0 V E 

### during exercise and ignoring the 

## 0 V E 

### during periods of rest.

### AX6-9 Ultman et al. (2004) measured O 3 

### uptake and pulmonary responses in 60 young heathy nonsmoking adults (32 M, 28 F). A bolus technique was used to quantify the uptake of O 3 

### as a function of the volume into the lung which the bolus penetrated. From these measurements, the volumetric depth at which 50% uptake occurred wa s calculated. This volumetric lung depth was correlated with conducting airways volume, i.e., a greater fraction of O 3 

### 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 O 3 

### for 1 h with CE at a target 

## 0 V E 

### of 30 L/min. The breath-by-breath uptake of O 3 

### was measured. There was a small but significant reduction in the breath-by-breath uptake of O 3 

### 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 f B 

### and smaller V T 

### of the females than males. Uptake was not correlated with spirometric responses. However, there was tendency for males to have greater O 3 

### -induced FEV 1 

### decrements than females, 15.9% versus 9.4%, respectively. There was considerable intersubject variability in FEV 1 

### 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 oz one 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 O 3 

### 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-O 3 

### relative to post-FA, there were significant reductions in FVC (FA, 5.23 ± 0.5; O 3 

### , 4.88 ± 0.5 liters) and midmaximal expiratory flow (FA, 3.82 ± 0.8; O 3 

### , 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 O 3 

### 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 O 3 

### 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-O 3 

### 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 hea lthy nonsmoking males (25.4 ± 2 years old) were randomly exposed to FA or 0.35 ppm O 3 

### for 2.2 h with IE. Subjects alternated between 30 min
periods of rest and treadmill exercise ( 

## 0 V 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-O 3 

### exposure, 12 of 15 subjects returned and completed an addition multibreath nitrogen washout maneuver. Pre- to post-O 3 

### exposure, the mean FVC and FEV 1 

### were significantly decreased by 12 and 14%, respectively. Exposure to FA did not appreciably affect sp irometry or the multibreath nitrogen washout. Following O 3 

### exposure, the washout of nitrogen was delayed and resembled a two-compartment washout, whereas pre-O 3 

### 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[N 2 

### ] per expired volume) of the nitrogen washout between 20% and 9% nitrogen. Post-O 3 

### , there was a pronounced slow phase evident in nitrogen washout which, on average, represented a 24% decrease in the washout rate relative to pre-O 3 

### . 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-O 3 

### . At 24-h post-O 3 

### , 6 of the 12 subjects who completed an additional nitrogen washout maneuver had a delayed washout relative to the pre-O 3 

### maneuver. This suggests a prolonged O 3 

### 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) O 3 

### 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 detailsTable AX6-2. Pulmonary Function Effects after Prolonged Exposures to OzoneaOzone ConcentrationbExposureDurationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Studies with 4 hr Exposures0.18 353 4 h IE(4 × 50 min)V.E= 35 L/min23 °C50% RH2 M, 2 F Adults NS, 21to 33 years oldFVC decreased 19% and FEV1decreased 29% in these fourpre-screened sensitive subjects.Adams(2000a)0.00.2003924 h IE(4 × 50 min cycleergometry ortreadmill running[ V.E= 40 L/min])20 °C50% RHFA: 11 M, 3FO3: 9 M, 3 FAdult NS, 19 to41 years oldDecrease in FVC, FEV1, VT, and SRaw and increase in fBwithO3exposure compared with FA; total cell count and LDHincreased in isolated left main bronchus lavage and inflammatorycell influx occurred with O3exposure compared to FA exposure.Aris et al.(1993)0.2 392 4 h IE(4 × 50 min)V.E= 25 L/min/m2BSA20 °C50% RH42 M, 24 F Adults NS,18 to 50 yearsoldFEV1decreased by 18.6%; Pre-exposure methacholineresponsiveness was weakly correlated with the functional responseto O3exposure. Symptoms were also weakly correlated with theFEV1response (r = -0.31 to!0.37)Aris et al.(1995)0.00.2404704 h IE(4 × 15 min).VE= 20 L/min24 °C40% RH10 M9 MHealthy NS,60 to 69 yearsCOPD59 to 71 yearsHealthy: small, 3.3%, decline in FEV1(p = 0.03 [not reported inpaper], paired-t on O3versus FA pre-post FEV1). COPD: 8%decline in FEV1(p = ns, O3versus FA). Adjusted for exercise,ozone effects did not differ significantly between COPD patientsand healthy subjects.See Section AX6.5.1.Gong et al.(1997a)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)0118157781181576.6 hIE (6 × 50min)V.E= 20 L/min/m2BSA25 °C40-60% RH15 M, 15 F Healthy NSMales23.5 ± 3.0 yrsFemales22.8 ± 1.2 yrsFEV1and symptom responses after 6.6 h exposure to 0.04 and0.06 ppm not significantly differentfrom FA. Following exposureto 0.08 ppm, O3-induced FEV1(!6.1%, square-wave;!7.0%,triangular) and symptom responses significantly greater than after0.04 and 0.06 ppm exposures. Triangular exposure to 0.08 ppmcaused peak decrement in FEV1at 5.6 h of exposure, whereas peakfor square-wave exposure occurred at 6.6 h.Adams (2006)0.00.040.080.120781572356.6 hIE (6 × 50min)V.E= 20 L/min/m2BSA23 °C50% RH15 M, 15 F Healthy NS,22.4 ± 2.4 yrsoldFEV1and total symptoms after 6.6 h exposure to 0.04 ppm notsignificantly different from FA. FEV1(!6.4%) and total symptomssignificant at 6.6 h exposure to 0.08 ppm. FEV1(!15.4%) at 6.6 hnot significantly different between chamber and face maskexposure to 0.12 ppm.Adams (2002)



### AX6-11Table AX6-2 (cont'd). Pulmonary Function Effects after Prolonged Exposures to OzoneaOzone ConcentrationbExposureDurationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.12 235 3 day-6.6h/dayIE (6 × 50 min)V.E= 17 L/min/m2,20 L/min/m2BSA, and 23L/min/m2BSA23 °C50% RH15 M, 15 F Healthy NS, 18to 31 years oldFEV1at 6.6 h decreased significantly by 9.3%, 11.7%, and 13.9%,respectively at three different exercise V.Erates, but were notsignificantly different from each other. Total symptoms at thehighest V.Eprotocol were significantly greater than for the lowestV.Eprotocol beginningat 4.6 h. Largest subjects (2.2 m2BSA)had significantly greater average FEV1decrement for the threeprotocols, 18.5% compared to the smallest subjects (1.4 m2BSA), 6.5%.Adams(2000b)(a) 0.08(b) 0.08(mean) variedfrom 0.03 to0.15235235(mean)6.6 hIE (6 × 50 min)V.E= 20 L/min/m2BSA23 °C50% RH15 M15 FHealthy NS,18 to 25 yearsold(a) FEV1decreased 6.2% after 6.6 h in square-wave exposures.Total symptoms significantly increased at 5.6 and 6.6 h.(b) FEV1decreased 5.6 to 6.2% after 4.6 to 6.6 h, respectively,in varied exposure; total symptoms significantly increased alsoafter 4.6 to 6.6 h. No significant difference between face maskand chamber exposures.Adams(2003a)(a) 0.08(b) 0.301575886.6 hIE (6 × 50 min)V.E= 20 L/min/m2BSA2 hIE (4 × 15 min)V.E= 35 L/min/m2BSA23 °C50% RH15 M15 FHealthy NS,18 to 25 yearsoldSignificantly greater FEV1decrement (12.4%) for 2-h, 0.30 ppmexposure than for 6.6-h, 0.08 ppm exposure (3.6%).Adams(2003b)(a) 0.12(b) 0.12(mean) variedfrom 0.07 to0.16(c) 0.12(mean) variedfrom 0.11 to0.13(d) 0.12235235(mean)235(mean)2356.6 h IE(6 × 50 min)(a,b,c) V.E= 20L/min/m2BSA(d) V.E= 12L/min/m2BSA23 °C50% RH6 M, 6 F Healthy NS,19 to 25 yearsold(a) FEV1decreased 11% at 6.6 h in square-wave exposure.Total symptoms significant from 4.6 to 6.6 h.(b) FEV1decreased 13% at 6.6 h; notsignificantly different fromsquare-wave exposure. Total symptoms significant from 4.6 to6.6 h.(c) FEV1decreased 10.3% at 6.6 h;not significantly different fromsquare-wave exposure. Total symptoms significant from 4.6 to6.6 h.(d) FEV1decreased 3.6% at 6.6 h; significantly less than for20 L/min/m2BSA protocols.Adams andOllison (1997)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.



### AX6-121 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 O 3 

### 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 O 3 

### concentrations of 0.08 ppm and higher. As with studies conducted at higher O 3 

### 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 O 3 

### 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 ( 

## 0 V 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, FEV 1 

### , and FEV 25-75 

### with duration of O 3 

### exposure. Correcting for FA responses, decrements of 8.2, 14.9, and 26.8% in FVC, FEV 1 

### , and FEV 25-75 

### occurred as a result

of the O 3 

### exposure. Using the same 6.6 h protocol, but a lower O 3 

### 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, FEV 1 

### , and FEV 25-75 

### , respectively, in 60 young adults (25 ± 5 years old). Horvath et al. (1991) observed a 4% (p = 0.03) 1 

### decrement in FEV 1 

### using the forementioned protocol (i.e., 6.6 h and 0.08 ppm O 3 

### ) 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 FEV 1 

### Response to 6.6 h Ozone Exposure
It is well known that response to O 3 

### exposure is a function of 

## 0 V 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 O 3 

### exposure is also function of 

## 0 V E 

### , although quantitative analyses are lacking.
In an attempt to quantify this effect, Adams and Ollison (1997) exposed 12 young adults
to an average O 3 

### concentration of 0.12 ppm for 6.6 h at varied exercise 

## 0 V E 

### . They observed a

mean FEV 1 

### decrements of 10 to 11% in two protocols having a mean exercise 

## 0 V E 

### of 33 L/min

### AX6-14 and a 14% decrement in a protocol with a mean exercise 

## 0 V E 

### of 36 L/min. These FEV 1 

### decrements were significantly greater than the average decrement of 3.6% (not significantly
different from FA response) observed at an exercise 

## 0 V E 

### of only 20 L/min. In a subsequent study

of 30 healthy adults (Adams, 2000b), the effect of smaller exercise 

## 0 V E 

### differences on pulmonary
function and symptoms responses to 6.6 h exposure to 0.12 ppm O 3 

### was examined. FEV 1 

### decrements of 9.3, 11.7, and 13.9% were observed for the exercise 

## 0 V E 

### of 30.2, 35.5, and

40.8 L/min, respectively. Along with the tendency for FEV 1 

### responses to increase with 

## 0 V E 

### , total

symptoms severity was found to be significantly greater at the end of the highest 

## 0 V E 

### protocol

relative to the lowest 

## 0 V E 

### protocol. Although the FEV 1 

### responses were not significantly different

from each other, the power of the study to detect differences between the three 

## 0 V 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 

## 0 V E 

### of 30 L/min.
Existing data for exposure to 0.12 ppm O 3 

### suggest that FEV 1 

### responses increase with increasing

exercise 

## 0 V E 

### until at least 35 L/min.

AX6.2.3.2 Exercise Ventilation Rate as a Function of Body/Lung Size on FEV 1 

### Response to 6.6 h Ozone Exposure Typically, with the assumption that the total inhaled O 3 

### dose should be proportional to the
lung size of each individual, exercise 

## 0 V 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 O 3 

### concentration, 

## 0 V E 

### , duration
of exposure, age, and body and lung size on FEV 1 

### response. They concluded that any effect of BSA, height, or baseline FVC on percent decrement in FEV 1 

### 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 O 3 

### for 1 h with CE ( 

## 0 V E 

### = 47 L/min). There was no significant difference between the

### AX6-15 Figure AX6-2. Average FEV 1 

### decrements (±SE) for prolonged 6.6 h exposures to 0.12 ppm O 3 

### as a function of exercise 

## 0 V E 

### . Since age affects response to O 3 

### exposure, selected studies had subjects with mean ages between 22 and 25 years. FEV 1 

### decrements were calculated as mean O 3 

### responses minus mean air responses. The SE bars illustrate variability in FEV 1 

### responses (pre minus post) on the O 3 

### exposure day in all cases except for Folinsbee et al. (1994), where post O 3 

### exposure variability is illustrated. In one case, the SE for 

## 0 V E 

### of 33 L/Min (10.3% decrement) was taken as the SE of data from protocol with 

## 0 V E 

### of 33 L/min (11% decrement). All studies used a constant 0.12 ppm O 3 

### exposure except two ( 

## % ) which used 0.115 ppm O 3 

### for hours 1-2 and 5-6 and 0.13 ppm O 3 

### for hours 3-4 of exposure.

group FEV 1 

### 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 O 3 

### with CE ( 

## 0 V E 

### . 

### 70 L/min) and found lung

size was not related to FEV 1 

### response. Adams (2000b) studied a group of 30 young adult men and women exposed to 0.12 ppm O 3 

### for 6.6 h on three occasions while exercising 50 min of each hour at one of three

different 

## 0 V E 

### levels (viz., 17, 20, and 23 1/min/m 2 

### BSA). Their postexposure FEV 1 

### responses were regressed as a function of BSA (which was directly related to the absolute amount of 

## 0 V E

### AX6-16 during exercise and, thus, primarily responsible for individual differences in total inhaled O 3 

### dose). The slope was significantly different fr om zero (p = 0.01), meaning that the smallest
subjects, who had the lowest exercise 

## 0 V E 

### ( . 

### 26 L/min), had a lower FEV 1 

### decrement (

! 

### 5%)

than the largest subjects (

! 

### 17%), whose exercise 

## 0 V E 

### was . 

### 44 L/min. This relationship was not
a gender-based difference, as the mean female’s FEV 1 

### 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 O 3 

### concentration and exposure duration used, responses are more
closely related to 

## 0 V E 

### than 

## 0 V 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 FEV 1 

### response in 2 h IE exposures. These authors state that the absence of an observed relationship between FEV 1 

### 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 O 3 

### dosimetry study of Bush et al. (1996) indicated that

normalization of the O 3 

### 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 O 3 

### concentration (Horstman et al., 1990) and higher 

## 0 V E 

### (Adams, 2000b) each elicit greater FEV 1 

### response in prolonged, 6.6-h exposures, but data on the

relative effect of O 3 

### concentration, 

## 0 V 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 FEV 1 

### response for a 2-h IE exposure to 0.30 ppm O 3 

### was

! 

### 12.4%, while that for a 6.6-h exposure to 0.08 ppm O 3 

### was

! 

### 3.5%. The total inhaled O 3 

### dose
(as the simple product of C × T × 

## 0 V E 

### ) was 1358 ppm

A 

### L for the 2-h exposure and 946 ppm

A 

### L for
the 6.6-h exposure. Thus, the FEV 1 

### decrement was 3.5 times greater and the total inhaled O 3 

### 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 O 3 

### 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 O 3 

### concentration (0.08 ppm) and the 2-h IE exposure at a relatively high O 3 

### 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 O 3 

### exposure reproducibility was first examined via a regression plot of the postexposure FEV 1 

### response to the 6.6-h chamber exposure as a function of postexposure FEV 1 

### response to the 2-h chamber exposure. The R 2 

### of 0.40, although statistically significant, was substantially less than that observed in a comparison

of individual FEV 1 

### response to two 2-h IE exposures by chamber and face mask, respectively (R 2 

### = 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

FEV 1 

### 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 O 3 

### 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 FEV 1 

### responses found in 6.6 h chamber and face mask exposures to 0.08 ppm O 3 

### , compared to an R of 0.91 observed for responses found for the 2 h chamber and face mask exposures to 0.30 ppm O 3 

### .



## AX6.2.4 Triangular Ozone Exposures
To further explore the factors that determine responsiveness to O 3 

### , Hazucha et al. (1992) designed a protocol to examine the effect of varying, rather than constant, O 3 

### concentrations. In this study, subjects were exposed to a constant level of 0.12 ppm O 3 

### for 8 h and to an O 3 

### 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 ( 

## 0 V E 

### . 

### 40 L/min) during the first 30 minutes of each hour. The total

inhaled O 3 

### dose (i.e., C × T × 

## 0 V E 

### ) for the constant versus the triangular concentration profile was

almost identical. FEV 1 

### responses are illustrated in Figure AX6-3. With exposure to the constant 0.12 ppm O 3 

### , FEV 1 

### 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 (FEV 1 

### ) 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; FEV 1 

### was measured at the end of the intervenin g rest period. Standard error of the mean for these FEV 1 

### 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 O 3 

### concentration profile after a minimal initial response over the first 3 h, Hazucha et al. (1992) observed a substantial change in FEV 1 

### corresponding to the higher average O 3 

### concentration that reached a maximum decrement of 10.3% at 6 h. Despite 2 h of continued exposure to a lower O 3 

### concentration (0.12 to 0.00 ppm, mean = 0.06 ppm), FEV 1 

### improved and was only reduced by 6.3% (relative to the preexposure FEV 1 

### ) at the end of the 8-h exposure.

The authors concluded that total inhaled O 3 

### dose (C × 

## 0 V E 

### × T) was not a sufficient index of O 3 

### exposure and that, as observed by others (Adams et al., 1981; Folinsbee et al., 1978; Hazucha, 1987; Larsen et al., 1991), O 3 

### 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 O 3 

### 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 FEV 1 

### responses of the last 4 hours (Figure AX6-3) follow a pattern similar to the total mean O 3 

### concentration over the same time period. It has become apparent that laboratory simulations of air-pollution risk-assessment need to employ O 3 

### 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 O 3 

### exposures or the one 8-h study by Hazucha et al. (1992) that utilized a triangular shaped varied O 3 

### exposure described above closely resembles the variable diurnal daylight O 3 

### concentration pattern observed in many urban areas experiencing air-pollution episodes (Lefohn and Foley, 1993). Recently, 6.6 h less abrupt triangular O 3 

### 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, Adam s and Ollison (1997) observed no significant differences in postexposure pulmonary function responses or symptoms between the 6.6-h, 0.12 ppm O 3 

### square-wave exposure and those observed for a triangular O 3 

### 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 FEV 1 

### 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 O 3 

### square-wave profile or for the triangular O 3 

### 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 FEV 1 

### and symptoms were not significantly different from the responses for the square-wave 0.08 ppm O 3 

### exposure. However, analysis showed that FEV 1 

### response for the square-wave protocol did not become statistically significant until the 6.6-h postexposure value, while that for the triangular exposure pr otocol was significant at 4.6 h (when O 3 

### concentration was 0.15 ppm). Earlier significant FEV 1 

### 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 O 3 

### concentration was 0.065 ppm. Symptoms for the square-wave 0.08 ppm exposure did not become statistically significant until 5.6 h.

The FEV 1 

### 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 O 3 

### 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 O 3 

### 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 FEV 1 

### 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 O 3 

### concentration was highest (0.14 ppm), with a very similar response at 7 h when total

mean O 3 

### 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 FEV 1 

### and symptoms during filtered air (0.0 ppm) and 0.04 ppm O 3 

### exposure were essentially the same. Similarly, there was no significant

difference in FEV 1 

### 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 O 3 

### concentration of 0.08 ppm) did not differ significan tly from those observed in the square-wave
exposure, FEV 1 

### and symptoms were significantly different from preexposure at 4.6 h (when the

O 3 

### 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 FEV 1 

### between the square-wave and triangular concentration profiles at the 0.08 ppm O 3 

### level. At the lower 0.06 ppm O 3 

### concentration, however, no temporal pattern differences in FEV 1 

### responses could be discerned between the square-wave and triangular exposure profiles. The author concluded that the results support previous evidence that O 3 

### concentration has a greater singular effect in

the total inhaled O 3 

### dose than do 

## 0 V E 

### and exposure duration.
Adams (2006) observed that at O 3 

### concentrations of 0.06 ppm and below differences in prolonged exposure profiles do not induce sta tistically different hourly responses.

### AX6-21 Decrements in FEV 1 

### during square-wave O 3 

### exposures between 0.08 to 0.12 ppm tend to increase with time of exposure (i.e., with steadily increasing total inhaled dose), whereas FEV 1 

### decrements during triangular exposures (Hazucha et al., 1992; Adams, 2003a) occurred 1 to 2 h after the peak O 3 

### concentration and 1 h to 2 h before the maximal total O 3 

### inhaled dose occurred at the end of exposure. This difference, especially because O 3 

### concentration profiles during summer daylight air-pollution episodes rarely mimic a square-wave, implies that triangular O 3 

### 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 FEV 1 

### responses than the square wave exposures at the overall equivalent ozone dose.



## AX6.2.5 Mechanisms of Pulmonary Function Responses

Inhalation of O 3 

### 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, O 3 

### 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 pe riods with considerable overlap of evolving and receding effects. Exposure to O 3 

### initiates reflex responses manifested as a decline in spirometric lung function parameters ( 9 

### FVC, 9 

### FEV 1 

### , 9 

### FEF 25-75 

### ), bronchoconstriction ( 8 

### SRaw) and altered breathing pattern ( 9 

### V T 

### , 8 

### f B 

### ), 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 O 3 

### (Hazucha et al., 1992; Adams, 2003a). Exposure to a uniform O 3 

### 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 O 3 

### 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 O 3 

### with IE, Nightingale et al. (2000) observed a 13.5% decrement in FEV 1 

### . By 3 h postexposure, however, only a 2.7% FEV 1 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### -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 V T 

### /T i 

### (T i 

### decreased more

than V T 

### ) was attributed to an increased inspiratory drive due to stimulation of rapidly adapting receptors and bronchial C-fibers by O 3 

### (Schelegle et al., 1993). Folinsbee and Hazucha (2000) also observed similar changes in V T 

### /T i 

### and other breath-timing parameters in humans exposed

to O 3 

### implying activation of the same mechanisms. They also reported that Pm 0.1 

### (pressure at Figure AX6-4a,b. Recovery of spirometric responses following a 2 h exposure to 0.4 ppm O 3 

### with IE. Immediately postexposure, there were significant decrements (**p < 0.001, ***p < 0.0005) in FVC (10%) and FEV 1 

### (13.5%) compared to preexposure values. At 3 h postexposure, FVC and FEV 1 

### 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 c ontrolled hypercapnia without a change in the slope

of Pm 0.1 

### versus pCO 2 

### relation suggesting that the primary mechanism is an increased inspiratory drive. Since no significant within-individual differences in ventilatory response to CO 2 

### between air exposure and O 3 

### exposure were found, the CO 2 

### chemoreceptors did not modulate the response. Therefore, the principal peripheral mechanism modulating changes in breathing pattern appears to be direct and indirect stim ulation of lung receptors and bronchial C-fibers by O 3 

### 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 O 3 

### has not yet been studied in humans. Laboratory animal studies have shown that the larynx, pharynx, and nasal mu cosa are densely populated by free-ending, unmyelinated sensory afferents resembling nocicep tive C-fibers (Spit et al., 1993; Sekizawa and Tsubone, 1994). They are almost certainly stimulated by O 3 

### and likely contribute to overall ventilatory and symptomatic responses. Nasal only exposure of rats produced O 3 

### -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, O 3 

### inhalation by humans will also induce a variety of symptoms, re duce vital capacity (VC) and related functional measures, and increase airway resistance. Hazucha et al. (1989) postulated that a reduction of VC by O 3 

### 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 O 3 

### is indeed reflex in origin and not a result of subjective discomfort and consequent premature voluntary termination of in spiration. They reported that inhalation of an aerosolized topical anesthetic tetracaine substantially reduced if not abolished O 3 

### -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 ne ural 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 hypothe sized 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 O 3 

### -induced inhibition of maximal inspiration. If this were so, pain suppressi on 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 O 3 

### and classified either as “weak” (FEV 1 

### $ 

### 95% of preexposure value), “strong” (FEV 1 

### # 

### 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) O 3 

### -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 O 3 

### , with 15 min IE at 17.5 l/min/m 2 

### 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 a gonist 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 FEV 1 

### observed in “weak” responders. However, as hypothesized, sufentanil rapidly reversed both the O 3 

### -induced symptomatic effects and spirometric decrements (FEV 1 

### ; p < 0.0001) in “strong” responders (Figure AX6-5). All the same, the reversal was not complete and the average post-sufentanil

FEV 1 

### 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’ O 3 

### responsiveness. These observations have demonstrated that nociceptive mechanisms play a key role in modulating O 3 

### -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 FEV 1 

### (% 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 O 3 

### -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-O 3 

### 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 O 3 

### -induced lung function decrements in humans, did not prevent induction of AHR when administered to guinea pigs prior to O 3 

### exposure (Yeadon et al., 1992). Neither does post-O 3 

### 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-O 3 

### 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 O 3 

### -induced airway sensitization involves changes in smooth muscle excitation-contraction coupling (Marthan, 1996). Characteristic O 3 

### -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; Yea don 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, O 3 

### -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 O 3 

### 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 O 3 

### 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 O 3 

### -induced pulmonary response in great detail.

Neurogenic airway inflammation Stimulation of bronchial C-fibers by O 3 

### 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) a nd 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 s ecretion (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 O 3 

### -induced leukotriene (LTC 4 

### /D 4 

### /E 4 

### ) production and spirometric decrements (Hazucha et al., 1996), and an increased level of postexposure PGE 2 

### , a mediator known to stimulate bronchial C-fibers, show that these mediators play an important role in attenuation of lung function due to O 3 

### 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-O 3 

### dysfunction of small airways assessed by decrement

in FEF 25-75 

### (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, O 3 

### -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 resolv ing airway inflammation. Bronchial biopsies performed 6 h postexposure have shown that O 3 

### caused a significant decrease in immunoreactivity to substance P in the submucosa (Krishna et al., 1997a). A strong negative

correlation with FEV 1 

### also suggests that the release of substance P may be a contributing mechanism to persistent post-O 3 

### 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 O 3 

### exposure on pulmonary function in subjects with preexisting disease by reviewing O 3 

### 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 O 3 

### , 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 O 3 

### exposure are discussed in Section AX6.8.



## AX6.3.1 Subjects with Chronic Obst ructive Pulmonary Disease

Five studies of O 3 

### -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 studi es) or at rest (1 study) for 1 to 2 hours to O 3 

### concentrations between 0.1 and 0.3 ppm. None of theses studies found significant O 3 

### -induced changes in pulmonary function. Of the four studies examining arterial oxygen saturation, two reported small but statistically significant O 3 

### -induced decreases in the COPD patients. These limited data suggest COPD patients experience minimal O 3 

### -induced effects for 0.3 ppm O 3Table AX6-3. Ozone Exposure in Subjects with Preexisting DiseaseaOzoneConcentrationbExposure Durationand ActivityExposureConditionNumber andGender of Subjects Subject Characteristics Observed Effect(s) Referenceppm μg/m3Subjects with Chronic Obstructive Pulmonary or Heart Disease0.00.2404724 h IE15 min exercise15 min restV.E.20 L/min24 °C40% RH9 M10 MCOPD patientsAge-matched healthy NSAll subjects 59-71 years oldNo significant changes in FEV1, FVC, or SRaw due toozone in COPD patients. Equivocal SaO2decrementduring 2ndand 3rdhours of ozone exposure in COPDpatients. Adjusted for exercise, ozone effects did notdiffer significantly betweenCOPD patients and healthysubjects.Gong et al.(1997a)Gong andTierney (1995)0.3 589 3 h IEV.E.30 L/min22 °C50% RH10 M6 MHypertension42-61 years oldHealthy41-49 years oldO3-induced FEV1decrements of 6.7 and 7.6% in healthyand hypertensive subjects, respectively. SignificantO3-induced reductions in alveolar-arterial oxygen tensionin both groups. No significant changes in cardiacenzymes or ECG telemetry.Gong et al.(1998)Subjects with Allergic Rhinitis0.00.203921 h CEat V.E= 25 L/min/m2BSA20 °C50% RH13 M, 1 F Dust mite sensitized asthmaticsmean age 29 ± 5 yearsFEV1decrement following O3of 10% not significantlydifferent from the 4% decrement following FA. Subjectsreceived dust mite antigen challenge at 0.5 h FA and O3postexposures and were lavaged 6 h post-challenge.Amount of allergen producing 15% FEV1decrement wasdecreased by O3compared to FA in 9 of 14 subjects.PMN in proximal airway lavage tended to be greater afterO3than FA (p = 0.06).Chen et al.(2004)0.1250.2500.1252454902453h IE(10 min rest, 15 minexercise on bicycle)V.E= 30 L/min3h IE × 4 days27 °C50 % RH5 F, 6 M6 F, 16 MMild bronchial asthma20-53 years oldAllergic rhinitis19-48 years oldMean early-phase FEV1response and number of$20%reductions in FEV1were significantly greater after0.25 ppm O3or 4 × 0.125 ppm O3. Most of the$15%late-phase FEV1responses occurred after 4 days ofexposure to 0.125 ppm O3, as well as significantinflammatory effects, as indicated by increased sputumeosinophils (asthma and allergic rhinitis) and increasedsputum lymphocytes, mast cell tryptase, histamine, andLDH (asthma only).Holz et al.(2002)0.00.2504903 h IE,V.E= 30 L/min15 min ex/10 minrest/5 min no O3;every 30 min.27/C54% RHmouthpieceexposure13 M, 11 F6 M, 6 F5 M, 5 FAtopic mild asthmaPositive allergen and IgE testsHealthy NSO3-induced FEV1decrements of 12.5, 14.1, and 10.2%in asthmatics, allergic rhinitics and healthy subjects,respectively (group differences not significant).Methacholine responsivenessincreased in asthmatics.Allergen responsiveness: increased significantly after O3exposure in asthmatics (.2 dose shift) and a smaller shiftis rhinitics. No change inhealthy. Neither allergen ormethacholine response correlated with lung function andwere not correlated with each.Jörres et al.(1996)



### AX6-30Table AX6-3 (cont’d). Ozone Exposure in Subjects with Preexisting DiseaseaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of Subjects Subject Characteristics Observed Effect(s) Referenceppm μg/m3Subjects with Asthma0.4 784 2h IE(15 min rest, 15 min exerciseon bicycle)V.E= 30 L/minNA 4 F, 5 M7 F, 6 MHealthy(25 ± 2 years old)Mild atopic asthma;beta agonists only(22 ± 0.7 years old)Significant reductions in FVC (12%, 10%) andFEV1(13%, 11%) for asthmatic and healthysubjects, respectively; attenuated by indomethacinin healthy subjects only. Significant reductions inmid-flows which tended to be greater in asthmaticsthan healthy subjects. Indomethacin treatmentattenuated mid-flow-reductions somewhat morein asthmatics than healthy subjects.Alexis et al.(2000)0.00.407842h IE4 × 15 min on bicycle,V.E= 40 L/minNA 159Healthy adults18-40 years oldMild atopic asthmatics18-40 years oldSputum collected 24 h before and 4-6 h post-O3exposure. Baseline CD11b expression positivelycorrelated with O3-induced PMN. Increasedexpression of mCD14 on macrophages followingO3compared to FA. Asthmatic PMN responsesimilar to healthy subjects (also see Table AX6-3).No spirometric data available.Alexis et al.(2004)0.12 236 Rest 22/C40% RH10 M, 5 F atopic asthma No effect of O3on airway response to grassallergen.Ball et al.(1996)0.00.203926 h30 min rest/30 min exerciseV.E.25 L/min22 °C50% RH5 M5 MHealthy NSAsthmatics, physiciandiagnosed,All 18-45 yearsSimilar spirometric responses in asthmatic andhealthy. However, preexposure FEV1 and FVCwere both ~0.4 L lower on O3-day than FA day.More PMN’s in asthmatics. IL-8 and IL-6 higherin asthmatics exposed to O3. No relationship ofspirometry and symptoms to inflammation.Basha et al.(1994)0.4 784 3h 6x15 min cycle ergometerV.E.32L/min5 consecutive days31/C35% RH8 M , 2 F Asthmatic NS adultsbeta-agonist use only19-48 years oldATS criteria for asthmaFEV1decreased 35% on first exposure day.Methacholine reactivity increased about ten-fold.Also see Table AX6-7 for repeated exposure results.Gong et al.(1997b)0.00.1202351 h restair-antigenO3-antigenNA 9 M, 6 F Mild allergic asthma; 18 to49 years of age.No effect of O3on airway response to grass orragweed allergen.Hananiaet al. (1998)0.4 784 2 h IE15 min exercise15 min restV.E.20L/minHead maskexposure.18/C60% RH5 M, 1 F6 MHealthy adultsAtopic asthmaticsFEV1responses of healthy and asthmatic similar(.15% decrease). Maximal FEV1response tomethacholine increased similarly in both groups(12 h postexposure). Larger increase in PC20inhealthy subjects. Both groups had increasedPMN’s in sputum no correlation of PMN’sand lung function.Hiltermannet al. (1995)



### AX6-31Table AX6-3 (cont’d). Ozone Exposure in Subjects with Preexisting DiseaseaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Adult Subjects with Asthma (cont’d)0.00.150.250.2502944904903 h IE15 min rest(V.E= 7 L/min)15 min on bicycle(V.E= 26 L/min)27 ± 1 °C56 ± 7 % RH10M, 11F5M, 10FHealthy NS28 ± 5 years oldMild Asthmatic30 ± 8 years oldNo significant O3-induced group differences in symptoms orspirometry. After 0.25 ppm O3, there were significantdecrements in FEV1and FVC that tended to be greater in theasthmatics than controls. Small but significant neutrophilincrease in asthmatics following 0.15 ppm O3. Significantneutrophil increases following 0.25 ppm O3that did not differbetween groups.Holz et al.(1999)0.00.1603147.6 h25 min treadmill,25 min cycle/10 min restper hour.V.E= 27-32 L/min18 °C40% RH13 M7 M, 10 FHealthy NS,age 19-32 years.Moderate Asthmatics,physician diagnosed,beta agonist users,age 19-32 years.FEV1decreased 19% in asthmatics and only 10% innonasthmatics. High responders had worse baseline airwaystatus. More wheeze in asthmatics after O3.Horstmanet al. (1995)0.00.2504903 h IE,V.E= 30 L/min15 min ex/10 min rest/5min no O3; every 30 min27 °C54% RHmouthpieceexposure13 M, 11 F6 M, 6 F5 M, 5 FAtopic mild asthmaPositive allergen andIgE testsHealthy NSO3-induced FEV1decrements of 12.5, 14.1, and 10.2% inasthmatics, allergic rhinitics and healthy subjects, respectively(group differences not significant). Methacholineresponsiveness increased in asthmatics. Allergen responsivenessincreased after O3exposure in asthmatics (=2 dose shift),a smaller shift occurred in rhinitics, no change occurred inhealthy subjects. Neither allergen nor methacholine responseswere correlated with each other or with lung function.Jörres et al.(1996)0.16 314 7.6 h25 min treadmill, 25 mincycle/10 min rest perhour.V.E= 25 L/min22 °C40 % RH4 M, 5 F Mild atopic asthma;no meds 12 hpre-exposure20-35 years oldSignificant FEV1decrease of 9.1 % following O3exposure;marked individual variability with responses ranging from 2% to 26 %.Kehrl et al.(1999)0.250.40490784V.E= 25-45 L/min NA 8 M, 4 F8 M, 10 F22 M, 16 FAsthmaticsAllergic rhiniticsHealthy adultsAll <26 years oldHealthy 12.2% decrease in FEV1, Rhinitics 10.1%,asthmatics 12.4%Magnussenet al. (1994)0.00.203922 h IE4 × 15 minat V.E= 20L/min/m2BSA20 °C50% RH6 M, 9 F9 M, 6 FHealthy adults24 years oldMild asthmatics29 years oldO3-induced FEV1decrement (8%, healthy adults; 3% asthmatics)and PMN increase (20.6%, healthy adults; 15.2% asthmatics).Primary goal was to investigate relationship between antioxidantdefenses and O3responses in asthmatics and healthy adults(see Tables AX6-3 andAX6 -13).Mudwayet al. (2001)Stenforset al. (2002)



### AX6-32Table AX6-3 (cont’d). Ozone Exposure in Subjects with Preexisting DiseaseaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Adult Subjects with Asthma (cont'd)0.2 396 2h IE(15 min rest, 15 minexercise on bicycle)V.E= 20 L/min/m2BSA22 °C40 % RH5 F, 4 M Mild atopic asthma; nomeds 8 h pre-exposure21-42 years oldSignificant decrease in FEV1and a trend toward decreasesin mean inspiratory flow, FEF25, and FEF75after O3exposure. No significant differences in FEF50, FVC, TLC,Raw, or sRaw. No correlation between sputum neutrophilsat 6 h postexposure and FEV1immediately after exposure.Newson et al.(2000)0.4 784 2 h rest 21 °C40% RH11 M , 11 F Asthmatics sensitiveto D Farinae,physician diagnosed,18 to 35 yearsOzone resulted in nasal inflammation (increased PMN’s)and caused augmented response tonasal allergen challenge.Peden et al.(1995)0.16 314 7.6 h25 min treadmill,25 min cycle/ everyhour.18 °C40% RH8 M Mild asthmatics,physician diagnosed,reactive to dust miteD. Farinae.Increased eosinophils and PMN’s after O3exposure morein initial (bronchial) fraction.No correlation of eosinophilsand PMN’s, FEV1& FVC decreased 14% and 9%respectively.Peden et al.(1997)0.00.203924h50 min exercise,10 min rest each hour.V.E.45-50 L/min21 °C50% RH12 M, 6 F 18 adult mildasthmatics mostlybeta agonist users.FVC, FEV1decreased 17.6% and 25% respectively.Trend for larger increase inSRaw in asthmatics. Largerincrease in PMN’s and protein in asthmatics indicatingmore inflammation. No increase in eosinophils.Spirometry changes in asthmatics similar to healthysubjects (Aris et al., 1995; Balmes et al., 1997).Scannell et al.(1996)aSee Appendix A for abbreviations and acronyms.bGrouped by rest and exercise; within groups listed from lowest to highest O3concentration.



### AX6-33

### AX6-34 exposures less than 2 hours in duration. These findings are also consistent decreasing O 3 

### 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 FEV 1 

### following both clean air (

! 

### 11%, p = 0.06) and O 3 

### (

! 

### 19%, p < 0.01) exposures.

These FEV 1 

### decrements, presumably due to exercise, were primarily attributable to four of the patients who lost greater than 14% of their FEV 1 

### following both the air and O 3 

### exposures. Relative to clean air, O 3 

### caused a statistically insignificant FEV 1 

### decrement of

! 

### 8% in COPD patients which was not statistically different from the decrement of

! 

### 3% in healthy subjects. Ozone-induced symptoms, sRaw, S

a 

### O 2 

### , 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 O 3 

### 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 O 3 

### . Exposure of adult asthmatics to 0.25 ppm O 3 

### for 2 h at rest also caused no significant responses. Preexposure to between 0.10 and 0.25 ppm O 3 

### 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 O 3 

### with heavy IE for 2 h), Kreit et al. (1989) and Eschenb acher et al. (1989) demonstrated significantly
greater FEV 1 

### and FEF 25-75 

### decrements in asthmatics than in healthy controls. With longer duration exposures to lower O 3 

### levels (0.12 ppm with moderate IE for 6.5 h), asthmatics have also shown a tendency for greater FEV 1 

### 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 O 3 

### -induced responses. Studies of less than 3 h duration have reported similar or tendencies for increased

O 3 

### -induced spirometric responses up to O 3 

### concentrations of 0.4 ppm. Similar group decrements

in FEV 1 

### and FVC were reported by Hiltermann et al. (1995), who exposed 6 asthmatics and 6 healthy subjects to 0.4 ppm O 3 

### 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 O 3 

### with IE ( 

## 0 V E 

### = 30 L/min). Similar

O 3 

### -induced group decrements in FEV 1 

### and FVC were also reported by these investigators. A tendency, however, for an increased O 3 

### -induced reduction in mid-flows (viz., FEF 25 

### , FEF 50 

### , FEF 60p 

### , FEF 75 

### ) 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 O 3 

### for 3 h with IE. Statistically significant O 3 

### -induced decreases in FEV 1 

### 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 O 3 

### for 3-h with light IE. After the 0.25 ppm O 3 

### exposure, there were significant decrements in FEV 1 

### and FVC that tended to be slightly greater in the asthmatics than controls. One study reported that asthmatics tended to have less of an FEV 1 

### response to O 3 

### 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 O 3 

### concentrations of 0.2 ppm or less, also suggest a tendency for increased O 3 

### -induced pulmonary function responses in asthmatics relative to healthy subjects. Scannell et al. (1996) exposed 18 asthmatics to 0.2 ppm O 3 

### for 4 h with
IE ( 

## 0 V E 

### . 

### 25 L/min/m 2 

### BSA). Baseline and hourly pulmonary function measurements of FEV 1 

### , 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 O 3 

### -induced increase in sRaw, FEV 1 

### and FVC. The O 3 

### -induced increase in sRaw tended to be greater in asthmatics than the healthy subjects, whereas similar group decrements in FEV 1 

### 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 O 3 

### for 6 h with IE. However, the mean preexposure FEV 1 

### in the asthmatics was about 430 mL less (i.e., ~12% decreased) on the O 3 

### -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 O 3 

### or FA with alternating periods of exercise (50 min, 

## 0 V E 

### . 

### 30 L/min) and rest (10 min). Both groups
had significant O 3 

### -induced decrements in FEV 1 

### , FVC, and FEV 25-75 

### . The asthmatic and healthy subjects had similar O 3 

### -induced reductions in FVC. The FEV 1 

### 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 O 3 

### -induced decrease in FEF 25-75 

### in asthmatics relative to the healthy subjects (24% versus 15%, respectively). With repeated O 3 

### exposures asthmatics, like healthy subjects ( see Section AX6.6 ) develop tolerance. Gong et al. (1997b) exposed 10 asthmatics to 0.4 ppm O 3 

### , 3 h per day with
IE ( 

## 0 V E 

### . 

### 32 L/min), for 5 consecutive days. Symptom and spirometric responses were greatest
on the first (

! 

### 35 % FEV 1 

### ) and second (

! 

### 34 % FEV 1 

### ) exposure days, and progressively diminished toward baseline levels (

! 

### 6 % FEV 1 

### ) by the fifth exposure day. Similar to healthy subjects, asthmatics lose their tolerance to O 3 

### after 4 to 7 days without O 3 

### 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 O 3 

### exposure ( see Section AX6.9 ). For instance, Scannell et al. (1996) performed lavages at 18 h post-O 3 

### 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 ne utrophils 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 O 3 

### exposure in subjects with allergic asthma for up to 24 h ( see Section AX6.8 ). One of the difficulties in comparing O 3 

### -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 FEV 1 

### ), 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 andTable AX6-4. Classification of Asthma Severity1Lung Function2Medications3Classification StepDays withsymptomsNights withsymptomsFEV1 or PEF% predictedoralPEFvariability(%) Daily Quick reliefSeverepersistent4 Continual Frequent#60 >30 High-dose inhaled steroids (ICS)and long-acting inhaled$2-agonistIf needed, add oral steroidsShort-acting inhaled$2-agonist, as needed; oralsteroids may be requiredModeratepersistent3 Daily >1/week between60 and 80>30 Low-to-medium-dose ICS andlong-acting$2-agonist (preferred)OrMedium-dose ICS (another preferredoption for children ages <5 years)OrLow-to-medium-dose ICS and eitherleukotriene modifier or theophyllineShort-acting inhaled$2-agonist, as needed;oral steroids may berequiredMildpersistent2 >2/week,but <1time/day>2/week$80 20-30 Low-dose inhaled steroids (preferred)OrCromolyn leukotriene modifier,or (except for children aged <5 years)nedocromil or sustained releasetheophylline to serum concentrationof 5-15 μg/mLShort-acting inhaled$2-agonist, as needed;oral steroids may berequiredMildintermittent1#2/week <2/month$80 <20 No daily medicine needed Short-acting inhaled$2-agonist, as needed;oral steroids may berequired1Sources: 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 atdifferent levels of severity. The preferred treatments, dosage, and type of medicationrecommended vary for adults and children and are detailed in theEPR-Update 2002stepwise approach to therapy.The stepwise approach emphasizes thattherapy should be stepped up as necessary and stepped down when possible to identify the least amount of medication requiredto achieve goals of therapy.The stepwise approach to care is intended to assist, not replace, the clinical decision-making required to meet individual patient needs.



### 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 O 3 

### -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 O 3 

### or to FA during mild
IE ( 

## 0 V E 

### = 30 L/m). The number and severity of O 3 

### -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 O 3 

### -induced reductions in FVC and FEV 1 

### . 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 O 3 

### -induced reductions in FVC and FEV 1 

### . As assessed by the magnitude of reductions in mid-flows (viz. FEF 25 

### , FEF 50 

### , FEF 60p 

### , FEF 75 

### ), 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 O 3 

### , which is consistent with the observed increases in inflammation and airway responsiveness. Indomethacin pretreatment attenuated some of

these O 3 

### -induced small airways effects (FEF 50 

### in healthy subjects, FEF 60p 

### in asthmatics).



## AX6.3.3 Subjects with Allergic Rhinitis

Most O 3 

### 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 O 3 

### . 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 O 3 

### . The allergic rhinitics were no more responsive to O 3 

### 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 O 3 

### with a relative order of airway responsiveness to O 3 

### being normal < allergic < asthmatic. Bascom et al. (1990) studied the upper respiratory response to acute O 3 

### inhalation, nasal challenge with antigen, and the combination of O 3 

### plus antigen in subjects with allergic rhinitis. Exposure to O 3 

### 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 O 3 

### exposure in atopic asthmatics. Peden et al. (1995), who studied allergic asthmatics exposed to O 3, 

### found

that O 3 

### 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 O 3 

### exposure. In a follow-up study, Michelson et al. (1999) reported that 0.4 ppm O 3 

### 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 O 3 

### 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 O 3 

### 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 FEV 1 

### 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 O 3 

### exposure when compared to FA exposure. In subjects with asthma and allergic rhinitis, a maximum percent fall in FEV 1 

### of 27.9 % and 7.8%, respectively,

### AX6-40 occurred 3 days after O 3 

### 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 O 3 

### 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 O 3 

### (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 FEV 1 

### ) 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 O 3 

### 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 in creased airway allergen responsiveness with O 3 

### . [ 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 O 3 

### while they were exercising continuously according to a protocol simulating their angina-symptom-limited exercise training
prescription (mean 

## 0 V E 

### = 35 L/min). No significant pulmonary function impairment or evidence
of cardiovascular strain induced by O 3 

### 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 O 3 

### 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 S

a 

### O 2 

### . 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, FEV 1 

### ) and symptoms of breathing discomfort were measured before and after the

O 3 

### exposures. There were significant O 3 

### -induced FEV 1 

### 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 O 3 

### in either the hypertensive or normal subjects. However, statistically significant O 3 

### effects for both groups combined were increases in HR, rate-pressure product, and the alveolar-to-arterial PO 2 

### 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 O 3 

### 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 O 3 

### exposures. Bates et al. (1972) noted that variation between individuals in sensitivity and response was evident in respiratory symptoms and pulmonary function following O 3 

### exposure. A large degree of intersubject variability in response to O 3 

### 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 FEV 1 

### responses increases with O 3 

### concentration. Similarly, McDonnell et al. (1983) observed FEV 1 

### decrements ranging from 3 to 48% (mean 18%) in 29 young adult males exposed to 0.40 ppm O 3 

### for 2 h during heavy IE. At a lower O 3 

### concentration of 0.18 ppm, 20 similarly exposed subjects had FEV 1 

### 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 FEV 1 

### 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 O 3 

### concentrations (0.0, 0.08, 0.10, and 0.12 ppm) are illustrated in Figure AX6-6. It is apparent that the FEV 1 

### responses in FA are small with most tightly grouped around zero. With increasing O 3 

### concentration, the mean response increases as does the variability about the mean. At higher O 3 

### concentrations, the distribution of response becomes asymmetric with a few individuals experiencing large FEV 1 

### 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 FEV 1 

### decrement in excess of 10%; however, 26%, 31%, and 46% exceeded a 10% decrement at 0.08, 0.10, and 0.12 ppm, respectively. FEV 1 

### 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 O 3 

### , Adams (2002) found that 6 of 30 subjects (20%) had >10%

decrements in FEV 1 

### . The response distributions in Figure AX6-6 underlines the wide range of response to O 3 

### under prolonged exposure conditions and reinforces the observations by others consequent to 2 h IE exposures at higher O 3 

### concentrations (Horvath et al.,1981; McDonnell et al., 1983).

Figure AX6-6. Frequency distributions of FEV 1 

### decrements following 6.6-h exposures to O 3 

### or filtered air. During each hour of the exposures, subjects were engaged in moderate exercise for 50 minutes. With increasing O 3 

### concentration, the distribution of responses becomes asymmetric, with a few individuals exhibiting large FEV 1 

### decrements. The percentage in each panel indicates the portion of subjects having a FEV 1 

### decrement in excess of 10%.

Source: McDonnell (1996).

### AX6-43 Some of the intersubject variability in response to O 3 

### inhalation may be due to intrasubject variability, i.e., how reproducible the measured responses are in an individual between several

O 3 

### 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 O 3 

### 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 O 3 

### 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 FEV 1 

### (R = 0.91). However, at the lowest concentration, 0.12 ppm, relatively
poor FEV 1 

### reproducibility was observed (R = 0.58) due, in part, to a lack of specific O 3 

### response or a uniformly small response in the majority of subjects. McDonnell et al. (1985a) concluded

that for 2 h IE O 3 

### exposures equal to or greater than 0.18 ppm, the intersubject differences in magnitude of change in FVC and FEV 1 

### are quite reproducible over time and likely due to differences in intrinsic responsiveness of indi vidual 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 O 3 

### . Reproducibility of FEV 1 

### 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 a nd health risks associated with acute O 3 

### exposures are complicated by a poor association between various O 3 

### -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 O 3 

### 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 O 3 

### concentrations at one of three activity levels, McDonnell et al. (1999) observed significant, but low, Spearman rank order correlations between FEV 1 

### 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 O 3 

### -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 O 3 

### 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 FEV 1 

### (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 f B 

### (R =

! 

### 0.20) and V T 

### (R =

! 

### 0.03) were not statistically significant. The effect of this large intersubject variability on the ability to predict individual responsiveness to O 3 

### 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 O 3 

### 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 FEV 1 

### response. Only age contributed significantly to intersubject responsiveness (younger subjects were more responsive), accounting for just 4% of the observed variance. Interestingly, O 3 

### concentration accounted for only 31% of the variance, strongly suggesting the importance of as yet undefined

individual characteristics that determine FEV 1 

### responsiveness to O 3 

### . A more general form of this model was developed to investigate the O 3 

### exposure FEV 1 

### 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 O 3 

### 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 FEV 1 

### response was more sensitive to changes in C than to changes in 

## 0 V 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, 

## 0 V E 

### , T, and age was 41%, with no evidence

that the sensitivity of FEV 1 

### response to 

## 0 V 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 FEV 1 

### response to O 3 

### remains unexplained.2 Personal communication from authors, correction to Table 2 in Gong et al. (1997a), the %FEV 1 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 laborator y studies that have examined the acute effects

of O 3 

### 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 O 3 

### 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 a dults (Linn et al., 1986; Avol et al., 1984) have shown comparable spirometric function response when exposed to low O 3 

### dose under similar conditions. Among adults, however, it has been repeatedly demonstrated that older individuals respond to O 3 

### inhalation with less intense lung function changes than younger adults. Thus, children, adolescents, and young adults appear to be about equally responsive to O 3 

### , but more responsive than middle-aged and older adults when exposed to a comparable dose of O 3 

### (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 O 3 

### while intermittently exercising every 15 min at a light load (~20 L/min) for 4 h. Healthy subjects showed a small but significant O 3 

### -induced FEV 1 

### decrement of 3.3% (p = 0.03 [not reported in paper] paired-t on O 3 

### versus FA pre-post FEV 1 

### ) 2 

### . Small but statistically nonsignificant changes were also observed for respiratory symptoms, airway resistance and arterial O 2 

### saturation. In the COPD patients, there was an 8% FEV 1 

### decrement due to O 3 

### exposure which was not significantly different from the response in the healthy subjects. The authors have concluded that typical ambient concentrations of O 3 

### are unlikely to induce “a clinically significant acute lung dysfunction” in exposed older men. However, they also acknowledged that the “worst

case” scenario of O 3 

### exposure used in their study causes acute spirometric responses.Table AX6-5. Age Differences in Pulmonary Function Responses to OzoneaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.400.427848232 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 °C40% RHtreadmill146 M94 FHealthy NS18 to 60 years oldYoung individuals of both gender (<35 years)significantly more responsive than oldersubjects. Strong responses are less commonover the age of 35 years, especially in women.The variability of an individual’s responsivenessto repeated exposures to O3decreases with age.Hazucha et al.(2003)0.00.4007842 h, IE (15' ex/15' rest).VE.18 L/min/m2BSA2 exposures: 25% of subj.exposed to air-air,75% exposed to O3-O321 °C40% RHtreadmill28 M34 FHealthy NS18 to 57 years oldHealthy NS18 to 59 years oldSignificant decrements in spirometric lungfunction in all groups. Young males and females(<35 years) were significantly more responsivethan older individuals (>35 years).Passannanteet al. (1998)0.00.2404704 h, IE (15' ex/15' rest).VE= 20 L/min24 °C40% RH10 M9 MHealthy NS60 to 69 years oldCOPD59 to 71 years oldHealthy: small, 3.3%, decline in FEV1(p = 0.03 [notreported in paper], paired-t on O3versus FA pre-postFEV1). COPD: 8% decline in FEV1(p = ns, O3versusFA). Adjusted for exercise, ozone effects did not differsignificantly between COPD patients and healthysubjects.Gong et al.(1997a)0.00.120.180.240.300.4002353534715897842 h rest or IE(4 × 15 minat V.E= 25 or 35L/min/m2BSA)22 °C40% RH485 WM (eachsubjectexposed at oneactivity levelto one O3concentration)Healthy NS18 to 36 years oldmean age 24 yearsStatistical analysis of 8 experimental chamberstudies conducted between 1980 and 1993 by theU.S. EPA in Chapel Hill, NC. O3-induceddecrement in FEV1predicted to decrease withage. FEV1response of a 30 year old predicted tobe 50% the response of a 20 year old.Also seeTable 6-1McDonnellet al. (1997)0.00.120.180.240.300.4002353534715897842.33 h IE(4 × 15 minat V.E= 25L/min/m2BSA)22 °C40% RH371 (WM,BM, WF, BF;~25% pergroup) eachsubjectexposed to oneO3concentrationHealthy NS18 to 35 years oldmean age 24 yearsStatistical analysis of experimental datacollected between 1983 and 1990 by the U.S.EPA in Chapel Hill, NC. O3-induced decrementin FEV1predicted to decrease with age. FEV1response of a 30 year old predicted to be 65%the response of a 20 year old. No effect ofmenstrual cycle phase on FEV1response.Inconsistent effect ofsocial economic status onFEV1response.Seal et al.(1996)



### AX6-46Table AX6-5 (cont’d). Age Differences in Pulmonary Function Responses to OzoneaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.180.240.300.403534705887842.33 hIE.VE= 20 L/min/m2BSANA 48 WF, 55 BF Healthy NS,18 to 35 years old,black and whiteOlder women had smaller changes in FEV1thanyounger women. No age- related differences inSRaw or cough score.Seal et al.(1993)0.45 882 1 h, CE.VE.26 L/min2 h, IE.VE.26 L/min.23 °C58% RHcycle/treadmill7 M5 FHealthy NS,60 to 79 years old(all in 60s exceptone 79 years old)Comparison of 1-h CE protocol and 2-h IEprotocol indicated no difference between thechanges in pulmonary function following thetwo protocols.DrechslerParks et al.(1990)0.45 882 2 h, IE (20' ex/20' rest)Male:.VE= 28.5 L/minFemale:.VE= 26.1 L/min23 °C46% RHcycle/treadmill10 M,6 FHealthy NS,60 to 89 years oldMean decrement in FEV1= 5.7%; eight subjectshad a 5% or greater difference between theirresponse to O3and FA, and the other eight hadless than a 5% difference between theirresponses to FA and 0.45 ppm O3.Bedi et al.(1989)0.45 882 2 h, IE (20' ex/20' rest).VE.26 L/min.24 °C63% RHcycle8 M8 FHealthy NS,51 to 69 years oldHealthy NS,56 to 76 years old13 subjects had decrements in FEV1on threeseparate exposures to 0.45 ppm within 5% oftheir mean response to the three exposures. Theother three subjects were not reproducible.Symptom reports did not correlate well withpulmonary function changes.Bedi et al.(1988)0.12 235 1 h IE (mouthpiece).VE= 4 to 5 × resting22 °C75% RHtreadmill5 M, 7 F Healthy NS,12 to 17 years oldNo significant changes in any pulmonaryfunction in healthy subjects.Koenig et al.(1988)0.200.303925881 h (mouthpiece)50' rest/10' ex for first 7males, 20' rest/10' ex forremaining subjectsMale:.VE.29 L/minFemale:.VE.23 L/min.22 °C$75% RHtreadmill9 M, 10 F Healthy NS,55 to 74 years oldNo spirometic changes for either group.Females had 13% increase in RTat 3 and22 min after 0.30-ppm exposure.Reisenaueret al. (1988)0.113c+otherambientpollutants221 1 h CE (bicycle).VE.22 L/min32.7 °C.43% RHcycle33 M, 33 F NS for both groups,mean age =9.4 years oldNo differences in responses of boys and girls.Similar decrements (<5% on average)following both purified air and ambient air (O3at 0.11 ppm) exposures.Avol et al.(1987)



### AX6-47Table AX6-5 (cont’d). Age Differences in Pulmonary Function Responses to OzoneaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.45 882 2 h, IE (20' ex/20' rest).VE.26 L/min.23 °C53% RHcycle8 M,8 FHealthy NS,51 to 76 years oldMean decrement in FEV1= 5.6 ± 13%; range ofdecrements = 0 to 12%.DrechslerParks et al.(1987a,b)0.120.1823535340 min (mouthpiece)IE, 10 min exercise at.VE= 32.6 L/min40 min (mouthpiece)IE, 10 min exercise at.VE= 41.3 L/minNAtreadmill3 M, 7 F4 M, 6 FHealthy NS,14 to 19 years oldNo significant change in FEV1; increased RTwith exposure to 0.18 ppm O3. Some subjectsresponded to 5 to 10 mg/mL methacholine after0.18-ppm O3exposure, whereas none respondedto 25 mg/mL methacholine at baselinebronchochallenge.Koenig et al.(1987)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.cOzone concentration is the mean ofa range of ambient concentrations.



### AX6-48

### AX6-49 Although Gong et al. (1997a) and others (see Table AX6-5) have examined responses to O 3 

### 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 FEV 1 

### responses to O 3 

### as a function of age. Seal et al. (1996) analyzed O 3 

### -induced spirometric responses in 371 young nonsmokers (18 to 35 years of age). The subject populati on 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 

## 0 V E 

### of 25 L/min/m 2 

### BSA. A logistic
function was used to model and test the significance of age, socioeconomic status (SES), and menstrual cycle phase as predictors of FEV 1 

### response to O 3 

### 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. FEV 1 

### responses decreased with subject age. On average, regardless of the O 3 

### 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, 

## 0 V E 

### = 25 L/min/m 2 

### BSA) a 5.4% decrement

in FEV 1 

### 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 FEV 1 

### responses immediately
postexposure in individuals exposed for 2.3 h during IE at a 

## 0 V E 

### of 25 L/min/m 2 

### BSA.
McDonnell et al. (1997) examined FEV 1 

### responses in 485 healthy white males (18 to 36 years of age) exposed once for 2 h to an O 3 

### 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 ( 

## 0 V E 

### of 25 and 35 L/min/m 2 

### BSA). FEV 1 

### was measured preexposure, after 1 h of exposure, and immediately postexposure. Decrements

in FEV 1 

### were modeled by sigmoid-shaped curve as a function of subject age, O 3 

### concentration,



## 0 V E 

### , and duration of exposure. Regardless of the O 3 

### 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 FEV 1 

### responses in while males exposed to O 3 

### for 2 h or less under IE conditions. Hazucha et al. (2003) analyzed the distribution of O 3 

### responsiveness in subjects (146 M, 94 F) between 18 and 60 years of age. Subjects were exposed to 0.42 ppm O 3 

### for 1.5 h with IE

### AX6-50 Figure AX6-7. Effect of O 3 

### exposure (0.42 ppm for 1.5 h with IE) on FEV 1 

### 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, FEV 1 

### 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 

## 0 V E 

### = 20 L/min/m 2 

### BSA. Figure AX6-7 illustrates FEV 1 

### responses to O 3 

### 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% FEV 1 

### decrement), 39% were moderate responders, and 43% were strong responders ( $ 

### 15% FEV 1 

### 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 FEV 1 

### 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 FEV 1 

### 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 FEV 1 

### responses immediately postexposure in individuals exposed to 0.42 ppm O 3 

### for 1.5 h during IE at a 

## 0 V E 

### of

20 L/min/m 2 

### BSA.

### AX6-51The pathophysiologic mechanisms behind the pronounced age-dependent, genderdifferential rate of loss of O 3 

### responsiveness are unclear. Passannante et al. (1998) have previously demonstrated that O 3 

### -induced spirometric decrements (FEV 1 

### ) 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 a nd indirect (possibly by PGE 2 " 

### ) 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 O 3 

### 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 O 3 

### 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 O 3 

### . With progressing age, the sensitivity

to O 3 

### declines and at an older age (>60 yrs) appears to be minimal except for some very responsive individuals. Endpoints other than FEV 1 

### 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 O 3 

### were inconsistent. Some studies have concluded that females might be more sensitive to O 3 

### 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-bas ed differences in lung function following O 3 

### exposure were completed (Table AX6-6). Protocols included mouthpiece and chamber exposures, young and old individuals, normalizati on of ventilation to BSA or FVC, continuous and intermittent exercise, control for menstrual cycle phase, and the use of equivalent effective

dose of O 3 

### during exposures. These studies have generally reported no statistically significant differences in pulmonary function between male s and females (Adams et al., 1987; Drechsler-Table AX6-6. Gender and Hormonal Differences in Pulmonary Function Responses to OzoneaOzoneConcentrationbExposure Durationand ActivityExposureConditionscNumber and Genderof SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.25490 1 h CEV.E= 30 L/minNAFace maskexposure32 M, 28 F Healthy NS22.6 ± 0.6 years oldMean O3-induced FEV1decrements of 15.9%in males and 9.4% in females (genderdifferences not significant). FEV1decrementsranged from!4 to 56%; decrements >15% in20 subjects and >40% in 4 subjects. Uptakeof O3greater in males than females, butuptake not correlated with spirometricresponses.Ultman et al.(2004)0.400.427848232 h, IE (15' ex/15' rest)V.E= 33-45 L/min1.5 h IE (20' ex/10' rest)V.E= 33-45 L/min22 °C40% RHtreadmill146 M94 FHealthy NS,18 to 60 years oldNo significant gender differences in FEV1among young (<35 years) and olderindividuals. Strong responses are lesscommon over the age of 35 years, especiallyin women.Hazuchaet al. (2003)0.00.3506861.25 h, IE(30' ex/15' rest/30' ex)V.E= 40 L/min22 °C40% RHtreadmill19 F O3responders22.1 ± 2.7 years oldFVC and FIVC changes about the same,!13%, FEV1!20%. Increased airwayresponsiveness to methacholine. Persistenceof small effects on both inspired and expiredspirometry past 18 h. Chemoreceptors notactivated but ventilatory drive wasaccelerated.Folinsbeeand Hazucha(2000)0.00.407842 h, IE (15' ex/15' rest)V.E.18 L/min/m2BSA2 exposures: 25% ofsubj. exposed to air-air,75% exposed to O3-O321 °C40% RHtreadmill28 M34 FHealthy NS, 20-59 years old Significant decrements in spirometric lungfunction. No significant differences in FEV1between young females and males and olderfemales and males either in responders ornonresponders subgroups.Passannanteet al. (1998)00.120.240.300.4002354705887842.33 h IE (15' ex/15' rest)V.E= 20 L/min/m2BSAone exposure per subject22 °C40% RHtreadmill48 WF, 55 BF Healthy NS,18 to 35 years oldSignificant menstrual cycle phase × raceinteraction for FEV1. No significantmenstrual cycle phase effect when blacks andwhites were analyzed separately.No significant menstrual phase effects forSRaw or cough score.Seal et al.(1996)



### AX6-52Table AX6-6 (cont’d). Gender and Hormonal Differences in Pulmonary Function Responses to OzoneaOzoneConcentrationbExposure Durationand ActivityExposureConditionscNumber and Genderof SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.3506862.15 h, IE(30' ex/30' rest)19-24 °C48-55% RHtreadmill12 M12 FHealthy NS,5 F follicular and 7 lutealphase exposure,regular menstrual cycles, 18to 35 years oldChanges in FVC, FEV1, FEF25-75,.Vmax50%, and.Vmax25%were similar during both the follicularand luteal phases. No significant differencebetween males and females.Weinmannet al. (1995)0.3 588 1 h CEV.E.50 L/minNA 9 F Healthy NS, regularmenstrual cycles,20 to 34 years oldFEV1decreased 13.1% during the mid-lutealphase and 18.1% during the follicular phase.Decrement in FEF25-75was significantly largerduring the follicular phase than the mid-lutealphase. Changes inFVC were similar inboth phases.Fox et al.(1993)00.120.180.240.300.4002353534705887842.33 h (15' ex/15' rest)V.E= 25 L/min/m2BSA(one exposure/subject)22 °C40% RHtreadmill30 to 33 F and 30 to33 M in eachconcentration group;total of372 individualsparticipatedHealthy NS, 18 to 35 yearsold, blacks and whitesDecrements in FEV1, increases in SRaw andcough, correlated with O3concentration.There were no significant differences betweenthe responses of males and females.Seal et al.(1993)00.180.3003535881 h (mouthpiece), CEV.E.47 L/minexposures$4 days apart21 to 25 °C45 to 60% RHcycle14 F14 FFVC = 5.11 ± 0.53 L,NS, 20 to 24 years oldFVC = 3.74 ± 0.30 L,NS, 19 to 23 years oldSmall lung group, FVC = 3.74 ± 0.30 L.Large lung group, FVC = 5.11 ± 0.53 L.Significant concentration-response effect onFVC and FEV1; lung size had no effect onpercentage decrements in FVC or FEV1.Messineoand Adams(1990)0.00.4508822 h, IE (20' ex/20' rest)V.E= 28.5 L/min for MV.E= 26.1 L/min for Frepeated O3exposures23.1 °C46.1% RHcycle/treadmill10 M6 FHealthy NS,60 to 89 years oldHealthy NS,64 to 71 years oldMean decrement in FEV1= 5.7%.Decrements in FVC and FEV1were the onlypulmonary functions significantly altered byO3exposure. No significant differencesbetween responses of men and women.Bedi et al.(1989)00.200.3003925881 h (mouthpiece) IE(50' rest/10' ex first 7 M)(20' rest/10' ex all others).VE.28 L/min for M.VE.23 L/min for F.22 °C$75% RHtreadmill9 M, 10 F Healthy NS,55 to 74 years oldNo change in any spirometic measure foreither group. Females had 13% increase in RTafter 0.30-ppm exposure. Gender differencesnot evaluated.Reisenaueret al. (1988)



### AX6-53Table AX6-6 (cont’d). Gender and Hormonal Differences in Pulmonary Function Responses to OzoneaOzoneConcentrationbExposure Durationand ActivityExposureConditionscNumber and Genderof SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.3 588 1 h (mouthpiece), CEV.E.70 L/min for menV.E.50 L/min forwomen21 to 25 °C45 to 60% RHcycle20 M20 FNS, 18 to 30 years oldNS, 19 to 25 years oldSignificant decrements in FVC, FEV1, andFEF25-75following O3exposure.No significant differences between men andwomen for spirometry or SRaw.Adams et al.(1987)0.00.4508822 h, IE (20' rest/ 20' ex)V.E.27.9 L/min for MV.E.25.4 L/min for Frepeated O3exposures24 °C58% RHcycle8 M8 FHealthy NS,51 to 69 years oldHealthy NS,56 to 76 years oldRange of responses in FEV1:0 to!12% (mean =!5.6%).No significant difference in responses of menand women.Tendency for women to have greater effects.DrechslerParks et al.(1987a,b)0.48 941 2 h, IEV.E.25 L/min21 °C(WBGT)cycle10 F Healthy NS,19 to 36 years oldMean decrement in FEV1= 22.4%.Significant decrements in all spirometricmeasurements. Results not significantlydifferent from a similar study on males(Drechsler-Parks et al., 1984).Horvathet al. (1986)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.cWBGT = 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 O 3 

### dose was calculated and normalized, the findings of at least three studies may be interpreted as showing that females are more sensitive

to O 3 

### than males. The findings of the seven studies are presented in detail in Section 7.2.1.3 of the previous O 3 

### criteria document (U.S. Environmental Protection Agency, 1996). Some support for a possible increased sensitivity of females to O 3 

### comes from a study of uric acid concentration in nasal lavage fluid (N LF). 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 O 3 

### 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 O 3 

### distribution and absorption, may influence O 3 

### sensitivity and potentially differential O 3 

### response. The study of Messinio and Adams (1990) have, however, convinci ngly demonstrated that the effective dose to the lung, and not the lung size, determines the magnitude of (FEV 1 

### ) response. Furthermore,

the O 3 

### dosimetry experiments of Bush et al. (1996) have shown that despite gender differences in longitudinal distribution of O 3 

### , 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### sensitivity status only minimal and not significant (Passannante et al., 1998). In another investigation, Folinsbee and Hazucha (2000) exposed a group of

19 O 3 

### -responsive young females (average age of 22 years, prescreened for O 3 

### responsiveness by earlier exposure) to air and 0.35 ppm O 3 

### . The randomized 75-min exposures included two 30-min exercise periods at a . V E 

### 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 O 3 

### effects. The average lung function decline from a pre-exposure value was 13%
for FVC, 19.9 % for FEV 1 

### , and 30% for FEF 25-75 

### . 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 w ith neurally mediated inhibition of inspiration. Persistence of small inspiratory and expiratory sp irometric effects, airway resistance, and airway responsiveness to methacholine for up to 18 h postexposure suggests that recovery of pulmonary

function after O 3 

### 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 CO 2 

### between air and O 3 

### exposures, suggesting that chemoreceptors were not affected by O 3 

### . However, O 3 

### 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 O 3 

### -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 O 3 

### 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 O 3 

### -responsive, however, the average post-O 3 

### decline in expiratory lung function from preexposure (13% for
FVC; 19.9% for FEV 1 

### ; 30% for FEF 25-75 

### ) 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 O 3 

### 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 O 3 

### 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 FEV 1 

### 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-O 3 

### exposure decline in FEV 1 

### for males, but only a 1.3% decline for females. These observations suggest that young females lose O 3 

### 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 % FEV 1 

### 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 FEV 1 

### . Two earlier studies of the effects of the menstrual cycle phase on O 3 

### responsiveness have reported conflicting results (U.S. Environmental Protection Agency, 1996). Weinmann et al. (1995) found no significant lung function effects re lated 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 O 3 

### responsiveness. In a more recent investigation of possible modulatory effects of hormonal changes during menstrual cycle on O 3 

### response, young women (n = 150) 18 to 35 years old were exposed once to one of multiple O 3 

### concentrations (0.0, 0.12, 0.18, 0.24, 0.30, 0.40 ppm) for 140 min with IE at 35 L/min/m 2 

### BSA. The women’s menstrual cycle phase was determined immediately prior to O 3 

### exposure. Post-O 3 

### , no significant differences in % predicted FEV 1 

### 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 O 3 

### 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 O 3 

### exposure. Additional studies presented in this section clarify an open-ended conclusion reached in the previous O 3 

### criteria document (U.S. Environmental Protection Agency, 1996) regarding the influence of age on O 3 

### responsiveness. Healthy young males and females are about equally responsive to O 3 

### , 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 O 3 

### than younger individuals.Within this range, males appear to be slightly more responsive than females, but the rate of agerelated loss in FEV 1 

### is about the same. The O 3 

### sensitivity may vary during the menstrual cycle; however, this variability appears to be minimal.



## AX6.5.3 Racial, Ethnic, and So cioeconomic Status Factors
In the only laboratory study designed to compare spirometric responses of whites and blacks exposed to a range of O 3 

### concentrations (0 to 0.4 ppm), Seal et al. (1993) reported inconsistent and statistically insignificant FEV 1 

### 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 O 3 

### 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 PM 10 

### - and O 3 

### -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 O 3 

### 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 O 3 

### for 140 min

### AX6-59 with 15 min IE at 35 L/min/m 2 

### 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 FEV 1 

### (4-5% @ 0.4 ppm O 3 

### ) than low and high SES groups. The authors did not ha ve an “immediately clear” explanation for this finding. The SES to %predicted FEV 1 

### 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 O 3 

### sensitivity.



## AX6.5.4 Influence of Physical Activity
Apart from the importance of increased minute ventilation on the inhaled dose of O 3 

### during increased physical activity, including work, recrea tional exercise, and more structured exercise like sports, no systematic effort has been made to study other potential physical factors that may

modulate O 3 

### 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 br eathing is through the nose. The nose not only humidifies air, among other physiologic functions, but also absorbs O 3 

### 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 O 3 

### (Kabel et al., 1994). Moreover, increasing inspiratory flow and tidal volume shifts the longitudinal

distribution of O 3 

### 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 O 3 

### 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 O 3 

### uptakes were 10% (upper airways), 65% (conducting airways), and
25% (small airways). These observations imply that equal O 3 

### dose (C × T × 

## 0 V E 

### ) will have a
greater effect on pulmonary function and infla mmatory 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 O 3 

### uptake. ( See Chapter 4 of this document for more information on the dosimetry of O 3 

### .) Other physiologic factors activated in response to physical activity are unlikely to have as much impact on O 3 

### responsiveness as does minute ventilation; however, their potential influence has not been investigated.



## AX6.5.5 Environmental Factors

Since the 1996 O 3 

### 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 admixt ures such as endotoxin on healthy individual’s pulmonary function changes due to O 3 

### (U.S. Environmental Protection Agency, 1996). Some of the unresolved issues, e.g., health effects of ETS and O 3 

### 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 O 3 

### -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 O 3 

### (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 alr eady have chronic airway inflammation do not seems to show exaggerated response with exposure to O 3 

### . 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 O 3 

### .

### 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 O 3 

### 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, FEV 1 

### 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 O 3 

### 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-O 3 

### 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 O 3 

### 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 O 3 

### exposure. This was demonstrated by the Torres et al. (1997) study that involved exposures of about equal si ze cohorts of otherwise healthy young smokers,

nonsmoker O 3 

### nonresponders (<5% FEV 1 

### post-O 3 

### decrement) and nonsmoker O 3 

### responders (>15% FEV 1 

### post-O 3 

### decrement) to air and two 0.22 ppm O 3 

### atmospheres for 4 hours, alternating 20 min of moderate exercise (25 L/min/m 2 

### BSA) with 10 min of rest. Both O 3 

### 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 O 3 

### responsiveness nor smoking alters the magnitude or the time course of O 3 

### -induced airway inflammation. The overall cell recovery was lower immediately postexposure but higher, particularly in nonsmokers, 18 h post-O 3 

### exposure when compared to control (air) in all groups. Recovery of lymphocytes, PMNs and AMs in both alveolar a nd bronchial lavage fluid showed the largest increase in response to O 3 

### in all groups, with nonsmokers showing greater relative increases thanTable AX6-7. Influence of Ethnic, Environmental, and Other FactorsOzoneConcentrationExposureDurationand ActivityExposureConditionsNumberand Genderof SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.407802 hIE, 15' ex/15' restV.E= 20 L/min/m2BSA20 °C40% RH15 M, 1 F13 M, 2 FPlacebo group:healthy NSavg age 27 yrs.Antiox. Suppl.Gr.: Healthy NSavg age 27 yrs.PF decrements in the supplementationgroup were signif. smaller for FVC(p < 0.046) and near significant for FEV1(p < 0.055). The inflammatory response(BAL) showed no significant differencesbetween the two groups either in therecovery of cellular components or theconcentrations and types of inflammatorycytokines.Samet et al.(2001)0.00.1202350.75 hIE, 15' ex/15' restV.E= 40-46 L/min60% RH 5 M, 12 F Asthmaticssensitive to SO219 to 38 yrs oldNo significant differences due to O3between placebo and antioxidantsupplement cohort in eitherspirometric responses or bronchialhyperresponsiveness to 0.1 ppm SO2.Trenga et al.(2001)0.00.220.2204314314 hIE, 20' ex/10' restV.E= 40-46 L/min21 °C37% RH25 (M/F) Healthy NSO3responders andnonresponders18 to 40 yrs oldGlutathione peroxidase (GPx) activity andeGPx protein level were significantly(p = 0.0001) depleted in ELF for at least18 h postexp. In BAL both endpointswere elevated (ns). No associationbetween cell injury, PF, or GPx activity.Avissar et al.(2000)b0.00.12-0.24a0235-470a2.17 hIE, 10' ex/ 10' restV.E= 36-39 L/min22 °C or 30 °C45-55% RH5 M, 4 F Healthy NS24 to 32 yrs oldFEV1decreased (p < 0.5) by ~8% at22 °C and ~6.5% at 30 °C. 19 h postexpdecline of 2.3% still signif. (p < 0.05).SGaw signif. (p < 0.05) declined at 30 °Cbut not at 22 °C. The AHR assessed 19 hpostexp. as PC50sGaw methacholinesignif. (p < 0.05) higher at bothtemperatures.Foster et al.(2000)



### AX6-62Table AX6-7 (cont’d). Influence of Ethnic, Environmental, and Other FactorsOzoneConcentrationExposureDurationand ActivityExposureConditionsNumberand Genderof SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.00.4007802 hIE, 20' ex/ 10' restV.E= mild to mod.6 M, 9 F Healthy NSavg age 31 yrs.Corticosteroid pretreatment had no effectson post-O3decline in PF, PMN response,and sputum cell count under both theplacebo and treatment conditions.Methacholine PC20FEV1was equallydecreased in both cond. 4 h afterexposure. No changes in exhaled NOand CO.Nightingaleet al. (2000)0.00.2204314 hIE20' ex/10' restV.E= 40-46 L/min21 °C37% RH90 M 56 never smokers34 currentsmokers18 to 40 yrs. oldSmokers are less responsive to O3asassessed by spirometric andplethysmographic variables. Neither age,gender, nor methacholine responsivenesswere predictive of O3response.Frampton et al.(1997a,c)b0.00.220.2204314314 hIE, 20' ex/10' restV.E= 25 L/min/m2BSA21 °C37% RH10 M, 2 F10 M, 3 F11 M, 2 FNS, O3nonresp.,avg age 25 yrs.;NS, O3resp.,avg age 25 yrs;smokers avgage 28 yrsNeither O3responsiveness nor smokinghas altered the magnitude and the timecourse of O3-induced airwayinflammation. Inflammation involvedall types of cells accessible by BAL.The recovery profile of these cells overtime was very similar for all groupsshowing highest values 18 hpostexposure.Torres et al.(1997)bFrampton et al.(1997a,c)baRamp 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 differe nces 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### at 22° and 30 °C, 45-55% RH. The order of exposures was randomized. The O 3 

### 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 V T 

### and increased f B 

### as compared to baseline at both temperatures. At the end of exposure FEV 1 

### 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 sm aller 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 PC 50 

### sGaw was significantly (p < 0.05) higher one day following O 3 

### 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 O 3 

### . 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 O 3 

### 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 O 3 

### levels. In contrast, matched control group of cyclists not pretreated with vitamin supplements experienced an almost 2% decline in FVC and FEV 1 

### and >5% reduction in PEF during the same activity period. Adjustment of data for confounders such as PM 10 

### and NO 2 

### did not change the findings. Apparently, substan tially elevated levels of plasma antioxidants may afford some protection against lung f unction 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 O 3 

### and NO 2 

### ( see Table AX6-7 ). As an extension of an earlier study focused on pulmonary function changes (F rampton 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 O 3 

### and NO 2 

### responsiveness. They exposed healthy young nonsmokers (n = 25), O 3 

### -responders, and nonresponders to filtered air and twice to 0.22 ppm O 3 

### for 4 h (IE, 20' ex /10' rest, @ . V E 

### 40 to 46 L/min). In the NO 2 

### part of the study, subjects were exposed to air and twice to NO 2 

### (0.6 and 1.5 ppm) for 3 h, with IE of 10 min of each 30 min @ . V E 

### 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 pos texposure. In contrast, both GPx and eGPx were slightly elevated in bronchoalveolar lavage fluid (BALF). However, neither of the two NO 2

### 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 NO 2 

### 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 O 3 

### exposure. Thus, it is unclear what role antioxidants may have

in modulation of O 3 

### -induced lung function and inflammatory responses. The authors found a negative association between lower baseline eGPx protein concentration in ELF and post-O 3 

### neutrophilia to be an important predictor of O 3 

### -induced inflammation; however, the causal relationship has not been established. The effects of dietary antioxidant supplementation on O 3 

### -induced pulmonary and inflammatory response of young healthy individuals has been investigated by Samet et al. (2001). Under controlled conditions, subjects receive d 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/m 2 

### 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 O 3 

### under otherwise similar conditions as in sham exposures. Serum concentration of antioxidants determined prior to O 3 

### 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 FEV 1 

### (p = 0.055) when compared to the placebo group. There was no significant correlation between individual lung function changes and respective plas ma levels of antioxidants. Individuals in both groups experienced typical post-O 3 

### 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-O 3 

### 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 O 3 

### . 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 ofantioxidant 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. Moreove r, 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 O 3 

### -induced lung function or inflammatory effects has been provided by a study of Blomberg et al. (1999). No asso ciation 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 O 3 

### (0.2 ppm/2 h,

intermittent exercise at 20 L/min/m 2 

### BSA). However, O 3 

### 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 baselin e antioxidant levels on response to a 2-h exposure to 0.2 ppm O 3 

### in 15 asthmatic and 15 healthy subjects. In the BALF of 15 healthy subjects, significant O 3 

### -induced reductions in ascorbate and increases in glutathione disulphide and EC-SOD were observed, whereas, levels were unaffected by O 3 

### exposure in the asthmatics. In both groups, BALF levels of uric acid and " 

### -Tocopherol were unaffected by O 3 

### . Trenga et al. (2001) studied the potential prot ective 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 SO 2 

### for 10 min while exercising on a treadmill and selected for study participation if they experienced a >8% decease

in FEV 1 

### . 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 O 3 

### (15 min IE, 

## 0 V E 

### . 

### 3×
resting rate) via mouthpiece were randomized. Each exposure was followed by two 10-min challenges to 0.10 and 0.25 ppm SO 2 

### 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 (FEV 1 

### , FVC, FEF 25-75 

### , and PEF) were significantly decreased from baseline at subsequent time points following both the FA and O 3 

### exposures. Exposure to O 3 

### caused significant decrements in FEV 1 

### and PEF. The post FA and O 3 

### exposure decrements in lung function were not affected by the treatment regimen (placebo versus vitamin). Bronchial hyperresponsiveness to 0.1 ppm SO 2 

### was also unaffected by treatment regimen. Based on the prescreening SO 2 

### challenge, subjects were ranked by their bronchial responsiveness to SO 2 

### as “less-severe” (8 to 16% FEV 1 

### decrements) and “more-severe” (27 to 44% FEV 1 

### decrements). The authors concluded O 3 

### exposure increases bronchial responsiveness to SO 2 

### 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 studi es (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 a ttenuating 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 FEV 1 

### 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 FEV 1 

### of only 40 mL. The post-ride serum level of Clara cell protein (CC16), a biomarker of airway permeab ility, 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 FEV 1 

### 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). Healt hy young (mean 30.1 yrs) individuals (12 M, 10 F) underwent a single exposure to 0.1 ppm O 3 

### 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, LTB 4 

### ) and oxidative stress (8-isoprostane, H 2 

### O 2 

### ) 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 incr eased by exposure. The DNA adduct 8-hydroxy-2'- deoxyguanosine (8-OHdG), a marker of oxidativ e 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 O 3 

### environment (Otto-Knapp et al., 2003). The influence of functional polymorphism of inflammatory and other genes on O 3 

### 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 O 3 

### 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/m 2 

### 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 O 3 

### responsiveness and asthma risk may be related to the presence of variant Ser allele for NQO1. In a field study of susceptibility to ambient O 3 

### 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 O 3 

### 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 O 3 

### (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 FEF 25-75 

### were related to the previous day 1-h daily max O 3 

### . 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 O 3 

### 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 FEV 1 

### responses to repeated daily exposure for up to 5 days is given in Table AX6-8. The FEV 1 

### responses to repeated O 3 

### 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 O 3 

### 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 inOne Second After Repeated Daily Exposure to OzoneaOzoneConcentrationbExposure Durationand ActivitycNumber and Genderof SubjectsPercent Change in FEV1on ConsecutiveExposure Days Referencesdppm μg/m3FirstSecondThirdFourthFifth0.12 235 6.6 h, IE (40) 17 M!12.79!8.73!2.54!0.6 0.2 Folinsbee et al. (1994)0.20 392 2 h, IE (30) 10 M +1.4 +2.7!1.6 — — Folinsbee et al. (1980)0.20 392 2 h, IE (18 and 30) 8 M, 13 F!3.0!4.5!1.1 — — Gliner et al. (1983)0.20 392 2 h, IE (18 and 30) 9!8.7!10.1!3.2 — — Gliner et al. (1983)0.20 392 1 h, CE (60) 15 M!5.02!7.8 — — — Brookes et al. (1989)0.25 490 1 h, CE (63) 4 M, 2 F!20.2!34.8 — — — Folinsbee and Horvath (1986)5 M, 2 F!18.8 —!22.3 — —0.35 686 2 h, IE (30) 10 M!5.3!5.0!2.2 — — Folinsbee et al. (1980)0.35 686 1 h, CE (60) 8 M!31.0!41.0!33.0!25.0 — Foxcroft and Adams (1986)0.35 686 1 h, CE (60) 10 M!16.1!30.4 — — — Schonfeld et al. (1989)10 M!14.4 —!20.6 — —0.35 686 1 h, CE (60) 15 M!15.9!24.6 — — — Brookes et al. (1989)0.40 784 3 h, IE (4-5 × resting) 13 Mf!9.2!10.8!5.3!0.7!1.0 Kulle et al. (1982)0.40 784 3 h, IE (4-5 × resting) 11 Ff!8.8!12.9!4.1!3.0!1.6 Kulle et al. (1982)0.4 784 2 h, IE (65) 8 M!18.0!29.9!21.1!7.0!4.4 Folinsbee et al. (1998)0.4 784 3 h, IE (32) 8 M, 2 Fh!34.7!31.1!18.5!12.0!6.2 Gong et al. (1997b)0.42 823 2 h, IE (30) 24 M!21.1!26.4!18.0!6.3!2.3 Horvath et al. (1981)0.45 882 2 h, IE (27) 1 M, 5 F!13.3 —!22.8 — — Bedi et al. (1985)0.45 882 2 h, IE (27) 10 M, 6 F!5.8!5.6!1.9 — — Bedi et al. (1989)0.47 921 2 h, IE (3 × resting) 8 M, 2 Fg!11.4!22.9!11.9!4.3 — Linn et al. (1982)0.5 980 2 h, IE (30) 8 M!8.7!16.5!3.5 — — Folinsbee et al. (1980)0.5 980 2.5 h, IE (2 × resting) 6!2.7!4.9!2.4!0.7 — Hackney et al. (1977a)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.cExposure duration and intensity of IE or CE were variable;.VE(number in parentheses) given in liters perminute or as a multiple of resting ventilation.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 O3as evidenced by a decrease in FEV1of more than 20%. These nine subjects are a subset of the total group of21 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 O 3 

### -induced damage for greater than 24 h may be important (Folinsbee et al., 1993). An enhanced Day 2 FEV 1 

### response was less obvious or absent in exposures at lower concentrations or those that caused relatively small group mean O 3 

### -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 O 3 

### . Three reports (Bedi et al., 1985; Folinsbee and Horv ath, 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 O 3 

### , FEV 1 

### responses are markedly diminished or absent. One study (Horvath et al., 1981) suggested that the rapidity of this decline

in FEV 1 

### response was related to the magnitude of the subjects’ initial responses to O 3 

### or their “sensitivity.” A summary of studies examining the effects of repeated exposures to O 3 

### on FEV 1 

### and other pulmonary function, symptoms, and ai rway 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 O 3 

### 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 O 3 

### 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 O 3 

### exposures, symptoms of cough and chest discomfort usually

associated with O 3 

### 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 O 3 

### 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 OzoneaOzoneConcentrationbExposureDuration andActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.25 490 2 h IE, (30 minrest, 30 minexercise),V.E= 39 L/min21.4 °C43.9% RH4 days consecutiveFA exposure; 4 daysconsecutive O3exposure5 M, 3 F Healthy, NS FVC and FEV1decrements were significantlyattenuated on Day 4 of O3exposure compared to day1 of O3exposure. Significant small airway functiondepression accompanied by significant neutrophiliain BALF one day following the end of O3exposure.Frank et al.(2001)0.2 392 4 h IE(4 × 30 minexercise), V.E=14.8 L/min/m2BSA1 day FA, 1 day, O3;4 days consecutiveexposure to O315 M, 8 F Healthy, NS21 to 35 years oldFEV1decrement and symptoms significantlyreduced on Day 4 of O3exposure compared to Day1 of O3exposure. Airway inflammation of mucosapersisted on Day 4 although some inflammatorymarkers in BALF attenuated significantly.Jörres et al.(2000)0.2 392 4 h IE(4 × 30 minexercise), V.E=25 L/min/m2BSA20 °C 50% RH(1 day, O3; 4 daysconsecutive exposureto O39 M, 6 F Healthy, NS23 to 37 years oldSignificant decrease in FVC, FEV1, SRaw, andsymptoms on Day 4 of O3exposure compared to asingle day of O3exposure. Number of PMNs,fibronectin, and IL6 in BALF were significantlydecreased on Day 4 compared to a single day of O3exposure.Christian et al.(1998)0.4 784 3h/day for 5daysIE (15 min rest,15 minexercise)V.E= 32 L/min31 °C35% RH5 consecutive daysplus follow up @ 4 or7 days8 M, 2 F Mild asthmaadultFEV1decreased 35% on day 1 and only 6% on day5. Bronchial reactivity increased after day 1 andremained elevated. Adaptation of asthmatics issimilar to healthy subjects but may be slower andless complete.Gong et al.(1997b)0.12 235 6.6 h50 minexercise/10 minrest, 30 minlunchV.E= 38.8L/min18 °C40% RHfive consecutivedaily exposures17 M Healthy NS FEV1responses were maximal on first day ofexposure (!13%), less on second day (!9%), absentthereafter. Symptoms only the first 2 days.Methacholine airway responsiveness was at leastdoubled on all exposure days, but was highest on thesecond day of O3. Airway responsiveness was stillhigher than air control after 5 days of O3exposure.Trend to lessened response, but it was not achievedafter 5 days.Folinsbee et al.(1994)



### AX6-73Table AX6-9 (cont'd). Pulmonary Function Effects with Repeated Exposures to OzoneaOzoneConcentrationbExposure Durationand Activity Exposure ConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.4 784 2 h IE (15 min rest,15 min exerciseV.E.60 L/min5 days consecutive O3exposure16 M Healthy NS O3-exposure FEV1decrement was greater onday 2, 29.9%, than day 1, 18.0%, thendecreased on day 3, 21.1%, day 4, 7% andday 5, 4.4%Folinsbee et al.(1998)Devlin et al.(1997)0.45 882 2 hIE(3 × 20 minexercise)V.E= 27 L/min23.3 °C63% RHExposed for3 consecutive days,not exposed for 2 days,then exposed to 0.45 ppmagain for 1 day10 M, 6 F Healthy NS60 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, but no singlesymptom increased significantly. FVCdecreased 111 mL and 104 mL on Days 1and 2, respectively. FEV1fell by 171 and164 mL, and FEV3fell by 185 and 172 mL.No significant changes on Days 3 and 4 orwith FA. FEV1changes were!5.8,!5.6,!1.9, and!1.7% on the four O3days.Bedi et al.(1989)0.20/0.200.35/0.200.35/0.35392/392686/392686/6861 hCE at 60 L/min21 to 25 °C40 to 60% RH(three 2-day setsof exposures)15 M Healthy aerobicallytrained NS,FVC = 4.24 to6.98 LConsecutive days of exposure to 0.20 ppmproduced similar FEV1responses on each day(!5.02,!7.80); 0.35/0.20 ppm pair causedincreased response to0.20 ppm on secondday (!8.74); 0.35/0.35 ppm caused muchincreased response on Day 2 (!15.9,!24.6).Symptoms were worse on the secondexposure to 0.35 ppm, but not with secondexposure to 0.20 ppm.Brookes et al.(1989)0.35 686 60 min CEV.E= 60 L/min21 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 oldNo differences between responses toexposures separated by 72 or 120 h.Enhanced FEV1response at 24 h (!16.1% vs.!30.4%). Possible enhanced response at 48 h(!14.4% vs.!20.6%). Similar trendsobserved for breathing pattern and SRaw.Schonfeld et al.(1989)0.45 882 2 h IE(3 × 20 minexercise)V.E= 26 L/min23.3 °C62.5% RH(three exposures witha minimum 1-weekinterval)8 M, 8 F Healthy NS, 61years old for M and65 years old for F(FVC = 4.97 L forM and 3.11 L for F)Spirometric changes were not reproduciblefrom time to time after O3exposureR < 0.50). Repeat exposures to air yieldedconsistent responses.Bedi et al.(1988)



### AX6-74Table AX6-9 (cont'd). Pulmonary Function Effects with Repeated Exposures to OzoneaOzoneConcentrationbExposure Durationand Activity Exposure ConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.18 353 2 hIE (heavy)V.E.60 to 70 L/min(35 L/min/m2BSA)31 °C35% RH(screen exposuresin spring 1986;second exposures insummer/fall 1986 andwinter 1987 and spring1987 for responders andnonresponders only)59 adultLos Angelesresidents12 responsive13nonresponsiveResponders:19 to 40 years old6 atopic,2 asthmatic,4 normalNonresponders:18 to 39 years old,13 normalResponders hadaFEV1=!12.4% after initialscreening; nonresponders had no change.Responders had nonsignificant response inlate summer or early winter, but wereresponsive again in early spring (spring 1986,!385 mL; Autumn 1986,!17 mL; winter1987, +16 mL; spring 1987,!347 mL).Nonresponders did not change with season.Suggests that responders responses may varywith ambient exposure, but nonrespondersgenerally remain nonresponsive.Linn et al.(1988)(also seeHackney et al.,1989)0.45(+0.30PAN)882 2 hIE (20 min rest,20 min exercise)V.E= 27 L/min22 °C60% RH5 days consecutiveexposure to PAN + O33 M, 5 F Healthy NS,Mean age =24 yearsFEV1decreased.19% with O3alone,.15%on Day 1 of O3+ PAN,.5% on Day 5 of O3+ PAN,.7% 3 days after 5 days of O3+PAN,.15% after 5 days of O3+ PAN.Similar to other repeated O3exposure studies,O3responses peaked after 2 days, weredepressed 3 days later, and responsesreturned 7 days later. PAN probably had noeffect on repeated to O3exposure responses.DrechslerParks et al.(1987b)(also seeTable AX6-14)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 trainedhealthy NS (somewere known O3sensitive),22.4 ± 2.2 years oldLargest FEV1decrease on second of 4 daysO3exposure (!40% mean decrease). Trendfor attenuation of pulmonary functionresponse not complete in 4 days..VO2maxdecreased with single acute O3exposure(!6%) but was not significant after 4 days ofO3exposure (!4%). Performance time wasless after acute O3(211 s) exposure than afterFA (253 s).Foxcroft andAdams (1986)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.



### 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 O 3 

### exposure. Inflammatory responses (Koren et al., 1989a), epithelial damage, and changes in permeability (Kehrl et al., 1987) might explain a portion of th ese responses. By blocking pulmonary function responses and symptoms with indomethacin pret reatment, 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 O 3 

### . 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 O 3 

### within

48 h. Response to laboratory O 3 

### 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 O 3 

### responsive subjects would remain responsive after regular ambient exposure during the “smog season”. The subjects were exposed to 0.18 ppm O 3 

### for 2 h with heavy IE on four occasions, spring, fall, winter, and the following spring. The marked difference in FEV 1 

### 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 O 3 

### during the following spring, the responsive subjects again had significantly larger changes in FEV 1 

### , suggesting a seasonal variation in response. Brookes et al. (1989) and Gliner et al. (1983) tested whether initial exposure to one O 3 

### concentration could alter response to subsequent exposure to a different O 3 

### concentration. Gliner et al. (1983) showed that FEV 1 

### response to 0.40 ppm O 3 

### was not influenced by previously being exposed to 0.20 ppm O 3 

### for 2 h on 3 consecutive days. Brookes et al. (1989) found

enhanced FEV 1 

### and symptoms upon exposure to 0.20 ppm after previous exposure to 0.35 ppm O 3 

### . These observations suggest that, although preexposure to low concentrations of O 3 

### may not influence responses to higher concentrations, preexposure to a high concentration of O 3 

### 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 O 3 

### with heavy CE were significantly less after 4 consecutive days exposure than they were after a single acute exposure. Further, exercise performance,

### AX6-77 

## 0 VO 2max 

### , 

## 0 V Emax 

### and HR

max 

### were not significantly different after 4 days of O 3 

### 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 FEV 1 

### response, although symptoms were significantly reduced. However, these investigators selected known O 3 

### -sensitive subjects

whose FEV 1 

### 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 O 3 

### -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 “O 3 

### sensitivity.” Drechsler-Parks et al. (1987b) examined the response to repeated exposures to 0.45 ppm O 3 

### plus 0.30 ppm peroxyacetyl nitrate (PAN) in 8 healthy subjects and found similar FEV 1 

### responses to exposures to O 3 

### (

! 

### 19%) and to O 3 

### plus PAN (

! 

### 15%). Thus, PAN did not increase responses to O 3 

### . Further, repeated exposure to the PAN plus O 3 

### mixture resulted in similar changes to those seen with repeated O 3 

### exposure alone. The FEV 1 

### 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 O 3 

### exposure. If the PAN responses are considered negligible, this study confirms the observation that the attenuation of O 3 

### responses with chamber exposures lasts no longer than 1 week. [ More discussion on the interaction of O 3 

### 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 O 3 

### for 2 h/day on
5 consecutive days. Subjects performed heavy IE ( 

## 0 V E 

### = 60 to 70 L/min). Decrements in FEV 1 

### averaged 18.0, 29.9, 21.1, 7.0, and 4.4% on the 5 exposure days. However, baseline preexposure

FEV 1 

### decreased from the first day’s preexposure measurement and was depressed by an averageof 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 O 3 

### exposure were also attenuated after 5 consecutive days of O 3

### 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 O 3 

### for 2 h with moderate
IE (exercise 

## 0 V E 

### = 40 L/min) on 4 consecutive days. In addition to standard pulmonary function

measures, isovolumetric FEF 25-75 

### , 

## 0 V max50 

### and 

## 0 V max75 

### were grouped into a single value representing
small airway function (SAW grp 

### ). 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 FEV 1 

### showed significant attenuation by Day 4 compared to Day
1 values. However, SAW grp 

### 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 O 3 

### 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 O 3 

### 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 FEV 1 

### (

! 

### 2.5%) on the first day, but no change on the second day. Linn et al. (1994)

observed a 1.7% decrease in FEV 1 

### in healthy subjects after 6.6 h exposure to 0.12 ppm O 3 

### . A second consecutive day exposure to O 3 

### yielded even smaller (<1%) responses. In a group of asthmatics exposed under similar conditions (Linn et al., 1994), the FEV 1 

### 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 observati ons 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 O 3 

### 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 

## 0 V E 

### (

! 

### 20%) and were residents
of Los Angeles who often encountered ambient levels of O 3 

### at or above 0.12 ppm. Folinsbee et al. (1994) exposed 17 subjects to 0.12 ppm O 3 

### for 6.6 h, with 50 min of
moderately heavy exercise ( 

## 0 V E 

### = 39 L/min) each hour, on 5 consecutive days. Compared with
FA, the percentage changes in FEV 1 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### for 4 h, with 30 mm of IE (exercise 

## 0 V E 

### = 25 L/min/m 2 

### ) each

hour. Measures of FEV 1 

### , 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 Da y 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 O 3 

### 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 si milar 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 O 3 

### for 4 h, with 30 min of IE (exercise 

## 0 V E 

### = 26 L/min) each

hour. The authors observed that FEV 1 

### was significantly reduced and symptoms were significantly increased on Day 1. On Day 2, FEV 1 

### was further decreased, while symptoms remained unchanged. By Day 4, both FEV 1 

### 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 O 3 

### 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 FEV 1 

### measured before exposure, thereby suggesting that there are different time scales of the functional responses

to O 3 

### , which may reflect different mechanisms. The levels of protein remaining elevated after repeated exposures confirms the findings of ot hers (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

O 3 

### can be found in Section AX6.9 .] Based on studies cited here and in the previous O 3 

### criteria documents (U.S. Environmental Protection Agency, 1986, 1996), several conclusions can be drawn about repeated 1- to 2-h O 3 

### exposures. Repeated exposures to O 3 

### 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 O 3 

### concentration and to some extent on the magnitude of the initial response. Small responses to the first O 3 

### exposure are less likely to result in an enhanced response on the second day of O 3 

### 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 O 3 

### , 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 O 3 

### 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 O 3 

### 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 ai r 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 O 2 

### availability could not be ruled out. Figure AX6-8. Regression curves were fitted to day-by-day postexposure FEV 1 

### values obtained after repeated daily acute exposures to O 3 

### for 2 to 3 h with intermittent exercise at a V E 

### 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 FEV 1 

### values obtained after exposure to 0.12 ppm O 3 

### for 10 h ( ! 

### ).

Source: Modified from Hazucha (1993).

### AX6-82 Subsequently, the effects of acute O 3 

### inhalation on endurance exercise performance have been examined in numerous controlled laboratory studies. These studies were discussed in the previous O 3 

### criteria document (U.S. Environmental Protection Agency, 1996) in two categories:
(1) those that examined the effects of acute O 3 

### inhalation on maximal oxygen uptake ( 

## 0 VO 2max 

### )
and (2) those that examined the effects of acute O 3 

### 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 

## 0 VO 2max 

### and endurance exercise performance consequent

to O 3 

### inhalation. A summary of major studies of O 3 

### 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 O 3 

### exposures on 0 

### VO 2max 

### were reviewed in an earlier O 3 

### criteria document (U.S. Environmental Protection Agency, 1986). Briefly, Folinsbee et al. (1977)

observed that 0 

### VO 2max 

### was significantly decreased (10.5%) following a 2-h exposure to 0.75 ppm O 3 

### with light (50 Watts) IE. Reduction in 0 

### VO 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 O 3 

### exposure resulted in a 22.3% decrease in FEV 1 

### and significant symptoms of cough and chest discomfort. In c ontrast, Horvath et al. (1979) did not observe a change in 0 

### VO 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 O 3 

### , Savin and Adams (1979) examined the effects of a 30-min exposure to 0.15 and 0.30 ppm O 3 

### while performing a progressively incremented exercise test to volitional fatigue (mean = 31.5 min in FA). No significant effect on maximal

work time or 0 

### VO 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 

## 0 V E 

### was significantly reduced 7% in the 0.30 ppm O 3 

### exposure. Results of these early studies suggest that 

## 0 VO 2max 

### is reduced if the incremented maximal exerciseTable AX6-10. Ozone Effects on Exercise PerformanceaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.06-0.070.12-0.13120-140245-260CE(V.E= 30 to 120 L/min)16 to 28 min progressivemaximum exerciseprotocol23 to 24.5 °C50 to 53% RH12 M, 12 F Athletic Reduced maximum performance time and increased symptomsof breathing discomfort during O3exposure.Linder et al.(1988)0.18 353 1 h CE or competitivesimulation at meanV.E= 94 L/minNA # not given;all malesWell-traineddistance runnersMaximal treadmill run time reduced from 71.7 min in FA to66.2 min during O3exposure with no decease in arterial O2saturation.Folinsbee et al.(1986)0.35 686 50 min CEV.E= 60 L/min22 to 25 °C35 to 50% RH8 M TrainednonathletesVTdecreased, fBincreased with 50-min O3exposures; decreasein FVC, FEV1, FEF25-75, performance time,.VO2max,.VEmax, andHRmaxfrom FA to 0.35-ppm O3exposure.Foxcroft andAdams (1986)0.120.202353921 h CEV.E= 89 L/min31 °C 15 M, 2 F Highly trainedcompetitivecyclistsDecrease in.VEmax,.VO2max, VTmax, workload, ride time, FVC,and FEV1with 0.20 ppm O3exposure, but not significant with0.12-ppm O3exposure, as compared to FA exposure.Gong et al.(1986)0.120.180.242353534701 h competitivesimulation exposures atmeanV.E= 87 L/min23 to 26 °C45 to 60% RH10 M Highly trainedcompetitivecyclistsDecrease in exercise time of 7.7 min and 10.1 min for subjectsunable to complete the competitive simulation at 0.18 and 0.24ppm O3, respectively; decrease in FVC and FEV1for 0.18-and0.24-ppm O3exposure compared with FA exposure.Schelegle andAdams (1986)0.21 412 1 h CE at 75% V.O2max 19 to 21 °C60 to 70% RH6 M, 1 F Well-trainedcyclistsDecrease in FVC, FEV1, FEF25-75, and MVV with 0.21 ppm O3compared with FA exposure.Folinsbee et al.(1984)0.200.353926861 h CE or competitivesimulation at meanV.E= 77.5 L/min23 to 26 °C45 to 60% RH10 M Well-traineddistance runnersVTdecreased and fBincreased with continuous 50-min O3exposures; decrease in FVC, FEV1, and FEF25-75from FA to0.20 ppm and FA to 0.35-ppm O3exposure in all conditions;three subjects unable to complete continuous and competitiveprotocols at 0.35 ppm O3.Adams andSchelegle (1983)0.250.500.754909801,4702 h rest NA 8 M, 5 F FVC decreased with 0.50- and 0.75-ppm O3exposurecompared with FA; 4% nonsignificant decrease in mean.VO2maxfollowing 0.75 ppm O3compared with FA exposure.Horvath et al.(1979)0.150.30294588 ~30 min, progressivelyincremented exercise tovoluntary exhaustion23 °C50% RH9 M Healthy, NS21 to 44 years oldExposure to 0.15 and 0.30 ppm O3did not decrease maximalexercise performance or.VO2maxcompared to FA.No significant pulmonary function or symptom responses wereobserved, although a trend (P < .10) was evident.Savin andAdams (1979)0.75 1,470 2 h IE(4 × 15 min light [50 W]bicycle ergometry)NA 13 M 4 light S,9 NSDecrease in FVC, FEV1, ERV, IC, and FEF50%after 1-h0.75-ppm O3exposure; decrease in V.O2max,.VTmax,.VEmax,maximal workload, and HRmax following 0.75-ppm O3exposure compared with FA.Folinsbee et al.(1977)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.



### AX6-83

### AX6-84 test is preceded by an O 3 

### exposure of sufficient total inhaled dose of O 3 

### 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 

## 0 VO 2max 

### exercise performance time (

! 

### 16.7%), 

## 0 VO 2max 

### (

! 

### 6.0%),

maximal 

## 0 V E 

### (

! 

### 15.0%), and maximal heart rate (

! 

### 5.6%) immediately following an initial 50-min

exposure to 0.35 ppm O 3 

### during heavy CE ( 

## 0 V E 

### = 60 L/min). These decrements were
accompanied by a significant reduction in FEV 1 

### (

! 

### 23%) and the occurrence of marked symptoms of breathing discomfort. Similarly, Gong et al. (1986) found significant reductions in
rapidly incremented 

## 0 VO 2max 

### exercise performance time (

! 

### 29.7%), 

## 0 VO 2max 

### (

! 

### 16.4%), maximal 

## 0 V E 

### (

! 

### 18.5%), and maximal workload (

! 

### 7.8%) in endurance cyclists immediately following a 1-h
exposure to 0.20 ppm O 3 

### with very heavy exercise ( 

## 0 V E 

### 89 L/min), but not following exposure to
0.12 ppm. Gong et al. (1986) observed only a 5.6% FEV 1 

### decrement and mild symptoms following exposure to 0.12 ppm, but a large decrement in FEV 1 

### (

! 

### 21.6%) and substantial symptoms of breathing discomfort following the 0.20 ppm exposure, which the authors
contended probably limited maximal performance and 

## 0 VO 2max 

### .



## AX6.7.3 Effect on Endurance Exercise Performance
A number of studies of well trained endurance athletes exposed to O 3 

### have consistently observed an impairment of 1-h continuous hea vy 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 O 3 

### 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 O 3 

### include a

! 

### 7.7% reduced endurance treadmill running time when exposed to 0.18 ppm O 3 

### (Folinsbee et al., 1986), which was accompanied by significantly decreased FEV 1 

### and significantly elevated symptoms of breathing di scomfort. 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 O 3 

### (30 min warm-up, followed immediately by 30 min at
the maximal workload that each subject could just maintain in FA; mean 

## 0 V 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 O 3 

### exposures, respectively. Following the 0.18 ppm and 0.24 ppm O 3 

### exposures, but not the 0.12 ppm exposure, FEV 1 

### was reduced significantly and symptoms were significantly in creased. 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 O 3 

### 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 FEV 1 

### at either O 3 

### concentration. Collectively, reduced endurance exercise performance and associated pulmonary responses are clearly related to the

total inhaled dose of O 3 

### (Adams and Schelegle, 1983; Avol et al., 1984; Schelegle and Adams, 1986).
Mechanisms limiting 

## 0 VO 2max 

### and maximal exercise performance upon O 3 

### exposure have
not been precisely identified. Schelegle and Ad ams (1986) observed no significant effect of O 3 

### on cardiorespiratory responses, and there wa s no indirect indication that arterial O 2 

### saturation

was affected. The latter is consistent with the observation that measured arterial O 2 

### saturation at the end of a maximal endurance treadmill run was not affected by O 3 

### (Folinsbee et al., 1986).

In studies in which O 3 

### inhalation resulted in a significant decrease in 

## 0 VO 2max 

### , and/or maximal
exercise performance, significantly decreased FEV 1 

### and marked symptoms of breathing discomfort were observed (Adams and Schelegl e, 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 FEV 1 

### 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 O 3 

### , probably limited maximal performance

and 

## 0 VO 2max 

### either voluntarily or involuntarily (Gong et al., 1986). Strong support for this

contention is provided by the observation of significant increases in 

## 0 VO 2max 

### (4.7%) and maximal
performance time (8.8%) following four consecutive days of 1 h exposure to 0.35 ppm O 3 

### with
heavy exercise ( 

## 0 V E 

### = 60 L/min) compared to initial O 3 

### exposure (Foxcroft and Adams, 1986).
These improvements, which were not signifi cantly different from those for FA, were accompanied by a significant reduction in symptoms of breathing discomfort with no significant

attenuation of FEV 1 

### and other pulmonary function responses. In this regard, Schelegle et al. (1987) observed a disparate effect of indometh acin pretreatment (an inhibitor of the cyclo-

### AX6-86 oxygenation of arachidonic acid to prostaglandins associated with inflammatory responses)

on O 3 

### -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, SO 2 

### , cold air) than they would be when

normoreactive. In order to determine the leve l 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 FEV 1 

### 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

“PD 20 

### FEV 1 

### ” or “PC 20 

### FEV 1 

### ” (i.e., the provocative dose or concentration that produced a 20% drop in FEV 1 

### ) or the “PD 100 

### SRaw” (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 PD 20 

### 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 PD 20 

### FEV 1 

### or PD 100 

### SRaw 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 O 3 

### (e.g., Golden et al., 1978; Table AX6-11). König et al. (1980) and Holtzman et al. (1979) found the increased airway responsiveness after O 3 

### exposure in healthy subjects appeared to be resolved after 24 h. Because atopic subjects had similar increases in responsiveness to histamine after O 3 

### exposure as nonatopic subjects, Holtzman et al. (1979) concluded that the increased nonspecific bronchial responsiveness after O 3 

### 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 O 3 

### . Taken together, these studies suggest that O 3 

### -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 O 3 

### 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 O 3 

### . Horstman et al. (1990) demonstrated significant decreases in the PD 100 

### SRaw in 22 healthy subjects immediately after a 6.6-h exposure

to concentrations of O 3 

### as low as 0.08 ppm. No relationship was found between O 3 

### -induced changes in airway responsiveness and changes in FVC or FEV 1 

### (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 O 3 

### -induced increases in nonspecific airway responsiveness after repeated O 3 

### exposure. Over 3 days of a 2 h/day exposure to 0.40 ppm O 3 

### , they found progressive attenuation of the increases in airway responsiveness such that, after the third day of O 3 

### exposure, histamine airway responsiveness was no longer different from the sham exposure le vels. 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 O 3 

### on airway responsiveness which was only partially attenuated after 5 consecutive days of O 3 

### exposure. The occurrence and duration of increased nonspecific airway responsiveness following O 3 

### exposure could have important clinical implications for asthmatics. Kreit et al. (1989) investigated changes in airway responsiveness to methacholine that occur after O 3 

### exposure inTABLE AX6-11. Airway Responsiveness Following Ozone ExposuresaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.1250.2500.1252454902453h IE(10 min rest, 15 minexercise on bicycle)V.E= 30 L/min3h IE × 4 days27 °C50 % RH5 F, 6 M20-53 years old6 F, 16 M19-48 years oldMild bronchialasthmaAllergic rhinitisMean early-phase FEV1response and numberof$20% reductions in FEV1weresignificantly greater after 0.25 ppm O3or4 × 0.125 ppm O3. Most of the$15% latephase FEV1responses occurred afterexposure to 4 × 0.125 ppm O3, as well assignificant inflammatory effects, as indicatedby increased sputumeosinophils (asthma andallergic rhinitis) and increased sputumlymphocytes, mast cell tryptase, histamine,and LDH (asthma only).Holz et al.(2002)0.4 784 2 h IE.VE= 20 L/min/m2BSANA 6 F1 M19-26 years oldStable mild asthma;no meds 8 hpreexposureIncreased bronchial responsiveness tomethacholine 16 h after exposure; inhaledapocynin treatment significantly reduced O3-induced airway responsiveness.Peters et al.(2001)0.12 235 45 min IEexercise, rest, exercise.VE= 3 × resting60% RH 12 F5 M19-38 years oldPhysician diagnosedasthma; SO2-inducedairwayhyperreactivityThe authors concluded O3exposure increasesbronchial responsiveness to SO2in asthmaticsand that antioxidant supplementation has aprotective effects against this responsiveness,especially in the “more-severe” responders.Trenga et al.(2001)0.2 392 4 h IE.VE= 25 L/min/m2BSA20 °C62% RH4F8M23-47 years oldHealthy nonsmokers Increased sputum total cells, % neurtophils,IL-6, and IL-8 at 18 h after exposure;increased airway responsiveness tomethacholine 2 h after postexposure FEV1returned to 5% of base-line; no antiinflammatory effect of azithromycin.Criqui et al.(2000)0.4 784 2 h IE40 min/h @ 50 WNA 15 healthy subjects ;9 F, 6 M; 31.1 ± 2.1years oldHealthy; nonatopic Decreased FEV1and FVC; increasedbronchial reactivity to methacholine4 h postexposure; no protection frominhaled corticosteroid, budesonide.Nightingaleet al. (2000)0.16 314 7.6 h IE50 min/h.VE–25 l/min22/C40% RH5 F4 MMild atopicasthma, HMDsensitive, 20-35 yearsoldMean 9.1% FEV1decrease 18 h after O3exposure; provocative dose of dust miteallergen decreased from 10.3 to 9.7 doseunits.Kehrl et al.(1999)



### AX6-88TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone ExposuresaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.2 392 4 h IE40 min/h @ 50 WNA 10 asthmatic(6 F, 4 M),26.6 ± 2.3 years old;10 healthy(4 F, 6 M),27.3 ± 1.4 years oldMild atopic asthma;nonatopic healthysubjects; no meds8 weeks pre-exposureDecreased FEV1in asthmatic (9.3%)and healthy (6.7%) subjects; increasedsputum neutrophils in both groups (NS);no change in methacholine airway reactivity24 h postexposure.Nightingaleet al. (1999)0.12Air-antigen235 1 h rest NA 6 F9 MMild allergic asthma;18 to 49 years if ageNo effect of O3 on airway response to grassor ragweed allergen.Hananiaet al. (1998)0.4 784 2 h IE.VE= 20 L/min/m2BSANA 5F1M18-27 years oldStable mild asthma;no meds 8 hpreexposureIncreased airway responsiveness tomethacholine 16 h postexposure;no effect of proteinase inhibitor, rALP.Hiltermannet al. (1998)0.2 392 4 h IE50 min/h.VE= 25 L/min/m2BSA20 °C50% RH6 F12 M18-36 years oldPhysician-diagnosedmild asthma; no medsprior to exposureDecreased FEV1and FVC, increased SRaw;lower respiratory Sx; increased% neutrophils, total protein, LDH,fibronectin, IL-8, GM-CSF, and MPOin BAL. Correlation between pre-exposuremethacholine challenge and O3-inducedSRaw increase.Balmes et al.(1997);Scannellet al. (1996)0.4 784 3 h/d for 5 days;alternating 15 min of restand exercise at.VE= 32 L/min31 °C35% RH2 F8 M19-48 years oldMild asthmarequiring onlyoccasionalbronchodilatortherapySignificant FEV1and Sx response on 1st and2nd O3exposure days, then diminishing withcontinued exposure; tolerance partially lost4 and 7 days postexposure; bronchialreactivity to methacholine peaked on 1st O3exposure day, but remained elevated withcontinued exposure.Gong et al.(1997b)0.12 236 Rest 22 °C40% RH5 F10 MatopicasthmaNo effect of O3on airway response to grassallergen.Ball et al.(1996)0.25 490 3 h IE.VE= 30 L/min15 min ex/10 min rest/5 min no O3; every30 min.27 °C54% RHmouthpieceexposure24 mild asthmatics11 F / 13 M12 allergic rhinitics6 M / 6 F10 healthy 5 M/5 Fatopic mild asthmaticNSIncreased allergen responsiveness afer O3exposure in subjects with allergic airwaydisease, with orwithout asthma.Jörres et al.(1996)



### AX6-89TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone ExposuresaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.2 392 4h IE50 min/10 minexercise/rest each hour22 °C50% RH42 M/24 F 18-50 yearsNS healthyFEV1(!18.6%), FVC (!14.6%), decreasedafter O3. Baseline PC100for methacholinewas not related to changes in FVC, FEV1,a weak association was seen for PC100andincreased SRaw.Aris et al.(1995)0.12 235 1 h R Ambient T& RH forexposure;23 °C &50% RH forexercisechallenge8 F7 M19-45 years oldMild stable asthma No significant difference in % fall FEV1orV40p; no increase in bronchial responsivenessto exercise challenge.Fernandeset al. (1994)0.12 235 6.6 h, IE x 5 days50 min exercise/10 minrest, 30 min lunch.VE= 38.8 L/min18 °C40% RH17 M25 ± 4 years oldHealthy nonsmokers FEV1responses were maximal on 1st day ofexposure (!13%), less on second day (!9%),absent thereafter. Sxresponses only the first2 days. Methacholineairway responsivenesswas at least doubled on all exposure days,but was highest on the second day of O3.Folinsbeeet al. (1994)0.100.250.401964907851 h light IE2 × 15 min on treadmill.VE= 27 L/min21 °C40% RH9 F12 M19-40 years oldStable mildasthmatics with FEV1>70% andmethacholineresponsivenessNo significant differences in FEV1or FVCwere observed for 0.10 and 0.25 ppm O3-FAexposures or postexposure exercise challenge;12 subjects exposed to 0.40 ppm O3showedsignificant reduction in FEV1.Weymeret al. (1994)Air-antigen0.12 ppmO3-antigen1 h at rest NA 4 M, 3 F Asthmatic,21 to 64 years oldIncreased bronchoconstrictor response toinhaled ragweed or grass after O3exposurecompared to air.Molfinoet al. (1991)0.080.100.121571962356.6 hIE at.39 L/min18 °C40% RH22 M Healthy NS,18 to 32 years old33, 47, and 55% decreases in cumulative doseof methacholine required to produce a 100%increase in SRaw after exposure to O3at 0.08,0.10, and 0.12 ppm, respectively.Horstmanet al. (1990)



### AX6-90TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone ExposuresaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.12 ppmO3-100 ppbSO20.12 ppmO3-0.12 ppmO3Air-100 ppb SO245 min in first atmosphereand 15 min in second IE22 °C75% RH8 M, 5 F Asthmatic,12 to 18 years oldGreater declines in FEV1and.Vmax50%andgreater increase in respiratory resistance afterO3-SO2than after O3-O3or air-SO2.Koenig et al.(1990)0.35 686 70 min with IE at40 L/minNA 18 F Healthy NS,19 to 28 years oldPD100decreased from 59 CIU after airexposure to 41 CIU and 45 CIU, 1 and18 h after O3exposure, respectively.Folinsbeeand Hazucha(1989)0.40 784 2 h with IE at.VE= 53 to 55 L/min22 °C50% RH8 M, 10 F 9 asthmatics (5 F,4 M),9 healthy (5 F, 4 M),18 to 34 years oldDecreased PC100SRaw from 33 mg/mL to8.5 mg/mL in healthy subjects after O3.PC100SRaw fell from 0.52 mg/mL to0.19 mg/mL in asthmatic subjects afterexposure to O3and from 0.48 mg/mLto 0.27 mg/mL after exposure to air.Kreit et al.(1989)0.12 235 6.6 h with IE at.25 L/min/m2BSANA 10 M Healthy NS,18 to 33 years oldApproximate doubling of meanmethacholine responsiveness after exposure.On an individual basis, no relationshipbetween O3-induced changes in airwayresponsiveness and FEV1or FVC.Folinsbeeet al. (1988)0.120.202353921 h at.VE= 89 L/minfollowed by 3 to 4 minat.150 L/min31 °C35% RH15 M, 2 F Elite cyclists,19 to 30 years oldGreater than 20% increase in histamineresponsiveness in one subject at 0.12 ppmO3and in nine subjects at 0.20 ppm O3.Gong et al.(1986)0.40 784 3 h/day for 5 days in arow13 M, 11 F Healthy NS,19 to 46 years oldEnhanced response to methacholine afterfirst 3 days, but this response normalized byDay 5.Kulle et al.(1982)0.200.400.403927847842 h with IE at 2 × resting2 h with IE at 2 × resting2 h/day for 3 days22 °C55% RH12 M, 7 F Healthy NS,21 to 32 years old110% increase in)SRaw to a 10-breathhistamine (1.6%) aerosol challenge afterexposure to O3at 0.40 ppm, but no changeat 0.20 ppm. Progressive adaptation of thiseffect over 3-day exposure.Dimeo et al.(1981)



### AX6-91TABLE AX6-11 (cont’d). Airway Responsiveness Following Ozone ExposuresaOzoneConcentrationbExposure Durationand ActivityExposureConditionsNumber andGender of SubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m30.100.321.001966271,9602 h NA 14 Health NS,24 ± 2 years oldIncreased airwayresponsivenessto methacholine immediately after exposureat the two highest concentrations of O3.König et al.(1980)0.60 1,176 2 h with IE at 2 × resting 22 °C55% RH11 M, 5 F 9 atopic,7 nonatopic,NS, 21 to 35 yearsoldTen-breath methacholine or histaminechallenge increased SRaw$150% in16 nonasthmatics after O3. On average, theatopic subjects had greater responses thanthe nonatopic subjects. The increasedresponsiveness resolved after 24 h. Atropinepremedication blocked the O3-inducedincrease in airway responsiveness.Holtzmanet al. (1979)0.6 1,176 2 h at rest NA 5 M, 3 F Healthy NS,22 to 30 years old300% increase in histamine-induced)Raw5 min after O3exposure; 84 and 50%increases 24 h and 1 week after exposure(p > 0.05), respectively. Two subjects hadan increased response to histamine 1 weekafter exposure.Golden et al.(1978)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.



### AX6-92

### AX6-93 mild asthmatics. They found that the baseline PC 100 

### SRaw declined from 0.52 to 0.19 mg/mL after a 2-h exposure to 0.40 ppm O 3, 

### 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 PC 100 

### SRaw was not statistically different between healthy and asthmatic subjects (74.2 and 63.5%, respectively). Two studies examined the effects of preexposure to O 3 

### on exacerbation of exercise-induced bronchoconstriction (Fernandes et al., 1994; Weym er et al., 1994). Fernandes et al. (1994) preexposed subjects with stable mild asthma and a history of >15% decline in FEV 1 

### after exercise to 0.12 ppm O 3 

### 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 O 3 

### 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 O 3 

### neither enhances nor produces exercise-induced asthma in asthmatic subjects, the relatively low total inhaled doses of O 3 

### 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

O 3 

### exposures in a manner similar to normal subjects; however, there were more persistent effects

of O 3 

### 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 O 3 

### , 3 h/d for 5 consecutive days, and follow-up exposures 4 and 7 days later. Symptom and FEV 1 

### responses were large on the 1st and 2nd exposure days, and diminished progressively toward filtered air responses by the 5 th 

### exposure day. A methacholine challenge was performed when postexposure FEV 1 

### returned to within 10% of preexposure baseline levels. The first O 3 

### exposure significantly decreased PD 20 

### FEV 1 

### 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 O 3 

### 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 O 3 

### exposures in healthy subjects, despite a much lower bronchial reactivity both before and after O 3 

### exposure.

### AX6-94 A larger number of studies examined the effects of O 3 

### 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 O 3 

### 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

O 3 

### exposure. Their findings suggested that allergen-specific airway responsiveness of mild

asthmatics is increased after O 3 

### 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 O 3 

### 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 O 3 

### exposure and better study design by Hanania and colleagues. In the original, Molfino et al. (1991) study, the control (air) and experimental (O 3 

### ) exposures were not randomized after the second subject because of long-lasting (3 months),

O 3 

### -induced potentiation of airway reactivity in that subject. For safety reasons, therefore, the air exposures were performed prior to the O 3 

### 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-O 3 

### ) antigen challenge. Jörres et al. (1996) later confirmed that higher O 3 

### 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 O 3 

### 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 O 3 

### exposure (Holz et al., 2002); however, the effects of a 3-h exposure to 0.25 ppm O 3 

### 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 O 3 

### -exposed subjects with allergic asthma is important. Bronchial provocation with allergen, and subse quent 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 FEV 1 

### ). 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 FEV 1 

### ( $ 

### 20%) occurred during the early-phase allergen response in subjects with rhinitis after a consecutive 4-day exposure to 0.125 ppm O 3 

### . 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 O 3 

### for 7.6 hours. These important observations indicate that O 3 

### 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 O 3 

### -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 O 3 

### , but not with O 3 

### -induced decreases in FEV 1 

### and FVC. The O 3 

### -induced increase in SRaw, in turn,

was correlated with O 3 

### -induced increases in neutrophils and total protein concentration in BAL fluid. Subjects with asthma had a significantly greater inflammatory response to the same O 3 

### exposures, but it was not correlated with increased SRaw, and nonspecific airway provocation
was not measured. Therefore, it is difficult to de termine 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 O 3 

### -induced changes in airway inflammation and lung volume measurements are not

correlated. Hiltermann et al. (1998) reported that neutr ophil-derived serine proteinases associated

with O 3 

### -induced inflammation are not important mediators for O 3 

### -induced nonspecific airway hyperresponsiveness. Subjects with mild asthma, prescreened for O 3 

### -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 O 3 

### for 2 h. Methacholine challenges were performed 16 h after exposure. Treatment

with rALP had no effect on the O 3 

### -induced decrease in FEV 1 

### or PC 20 

### FEV 1 

### in response to methacholine challenge. The authors speculated that proteinase-mediated tissue injury caused by O 3 

### may not be important in the development of airway hyperresponsiveness of asthmatics

to O 3 

### . In a subsequent study using a similar prot ocol (Peters et al., 2001), subjects with mild

asthma were administered an aerosol of a pocynin, 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 O 3 

### exposure showed treatment-related effects on PC 20 

### FEV 1 

### , without an effect on FEV 1 

### . The authors concluded that apocynin could prevent O 3 

### -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 exposur es of healthy subjects and subjects with mild atopic asthma to a lower O 3 

### 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 O 3 

### exposure in either group. There were, however, significant decreases in FEV 1 

### of 6.7 and 9.3% immediately after O 3 

### 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 O 3 

### for 2 h (Nightingale et al., 2000). In the latter study, preexposure treatment with inhaled budesonide (a corticosteroid) did not protect against O 3 

### -induced effects on spirometry, methacholine challenge, or sputum neutrophils. These studies also confirm the earlier reported findings that O 3 

### -induced increases in airway responsiveness usually resolve by 24 h after exposure. Ozone-induced airway inflammation and hyperres ponsiveness 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 O 3 

### 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 FEV 1 

### and FVC also were found in both subject groups. Airway responsiveness to methacholine was not significantly different between azithromycin-treated and place bo-treated subjects when they were challenged

### AX6-97 2 h after postexposure FEV 1 

### decrements returned to within 5 % of baseline. Thus, azithromycin did not have anti-inflammatory effects in this study. The effects of dietary antioxidants on O 3 

### -induced bronchial responsiveness to SO 2 

### 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 SO 2 

### 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 O 3 

### for 45 min during
IE ( 

## 0 V E 

### . 

### 3× resting rate) followed by two sequential 10 min exposures to 0.1 and 0.25 ppm SO 2 

### . Vitamin treatment was not associated with decreased bronchial responsiveness following the 0.1 ppm SO 2 

### challenge. However, the change in spirometric responses (FEV 1 

### , FVC, FEF 25-75 

### , and PEF) between the 0.1 and 0.25 ppm SO 2 

### challenges were more severe for the placebo than the vitamin treatment regimen (p = 0.009). The authors concluded O 3 

### exposure increases bronchial responsiveness to SO 2 

### 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 O 3 

### 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 O 3 

### 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 prim arily 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 O 3 

### -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 O 3 

### 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 infla mmation such as the cytokines (IL-6, IL-8) and arachidonic acid metabolites (e.g., PGE 2 

### , PGF 2 " 

### , thromboxane, and leukotrienes [LTs] such as

LTB 4 

### ) have been measured in the BAL fluid of humans exposed to O 3 

### . In addition to their role in inflammation, many of these compounds have bronchoconstrictive properties and may be involved in increased airway responsiveness following O 3 

### exposure. Some recent evidence suggests that changes in small airways function may provide a

sensitive indicator of O 3 

### 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 follo wing 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 e xogenous 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. O 3 

### 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 O 3 

### . Other soluble factors that have been studied include those involved with fibrin depos ition 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 Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Upper Airway Studies0.4 784 2 h At rest 12 mild,asymptomatic dustmite-sensitiveasthmatics;18-35 years of ageRelease of early-onset mast cell-derived mediators into NL inresponse to allergen not enhanced following O3exposure.Neutrophil and eosinophil inflammatory mediators were notincreased after O3exposure or enhanced after allergenchallenge. O3increased eosinophil influx following allergenexposure.Michelsonet al. (1999)0.2 392 2 h IE(15 min/30 min);(.VE).20L/min/m2BSA8 M, 5 F healthy NS20-31 years of ageNo neutrophilia in NL samples by 1.5 h postexposure.Depletion of uric acid in NL fluid by 30% during h 2 ofexposure with increase inplasma uric acid levels.No depletion of ascorbic acid, reduced glutathione,extracellular superoxide dismutase.Mudway et al.(1999)0.4 980 2 h At rest 10 mild NSasthmatics18-35 years oldResponse to allergen increased (NS). PMN andeosinophils increased after O3plus allergen challenge.Ozone alone increased inflammation in the nose.Peden et al.(1995)0.120.242354701.5 h IE(20 L/min) at15-min intervals5 M, 5 F, asthmatic;4 M, 4 F,nonasthmatic;18 to 41 years oldNL done immediately and 24 h after exposure.Increased number of PMNs at both times in asthmatic subjectsexposed to 0.24 ppm O3; no change in nonasthmatic subjects.No change in lung or nasal function.McBride et al.(1994)0.5 980 4 h Resting 6 M, 6 F,allergic rhinitics,31.4 ± 2.0 (SD)years oldNL done immediately after exposure. Increased upperand lower respiratory symptoms and increased levels of PMNs,eosinophils, and albumin in NL fluid.Bascom et al.(1990)0.4 784 2 h IE(70 L/min) at15-min intervals11 M,18 to 35 years oldNL done immediately before, immediately after, and 22 h afterexposure. Increased numbersof PMNs at both times afterexposure; increased levels of tryptase, a marker of mast celldegranulation, immediately after exposure; increased levelsof albumin 22 h after exposure.Graham andKoren (1990)Koren et al.(1990)0.5 980 4 h on2 consecutive daysResting 41 M(21 O3-exposed,20 air-exposed),18 to 35 years oldNL done immediately before and after each exposureand 22 h after the second exposure.Increased levels of PMNsat all times after the first exposure, with peak values occurringimmediately prior to the second exposure.Graham et al.(1988)



### AX6-99Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Lower Airway Studies0.2 392 2 h IE(15 min/30 min);(.VE).20L/min/m2BSA6M, 6F healthy,nonatopic and9 M, 6F mildasthmatic subjects,19-48 years of ageSignificantly higher baseline expression of IL-4 and IL-5 inbronchial mucosal biopsies fromasthmatic vs. healthy subjects6 h postexposure. Following O3exposure, epithelialexpression of IL-5, GM-CSF, ENA-78, and IL-8 increasedsignificantly in asthmatics, as compared to healthy subjects.Bosson et al.(2003)0.1 196 2 h mild IE 12 M, 10 Fhealthy subjectsmean age ~30yearsMarkers of exposure in exhaled breath condensate, includingincreased 8-isoprostane, TBARS and LTB-4, and a marker ofROS-DNA interaction in peripheral blood leukocytes(8-OHdG), were increased in a sub-set of subjects bearing thewild genotype for NAD(P)H:quinone oxidoreductase and thenull genotype for glutathione-S-transferase M1.Corradi et al.(2002)0.2 392 2 h IE(15 min/30 min);(.VE).20L/min/m2bodysurface area6M, 9F healthysubjects and9 M, 6F mildasthmaticsNo evidence seen for increased responsiveness to theinflammatory effects of O3in mild asthmatics versus healthysubjects at 6 h following exposure. Used neutrophilrecruitment and exacerbation of pre-existing inflammation.Stenfors et al.(2002)0.27 529 2 h IE(20 min/ 60 min);(.VE).25L/min/m2BSA12 subjects withintermittent-mildasthma exhibiting adual response; 18-37years of ageExposure to O324 h following allergen challenge resulted in asignificant decrease in FEV1, FVC and VC and increase insymptom scores compared to air exposure. The percentage ofeosinophils, but not neutrophils,in induced sputum was higher6 h after O3than after air.Vagagginiet al. (2002)0.22 431 4 h IE(15 min/30 min);(.VE) = 25L/min/m2BSA12 nonsmoker,nonresponders;13 nonsmoker,responders;13 smokers;18-40 years of ageRecovery of AM was approximately 3-fold higher in BALfrom smokers versus nonsmokers. Unstimulated AM fromsmokers released ~2-fold greateramounts of superoxide anionthan from nonsmokers at 30 min and 18 h postexposure, butrelease was not further enhancedby stimulation of the cells.ROS generation by AM from nonsmokers decreased followingexposure at 18 h; markers ofepithelial permeability increased.No relationship was found between measures of ROSproduction and lung function responsiveness to O3.Voter et al.(2001)



### AX6-100Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Lower Airway Studies(cont’d)0.2 392 2 h IE(15 min/30 min);(.VE).20L/min/m2BSA8M, 5F healthynonsmokers;20-31 years of ageEarly (1.5 h postexposure) increase in adhesion moleculeexpression, submucosal mastcell numbers and alterations inlining fluid redox status. No clear relationship between earlymarkers of response and lung function deficits. 2.5-foldincrease in % human leukocyteantigen (HLA)-DR+ alveolarmacrophages in BAL.Blomberget al. (1999)0.4 784 2 h IE(15 min/30 min);(.VE).20L/min/m2BSA10M, 6F subjectswith intermittentasthma;19-35 years of ageIn a cross-over study, levels of eosinophil cationic protein, IL-8and percentage eosinophils were found to be highly correlatedin induced sputum and BAL 16 h following O3exposure.Hiltermannet al. (1999)0.4 784 2 h At rest 12 mild,asymptomatic dustmite-sensitiveasthmatics;18-35 years of ageRelease of early-onset mast cell-derived mediators into NL inresponse to allergen not enhanced following O3exposure.Neutrophil and eosinophil inflammatory mediators were notincreased after O3exposure or enhanced after allergenchallenge. O3increased eosinophil influx following allergenexposure.Michelsonet al. (1999)0.4 784 1 h Continuousexercise;(.VE).30L/min/m2BSA4 healthy subjects Apoptosis was observedin cells obtained by airway lavage6 h following exposure. AM obtained by BAL showed thepresence of a 4-hydroxynonenal (HNE) protein adduct and thestress proteins, 72-kD heat shock protein and ferritin. Theseeffects were replicated byin vitroexposure of AM to HNE.Hamilton et al.(1998)0.2 392 2 h 15 healthynonsmokersIncreased numbers of CD3+,CD4+, and CD8+ T lymphocytesubsets, in addition to neutrophils, in BAL 6 h postexposure.Blomberget al. (1997)0.4 784 2 h/day for 5 days,2 h either 10 or20 days laterIE(40 L/min) at15-min intervals16 M; 18 to 35 yearsof ageBAL done immediately after fifth day of exposure and againafter exposure 10 or 20 days later. Most markers ofinflammation (PMNs, IL-6, PGE2, fibronectin) showed partialto complete attenuation; markers of damage (LDH, IL-8,protein,"1-antitrypsin, elastase,) did not. Reversal ofattenuation was not complete for some markers, even after20 days.Devlin et al.(1997)



### AX6-101Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Lower Airway Studies(cont’d)0.22 431 4 h IE20 min ex/19 minrest(.VE).39-45 l/min31M, 7Fsmokers andnonsmokersPost-O3exposure FEV1in 3 groups: Smokers (!13.9%);nonresponders (!1.4%) and responders (!28.5%). PMN’sincreased immediately and at 18 h in all groups. Eosinophilsand lymphocytes increased after O3. IL-6 increased more innonsmokers. No relationship ofsymptoms with inflammation,lung function changes not related to inflammation. Nasallavage indicators did not predict bronchial or alveolarinflammation.Framptonet al. (1997a)Torres et al.(1997)0.12 235 2 h IE(15 min/30 min);(.VE).20L/min/m2BSA9M, 3F healthynonsmokers; meanage ~28 yearsIncrease in the percentage of vessels expressing P-selectin inbronchial biopsies at 1.5 h postexposure. No changes in FEV1,FVC, inflammatory cells or markers in BAL, or vesselsexpressing VCAM-1, E-selectin or ICAM-1 in biopsies.Krishna et al.(1997b)0.16 314 7.6 h IE50 min/hr(.VE) = 25 L/min8 asthmatics sensitiveto dust mitesIncreased numbers of eosinophils in BAL after O3exposure. Peden et al.(1997)0.2 392 4 hT = 20 °CRH = 50%IE(50 min/60 min);(.VE).44 L/min14 M, 6 Fhealthy NSOzone increased PMN, protein, IL-8, for all subjects.No relationship of inflammation with spirometric responses.Balmes et al.(1996)0.4 784 2 hT = 22 °CRH = 50%15 min rest15 min exercisecycle ergometer(.VE).55 l/min11 healthynonsmokers;18-35 yearsMean FEV1, change =!10%. BAL occurred at 0, 2, or 4 hpostexposure. Small nlimits statistical inference. Trend forPMN’s to be highest at 4 h. LTC4increased at all time points.No change in PGE2or thromboxane.Coffey et al.(1996)0.4 784 2 h15 min,ex/15 min, rest(.VE) = 66 l/min 8 Mhealthy nonsmokersComparison of BAL at 1 h postexposure vs. 18 h postexposure.At 1 h, PMN’s, total protein, LDH,"1-antitrypsin, fibronectin,PGE2, thromboxane B2, C3a, tissue factor, and clotting factorVII were increased. IL-6 and PGE2were higher after 1 h than18 h. Fibronectin and tissue plasminogen activator higher after18 h. No time differences for PMN and protein.Devlin et al.(1996)(compare withKoren et al.(1989a)0.2 392 4 hT = 20 °CRH = 50%IE(50 min/60 min);(.VE).44 L/min17 M, 6Fmild asthmaticsIncreased PMN, protein, IL-8, LDH, in BAL. Inflammatoryresponses were greater than a group of nonasthmatics(Balmes et al., 1996)Scannell et al.(1996)



### AX6-102Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Lower Airway Studies(cont’d)0.4 784 2 h mouthpieceexposure20 °C42% RH15 min exercise15 min rest(.VE).40 l/min5M, 5Fhealthy; age.30Sputum induction 4 h after O3exposure 3-fold increase inneutrophils and a decrease in macrophages after O3exposure.IL-6, IL-8, and myeleperoxidase increased after O3. Possiblerelationship of IL-8 and PMN levels.Fahy et al.(1995)0.2 392 4 h IE(50 min/60 min);(.VE) = 40 L/min15 M, 13 F,21 to 39 years oldBronchial lavage, bronchial biopsies, and BAL done 18 hafter exposure. BAL shows changes similar to other studies.Airway lavage shows increased cells, LDH, IL-8. Biopsiesshow increased number of PMNs.Aris et al.(1993)0.080.101571966.6 h IE(50 min/60 min) +35 min lunch;(.VE) = 40 L/min18 M,18 to 35 years of ageBAL fluid 18 h after exposure to 0.1 ppm O3had significantincreases in PMNs, protein, PGE2, fibronectin, IL-6, lactatedehydrogenase, and"-1 antitrypsin compared with the samesubjects exposed to FA. Similar but smaller increases in allmediators after exposure to 0.08 ppm O3except for protein andfibronectin. Decreased phagocytosis of yeast by alveolarmacrophages was noted at both concentrations.Devlin et al.(1990, 1991)Koren et al.(1991)0.4 784 2 h IE(15 min/30 min);(.VE) = 70 L/min10 M,18 to 35 years oldBAL fluid 1 h after exposure to 0.4 ppm O3had significantincreases in PMNs, protein, PGE2, TXB2, IL-6, LDH,"-1antitrypsin, and tissue factor compared with the same subjectsexposed to FA. Decreased phagocytosis of yeast by alveolarmacrophages.Koren et al.(1991)0.3 588 1 h(mouth-piece)CE (60 L/min) 5 M Significantly elevated PMNs in the BAL fluid 1, 6, and 24 hafter exposure, with peak increases at 6 h.Schelegleet al. (1991)0.40 784 2 h IE(15 min/30 min);(.VE) = 70 L/min11 M, 18 to35 years oldMacrophages removed 18 h after exposure had changes in therate of synthesis of 123 different proteins as assayed bycomputerized densitometry oftwo-dimensional gel proteinprofiles.Devlin andKoren (1990)0.40 784 2 h IE(15 min/30 min);(.VE) = 70 L/min11 M,18 to 35 years oldBAL fluid 18 h after exposure contained increased levels of thecoagulation factors, tissue factor, and factor VII. Macrophagesin the BAL fluid had elevated tissue factor mRNA.McGee et al.(1990)0.4 784 2 h IE(15 min/30 min);(.VE) = 70 L/min11 M,18 to 35 years oldBAL fluid 18 h after exposure had significant increases inPMNs, protein, albumin, IgG, PGE2, plasminogen activator,elastase, complement C3a, and fibronectin.Koren et al.(1989a,b)



### AX6-103Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Repeated Exposure Studies0.1250.252454903 h exposures toboth O3concs. andto FA;3 h on fourconsecutive days to0.125; study armsseparated by>4 wksIE(15 min/30 min)5M, 6F allergicasthmatic and16M, 6F allergicrhinitic subjects;19-53 years of ageAll subjects underwent 4 exposure arms and were challengedwith allergen 20 h following thelast exposure in each. Sputumwas induced 6-7 h later. In rhinitics, but not asthmatics, theincidence and magnitude of early phase FEV1decrements toAg were greater after 0.25 and 4x 0.125 ppm O3. Repeatedexposure caused increases in neutrophil and eosinophilnumbers in both subject groups, as well as increasedpercentage and number of lymphocytes in the asthmatics.Holz et al.(2002)0.25 490 2 h on fourconsecutive days;O3and FA exposurestudy armsseparated by$3 wksIE(30 min/60 min);(.VE).8 times theFVC/min5M, 3F healthysubjects;25-31 years of ageMaximal mean reductions in FEV1and FVC were observed onday 2, and became negligible by day 4. FEF25-75, Vmax50, andVmax75 were combined into asingle value representing smallairway function (SAWgrp). Thisvariable was the only one toshow persistent depression ofthe 24 h postexposure baselinefrom day 2 to day 5 measurements. Numbers of PMNs in BALfluid on day 5 were significantly higher in subjects followingO3, compared to air, exposures.Frank et al.(2001)0.2 392 single,4 h exposures to O3and to FA;4 h on fourconsecutive days toO3; study armsseparated by>4 wksIE(15 min/30 min);(Mean.VE) =14.8 L/min/m2BSA15M, 8F healthysubjects;21-35 years of ageAll subjects underwent 3 exposure arms with BAL andbronchial mucosal biopsies performed 20 h following the lastexposure in each. After repeated exposure, functional andBAL cellular responses were notdifferent from those after FA,whereas total protein, IL-6, IL-8, reduced glutathione andortho-tyrosine remained elevated. Also at this time,macroscopic scores of inflammation and tissue neutrophilswere increased in mucosal biopsies. IL-10 was detected onlyin BAL fluid following repeated O3exposure.Jörres et al.(2000)0.2 392 single, 4 hexposure;4 h exposures onfour consecutivedays; study armsseparated by>4 wksIE(30 min/60 min);(Mean.VE) = 25L/min/m2BSA9M, 6F healthy NS23-37 years of ageSubjects were randomly assigned to each of the exposureregimens in a crossover design. Compared to single exposure,repeated exposure resulted in an initial progression followed byan attenuation of decrements in FEV1, FVC and specificairways resistance by day 4. Bronchial and BAL washingsshowed decreases in the numbers of PMNs and fibronectinlevels and IL-6 was decreased in BAL fluid on day 4.Christian et al.(1998)



### AX6-104Table AX6-12 (cont’d). Studies of Respiratory Tract Inflammatory Effects from Controlled Human Exposure to OzoneaOzone ConcentrationbExposureDurationActivity Level(.VE)Number and Genderof Subjects Observed Effect(s) Referenceppm μg/m3Repeated Exposure Studies(cont’d)0.4 784 2 h/day for 5 days,2 h either 10 or20 days laterIE(60 L/min) at15-min intervals16 M;18 to 35 years of ageBAL done immediately after fifth day of exposure and againafter exposure 10 or 20 days later. Most markers ofinflammation (PMNs, IL-6, PGE2, fibronectin) showedcomplete attenuation; markers ofdamage (LDH, IL-8, protein,"1-antitrypsin, elastase) did not. Reversal of attenuation wasnot complete for some markers, even after 20 days.Devlin et al.(1997)0.400.60784 2 h IE(83 W for women,100 W for men)at 15-min intervals7M, 3F23 to 41 years of ageBAL fluid 3 h after exposure had significant increasesin PMNs, PGE2, TXB2, and PGF2"at both O3concentrations.Seltzer et al.(1986)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.



### AX6-105Table AX6-13. Studies of Effects on Host Defense, on DrugEffects and Supportive In Vitro Studies Relating to ControlledHuman Exposure to OzoneaOzoneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Host Defense0.2 392 2 h IE (15 min/30min);(.VE).20L/min/m2BSA4M, 5Fmild atopicasthmatics;21-42 years of ageA significant decline in FEV1and VC immediately following exposure.A 2-fold increase in percent PMNs, with no changes in otherbiomarkers, was observed at 6 hpostexposure. By 24 h postexposure,PMNs had decreased, but albumin, total protein, myeloperoxidase andeosinophil cationic protein had increased.Newson et al.(2000)0.3 588 6 h/day for5 consecutivedaysIE (light treadmill) 24 M(12 O3, 12 air)Subjects inoculated with type 39 rhinovirus prior to exposure. NL wasperformed on the morning of Days 1 to5, 8, 15, and 30. No differencein virus titers in NL fluid of air and O3-exposed subjects at any timetested. No difference in PMNs or interferon gamma in NL fluid, or inblood lymphocyte proliferativeresponse to viral antigen.Hendersonet al. (1988)0.2 382 2 h IE(15 min/30 min);(.VE).30 L/min10M, 2Fhealthy NSmean ~28 yearsof ageSubjects were exposed to O3and FA in a cross-over design andunderwent BAL 6 h postexposure. O3exposure induced a 3-foldincrease in % PMNs and epithelial cells, and increased IL-8, Gro-",and total protein in BAL fluid.% PMNs correlated positively withchemokine levels. Exposure alsoresulted in a significant decrease inthe CD4+/CD8+ ratio and the % ofactivated CD4+ and CD8+ T cellsin BAL fluid.Krishna et al.(1998)Host Defense-Mucous Clearance0.4 784 1 h CE (40 L/min) 15 healthy NS18 to 35 years oldSubjects inhaled radiolabeled iron oxide particles 2 h after exposure.No significant O3-induced effect on clearance of particles during thenext 3 h or the following morning.Gerrity et al.(1993)0.200.403927842 h IE (light treadmill) 7 M,27.2 ± 6.0 (SD)years oldSubjects inhaled radiolabeled ironoxide particles immediately beforeexposure. Concentration-dependentincrease in rate of particleclearance 2 h after exposure, although clearance was confinedprimarily to the peripheral airways at the lower O3concentration.Foster et al.(1987)



### AX6-106Table AX6-13 (cont’d). Studies of Effects onHost Defense, on Drug Effects and SupportiveIn VitroStudies Relating toControlled Human Exposure to OzoneaOzoneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Host Defense-Epithelial Permeability0.00.203922 h IE4 × 15 minat V.E= 20L/min/m2BSA10 M, 12 FHealthy NS;mean 24 years ofageClara cell protein (CC16) levels, a biomarker of epithelialpermeability, were elevated by O3exposure and remained high at 6 hpostexposure. By 18 h postexposure,CC16 levels had returned tobaseline. No correlation between CC16 and FEV1decrements.Blomberg et al.(2003)0.150.35294686130 min IE10 exercise/10 rest(.VE).8×FVC8M,1FNSSubjects inhaled99mTc-DTPA 19 h after exposure to O3. Clearancewas increased in the lung periphery. Clearance was not related tospirometry.Foster andStetkiewicz(1996)0.5 784 2.25 h IE(70 L/min) at15-min intervals16 M,20 to 30 years oldSimilar design and results as earlier study (Kehrl et al., 1987).For the combined studies the average rate of clearance was 60% fasterin O3-exposed subjects.Kehrl et al.(1989)0.4 784 2 h IE(70 L/min) at15-min intervals8 M,20 to 30 years oldSubjects inhaled99mTc-DTPA 75 min after exposure. Significantlyincreased clearance of99mTc-DTPA from the lung in O3-exposedsubjects. Subjects had expected changes in FVC and SRaw.Kehrl et al.(1987)Drug Effects on Inflammation0.25 490 3 h IE15-minintervals4 O3exposures:screening,placebo, andtwo treatments27 °C56 % RH(values from Holzet al. 1999)14M, 4FHealthy NSozone responders31.4 ± 8.4 years oldOn average, the screening and placebo O3exposures caused greaterthan a 9-fold increase in sputum neutrophils relative to baseline levels.Relative to placebo, the inhaled or oral corticosteroids significantlyreduced neutrophil levels by 62 and 64%, respectively. Post-O3,spirometry not significantly different from baseline.Holz et al.(2005)0.4 784 2 h 23 healthy adults Subjects were exposed to O3following random selection for a 2 wkdaily regimen of antioxidants, including vegetable juice high in thecarotenoid, lycopene, or placebo. Concentrations of lycopene in thelungs of supplemented subjects increased by 12% following treatment.Supplemented subjects showed a 20%decrease in epithelial cell DNAdamage as assessed by the Comet Assay. Effects attributable tolycopene could not be separatedfrom those of other antioxidants.Arab et al.(2002)



### AX6-107Table AX6-13 (cont’d). Studies of Effects onHost Defense, on Drug Effects and SupportiveIn VitroStudies Relating toControlled Human Exposure to OzoneaOz oneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Drug Effects on Inflammation(cont’d)0.00.407842 h IE20 minmild-mod.exercise,10 min rest4 M, 5 F Healthy NS30 ± 3 years oldSubjects previously in Nightingale et al. (2000) study. Placebocontrol: Immediately postexposure decrements in FVC (9%) andFEV1(14%) relative to pre-exposure values. FEV1decrement only9% at 1 hr postexposure. By 3h postexposure, recovery in FVC to97% and FEV1to 98% of preexposure values. Significant increases in8-isoprostane at 4 h postexposure.Budesonide for 2 wk prior toexposure did not affect responses.Montuschi et al.(2002)0.2 392 2 hAll exposuresseparated by atleast 2 wks(mean.30d)IE(15 min/30 min);(.VE).20L/min/m2BSAHealthy (6 M, 9 F)and mild asthmatic(9 M, 6 F) subjectsComparison was made of responsesin healthy subjects, who hadhigher basal ascorbate (ASC) levelsand lower glutathione disulfide(GSSG) levels than those of asthmatics. 6 h after exposure, ASC levelswere decreased and GSSG levels were increased in BAL fluid ofnormals, but not asthmatics. Despite these differences in basalantioxidant levels and response to O3, decrements in FEV1andneutrophil influx did not differ in the two subject groups.Mudway et al.(2001)0.4 784 2 h IE15-min intervals;.VE.20 L/min/m2BSAPlacebo group15 M, 1 FAntioxidant group13 M, 2 FMean age 27 yearsAll subjects were exposed to FA and then entered a 2 wk regimenof placebo or 250 mg Vit C, 50IU"-tocopherol, and 12 oz veg.cocktail/day prior to O3exposure. O3-induced decrements in FEV1andFVC were 30% and 24% less, respectively, in supplemented subjects.Percent neutrophils and IL-6 levels in BAL fluid obtained 1 hpostexposure were not different in the two treatment groups.Samet et al.(2001)Stech-Scottet al. (2004)0.27 529 2 hAll exposuresseparated by atleast 1 wk(mean.14 d)Continuousexercise;(.VE).25L/min/m2BSA7 M, F subjectswith mild asthma;20-50 years of ageSubjects were randomly exposed to FA and to O3before and after4 wks of treatment with 400 μg budesonide, b.i.d. Budesonide did notinhibit the decrement in FEV1or increase in symptom scores, butsignificantly reduced the increase in% neutrophils and IL-8 in sputuminduced 6 h postexposure.Vagaggini et al.(2001)0.4 784 2 h IE15-min intervals.VEmin.30 L/min5 M, 4 F healthy6 M, 7 F asthmaticsSubjects were pretreated for 3 days prior to exposure withindomethacin (75 mg/day) or placebo. Similar reductions in FEV1andFVC were seen in both groups following placebo, whereas mid-flowsshowed greater decline in asthmatics than normals. Indomethacinattenuated decrements in FEV1and FVC in normals, but notasthmatics. Attenuation of decrements was seen for FEF60pinasthmatics and for FEF50in normals.Alexis et al.(2000)



### AX6-108Table AX6-13 (cont’d). Studies of Effects onHost Defense, on Drug Effects and SupportiveIn VitroStudies Relating toControlled Human Exposure to OzoneaOzoneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Drug Effects on Inflammation(cont’d)0.4 784 2 h IE(20 min/30 min);workload @50 watts6 M, 9 F healthyNSmean ~31 yearsof ageSubjects were randomly exposed to FA and to O3before and after2 wks of treatment with 800 μg budesonide, b.i.d. O3causedsignificant decrements in FEV1and FVC immediately followingexposure, and a small increase inMCh-reactivity and increases inneutrophils and myeloperoxidase in sputum induced at 4 hpostexposure. No differences weredetected betweenresponses in thetwo treatment groups.Nightingaleet al. (2000)0.00.4784 2 h IE4 × 15 min at.VE= 18L/min/m2BSA2 exposures:25% subjectsexposed to airair, 75% toO3-O321 °C40% RHWeak responders7 M, 13FStrong responders21 M, 21 FHealthy NS20 to 59 years oldSignificant O3-induced decrements in spirometric lung function.Young adults (<35 years) were significantly more responsive thanolder individuals (>35 years). Sufentanil, a narcotic analgesic, largelyabolished symptom responses and improved FEV1in strongresponders. Naloxone, an opioid antagonist, did not affect O3effects inweak responders.See Section AX6.2.5.1Passannanteet al. (1998)0.4 784 2 h IE(60 L/min) at15-min intervals10 M Subjects given 800 mg ibuprofen or placebo 90 min before exposure.Subjects given ibuprofen had less of a decrease in FEV1after O3exposure. BAL fluid 1 h after exposure contained similar levels ofPMNs, protein, fibronectin, LDH,"-1 antitrypsin, LTB4, and C3a inboth ibuprofen and placebo groups.However, subjects given ibuprofenhad decreased levels of IL-6, TXB2, and PGE2.Hazucha et al.(1996)0.4 784 2 h IE(15 min/ 30 min);(.VE) = 30L/min/m2BSA13 healthy malesubjectsSubjects received either placebo or 150 mg indomethacin/day fourdays prior to O3exposure. Indomethacin treatment attenuated theO3-induced decrease in FEV1, but had no effect on the O3-inducedincrease in MCh responsiveness.Ying et al.(1990)0.35 686 1 h Continuousexercise;(.VE).60 L/min14 healthy collegeage malesIn a placebo- and air-controlled random design, subjects were treatedwith 75 mg indomethacin every 12 h for 5 days prior to exposure.Indomethacin significantly reduced O3-induced decrements in FEV1and FVC.Schelegle et al.(1987)



### AX6-109Table AX6-13 (cont’d). Studies of Effects onHost Defense, on Drug Effects and SupportiveIn VitroStudies Relating toControlled Human Exposure to OzoneaOzoneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Supportive In Vitro Studies0.01 to0.1019.6 to1966 h bronchialepithelial cellsNonatopic,nonasthmatic andatopic, mildasthmatic bronchialbiopsy samplesExposure to 0.01-0.10 ppm O3significantly decreased the electricalresistance of cells from asthmaticsources, compared to nonasthmaticsources. This range of O3concentrations also increased the movementof14C-BSA across the confluent cultures of “asthmatic” cells to anextent that was greater thanthat in “nonasthmatic” cells.Bayram et al.(2002)0.1 196 24 h Nasal mucosa Allergic andnonallergic patientsIncreased concentrations of neurokinin A and substance P in mediumfollowing O3exposure. Levels of release of both neuropeptides werehigher from tissues derived from allergic compared to nonallergicpatients.Schierhornet al. (2002)0.2 392 3 h Nasal epithelialcells and airwayepithelial cell lineSynergistic effect of O3exposure on rhinovirus-induced release of IL-8at 24 h through mechanisms abrogated by antioxidant pretreatment.Additive enhancement of ICAM-1 expression.Spannhakeet al. (2002)1 1,690 4 h Macrophage-likeTHP-1 cellsTHP-1 cells were treated with samples of human surfactant protein A(SP-A) genetic variants (SP-A1 and SP-A2) that had been previouslyexposed to O3. O3-exposed variants differed in their ability to stimulatethe production of TNF-"and IL-8 by these cells.Wang et al.(2002)0.01 to0.1019.6 to1966 h bronchialepithelial cellsNonatopic,nonasthmatic andatopic, mildasthmatic bronchialbiopsy samplesNo difference in constitutive release of IL-8, GM-CSF, sICAM-1 andRANTES from cells from nonasthmaticand asthmatic sources, exceptfor detection of RANTES in latter cells only. Increased release of allmediators 24 h after 0.05 to 0.10 ppm O3in “asthmatic” cells, but onlyIL-8 and sICAM-1 in “nonasthmatic” cells.Bayram et al.(2001)0.120.240.502354709803 h Nasal epithelialcellsSmall dose-response activation of NF-6B coinciding with O3-inducedproduction of free radicals assessedby electron spin resonance.Increased TNF-"at two higher concentrations of O3at 16 hpostexposure.Nichols et al.(2001)



### AX6-110Table AX6-13 (cont’d). Studies of Effects onHost Defense, on Drug Effects and SupportiveIn VitroStudies Relating toControlled Human Exposure to OzoneaOzoneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Supportive In Vitro Studies(cont’d)0.06 to0.20118 to39224 h Nasal mucosa 105 surgicalsamples fromatopic andnonatopic patientsIncreased histamine release correlated with mast cell degranulation.Increased release of IL-1, IL-6, IL-8 and TNF-"following O3exposureat 0.10 ppm. Release of IL-4, IL-6, IL-8 and TNF-"atthis concentration was significantly greater from tissues from atopicversus nonatopic patients.Schierhornet al. (1999)0.5 980 1 h Lung fibroblastcell line with anairway epithelialcell lineBEAS-2B cells in the presence or absence of HFL-1 cells wereexposed and incubated for 11 or 23 h. Steady-state mRNA levelsof alpha 1 procollagens type I and II, as well as TGF$1, were increasedin O3-exposed co-cultured fibroblasts compared to air controls. Datasupport interactions between the cell types in the presence and theabsence of O3-exposure.Lang et al.(1998)0.5 980 1 h tracheal epithelialcellsO3exposure caused an increase inROS formation and a decline inPGE2production. No differences in mRNA and protein levels ofprostaglandin endoperoxide G/H synthase 2 (PGHS-2) or the rate of itssynthesis were detected, suggesting a direct effect of O3-generatedoxidants on PGHS-2 activity.Alpert et al.(1997)0.4 784 1 h Lung fibroblasts;airway epithelialcell lineCells incubated with O3-exposed arachidonic acid (AA) were found tocontain DNA single strand breaks.Pretreatment of the exposed AAsolution with catalase eliminated the effect on DNA, indicating itsdependence on H2O2production. The effect was potentiated by thenon-carbonyl component of ozonized AA.Kozumbo et al.(1996)0.250.504909806 h Human nasalepithelial cellsIncreased in ICAM-1, IL-6, IL-1, and TNF expression at 0.5 ppm.No increase in IL-8 expression. No increases at 0.25 ppm.Beck et al.(1994)0.250.501.004909801,9601 h Airway epithelialcell line andalveolarmacrophagesIncreased secretion of IL-6, IL-8, and fibronectin by epithelial cells,even at lowest O3concentration. No O3-induced secretion of thesecompounds by macrophages.Devlin et al.(1994)



### AX6-111Table AX6-13 (cont’d). Studies of Effects onHost Defense, on Drug Effects and SupportiveIn VitroStudies Relating toControlled Human Exposure to OzoneaOzoneConcentrationbExposureDurationActivity Level(.VE)Number andGender of Subjects Observed Effect(s) Referenceppm μg/m3Supportive In Vitro Studies(cont’d)0.20 to1.0392 to19602 h or 4 h Airway epithelialcell lineO3caused a dose-related loss in cellular replicative activity at exposurelevels that caused minimal cytotoxicity. DNAsingle strand breakswere not detected. These effects were different from those of H2O2and, thus, not likely related to production of this oxidant within thecells.Gabrielsonet al. (1994).0.250.501.004909801,9601 h Airway epithelialcell lineConcentration-dependent increased secretion of PGE2, TXB2,PGF2", LTB4, and LTD4. More secretion basolaterally than apically.McKinnonet al. (1993)0.301.005881,9601 h AlveolarmacrophagesConcentration-dependent increases in PGE2production, and decreasesin phagocytosis of sheep erythrocytes. No O3-induced secretion of IL1, TNF, or IL-6.Becker et al.(1991)aSee Appendix A for abbreviations and acronyms.bListed from lowest to highest O3concentration.



### 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 O 3 

### 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 c ontact 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 O 3 

### -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 O 3 

### 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 O 3 

### at rest for 4 h, and found increases in PMNs, eosinophils, and mononuclear cells following O 3 

### exposure. Graham and Koren (1990) compared inflammatory mediator s present in both the NL and BAL fluids of humans exposed to 0.4 ppm O 3 

### 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 O 3 

### 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 afte r exposure, as seen by Bascom et al. (1990).

### AX6-114 Tryptase, a constituent of mast cells, was also elevated after O 3 

### exposure at 0.4 ppm for 2 h (Koren et al., 1990). McBride et al. (1994) repor ted that asthmatic subjects were more sensitive than nonasthmatics to upper airway inflammation at an O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### for 2 h, Mudway and colleagues (1999) observed a significant depletion of uric aci d 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 O 3 

### 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 O 3 

### 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- 6 

### B transcription factor following exposure to O 3 

### at 0.12 to 0.5 ppm for 3 h. They found a dose-related activation of NF- 6 

### B within the cells that coincided with O 3 

### -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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### resulted in inflammation in the lung. Bronchoalveolar lavage fluid (3 h postexposure) from subjects exposed to O 3 

### contained increased PMNs as well as increased levels of PGE 2 

### , PGF 2 " 

### , and TXB 2 

### compared to fluid from air-exposed subjects. Koren et al. (1989a,b) described inflammatory changes 18 h after O 3 

### exposure. In addition to an eightfold increase in PMNs, Koren et al. reported a two-fold increase in BAL fluid prot ein, 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 PGE 2 

### , 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 O 3 

### -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 O 3 

### exposure and that this effect was mediated by

the O 3 

### -exposed epithelial cells. This group of studies demonstrated that exposure to O 3 

### 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 O 3 

### 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 O 3 

### -induced changes in the large airways. Studies collecting lavage fluid from isolated airway segments after O 3 

### exposure indicate increased neutrophils in the airways (Aris et al., 1993; Ba lmes 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 O 3 

### exposure, neutrophil numbers are elevated (Fahy et al., 1995). Increased BAL protein, suggesting O 3 

### -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 ( 99m 

### Tc-DTPA) from the lungs of humans exposed to O 3 

### , 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 O 3 

### 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 conclude d 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 O 3 

### for 6.6 h. Increased numbers of PMNs and levels of IL-6 were found at

both O 3 

### concentrations, suggesting that lung inflammation from O 3 

### can occur as a consequence of prolonged exposure to ambient levels while ex ercising. 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).

### AX6-117 As indicated above, a variety of potent proinflammatory mediators have been reported to be released into the airway lumen following O 3 

### exposure. Studies of human alveolar macrophages (AM) and airway epithelial cells exposed to O 3 

### in vitro suggest that most mediators

found in the BAL fluid of O 3 

### -exposed humans are produced by epithelial cells. Macrophages exposed to O 3 

### in vitro showed only small increases in PGE 2 

### (Becker et al., 1991). In contrast, airway epithelial cells exposed in vitro to O 3 

### showed large concentration-dependent increases

in PGE 2 

### , TXB 2 

### , LTB 4 

### , LTC 4 

### , and LTD 4 

### (McKinnon et al., 1993) and increases in IL-6, IL-8, and

fibronectin at O 3 

### 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 O 3 

### in vitro showed changes in only six proteins, suggesting that macrophage function wa s 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 O 3 

### -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 O 3 

### -induced lipid peroxidation is 4-hydroxynonenal (HNE). Healthy human subjects exposed to 0.4 ppm O 3 

### 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 O 3 

### - versus air-exposed subjects (Hamilton et al., 1998). In a recent study of healthy subjects exposed to 0.1 ppm O 3 

### for 2 h (Corradi et al., 2002), formation of 8-hydroxy-2'- deoxyguanosine (8-OHdG), a biomarker of reac tive 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 in terest, the increase in 8-OHdG was only significant in a subgroup of subjects with the wild genot ype 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 O 3 

### in some individuals. The generation of ROS following exposure to O 3 

### has been shown to be associated with a wide range of responses. In a recent study, ROS production by alveolar macr ophages 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 O 3 

### indicated that generation of ROS resulted in decrease in synthesis of the bronchodilatory prostaglandin, PGE 2 

### , as a result of inactivation of prostaglandin e ndoperoxide G/H synthase 2 (Alpert et al., 1997). These and similar studies indicate that the responses to products of O 3 

### 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 O 3 

### 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 O 3 

### (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-O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### than after air. Studies such as these suggest that the time course of eosinophil and neutrophil influx following O 3 

### 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 O 3 

### . 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 O 3 

### 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 O 3 

### of existing inflammatory processes within asthmatics. In a study of healthy and allergic asthmatic subjects exposed to 0.2 ppm O 3 

### 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 O 3 

### 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 O 3 

### exposure. The time course of the inflammatory response to O 3 

### in humans has not been explored fully. Nevertheless, studies in which BAL was perfor med 1-3 h (Devlin et al., 1990; Koren et al., 1991; Seltzer et al., 1986) after exposure to 0.4 ppm O 3 

### 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 PGE 2 

### are greater immediately after O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### in the modulation of immune inflammatory processes.



## AX6.9.4 Adaptation of Inflammatory Responses
Residents of areas with high oxidant con centrations tend to have somewhat blunted pulmonary function responses and symptoms to O 3 

### exposure (Hackney et al., 1976, 1977b, 1989; Avol et al., 1988; Linn et al., 1988). Animal st udies 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 O 3 

### for 5 consecutive days. Several indicators of inflammation (e.g., PMN
influx, IL-6, PGE 2 

### , 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 O 3 

### .

### 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 O 3 

### for 4 h. As reported by others, they found an

attenuation of FEV 1 

### , 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 FEV 1 

### and increases in the percentages of neutrophils and lymphocytes, in concentrations of total protei n, 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 O 3 

### 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 func tion, inflammation within the airways persists following repeated exposure to O 3 

### . In another study, Frank and colleagues (2001) exposed healthy subjects to filtered air and

to O 3 

### (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 O 3 

### arm compared to air control. Of particular note in this study was the observation that small airway function,
assessed by grouping values for isovolumetric FEF 25-75 

### , 

## 0 V max50 

### , and 

## 0 V 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 O 3 

### deposition in the lung, may provide important information regarding the

cumulative effects of O 3 

### exposure. Holz et al. (2002) made a comparison of early and late responses to allergen challenge following O 3 

### in subjects with allergic rhinitis or allergic asthma. With some variation, both early and late FEV 1 

### and cellular responses in the two subject groups were significantly enhanced by 4 consecutive days of exposure to 0.125 ppm O 3 

### for 3 h.

### AX6-122 

## AX6.9.5 Effect of Anti-Inflammato ry 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 O 3 

### (Schelegle et al., 1987; Ying et al ., 1990). Indomethacin did not alter

the O 3 

### -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 FEV 1 

### in normals, but not asthmatics (Alexis et al., 2000). Subjects have also been given ibuprofen, another NSAID agent that blocks cyclooxygenase metabolism, prior to O 3 

### exposure. Ibuprofen blunted decrements in lung function following O 3 

### exposure (Hazucha et al., 1996). Subjects given ibuprofen also had reduced BAL levels of the cyclooxygenase product PGE 2 

### and thromboxane B 2 

### , as well as IL-6, but no decreases were observed in PMNs, fibronectin, permeability, LDH activity, or macrophage phagocytic function. These studi es suggest that NSAIDs can blunt O 3 

### -induced

decrements in FEV 1 

### with selective (perhaps drug-specific) affects on mediator release and other

markers of inflammation.

At least two studies have looked at the effect s of the inhaled corticosteroid, budesonide, on

the effects of O 3 

### , with differing outcome perhaps associated with the presence of preexistent disease. Nightingale and colleagues (2000) exposed healthy nonsmokers to 0.4 ppm O 3 

### 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 O 3 

### exposure resulted in significant decreases in spirometric measures and increases in methacholine reactivity and neutrophils and myeloperoxidase in induced sputum. No signifi cant 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 O 3 

### for 2 h. Prior to exposure, at the midpoint and end of exposure, and at 6 h postexposure, FEV 1 

### was measured and a symptom questionnaire was administered; at 6 h postexposure, sputum was induced.

Budesonide treatment did not inhibit the decrement in FEV 1 

### 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 O 3 

### exposure levels, that basis remains unclear. Holz et al. (2005) investigated the mitigation of O 3 

### -induced inflammatory responses in subjects pretreated with single doses of inhale d fluticasone and oral prednisolone. Eighteen healthy ozone-responders (>10% increase in sputum neutrophils from O 3 

### 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 O 3 

### . Sputum was collected 3-h post-O 3 

### exposure. The 18 ozoneresponders were selected from 35 screened subject s. Twelve subjects were disqualified from the study (6 produced insufficient sputum and 6 had inadequate neutrophil responses to O 3 

### ), the remaining 5 subjects were [presumably] qualified but did not participate. The O 3 

### exposure caused small changes in FEV 1 

### (

! 

### 3.6% ±6.8%) that were not significantly different from baseline or between treatment groups (i.e., prescreen ing, placebo, fluticasone, and prednisolone). On average, the prescreening and placebo O 3 

### 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 O 3 

### 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 O 3 

### exposure.
Because the O 3 

### 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 O 3 

### . 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 O 3 

### for 2 h were assessed in both groups at the

end of treatment. O 3 

### -induced decrements in FEV 1 

### 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 unaffect ed 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 O 3 

### after 2 wk of antioxidant supplementation or placebo (Arab et al., 2002). Th ese 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 O 3 

### 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 Ca pability Following Ozone Exposure

Concern about the effect of O 3 

### on human host defense capability derives from numerous animal studies demonstrating that acute exposure to as little as 0.08 ppm O 3 

### 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 O 3 

### 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 (10 3 

### TCID 50 

### ). There was no difference

between the O 3 

### -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 O 3 

### 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 O 3 

### 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 O 3 

### for 6.6 h while undergoing moderate exercise. Alveolar macrophages from O 3 

### -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 O 3 

### in vitro has also been shown Becker et al. (1991). Although the

### AX6-125 evidence is inconclusive at present, there is a concern that O 3 

### 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 O 3 

### 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 O 3 

### (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 O 3 

### during CE (40 L/min) for 1 h; at 2 h post-O 3 

### 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 O 3 

### . The Foster et al. (1987) study suggested there is a stimulatory affect of O 3 

### on mucociliary clearance; whereas, Gerrity et al. (1993) found that in the recovery period following O 3 

### 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 O 3 

### -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 w ithin 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 O 3 

### exposure previously cited above have reported increases in markers of airway permeability after both acute exposures and repeated exposures. These findings suggest that O 3 

### 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 O 3 

### or air and their permeability was assessed by measuring the paracellular flux of 14 

### C-BSA. The increase in permeability 24 h following O 3 

### 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 O 3 

### , 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 O 3 

### . As referenced in Section 6.9.3, the O 3 

### -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 sa me group, Krishna et al. (1998) exposed healthy subjects to 0.2 ppm O 3 

### 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 O 3 

### 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 O 3 

### with respiratory system fluids or tissues may produce effects measured outside the respiratory tract—either in the blood, as changes in circulating blood lymphocytes, erythrocyt es, 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 O 3 

### could cause these extrapulmonary effects. ( See Section 5.4 for a discussion of the systemic effects of O 3 

### 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 pe ripheral blood lymphocytes collected from human volunteers did not find any significant ge notoxic or functional changes at O 3 

### exposures of 0.4 to 0.6 ppm for up to 4 h/day. Limited data on human subjects indicated that 0.5 ppm O 3 

### 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 O 3 

### exposures under 0.5 ppm. Other human exposure studies have attempted to identify specific markers of exposure

to O 3 

### in blood. For example, Schelegle et al. (1989) showed that PGF 2 " 

### was elevated after O 3 

### exposure (0.35 ppm); however, no increase in " 

### -1 protease inhibitor was observed by Johnson et al. (1986). Foster et al. (1996) found a re duction in the serum levels of the free radical

scavenger " 

### -tocopherol after O 3 

### 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 O 3 

### for 7.5 h while intermittently exercising. Liu et al. (1997, 1999) used a salicylate metabolite, 2,3-dihydroxybenzoic acid (DHBA), to i ndicate increased levels of hydroxyl radical which hydroxylates salicylate to DHBA. Increased DHBA levels after exposure to 0.12 and 0.40 ppm suggest that O 3 

### increases production of hydroxyl radical. The levels of DHBA were correlated with changes in spirometry. Only a few experimental human studies have examined O 3 

### effects in other nonpulmonary organ systems besides blood. Early studies on th e 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 O 3 

### 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 O 3 

### using a noninvasive impedance cardiographic method. No changes were found at this high O 3 

### concentration after 2 h of exposure while the subjects exercised intermittently at 25 L/min. Gong et al. (1998) monitored ECG, HR, car diac 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 ( 

## 0 V E 

### . 

### 30 L/min) to FA
and on the subsequent day to 0.3 ppm O 3 

### . S ee Section AX6.3 for more details about this study

. Statistically significant O 3 

### effects for both groups combined were increases in HR, rate-pressure product, and the alveolar-to-arterial PO 2 

### gradient. Gong et al. (1998) suggested that by impairing alveolar-arterial oxygen transfer, the O 3 

### 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. Howe ver, Gong et al. (1998) concluded that O 3 

### 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 O 3 

### 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), O 3 

### exposure can cause ventilation to shift away from the well perfused basal lung ( see Section AX6.2.3 for more details ). This effect of O 3 

### on ventilation distribution [and by association the small airways] may persist beyond 24-h postexposure (Foster et al., 1997). Hypoxic pulmonary artery vasoconstr iction 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 me diated 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 O 3 

### 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 O 3 

### (0.12 ppm) in tandem with fine particulate ( . 

### 150 μg/m 3 

### ) (Brook et al., 2002). Delaunois et al. (1998) also found that O 3 

### 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 O 3 

### exposure. This

notion is consistent with the O 3 

### -induced reduction in alveolar-arterial oxygen transfer observed by Gong et al. (1998).

Effects of O 3 

### 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 FEV 1 

### /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 SaO 2 

### of only 82% (inspired oxygen, 20.93%). Thus, even prior to O 3 

### exposure, COPD patients may have reduced gas exchange and low SaO 2 

### . Based on model predictions, increasing

tidal volume increases the O 3 

### 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 O 3 

### doses. Any inflammatory or edematous responses due to O 3 

### 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, O 3 

### 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 O 3 

### 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 O 3 

### exposure with age ( see Section AX6.5.1 ). It is conceivable, therefore, that COPD patients a nd elderly individuals (due to their decreased symptomatic responses to ambient O 3 

### ) 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 conditi ons 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 O 3 

### and SO

x 

### 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 O 3 

### criteria document (Table AX6-14) reported, except for one study (Linn et al., 1994), no significant effects on healthy individuals exposed to mixtures of O 3 

### and SO 2 

### or H 2 

### SO 4 

### aerosol. In the study of Linn et al. (1994), which was a repeated 6.5 h exposure protocol, O 3 

### alone and O 3 

### + H 2 

### SO 4 

### 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 O 3 

### (U.S. Environmental Protection Agency, 1996). Thus, in both healthy and asthmatic subjects, the interactive effects

of O 3 

### and other pollutants were marginal and the response was dominated by O 3 

### . Since 1994, the only laboratory study that examined the health effects of a mixture of O 3 

### and sulfur oxides (SO 2 

### and H 2 

### SO 4 

### ) 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.



## 0 V E 

### 22 L/min) in random order to air and a mixture of 0.10 ppm O 3 

### , 0.10 ppm SO 2 

### and 42 to
198 mg/m 3 

### H 2 

### SO 4 

### (mean conc. 101 mg/m 3 

### , 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 H 2 

### SO 4 

### (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 we re minimal and not significant. The divergent observations of the two studies have been explained by the presence of an unidentified
environmental factor in Uniontown, differen ces in physico-chemical properties of acid,Table AX6-14. Ozone Mixed with Other PollutantsaConcentrationbPollutantExposure Durationand ActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Sulfur-Containing Pollutants0.00.1 +0.1 +0196b+262b+101bAirO3+SO2+H2SO44 hIE 15' ex/ 15' restVE= 22 L/min25 °C50% RH8 M, 7 F1 M, 4 F10 M, 11 FHealthyAsthmaticAllergicAll NS,9 to 12 yrs. oldSpirometry, PEFR and subjectivesymptoms score showed no meaningfulchanges between any condition for atotal study population. The symptomsscore reported by a subset ofasthmatics/allergics were positivelyassociated with inhaled concentrationof H2SO4(p = 0.01).Linn et al.(1997)0.20.3392564O3NO2H2SO490 min.V.E.32 L/minIE 3 × 15 min21 °C50% RH24(17 M, 7 F)Asthmatic NS,11 to 18 years oldH2SO4/O3/NO2, O3/NO2and clean airproduced similar responsesLinn et al.(1995)0.120.300.0523556470O3NO2H2SO4HNO31.5 h with IE for2 consecutive days;V.E.23.2 L/min22 °C65% RH22 completedstudy;15 M, 7 FAsthmatic NS,adolescents; NS, 12 to19 years oldNo significant pulmonary functionchanges following any exposurecompared to response to clean air.Six additional subjects started thestudy, but dropped out due touncomfortable symptoms.Koenig et al.(1994)0.12 235100O3H2SO46.5 h2 consecutive days50 min exercise/hV.E= 29 L/min21 °C50% RH8 M, 7 F13 M, 17 FNonasthmatic NS,22 to 41 years oldAsthmatic NS,18 to 50 years oldExposure to O3or O3+ H2SO4inducedsignificant decrements inforced expiratory function. Differencesbetween O3and O3+ H2SO4were, atbest, marginally significant. O3is themore important pollutant for inducingrespiratory effects. A few asthmaticand nonasthmatic subjects were moreresponsive to O3+ H2SO4than toO3alone.Linn et al.(1994)0.080.120.18157235353100100O3O3O3NaClH2SO43-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% RH16 M, 14 F10 M, 20 FNonasthmatic NS,18 to 45 years oldAsthmatic NS,21 to 42 years oldNo significant changes in symptoms orlung function with any aerosol/O3combination in the healthy group.In asthmatics, H2SO4preexposureenhanced the small decrements in FVCthat occurred following exposure to0.18 ppm O3. Asthmatics had nosignificant changes on FEV1with anyO3exposures, but symptoms weregreater.Utell et al.(1994)Framptonet al. (1995)



### AX6-131 DRAFT-DO NOT QUOTE OR CITETable AX6-14 (cont’d). Ozone Mixed with Other PollutantsaConcentrationbPollutantExposure Durationand ActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Sulfur-Containing Pollutants (cont’d)0.120.10235262O3SO21 h (mouthpiece)IE V.E.30 L/min45-min exposure to air orO3, followed by 15-minexposure to O3or SO222 °C75% RH8 M, 5 F Allergic asthmatics,12 to 18 years old,medications withheldfor at least 4 h beforeexposuresPrior exposure to O3potentiatedpulmonary function responses to SO2;decrements in FEV1were!3,!2, and!8% for the air/O3, O3/O3, and O3/SO2exposures, respectively.Koenig et al.(1990)0.25 4901,200to1,600O3H2SO42 hIEV.E= 30 to 32 L/min35 °C83% RH9 M Healthy NS,19 to 29 years oldNo significant effects of exposure to O3alone or combined with H2SO4aerosol.Horvathet al. (1987)Nitrogen-Containing Pollutants0.00.20.40.2+0.40.10.20.1+0.20392752196376AirO3NO2O3+NO2O3NO2O3+NO23 hIE 10' ex/ 20' restV.E=32 L/min6 hIE 10' ex/ 20' restV.E=32 L/minT = 25 °CRH = 50%9 M, 2 F Atopic asthmatics22 to 41 yrs. oldExposure to NO2alone had minimaleffects on FEV1. However, O3alone orin combination elicited significantlygreater decline in FEV1in a short (3 h)exposure (higher concentrations) than along (6 h) exposure where the effectswere nonsignificant. Allergenchallenge inhalation significantlyreduced PD20FEV1in all short but notthe long exposures. No additive orpotentiating effects have beenobserved.Jenkins et al.(1999)0.00.360.360.750.3607066771,411943AirO3NO2NO2SO22 hrestHead onlyexposure6 M, 6 F Healthy NS19 to 33 yrs. oldFor NO2and SO2the absorbed fractionof O3increased relative (to baseline)whereas after O3exposure it decreased.The differences explained by anincreased production of O3-reactivesubstrate in ELF due to inflammation.Rigas et al.(1997)0.450.608831,129O3NO22-h random exposures toFA, O3, NO2, and O3+NO2; IE; V.E= 26-29L/min23.6 °C62% RH6 M2 FHealthy, NS, 56 to85 years oldExercise-induced cardiac output wassmaller with O3+ NO2exposurecompared to FA or O3alone.DrechslerParks et al.(1995)



### AX6-132 DRAFT-DO NOT QUOTE OR CITETable AX6-14 (cont’d). Ozone Mixed with Other PollutantsaConcentrationbPollutantExposure Durationand ActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Nitrogen-Containing Pollutants (cont’d)0.300.605891,129O3NO22-h exposure to NO2orFA, followed 3 h later by2-h exposure to O3, IEV.E= 20 L/min/m2BSA21 °C40% RH21 F Healthy NS,18 to 34 years oldNo significant effect of NO2exposureson any measured parameter. Sequentialexposure of NO2followed by O3induced small but significantly largerdecrements in FEV1and FEF25-75thanFA/O3sequence. Subjects hadincreased airway responsiveness tomethacholine after both exposures, withsignificantly greater responsivenessafter the NO2/O3sequences than afterthe FA/O3sequence.Hazuchaet al. (1994)0.2 392500O3HNO3H2O5 hIE (50 min/h exercise)V.E.40 L/min2 h HNO3or H2O fog orair, followed by 1-h break,followed by 3 h O320 °C5% RH6 M, 4 F Healthy NS,minimum of 10%decrement in FEV1after 3 h exposure to0.20 ppm O3with50 min exercise/hExposure to HNO3or H2O fog followedby O3induced smaller pulmonaryfunction decrements than air followedby O3.Aris et al.(1991)0.00.120.300.12+0.300235564AirO3NO2O3+ NO21 h (mouthpiece)IEV.E= 33 L/minV.E= 35 L/min22 °C75% RH5 M, 7 F9 M, 3 FHealthy NS,12 to 17 years oldAsthmatic13 to 18 years oldFindings inconsistent across cohortsand atmospheres. No significantdifferences in FEV1and RTbetweenasthmatics and healthy, or betweenatmospheres and cohorts.Koenig et al.(1988)0.300.605891,129O3NO21 h (mouthpiece)CEV.E.70 L/min for menV.E.50 L/min for women20 M, 20 F Healthy NS,21.4 ± 1.5 (SD)years old for F,22.7 ± 3.3 (SD) yearsold for MNo differences between responses toO3and NO2+ O3for spirometricparameters. Increase in SRaw withNO2+ O3was significantly less than forO3alone.Adams et al.(1987)0.300.300.150.150.150.150.15589564200294284200294282393200O3NO2H2SO4O3NO2H2SO4O3NO2SO2H2SO42 h CE for 20 minV..25 L/min2 h, 60 mintotal exerciseV..25 L/min2 h, 60 mintotal exerciseV..25 L/min28 to 29 °C50 to 60% RH6 M6 M3 MHealthy subjects,some smokersPossible small decrease in SGawPossible small decrease in SGawPossible small decrease in FEV1Kagawa(1986)



### AX6-133 DRAFT-DO NOT QUOTE OR CITETable AX6-14 (cont’d). Ozone Mixed With Other PollutantsaConcentrationbPollutantExposure Durationand ActivityExposureConditionscNumber andGender ofSubjectsSubjectCharacteristics Observed Effect(s) Referenceppm μg/m3Peroxyacetyl Nitrate0.450.600.138831,129644O3NO2PAN2 hIEV.E.25 L/min24 °C55 to 58% RH8 M, 8 F8 M, 8 FHealthy NS;19 to 26 years old;51 to 76 years oldNo differences betweenresponses to O3alone, O3+ NO2, O3+PAN, or O3+ NO2+ PAN.DrechslerParks et al.(1989)0.450.308831,485O3PAN2 hIEV.E.27 L/min22 °C60% RH3 M, 5 F Healthy NS,mean age = 24 yearsNo differences betweenresponses to exposure toO3alone and O3+ PAN.DrechslerParks et al.(1987b)0.4850.279521,337O3PAN2 hIEV.E.25 L/min21 °CWBGT10 F Healthy NS,19 to 36 years oldExposure to the mixture of PAN + O3induced decrements in FVC and FEV1averaging 10% greater than observedfollowing exposure to O3alone.Horvathet al. (1986)Particle-Containing Pollutants0.00.120235b+153bAirO3+PM2.52-2.5 hrest22 °C30% RH15 M, 10 F Healthy NS18 to 50 yrs. oldNeither systolic nordiastolic pressurehas been affected by pollutantsexposure despite a significant brachialartery constriction and a reduction inarterial diameter when compared tofiltered air (p = 0.03). Absence offlow- and nitroglycerin-mediatedbrachial artery dilatation.Brook et al.(2002)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 histor y 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 O 3 

### . Both gases are almost invariably present in ambient atmosphere. Compared to O 3 

### , NO

x 

### species have limited solubility and moderate oxidizing capability. Both O 3 

### and NO 2 

### are irritants and tissue oxidants and exert their toxic actions through many common mechanisms. The regional dosimetry and the primary sites of action of O 3 

### and NO 2 

### 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 O 3 

### criteria document (Table AX6-14) generally reported only small pulmonary function changes after combined exposures of NO 2 

### or nitric acid (HNO 3 

### ) with

O 3 

### , regardless if the interactive effects were potentiating or additive. In two of these studies, the effects reached statistical significance, but th ey were not coherent. Preexposure with NO 2 

### potentiated both spirometric and nonspecific airway reactivity response following subsequent O 3 

### exposure (Hazucha et al., 1994); however, exposure to NO 2 

### + O 3 

### mixture blunted SRaw increase as compared to O 3 

### alone (Adams et al.,1987). As with O 3 

### and SO

x 

### mixtures, the effects have been dominated by O 3 

### (U.S. Environmental Protection Agency, 1996). Combined exposure to O 3 

### and NO 2 

### also blunted the exercise-induced increase in cardiac output found with FA and O 3 

### 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 NO 2 

### , 0.45 ppm O 3 

### , and to 0.60 ppm NO 2 

### + 0.45 ppm O 3 

### while alternating 20-min periods of rest and exercise. Cardiac output, HR, stroke volume, and systolic time in tervals 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 ( 

## 0 V E 

### , 

## 0 VO 2 

### , f B 

### ) also were measured. There
were no statistically significant differences between exposures for HR, 

## 0 V E 

### , 

## 0 VO 2 

### , f B 

### , 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 O 3 

### and NO 2 

### exposures. The authors speculated that nitrate and nitrite reaction products from the

interaction of O 3 

### and NO 2 

### cross the air/blood interface in the lungs, causing peripheral

### AX6-136 vasodilation and a subsequent drop in cardiac out put. No major cardiovascular effects of O 3 

### only exposures have been reported in human subjects ( see Section AX6.10 ). Despite suggested potentiation of O 3 

### response by NO 2 

### 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 O 3 

### , 0.2 ppm NO 2 

### , and 0.1 ppm O 3 

### + 0.2 ppm NO 2 

### 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 O 3 

### , 0.4 ppm NO 2 

### , and 0.2 ppm O 3 

### + 0.4 ppm NO 2 

### ) employing the same exercise regimen. Immediately following each exposure, subjects were challenged with allergen ( D. pteronyssinus ) and PD 20 

### FEV 1 

### was determined. Exposure to NO 2 

### alone had minimal effects on FEV 1 

### or airway responsiveness. However, O 3 

### alone or in

combination with NO 2 

### elicited a significantly (p < 0.05) greater decline in FEV 1 

### 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 PD 20 

### FEV 1 

### 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 (O 3 

### + NO 2 

### ) on lung function (FVC, FEV 1 

### ) was not significantly greater than the effect of individual gases for 6-h exposures, t hus no additive or potentiating effects have been observed. Shorter 3-h exposures using twice as high NO 2 

### concentrations, however, showed significant FEV 1 

### decrements following exposures to atmospheres containing O 3 

### . 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 O 3 

### and other gas mixtures was studied by Rigas et al. (1997). They used an O 3 

### bolus absorption technique to determine how exposures to O 3 

### , NO 2 

### , and SO 2 

### will affect distribution of O 3 

### adsorption by airway mucosa. The selected O 3 

### 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 O 3 

### , 0.36 ppm NO 2 

### , 0.75 ppm NO 2 

### and 0.75 ppm SO 2 

### for 2 h. The rationale for the selection of these gases was their differential absorption. Because O 3 

### and NO 2 

### are much less soluble in liquid (i.e., ELF) than SO 2 

### , they are expected to penetrate deeper into the lung than SO 2 

### 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 NO 2 

### and SO 2 

### exposure the absorbed fraction of an O 3 

### bolus in lower conducting airways increased relative to baseline, whereas during continuous O 3 

### exposure the O 3 

### bolus fraction in lower conducting airways decreased. The authors attempted to explain the differences by suggesting that there may be increased production of an O 3 

### -reactive substrate in epithelial lining fluid due to airway inflammation. As interpreted by the investigators, during NO 2 

### and SO 2 

### exposures the substrate was not depleted by these gases and so could react

with the O 3 

### bolus, whereas during O 3 

### exposure the substrate was depleted, causing the fractional absorption of the O 3 

### 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 Mix tures Including Particulate Matter
Almost all of the studies published over the last twenty years investigating the health

effects of mixtures of O 3 

### 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 O 3 

### and PAN as in previous
studies, which is attributable to O 3 

### 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 O 3 

### , SO 2 

### , and NO 2 

### absorption in the lower conducting airways of young healthy subjects may modulate pathophysiologic response as well. Exposure

to SO 2 

### and NO 2 

### increased, while exposure to O 3 

### decreased, the absorbing capacity of the airways

for O 3 

### . The authors have suggested that SO 2 

### or NO 2 

### -inflamed airways release additional substrates into the epithelial lining fluid that react with O 3 

### , thus progressively removing O 3 

### 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 O 3 

### 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 O 3 

### and 153 μg/m 3 

### of

concentrated ambient PM 2.5 

### , and a control atmosphere of filtered air with a trace of O 3, 

### 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 O 3 

### 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 res ponses originated from field studies using a mobile laboratory. These field studies involve d subjects exposed to ambient air, FA without pollutants, or FA containing artificially generated concentrations of O 3 

### 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 O 3 

### concentration and level of exercise (A vol 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### concentration of 0.153 ppm) and purified air containing a controlled concentration of generated O 3 

### 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 la boratory finding of no significant difference in pulmonary function effects between O 3 

### and O 3 

### 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 O 3 

### in commercial aircraft flying at high altitudes, and in altitude-simulation studies, have been reviewed elsewhere (U.S. Environmental Prot ection Agency, 1986, 1996). Flight attendants,Table AX6-15. Acute Effects of Ozone in AmbientAir in Field Studies with a Mobile LaboratoryaMean OzoneConcentrationbAmbientTemperaturec(°C)ExposureDurationActivity Level(.VE) Number of Subjects Observed Effect(s) Referenceppm μg/m30.113 ± .033 221 ± 65 33 ± 1 1 h CE (22 L/min) 66 healthy children,8 to 11 years oldNo significant changes in forced expiratoryfunction and symptoms of breathingdiscomfort after exposure to 0.113 ppm O3inambient air.Avol et al.(1987)0.144 ± .043 282 ± 84 32 ± 1 1 h CE (32 L/min) 59 healthyadolescents,12 to 15 years oldSmall significant decreases in FVC (!2.1%),FEV0.75(!4.0%), FEV1(!4.2%), and PEFR(!4.4%) relative to control with no recoveryduring a 1-h postexposure rest; no significantincreases in symptoms.Avol et al.(1985a,b)0.153 ± .025 300 ± 49 32 ± 2 1 h CE (53 L/min) 50 healthy adults(competitivebicyclists)Mild increases in symptoms scores andsignificant decreases in FEV1(!5.3%) andFVC; mean changes in ambient air were notstatistically different from those in purified aircontaining 0.16 ppm O3.Avol et al.(1984, 1985c)0.156 ± .055 306 ± 107 33 ± 4 1 h CE (38 L/min) 48 healthy adults,50 asthmatic adultsNo significant changes for total symptomscore or forced expiratory performance innormals or asthmatics; however, FEV1remained low or decreased further (!3%) 3 hafter ambient air exposure in asthmatics.Linn et al.(1983)Avol et al.(1983)0.165 ± .059 323 ± 115 33 ± 3 1 h CE (42 L/min) 60 "healthy" adults(7 were asthmatic)Small significant decreases in FEV1(!3.3%)and FVC with no recovery during a 1-hpostexposure rest; TLC decreased and)N2increased slightly.Linn et al.(1983)Avol et al.(1983)0.174 ± .068 341 ± 133 33 ± 2 2 h IE (2 times resting)at 15-min intervals34 "healthy" adults,30 asthmatic adultsIncreased symptom scores and smallsignificant decreases in FEV1(!2.4%), FVC,PEFR, and TLC in both asthmatic and healthysubjects; however, 25/34 healthy subjects wereallergic and "atypically" reactive to pollutedambient air.Linn et al.(1980, 1983)aSee Appendix A for abbreviations and acronyms.bRanked by lowest level of O3in ambient air, presented as the mean ± SD.cMean ± SD.



### AX6-140

### AX6-141 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 O 3 

### 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 O 3 

### 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 O 3 

### 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 O 3 

### -scrubbing catalytic filters (Melton, 1990). However, in-flight O 3 

### exposure can still occur because catalytic filters are not necessarily in continuous use during flight. Other factors to consider in ai rcraft 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 O 3 

### 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.

-

### AX6-142 

## REFERENCES

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V 

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### AX6-152 McDonnell, W. F.; Kehrl, H. R.; Abdul-Salaam, S.; Ives, P. J.; Folinsbee, L. J.; Devlin, R. B.; O'Neil, J. J.; Horstman, D. H. (1991) Respiratory response of humans exposed to low levels of ozone for 6.6 hours. Arch. Environ. Health 46: 145-150. McDonnell, W. F.; Muller, K. E.; Brombe rg, P. A.; Shy, C. M. (1993) Predicto rs of individual differences in acute response to ozone exposure. Am. Rev. Respir. Dis. 147: 818-825. McDonnell, W. F.; Stewart, P. W.; Andreoni, S.; Seal, E., Jr .; Kehrl, H. R.; Horstman, D. H.; Folinsbee, L. J.; Smith, M. V. (1997) Prediction of ozone-induced FEV 1 changes: effects of concentration, duration, and ventilation. Am. J. Respir. Crit. Care Med. 156: 715-722. McDonnell, W. F.; Stewart, P. W.; Smith, M. V.; Pan, W. K.; Pan, J. (1999) Ozone-induced respiratory symptoms: exposure-response models and association with lung function. Eur. Respir. J. 14: 845-853. McGee, M. P.; Devlin, R.; Saluta, G.; Koren, H. (1990) Tissue factor and factor VII messenger RNAs in human alveolar macrophages: effects of breathing ozone. Blood 75: 122-127. McKinnon, K. P.; Madden, M. C.; Noah, T. L.; Devlin, R. B. (1993) In vitro ozone exposure increases release of arachidonic acid products from a human bronchial ep ithelial cell line. Toxicol. Appl. Pharmacol. 118: 215-223. Melton, C. E. (1990) Airliner cabin ozone: an updated review. Washington, DC: Federal Aviation Administration, Office of Aviation Medicine; report no. DOT/FAA/AM -89/13. Available from: NTIS, Springfield, VA; AD-A219 264. Messineo, T. D.; Adams, W. C. (1990) Ozone inhalation e ffects in females varying widely in lung size: comparison with males. J. Appl. Physiol. 69: 96-103. Michelson, P. H.; Dailey, L.; Devlin, R. B.; Peden, D. B. (1999) Ozone e ffects on the immediate-phase response to allergen in the nasal airways of allergic asthma tic subjects. Otolaryngol. Head Neck Surg. 120: 225-232. Mohammed, S. P.; Higenbottam, T. W.; Adcock, J. J. ( 1993) Effects of aerosol-applie d capsaicin, histamine and prostaglandin-E2 on airway sensory receptors of anaesthetized cats. J. Physiol. Lond. 46: 951-966. Molfino, N. A.; Wright, S. C.; Katz, I. ; Tarlo, S.; Silverman, F.; McClean, P. A.; Szalai, J. P.; Raizenne, M.; Slutsky, A. S.; Zamel, N. (1991) Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects. Lancet 338(8761): 199-203. Molfino, N. A.; Slutsky, A. S.; Zame l, N. (1992) The effects of air pollution on allergic bronchial responsiveness. Clin. Exp. Allergy 22: 667-672. Montuschi, P.; Nightingale, J. A.; Kharitonov, S. A.; Barnes, P. J. (2002) Ozone-induced increase in exhaled 8-isoprostane in healthy subjects is resistant to inhaled budesonide. Free Radical Biol. Med. 33: 1403-1408. Mudway, I. S.; Kelly, F. J. (2000) Ozone and the l ung: a sensitive issue. Mol. Aspects. Med. 21: 1-48. Mudway, I. S.; Blomberg, A.; Frew, A. J.; Holgate, S. T.; Sandström, T.; Kelly, F. J. (1999) Antioxidant consumption and repletion kinetics in nasal lavage fluid following exposure of healthy human volunteers to ozone. Eur. Respir. J. 13: 1429-1438. Mudway, I. S.; Stenfors, N.; Blomberg, A.; Helleday, R.; Dunster, C.; Marklund, S. L.; Frew, A. J.; Sandström, T.; Kelly, F. J. (2001) Differences in basal airway antioxi dant concentrations are not predictive of individual responsiveness to ozone: a comparison of healthy a nd mild asthmatic subjects. Free Radical Biol. Med. 31: 962-974. Nagda, N. L.; Fortmann, R. C.; Koontz, M. D.; Baker, S. R.; Ginevan, M. E. (1989) Airliner cabin environment: contaminant measurements, health risks, and mitig ation options. Washington, DC: U.S. Department of Transportation, Office of the Secretary. Av ailable from: NTIS, Springfield, VA; PB91-159384. National Institutes of Health. (1997) Guidelines for the di agnosis and management of asthma: expert panel report 2. Bethesda, MD: U.S. Department of Health and Huma n Services, National Heart, Lung, and Blood Institute; publication no. 97-4051. Available: http://www.nhlbi.nih .gov/guidelines/asthma/asthgdln.pdf (11 April 2003). National Institutes of Health. (2003) Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics 2002. Bethesda, MD: U.S. Department of Health and Human Services, National Heart, Lung, and Blood Institute; NI H publication no. 02-5074. Available: http://www.nhlbi.nih.gov/guidelines/asthma/ asthmafullrpt.pdf [26 August, 2004]. Neas, L. M.; Dockery, D. W.; Koutrakis, P.; Tollerud, D. J.; Speizer, F. E. (1995) The association of ambient air pollution with twice daily peak expiratory flow rate measurements in children. Am. J. Epidemiol. 141: 111-122. Newson, E. J.; Krishna, M. T.; Lau, L. C. K.; Howarth, P. H.; Holgate, S. T.; Frew, A. J. (2000) Effects of short-term exposure to 0.2 ppm ozone on biomarkers of inflammation in sputum, exhaled nitric oxide, and lung function in subjects with mild atopic as thma. J. Occup. Environ. Med. 42: 270-277.

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### 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)

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..................................................... AX7-48 Brauer and Brook (1997)

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...................................................... AX7-18 Bremner et al. (1999)

..................................................... AX7-87 Burnett et al. (1995)

...................................................... AX7-57 Burnett et al. (1997a)

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..................................................... 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)

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.................................................. AX7-48 Castillejos et al. (1995)

................................................... AX7-27 Chan and Wu (2005)

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........................................................ AX7-89 De Leon et al. (2003)

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Delfino et al. (1997a)

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................................................ AX7-20 Díaz et al. (1999)

........................................................ AX7-94 Dockery et al. (1992)

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..................................................... AX7-36 Dominici et al. (2003)

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...................................................... AX7-56 Ha et al. (2001)

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Ha et al. (2003)

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............................................................ AX7-90 Hoek and Brunekreef (1995)

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...................................................... AX7-112 Ilabaca et al. (1999)

...................................................... AX7-50 Ito (2003; 2004)

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.......................................................... AX7-72 Jaffe et al. (2003)

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......................................................... 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)

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Lee and Schwartz (1999)

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.................................................. AX7-55 Morgan et al. (1998a)

..................................................... AX7-67 Morgan et al. (1998b)

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Park et al. (2005)

........................................................ AX7-34 Peel et al. (2005)

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...................................................... AX7-33 Peters et al. (2000b)

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Sheppard et al. (1999)

.................................................... AX7-53 Simpson et al. (1997)

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...................................................... AX7-89 Zmirou et al. (1998)

...................................................... AX7-86Table AX7-1. Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited 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, NYJun-Aug 1993National Cooperative InnerCity Asthma Study(NCICAS) cohort. This panelstudy examined 846asthmatic children aged4-9 years for O3exposureeffects 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,SO2No associations were seen betweensingle or multiday O3measures and anyevening outcome measure. The effectsof O3on morning outcomes increasedover several days with the strongestassociations seen for multiday lags.Joint modeling of O3with NO2or SO2resulted in slightly reduced estimates foreach pollutant. Closed cohort.Approximately 60% of NCICAS cohortreturned diary, characterizations similarto entire cohort.8-h avg O3(per 15 ppb):% change in morning PEF:Lag 1-5:All areas: –0.59% (–1.05, –0.13)St. Louis: –0.86% (–2.10, 0.38)Chicago: –0.62% (–2.41, 1.16)Detroit: –0.75% (–2.36, 0.86)Cleveland: –0.62% (–2.23, 0.99)Washington: –0.54% (–2.02, 0.93)Baltimore: 0.24% (–0.95, 1.43)East Harlem: –0.73% (–1.63, 0.17)Bronx: –0.69% (–1.54, 0.15)Odds ratios:Morning symptoms:Lag 1-4:All areas: 1.16 (1.02, 1.30)St. Louis: 0.82 (0.59, 1.14)Chicago: 1.09 (0.69, 1.72)Detroit: 1.72 (1.12, 2.64)Cleveland: 1.20 (0.81, 1.79)Washington: 1.11 (0.72, 1.72)Baltimore: 1.19 (0.89, 1.60)East Harlem: 1.22 (0.97, 1.53)Bronx: 1.23 (0.98, 1.54)



### AX7-9Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited 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, NYJun-Aug 1993A cohort of 846 asthmaticchildren aged 4-9 yearsexamined for effects ofsummer O3exposure on PEFand 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 prematureasthmatic children had greater declinesin PEF and higher incidence of morningsymptoms than normal birth weight andfull-term asthmatic children.8-h avg O3(per 15 ppb):% change in morning PEF:Low birth weight:Lag 1-5:!1.83% (!2.65,!1.01)Normal birth weight:Lag 1-5:!0.30% (!0.79, 0.19)Interaction term for birth weight,p < 0.05Odds ratios:Morning symptoms:Low birth weight:Lag 1-4: 1.42 (1.10, 1.82)Normal birth weight:Lag 1-4: 1.09 (0.95, 1.24)Interaction term for birth weight,p < 0.05Avol et al. (1998)Southern CaliforniacommunitiesSpring-summer 1994Three 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 O3exposure, vialogistic regression and GLM.Stratified analysisof low and highO3:Fixed site 1-hmax O3:Low: <100 ppbHigh: >100 ppbPersonal 24-havg O3:Low:#15.6 ppbHigh:$32.4 ppbNone The three groups responded similarly.Few pulmonary function or symptomassociations. Asthmatic children hadthe most trouble breathing, the mostwheezing, and the most inhaler use onhigh O3days in the spring. Ozone levelswere considered too low during theperiod of the study. Noncomplianceby subjects may have been a problem.Other analysis methods may have beenmore appropriate.Multiple endpoints analyzed. Fewconsistent or statistically significantresponses to O3exposure reported.



### AX7-10Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Gilliland et al. (2001)12 SouthernCaliforniacommunitiesJan-Jun 1996Time-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, NO2Ozone strongly associated with illnessrelated and respiratory absences. PM10only associated with upper respiratoryabsences. Long distributed lag effectsfor O3raise questions about adequacyof control for seasonal changes.8-h avg O3(per 20 ppb):% change in school absences:All illness:62.9% (18.4, 124.1)Nonrespiratory illnesses:37.3% (5.7, 78.3)Respiratory illnesses:82.9% (3.9, 222.0)Upper respiratory:45.1% (21.3, 73.7)Lower respiratory with wet cough:173.9% (91.3, 292.3)Linn et al. (1996)Three towns inCalifornia: Rubidoux,Upland, TorranceFall-spring 1992-1993and 1993-1994Panel 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 ppbSD 3Range 1-16Central site:23 ppbSD 12Range 3-53PM2.5, NO2Central site O3correlated with personalexposures, r = 0.61. Ozone effectsobserved on lung function but onlysignificant for FEV1in one analysis.No effects on symptoms. Ozone effectswere not robust to NO2or PM2.5. Powermay have been limited by short followupwithin seasons (limiting both persondays and variability in exposures).Change in lung function (per ppb):FEV1next morning:!0.26 mL (SE 0.25), p = 0.30FEV1afternoon:!0.18 mL (SE 0.26), p = 0.49FEV1crossday difference:!0.58 mL (SE 0.23), p = 0.01FVC next morning:!0.21 mL (SE 0.22), p = 0.34FVC afternoon:!0.20 mL (SE 0.29), p = 0.48FVC crossday difference:!0.25 mL (SE 0.25), p = 0.32



### AX7-11Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Ostro et al. (2001)Central Los Angelesand Pasadena, CAAug-Oct 1993Panel 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 49.0PM10, NO2,pollen, moldCorrelation between PM10and O3wasr = 0.35. Significant O3effect seen forextra medication use (above normal use).No O3effect on symptoms in expecteddirection observed. Inverse associationseen for cough. PM10effects seen at alag of 3 days. Time factors not explicitlycontrolled in analysis; may have led toconfounding of O3effects.1-h max O3(per 40 ppb):Odds ratios:Extra medication use:Lag 1: 1.15 (1.12, 1.19)Respiratory symptoms:Shortness of breath:Lag 3: 1.01 (0.92, 1.10)Wheeze:Lag 3: 0.94 (0.88, 1.00)Cough:Lag 3: 0.93 (0.87, 0.99)Delfino et al. (2003)Los Angeles, CANov 1999-Jan 2000A 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 9.6NO2, SO2, CO,volatileorganiccompounds,PM10Support the view that air toxics inthe pollutant mix from traffic mayhave adverse effects on asthma inchildren.1-h max O3(per 14.0 ppb):Odds ratio:Symptoms interfering withdaily activities:Lag 0: 1.99 (1.06, 3.72)Delfino et al. (1997a)Alpine, CAMay-Aug1994Panel study of 22 asthmaticsaged 9-46 years followed forrespiratory symptoms,morning-afternoon PEF, and$2agonist inhaler use.Personal O3measured for12 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 14PM10, pollen,fungiNo O3effects observed. No quantitative results for O3.



### AX7-12Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Delfino et al. (1998a)Alpine, CAAug-Oct 1995A panel of 24 asthmatics aged9-17 years followed for dailysymptoms. Analysis usingGEE model.1-h max O3:90 ppbSD 18PM10Asthma symptoms were significantlyassociated with both ambient O3andPM10in single-pollutant models. Ozoneeffects generally robust to PM10. Currentday O3effects strongest in asthmatics noton anti-inflammatory medication.Effects of O3and PM10were largelyindependent. The largest effects forPM10were seen for a 5-day distributedlag. For O3effects, there were no lagday effects; current day results showedthe greatest effect.1-h max O3(per 58 ppb):Odds ratios:O3only model:Lag 0: 1.54 (1.02, 2.33)O3with PM10model:Lag 0: 1.46 (0.93, 2.29)Delfino et al. (2004)Alpine, CAAug-Oct 1999, AprJun 2000Panel 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 22.0PM2.5, PM10,NO2Significant declines in FEV1associatedwith various PM indices (personal,indoor home, etc.), but not ambient O3levels.No quantitative results for O3.Delfino et al. (1996)San Diego, CASep-Oct 1993Panel 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 O3measured 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 11.2PM2.5, SO42!,H+, HNO3,pollen, fungalsporesNo effect of ambient O3on symptomscore. Personal O3significant forsymptoms, but effect disappeared whenconfounding day-of-week effect wascontrolled with weekend dummyvariable.$2inhaler used among7 subjects was significantly related topersonal O3. Results of this small studysuggest the value of personal exposuredata in providing more accurateestimates of exposures. However, nearly50% of personal O3measurements werebelow limits of detection, diminishingvalue of these data. Pollen and fineparticulate (low levels) were notassociated with any of the outcomes.Change in$2-agonist inhaler use(per ppb personal O3):0.0152 puffs/day (SE 0.0075),p = 0.04



### AX7-13Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Chen et al. (2000)Washoe County, NV1996-1998Time-series study of schoolabsenteeism examined among27,793 students (kindergartento 6th grade) from 57elementary schools.First-order autoregressionmodels used to assessrelationship between O3andschool 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 13.37PM10, 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 PM10and COconcentrations on the concurrent daywere associated with school absenteeism,but the estimate for PM10was a negativevalue.1-h max O3(per 50 ppb):Total absence rate:O3with PM10and CO model:Lag 1-14: 3.79% (1.04, 6.55)Newhouse et al.(2004)Tulsa, OKSep-Oct 2000Panel 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 10-70PM2.5, CO,SO2, pollen,fungal sporesAmong ambient air pollutants, O3seemed to be most significant factor.Morning PEF values significantlyassociated with average and maximumO3levels 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.Pearson correlation coefficient:Morning PEF:Mean O3levels:Lag 1:!0.274, p < 0.05Maximum O3levels:Lag 1:!0.289, p < 0.05



### AX7-14Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Ross et al. (2002)East Moline, IL andnearby communitiesMay-Oct 1994Panel 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 20PM10, SO2,NO2, pollen,fungiSaw significant associations betweenO3and both PEF declines andsymptom 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 max O3(per 20 ppb):Change in PEF (L/min):Morning:Lag 0-1:!2.29 (!4.26,!0.33)Afternoon:Lag 0:!2.58 (!4.26,!0.89)Symptom score (on scale of 0-3):Morning:Lag 1-3: 0.08 (0.03, 0.13)Afternoon:Lag 1-3: 0.08 (0.04, 0.12)Neas et al. (1995)Uniontown, PASummer 1990Panel 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 ppbSO2, PM10, H+Evening cough was associated with O3levels weighted by hours spent outdoorsduring the prior 12 h. A decrease in PEFwas associated with O3levels weightedby hours spent outdoors. When particlestrong acidity was added to the model,the decrement was decreased and nolonger significant.12-h avg O3(per 30 ppb):Evening PEF:!2.24 L/min (!4.43,!0.05)Odds ratio:Evening cough:1.36 (0.86, 2.13)Concentration weighted byproportion of time spent outdoorsduring prior 12 h:Evening PEF:!2.79 L/min (!6.69,!1.12)Odds ratio:Evening cough:2.20 (1.02, 4.75)



### AX7-15Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Neas et al. (1999)Philadelphia, PAJul-Sep 1993Panel study of 156 childrenaged 6-11 years at twosummer camps followed fortwice-daily PEF. Analysisusing mixed effects modelsadjusting for autocorrelatederrors.Daytime12-h avg O3(9 a.m-9 p.m.):SW camp:57.5 ppbIQR 19.8NE camp:55.9 ppbIQR 21.9H+, SO42!,PM2.5, PM10,PM10-2.5Some O3effects detected as well as PMeffects. Similar O3-related decrementsobserved in both morning and afternoonPEF. Ozone effects not robust to SO42!in two-pollutant models, whereas SO42!effects relatively robust to O3.12-h avg O3(per 20 ppb):Morning and evening PEF:O3only models:Lag 0:!1.38 L/min (!2.81, 0.04)Lag 1-5:!2.58 L/min (!4.81,!0.35)O3with SO42!model:Lag not specified:!0.04 L/minGent et al. (2003)Southern NewEnglandApr-Sep 2001Panel 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 15.5PM2.5Correlation between 1-h max O3anddaily PM2.5was 0.77 during this warmseason study. Large numbers ofstatistical tests performed. Significantassociations between symptoms and O3seen only in medication users, asubgroup considered to be moresensitive. PM2.5significant for somesymptoms, but not in two-pollutantmodels. Ozone effects generally robustto PM2.5. Study limitations includelimited control for meteorological factorsand the post-hoc nature of the populationstratification by medication use.1-h max O3(per 50 ppb):Odds ratios:Regular medication users (n = 130):Chest tightness:O3only model:Lag 1: 1.26 (1.00, 1.48)O3with PM2.5model:Lag 1: 1.42 (1.14, 1.78)Shortness of breath:O3only model:Lag 1: 1.22 (1.02, 1.45)



### AX7-16Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Korrick et al. (1998)Mount Washington,NHSummers 1991, 1992Cross-sectional studyevaluating the acute effects ofambient O3on pulmonaryfunction 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 21-74PM2.5, smoke,acidityWith prolonged outdoor exercise lowlevel exposures to O3were associatedwith significant effects on pulmonaryfunction. Hikers with asthma had a4-fold greater responsiveness to exposureto O3.% change in lung function(per 50 ppb O3):FEV1:!2.6% (!4.7,!0.4)FVC:!2.2% (!3.5,!0.8)Thurston et al. (1997)Connecticut RiverValley, CTJune 1991, 1992, 1993Panel 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 ppbH+, SO42!Ozone was most consistently associatedwith 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 max O3(per 83.6 ppb):Relative risks:$2-agonist use: 1.46 (t = 3.57)Chest symptoms: 1.50 (t = 4.77)Change in PEF (per ppb):!0.096 L/min (t = 1.92)Naeher et al. (1999)Vinton, VASummers 1995, 1996Panel study evaluated therelationship between O3anddaily change in PEF studiedin a sample of 473nonsmoking 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 8.74-56.63PM2.5, PM10,SO42!, H+Ozone was the only exposure related toevening PEF with 5-day cumulative lagexposure showing the greatest effect.24-h avg O3(per 30 ppb):Morning PEF:Lag 1:!2.13 L/min (!4.72, 0.46)Lag 1-3:!3.60 L/min (!7.66, 0.46)Evening PEF:Lag 0:!2.49 L/min (!5.02, 0.04)Lag 1-5:!7.65 L/min (!13.0,!2.25)



### AX7-17Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsCanadaBrauer et al. (1996)Fraser Valley, BritishColumbia, CanadaJun-Aug 1993Panel 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 11.8PM2.5, SO42!,NO3!, NH4+,H+End shift FEV1and FVC significantlydiminished in relation to O3levels.PM2.5also related to lung functiondeclines, but O3remained significant intwo-pollutant models. Next morninglung function remained diminishedfollowing high O3days. Ozone effectsstill 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.Change in lung function (per ppb1-h max O3):Endshift lung function:FEV1:!3.8 mL (SE 0.4)FVC:!5.4 mL (SE 0.6)Next morning function:FEV1:!4.5 mL (SE 0.6)FVC:!5.2 mL (SE 0.7)Brauer and Brook(1997)Fraser Valley, BritishColumbia, CanadaJun-Aug 1993Additional 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 13-84PM2.5, SO42!,NO3!, NH4+,H+Group 1: 9.0% sampling time (24-h)outdoors. Personal to ambient O3ratiowas 0.28.Group 2: 25.8% sampling time (24-h)outdoors. Personal to ambient O3ratiowas 0.48.Group 3: 100% sampling time(11-h work shift) outdoors. Personalto ambient O3ratio was 0.96.One of the first direct demonstrationsthat magnitude of personal exposure toO3is related to amount of time spentoutdoors. Further showed that, onaverage, outdoor fixed O3monitors wererepresentative of day-to-day changes inO3exposure experienced by the studypopulation.Same outcomes as reported inBrauer et al. (1996).



### AX7-18Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEuropeScarlett et al. (1996)Surrey, EnglandJun-Jul 1994Panel study examined154 children aged 7 years in aprimary school next to amajor motorway for O3exposure effects on PEF0.75,FVC, and FEV1usingautoregression for %change in function.8-h max O3:50.7 ppbSD 24.48PM10, NO2,pollenNo significant association was seenbetween pulmonary function measuresand O3levels. No pollen effects.Change in lung function (per ppb O3weighted by inverse of variance):FEV0.75:Lag 1: 0.01 mL (!0.12, 0.13)FVC:Lag 1: 0.07 mL (!0.09, 0.23)FEV0.75/FVC:Lag 1:!0.1% (!5.1, 4.8)Ward et al. (2002)Birmingham andSandwell, EnglandJan-Mar 1997May-Jul 1997A 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 andsymptoms. 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 ppbRange 2-33Summer:Median 22.0 ppbRange 10-41PM10, 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 betweenO3and PEF was generally negative in thesummer and positive in the winter. Moreassociations between O3and symptomswere 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 avg O3(per 21.5 ppb forwinter; per 10.2 ppb for summer):Change in PEF (L/min):Morning (lag 0-6):Winter: 17.53 (6.56, 28.52)Summer:!5.66 (!11.21,!0.09)Afternoon (lag 0-6):Winter: 0.28 (!9.03, 9.79)Summer:!0.14 (!5.34, 5.04)Odds ratios:Symptoms:Cough (lag 0-6):Winter: 0.88 (0.42, 1.81)Summer: 0.95 (0.76, 1.19)Shortness of breath (lag 0-6):Winter: 2.79 (1.56, 4.95)Summer: 1.35 (0.95, 1.94)Wheeze (lag 0-6):Winter: 1.59 (0.77, 3.31)Summer: 0.88 (1.38, 0.57)



### AX7-19Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Taggart et al. (1996)Runcorn and Widnesin NW EnglandJul-Sep 1993Panel 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/m324-h avg O3:Maximum24.5 μg/m3SO2, NO2,smokeNo 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 avg O3(per 10 μg/m3):% change in bronchialhyperresponsiveness:Lag 1: 0.3% (!16.6, 20.6)Lag 2: 2.6% (!22.1, 34.9)Desqueyroux et al.(2002a)Paris, FranceNov 1995-Nov 1996Panel 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 10PM10Significant associations between PM10,O3, and incident asthma attacks werefound. Low O3levels raise plausibilityconcerns.8-h avg O3(per 10 μg/m3):Odds ratio:Lag 2: 1.20 (1.03, 1.41)Desqueyroux et al.(2002b)Paris, FranceOct 1995-Nov 1996Panel 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 10PM10, SO2,NO250 COPD exacerbations observed overfollow-up period. 1-, 2-, and 3-day lagO3significantly related to exacerbations.No other pollutants significant. Low O3levels raise plausibility and confoundingconcerns.8-h avg O3(per 10 μg/m3):Odds ratio:Lag 1: 1.56 (1.05, 2.32)Effects appeared larger amongsmokers and those with worse gasexchange lung function.



### AX7-20Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Just et al. (2002)Paris, FranceApr-Jun 1996Panel study of 82 medicallydiagnosed asthmatic children(mean age 10.9 years)followed for O3exposure andPEF, asthmatic attacks,cough, supplementary use of$2-agonists, and symptoms ofairway irritation. Analysis byGEE.24-h avg O3:58.9 μg/m3SD 24.5Range 10.0-121.0PM10, NO2In asthmatic children, O3exposure wasrelated to the occurrence of asthmaattacks and additional bronchodilatoruse. O3was the only pollutant associatedwith changes in lung function, as shownby an increase in PEF variability anddecrease in PEF.24-h avg O3(per 10 μg/m3):% change in daily PEF variability:Lag 0-2: 2.6%, p = 0.05Odds ratio:Supplementary use of$2-agoniston days on which no steroidswere used:Lag 0: 1.41 (1.05, 1.89)Lagerkvist et al.(2004)Brussels, BelgiumMay 2002Panel 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, O3levels indoorsassumed to be 50% of themean outdoor O3concentration.Daytime outdoorO3:Range 77-116μg/m3Exposure dose:Range 352-914μg/m3·hNone Ozone levels did not have any adverseeffect on FEV1after 2 h of outdoorexercise. In addition, no significantdifferences were observed between Claracell protein levels before and afterexercise. A marginally significantpositive correlation between ambient O3dose and Clara cell protein levelsobserved among the nonswimmers,indicating increased antioxidant activityfollowing O3exposure in this group.The lack of a clear relationship betweenClara cell protein levels and O3dose maybe attributable to the short period of timebetween measurements and diurnalvariability of the protein levels.Pearson correlation:O3exposure dose and Clara cellprotein levels in serum:All subjects (n = 54):r = 0.17, p = 0.21Nonswimmers (n = 33):r = 0.34, p = 0.06Swimmers (n = 21):r =!0.08, p = 0.74



### AX7-21Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Schindler et al. (2001)Eight communitiesof SwitzerlandMay-Sep 1991A random sample of 3,912adult never-smokers, aged18-60 years, examined forshort-term O3-related changesin lung function. Naturallogarithms of FVC, FEV1,and FEF25-75were regressedagainst the individualpredictor variables and O3.Spline functions were used tocontrol potential trends.Sensitivity analyses for grassand pollens, and NO2andTSP involved lineartime-trend variables.8 h-avg O3(10 a.m.-6 p.m.):90.3 μg/m3Range 2.9-247.1NO2, TSP Daily average concentrations of O3wereassociated with daily sample means ofFEV1and FEF25-75in this random adultcross-sectional sample. The associationsbetween daily O3levels and daily meansof lung function were smaller inmagnitude than the association betweenannual O3levels 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 avg O3(per 10 μg/m3):% change in lung function:FEV1:!0.51% (!0.88,!0.13)FVC:!0.24% (!0.59, 0.11)FEF25-75:!1.04% (!1.85,!0.22)Frischer et al. (1993)Umkirch, GermanyMay-Oct 1991Panel 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” O3days. Nasal lavagesamples analyzed forpolymorphonuclear leukocytecounts, albumin, tryptase,eosinophil cationic protein,and myeloperoxidase.Analysis using individualregression methods.Stratified analysisof 1⁄2-h avg O3at3 p.m.:Low:<140 μg/m3High:>180 μg/m3None Significant higher polymorphonuclearleukocyte counts after high O3days.In children without symptoms of rhinitis,significantly elevated myeloperoxydaseand eosinophil cationic proteinconcentrations detected. Results suggestthat ambient O3produces aninflammatory response in the upperairways of healthy children.Children without symptoms ofrhinitis (n = 30):Myeloperoxydase:Low O3: median 77.39 μg/LHigh O3: median 138.60 μg/Lp < 0.05; Wilcoxon sign rank testEosinophilic cationic protein:Low O3: median 3.49 μg/LHigh O3: median 5.39 μg/Lp < 0.05; Wilcoxon sign rank test



### AX7-22Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Frischer et al. (1997)Umkirch, GermanyMay-Oct 1991Panel study examined 44school children aged 9-11years for ratio oforthotyrosine topara-tyrosine innasal 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 O3at3 p.m.:Low:<140 μg/m3High:>180 μg/m3None Ambient O3was associated with thegeneration of hydroxyl radicals in theupper airways of healthy children andsignificant lung function decrements.However, theortho/pararatio was notrelated to polymorphonuclear leukocytecounts. Passive smoking was not relatedto outcomes.FEV1(% predicted):Low: 105.4 (SD 15.6)High: 103.9 (SD 15.0)): 1.5, p = 0.031Ortho/pararatio:Low: 0.02 (SD 0.07)High: 0.18 (SD 0.16)): 0.17, p = 0.0001Höppe et al. (1995a,b)Munich, GermanyApr-Sep 1992-1994Panel 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 O3and4 days with low O3. Analysisusing 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 ppbNone No indication that senior citizensrepresent 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 max O3(per 100 ppb):Change in lung function:Seniors:FEV1: 0.034 L (SD 0.101)PEF: 0.006 L/s (SD 0.578)Asthmatics:FEV1:!0.210 L (SD 0.281)PEF:!0.712 L/s (SD 0.134)*Forestry workers:FEV1:!0.140 L (SD 0.156)PEF:!1.154 L/s (SD 0.885)*Athletes:FEV1:!0.152 L (SD 0.136)*PEF:!0.622 L/s (SD 0.589)*Clerks:FEV1:!0.158 L (SD 0.114)*PEF:!0.520 L/s (SD 0.486)**p < 0.05



### AX7-23Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Höppe et al. (2003)Munich, GermanyApr–Sep 1992-1995Three 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 ppbNO2Stratified analyses by group did not showconsistent O3effects 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% forsRaw. Most of the responders werefound in the asthmatic and childrengroups. In these responders, a significantO3concentration-response relationshipwas observed in individual regressions(results not presented). The sample sizemay limit quantitative extrapolation tolarger populations, but may allowcautious first estimates.1⁄2-h max O3(per 50 ppb):% change in lung function, lag 0:Asthmatics:FEV1: 4.26% (!3.13, 11.66)PEF: 6.67% (!1.55, 14.89)Athletes:FEV1: 0.01% (!0.13, 0.11)PEF:!0.13% (!0.29, 0.03)Children:FEV1:!1.81% (!5.34, 1.73)PEF:!11.88% (!18.98,!4.78)Elderly:FEV1: 2.10% (!4.65, 8.84)PEF: 7.29% (!2.84, 17.43)Ozone responders:Asthmatics: 21%Athletes: 5%Children: 18%Elderly: 5%Kopp et al. (1999)Two towns in BlackForest, GermanyMar-Oct 1994Panel 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/m35th %-95th %1-140Freudenstadt:105 μg/m35th %-95th %45-179PM10, NO2,SO2, TSPEosinophil cationic protein andleukocyte levels peaked soon after firstmajor O3episode of summer, but did notshow response to later, even higher,O3episodes. These observations areconsistent with anadaptive responsein terms of nasal inflammation.Change in log eosinophil cationicprotein concentration (per μg/m3O3):Early summer:0.97 (0.03, 1.92)Late summer:!0.43 (!1.34, 0.47)



### AX7-24Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Ulmer et al. (1997)Freudenstadt andVillingen, GermanyMar-Oct 1994Panel study of 135 childrenaged 8-11 years in two townswere evaluated. Pulmonaryfunction was associated withthe highest O3concentrationin 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 %0.5-70.1None In the cross-sectional analysis,a significant negative associationbetween O3exposure 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 O3exposure, and FVC and FEV1for thesubpopulation living in the town withhigher O3levels, Freudenstadt. Theassociations were more pronouncedin males than females.Change in lung function (per μg/m31⁄2-h max O3):FEV1:Freudenstadt:!1.13 mL, p = 0.002Villingen:!0.19 mL, p = 0.62FVC:Freudenstadt:!1.23 mL, p = 0.002Villingen:0.02 mL, p = 0.96Cuijpers 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/m3Smog episode:1-h max O3:Exceeded160 μg/m3on11 daysPM10, SO2,NO2Small decrements in FEV1and 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.Change in lung function andimpedance between baseline andsmog episode:FEV1:!0.032 L (SD 0.226), p#0.05FEF25-75:!0.086 L/s (SD 0.415), p#0.01Resistence at 8 Hz:!0.47 cmH2O/(L/s) (SD 1.17),p#0.05Gielen et al. (1997)Amsterdam, theNetherlandsApr-Jul 1995Panel 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 14.9PM10, BS,pollenMorning PEF significantly associatedwith 8-h max O3at a lag of 2 days.BS also associated with PEF. Among14 symptom models tested, only oneyielded a significant O3finding (forupper respiratory symptoms). PM10and BS, but not O3, were related to$2-agonist inhaler use.8-h max O3(per 83.2 μg/m3):% change in PEF:Morning:Lag 2:!1.86% (!3.58,!0.14)Afternoon:Lag 2:!1.88% (!3.94, 0.18)



### AX7-25Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsEurope(cont’d)Hiltermann et al.(1998)Bilthoven, theNetherlandsJul-Oct 1995Panel 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 6-94PM10, NO2,SO2, BSOzone had strongest association withsymptoms of any pollutant analyzed.PEF lower with O3but not statisticallysignificant. No effect on medication use.No effect modification by steroid use orhyperresponsiveness.8-h max O3(per 100 μg/m3):Odds ratios:Respiratory symptoms:Shortness of breath:Lag 0: 1.18 (1.02, 1.36)Sleep disturbed by breathing:Lag 0: 1.14 (0.90, 1.45)Pain on deep inspiration:Lag 0: 1.44 (1.10, 1.88)Cough of phlegm:Lag 0: 0.94 (0.83, 1.07)Bronchodilator use:Lag 0: 1.05 (0.94, 1.19)Hoek and Brunekreef(1995)Deurne andEnkhuizen, theNetherlandsMar-Jul 1989The 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 O3concentration fromprevious week wereinvestigated. Analyses using1st-order autoregressivemodels and logistic regressionmodels.1-h max O3:Deurne:57 ppbSD 20Range 22-107Enkhuizen:59 ppbSD 14Range 14-114PM10, NO2,SO2No consistent association betweenambient O3concentrations 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 max O3(per 50 ppb):Prevalence of symptoms:Deurne:Any respiratory symptom:Lag 0:!0.06 (SE 0.04)Cough:Lag 0:!0.07 (SE 0.07)Upper respiratory symptoms:Lag 0:!0.06 (SE 0.05)Enkhuizen:Any respiratory symptom:Lag 0: 0.12 (SE 0.07)Cough:Lag 0:!0.07 (SE 0.18)Upper respiratory symptoms:Lag 0: 0.18 (SE 0.09)**p < 0.05



### AX7-26Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsLatin AmericaCastillejos et al.(1995)SW Mexico CityAug 1990-Oct 1991Panel study of children aged71⁄2-11 years (22 males, 18females) tested up to 8 timesfor FEV1and FVC, beforeand after exercise. Targetminute ventilation was35 L/min/m2. Analysis usingGEE models.1-h max O3:112.3 ppbRange 0-3655th quintile mean229.1 ppbPM10The mean % decrements in lung functionwere significantly greater than zero onlyin the fifth quintile of O3exposure(183-365 ppb).% change with exercise in5th quintile of O3exposure(183-365 ppb):FEV1:!2.85% (!4.40,!1.31)FVC:!1.43% (!2.81,!0.06)Gold et al. (1999)SW Mexico City1991Panel 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 25PM2.5, PM10Reported significant declines in PEFin relation to 24-h avg O3levels.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 O3at a 1-day lag.24-h avg O3(per 25 ppb):% change in PEF:Morning:Lag 1-10:!3.8% (!5.8,!1.8)Afternoon:Lag 0-9:!4.6% (!7.0,!2.1)% change in phlegm:Morning:Lag 1: 1.1% (1.0, 1.3)



### AX7-27Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsLatin America(cont’d)Romieu et al. (1996)N Mexico CityApr-Jul 1991,Nov 1991-Feb 1992Panel 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 80PM2.5, PM10,NO2, SO2Ozone effects observed on both PEF andsymptoms. Symptom, but not PEF,effects robust to PM10in two-pollutantmodels. Symptoms related to O3included cough and difficulty breathing.1-h max O3(per 50 ppb):Change in PEF (L/min):Morning:Lag 0:!2.44 (!4.40,!0.49)Lag 1:!0.23 (!0.41, 1.62)Lag 2:!1.49 (!3.80, 0.80)Afternoon:Lag 0:!0.56 (!2.70, 1.60)Lag 1:!1.27 (!3.20, 0.62)Lag 2:!1.92 (!4.50, 0.66)Odds ratios:Lower respiratory symptoms:Lag 0: 1.09 (1.03, 1.15)Lag 1: 1.10 (1.04, 1.17)Lag 2: 1.04 (0.97, 1.12)Romieu et al. (1997)SW Mexico CityApr-Jul 1991,Nov 1991-Feb 1992Same 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 78PM10Ozone had significant effects on PEF andsymptoms, with largest effects at lags 0and 1 day. Symptoms related to O3included cough and phlegm. Ozoneeffects stronger than those for PM10.1-h max O3(per 50 ppb):Change in PEF (L/min):Morning:Lag 0:!1.32 (!3.21, 0.57)Lag 1:!0.39 (!2.24, 1.47)Lag 2:!0.97 (!2.94, 0.99)Afternoon:Lag 0:!1.81 (!3.60,!0.01)Lag 1:!2.32 (!4.17,!0.47)Lag 2:!0.21 (!2.44, 2.02)Odds ratios:Lower respiratory symptoms:Lag 0: 1.11 (1.05, 1.19)Lag 1: 1.08 (1.01, 1.15)Lag 2: 1.07 (1.02, 1.13)



### AX7-28Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsLatin 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"-tocopherolmeasured. Analysis usingGEE models.1-h max O3:123 ppbSD 4055% of days >110ppb.Workday hourlyaverage duringworkday prior topulmonaryfunction test:67.3 ppbSD 24PM10, NO2During the 1st phase, O3levels weresignificantly 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 max O3(per 10 ppb):Placebo group:1st phase:FEV1:Lag 0:!17.9 mL (SE 5.4)*FVC:Lag 0:!14.8 mL (SE 7.1)*2nd phase:FEV1:Lag 0:!3.3 mL (SE 6.5)FVC:Lag 0:!0.27 mL (SE 7.8)No significant associations with O3observed when taking supplements.Romieu et al. (2002)Mexico CityOct 1998-Apr 2000Panel 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 47PM10, NO2Ozone levels were significantlycorrelated 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 O3exposure onthe small airways of children withmoderate to severe asthma.1-h max O3(per 10 ppb):Children with moderate to severeasthma:Placebo group:O3with PM10and NO2models:FEV1:Lag 1:!4.59 mL, p = 0.04FEF2.5-75:Lag 1:!13.32 mL/s, p#0.01PEF:Lag 1:!15.01 mL/s, p = 0.04No association observed in thevitamin supplement group.



### AX7-29Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsLatin America(cont’d)Romieu et al. (2004)Mexico CityOct 1998-Apr 2000Additional 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 47None In the placebo group, O3exposure wassignificantly and inversely associatedwith FEF2.5-75in 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 O3onsmall airways function.1-h max O3(per 50 ppb):FEF25-75in children with moderate tosevere asthma:Placebo group:GSTM1 null:Lag 1:!80.8 mL/s, p = 0.002GSTM1 positive:Lag 1:!34.4 mL/s, p > 0.10Supplement group:GSTM1 null:Lag 1:!7.3 mL/s, p > 0.10GSTM1 positive:Lag 1: 2.0 mL/s, p > 0.10AustraliaJalaludin et al. (2000)Sydney, AustraliaFeb-Dec 1994Panel 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 O3using GEE model andpopulation regression models.Mean daytime O3(6 a.m.-9 p.m.):12 ppbSD 6.8Maximumdaytime O3(6 a.m.-9 p.m.):26 ppbSD 14.4PM10, NO2A significant negative association wasfound between daily mean deviation inPEF and same-day mean daytime O3concentration after adjusting forcopollutants, time trend, meteorologicalvariables, pollen count, andAlternariacount. The association was stronger ina subgroup of children with bronchialhyper-reactivity and doctor-diagnosedasthma. In contrast, the same-daymaximum O3concentration was notstatistically associated.Change in PEF (per 10 ppb meandaytime O3):All children (n = 125):O3only model:!0.9178 (SE 0.4192), p = 0.03O3with PM10model:!0.9195 (SE 0.4199), p = 0.03O3with PM10and NO2model:!0.8823 (SE 0.4225), p = 0.04



### AX7-30Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsAustralia(cont’d)Jalaludin et al. (2004)Sydney, AustraliaFeb-Dec 1994Same three groups of childrenas studied in Jalaludin et al.,2000. Examined relationshipbetween O3and eveningrespiratory symptoms(wheeze, dry cough, and wetcough), evening asthmamedication use (inhaled$2-agonist and inhaledcorticosteroids), 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 14.4PM10, NO2No significant O3effects observed onevening 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 PM10concentrations and doctorvisits for asthma.Mean daytime O3(per 8.3 ppb):Odds ratios:All children (n = 125):Wheeze:Lag 1: 1.00 (0.93, 1.08)Dry cough:Lag 1: 1.03 (0.96, 1.11)Wet cough:Lag 1: 0.97 (0.92, 1.03)Inhaled$2-agonist use:Lag 1: 1.02 (0.97, 1.07)Inhaled corticosteroid use:Lag 1: 1.02 (0.99, 1.04)Doctor visit for asthma:Lag 1: 1.05 (0.77, 1.43)Chen et al. (1998)Six communities inTaiwan1994-19954,697 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 ppbSO2, CO,PM10, NO2School children in urban communities,but not in petrochemical industrial areas,had significantly more respiratorysymptoms and diseases vs. those livingin the rural community. However, meanO3levels in the urban communities werelower than that of the rural community.No causal relationship could be derivedbetween O3and respiratory symptomsand diseases in thiscross-sectional study.Urban areas vs. rural area:Odds ratios:Respiratory symptoms:Morning cough:1.33 (0.98, 1.80)Day or night cough:1.67 (1.21, 2.29)Shortness of breath:1.40 (1.04, 1.91)Wheezing or asthma:1.68 (1.11, 2.54)



### AX7-31Table AX7-1 (cont’d). Effects of Acute O3Exposure on Lung Function and Respiratory Symptoms in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsAsiaChen et al. (1999)Three towns inTaiwan: Sanchun,Taihsi, LinyuanMay 1995-Jan 1996Valid 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, NO2FEV1and FVC significantly associatedwith day 1-day lag O3. FVC also relatedto NO2, SO2, and CO. No PM10effectsobserved. Only O3remained significantin multipollutant models. No PM10effects. A significant O3effect was notevident at O3levels below 60 ppb.Change in lung function:O3only models:Lag 1:FEV1:!0.64 mL/ppb (SE 0.34)*FVC:!0.79 mL/ppb (SE 0.32)*O3with NO2models:Lag 1:FEV1:!0.85 mL/ppb (SE 0.34)*FVC:!0.91 mL/ppb (SE 0.37)**p < 0.05Chan 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 O3exposure 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 7.6-65.1PM10, NO2Significant associations observedbetween evening PEF and O3concentrations at lags of 0, 1 and 2 days.Largest effect observed at a day 1-daylag. Similar O3effects on morning PEFalso noted (data not presented). NeitherPM10nor NO2showed consistentassociations with PEF. Ozone resultswere robust to adjustment for PM10andNO2.8-h avg O3(per 10 ppb):% change in evening PEF:Lag 0: 0.54%, p < 0.05Lag 1: 0.69%, p < 0.05Lag 2: 0.52%, p < 0.05



### AX7-32Table AX7-2. Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited StatesLiao et al. (2004)Three locations in U.S.:Minneapolis, MN;Jackson, MS; ForsythCounty, NC1996-1998Cross-sectional study of5,431 cohort members ofthe Atherosclerosis Risk inCommunities study, menand women aged 45-64years at entry in 1987.Association between O3andcardiac 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 16PM10, CO,SO2, NO2Significant interaction between O3andethnicity in relation to high-frequencypower (p < 0.05). Ambient O3significantly associated with highfrequency power among whites, but notblacks. No significant O3effect on otherheart rate variability indices, includinglow-frequency power and SD of normalR-R intervals. More consistentrelationships observed between PM10and heart rate variability indices.8-h avg O3(per 16 ppb):Log-transformed high-frequencypower:White race:Lag 1:!0.069 (SE 0.019)*Black race:Lag 1: 0.047 (SE 0.034)Log-transformed high-frequencypower:Lag 1:!0.010 (SE 0.016)SD of normal R-R intervals:Lag 1:!0.336 (SE 0.290)*p < 0.05Peters et al. (2000a)Eastern Massachusetts1995-1997Records 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 14.0PM2.5, PM10,BC, CO, NO2,SO2No significant O3effects observed fordefibrillator discharge interventions.For patients with 10 or moreinterventions, increased arrhythmiaswere associated significantly withPM2.5, CO, and NO2at various lagperiods, but not O3.24-h avg O3(per 32 ppb):Odds ratios:Defibrillator discharges:Patients with at least one event:Lag 0: 0.96 (0.47, 1.98)Patients with at least 10 events:Lag 0: 1.23 (0.53, 2.87)



### AX7-33Table AX7-2 (cont’d). Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Peters et al. (2001)Greater Boston area,MAJan 1995-May 1996Case-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%6-36PM2.5, PM10,PM10-2.5, BC,CO, NO2, SO2None of the gaseous pollutants, includingO3, were significantly associated withthe triggering of myocardial infarctions.Significant associations reported forPM2.5and PM10. Note that the use ofunidirectional 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 ratios:Myocardial infarctions:2-h avg O3(per 45 ppb):Lag 1 h:1.31 (0.85, 2.03)24-h avg O3(per 30 ppb):Lag 24 h:0.94 (0.60, 1.49)Park et al. (2005)Greater Boston area,MANov 2000-Oct 2003Cross-sectional studyexamining the effect of O3on 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 13.0PM2.5, particlenumberconcentration,BC, NO2, SO2,COOf the pollutants examined, only PM2.5and O3showed significant associationswith heart rate variability outcomes.The 4-h averaging period was moststrongly associated with heart ratevariability indices. The O3effect wasrobust in models including PM2.5. Theassociations between O3and heart ratevariability indices were stronger insubjects with hypertension (n = 335) andischemic heart disease (n = 142).In addition, calcium-channel blockerssignificantly influenced the effect of O3on 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 avg O3(per 13 ppb):Change in low frequency power:All subjects:!11.5% (!21.3,!0.4)Subjects with hypertension:!12.6% (!25.0, 1.9)Subjects without hypertension:!5.4% (!21.6, 14.1)Subjects with ischemic heartdisease:!25.8% (!41.9,!5.3)Subjects without ischemic heartdisease:!4.8% (!16.7, 8.8)



### AX7-34Table AX7-2 (cont’d). Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Gold et al. (2000;reanalysis Gold et al.,2003)Boston, MAJun-Sep 1997Panel 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 O3during HRVmeasurement:25.7 ppbIQR 23.0PM2.5, NO2,SO2Increased levels of O3were associatedwith reduced r-MSSD (square root of themean of the squared differences betweenadjacent normal RR intervals) during theslow breathing period after exerciseoutdoors. The estimated O3effects weresimilar to those of PM2.5. Results suggestthat O3exposure may decrease vagaltone, leading to reduced heart ratevariability.1-h avg O3(per 23.0 ppb):Change in r-MSSD:During first rest period:O3only model:!3.0 ms (SE 1.9), p = 0.12During slow breathing period:O3only model:!5.8 ms (SE 2.4), p = 0.02O3with PM2.5model:!5.4 ms (SE 2.5), p = 0.03Schwartz et al. (2005)Boston, MA12 weeks during thesummer of 1999A 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 O3during HRVmeasurement:Median 34 ppbIQR 26BC, PM2.5,CO, SO2, NO2HRV 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/highfrequency 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 O3mightrepresent a secondary particle effect andnot a true O3effect, and suggested thatpersonal exposure measurements mightbe necessary to assess the effect of O3oncardiovascular outcomes.1-h avg O3(per 26 ppb):Change in HRV parameters:SDNN:!3.1 ms (!7.0, 0.9)r-MSSD:!8.5 ms (!16.6, 0.3)PNN50:!6.5% (!18.9, 7.8)



### AX7-35Table AX7-2 (cont’d). Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Dockery et al. (2005)Boston, MAJul 1995-Jul 2002Effect 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 15.4PM2.5, BC,SO42!, particlenumber, CO,NO2, SO2No 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 avg O3(per 15.4 ppb):Odds ratios:All events:1.09 (0.93, 1.29)Prior arrhythmia event <3 days:1.01 (0.76, 1.35)Prior arrhythmia event >3 days:1.14 (0.92, 1.40)



### AX7-36Table AX7-2 (cont’d). Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsUnited States(cont’d)Rich et al. (2005)Boston, MAJul 1995-Jul 2002Same 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!lags0-2, 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 15.7PM2.5, BC,CO, NO2, SO2Associations observed for PM2.5and O3with a 24-h moving average, and for NO2and SO2with a 48-h moving average. Intwo-pollutant analyses, only PM2.5and O3appeared to act independently. Incontrast to results from other pollutants,stratified analyses indicated that O3wasassociated 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 ratios:24-h moving average O3(per15.9 ppb):O3only model:All events:1.21 (1.00, 1.45)Prior arrhythmia event <3 days:1.04 (0.78, 1.37)Prior arrhythmia event >3 days:1.28 (1.05, 1.58)O3with PM2.5model:All events:1.18 (0.94, 1.49)24-h calendar day O3(per 15.7 ppb):O3only model:All events:0.96 (0.80, 1.15)CanadaRich et al. (2004)Vancouver, BritishColumbia, CanadaFeb-Dec 2000Case-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 13.4PM2.5, PM10,EC, OC,SO42!, CO,NO2, SO2No 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 quantitative results for O3.



### AX7-37Table AX7-2 (cont’d). Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsCanada(cont’d)Vedal et al. (2004)Vancouver, BritishColumbia, Canada1997-2000Retrospective, 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 13.8PM10, CO,NO2, SO2No consistent association between anyof the air pollutants and % change inarrhythmia. Among patients with at least2 arrhythmia event-days per year, asignificant negative relationship betweenO3and arrhythmias was observed at lag3-day during the summer, but noassociations were found during thewinter. These results do not provideevidence for an O3effect on cardiacarrhythmias in susceptible patients.No quantitative results for O3.EuropeRuidavets et al. (2005)Toulouse, FranceJan 1997 - Jun 1999MONICA 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/m3SD 28.1Range 3.8-160.2NO2, SO2After adjustment for temperature, relativehumidity, and influenza epidemics, anassociation between O3and acute MI wasfound 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 NO2and SO2were observed. NO2andSO2were not associated with acute MI.No PM data was reported.8-h max O3(per 5 μg/m3):Relative risk:All cases (n = 635):Lag 0: 1.05 (1.01, 1.08)Lag 1: 1.05 (1.01, 1.09)Age group:Age 35-54 years (n = 281):Lag 0: 1.04 (0.99, 1.09)Age 55-64 years (n = 283):Lag 0: 1.06 (1.01, 1.12)History of ischemic heart disease:Yes (n = 127):Lag 0: 1.03 (0.96, 1.12)No (n = 437):Lag 0: 1.05 (1.01, 1.09)Age 55-64 years with no historyof ischemic heart disease (n =225):Lag 0: 1.07 (1.01, 1.13)Lag 1: 1.11 (1.04, 1.19)



### AX7-38AX7-39Table AX7-2 (cont’d). Effects of Acute O3Exposure on Cardiovascular Outcomes in Field StudiesReference, StudyLocation and Period Outcomes and Methods Mean O3LevelsCopollutantsConsidered Findings, Interpretation EffectsLatin AmericaHolguín et al. (2003)Mexico CityFeb-Apr 2000Panel study of theassociation between O3and 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 O3levels obtainedfrom 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 40PM2.5(indoor,outdoor,total), NO2,SO2, COOnly PM2.5and O3were significantlyassociated with heart rate variabilityoutcomes. A significant effect of O3onheart rate variability was limited tosubjects with hypertension (n = 21).In two-pollutant models, the magnitudeof the PM2.5effect decreased slightly butremained significant, whereas O3wasno longer associated with heart ratevariability indices.1-h max O3(per 10 ppb):Log10high frequencypower/100,000 ms2:All subjects:!0.010 (!0.022, 0.001)Subjects with hypertension:!0.031 (!0.051,!0.012)Subjects without hypertension:0.002 (!0.012, 0.016)Log10low frequencypower/100,000 ms2:All subjects:!0.010 (!0.021, 0.001)Subjects with hypertension:!0.029 (!0.046,!0.011)Subjects without hypertension:0.001 (!0.012, 0.015)



### AX7-39Table AX7-3. Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United StatesJaffe et al. (2003)Cincinnati, Cleveland,and Columbus, OHJun-Aug 1991-1996Daily time-seriesstudy of emergencydepartment visits forasthma amongMedicaid recipientsaged 5-34 years.8-h max O3:Cincinnati:60 ppbSD 20Cleveland:50 ppbSD 17Columbus:57 ppbSD 16PM10, NO2,SO21, 2, 3 Poisson regression with controlfor 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. PM10available onlyevery 6th day. Positiverelationships betweenemergency department visitsfor asthma and 8-h max O3levels lagged 2 to 3 days.Results of borderline statisticalsignificance. Other pollutantsalso related to asthmaemergency department visitsin single-pollutant models.8-h max O3(per 30 ppb):Cincinnati:Lag 2: 1.16 (1.00, 1.37)Cleveland:Lag 2: 1.03 (0.92, 1.16)Columbus:Lag 3: 1.16 (0.98, 1.37)Three cities: 1.09 (1.00,1.19)Jones et al. (1995)Baton Rouge, LAJun-Aug 1990Daily 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 ppbSD 28.724-h avg O3:28.2 ppbSD 11.7Mold, pollen Not specified. Relatively simple statisticalapproach using ordinary leastsquares regression to modeleffects of O3by itself and of O3along 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-h avg O3(per 20 ppb):Pediatric: 0.87 (0.65, 1.09)Adult: 1.20 (1.01, 1.39)Geriatric: 1.27 (0.93, 1.61)



### AX7-40Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Wilson et al. (2005)Portland, ME1998-2000Manchester, NH1996-2000Daily 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 14.6SO20 Poisson GAM with stringentconvergence criteria. Positiveassociations for asthma in thelarger city, Portland. Authorsexpressed the view that largercities might be needed toconduct such studies.8-h max O3(per 30 ppb):Warm season (Apr-Sep):All ages:Portland:Total respiratory:0.970 (0.915, 1.029)Asthma:1.094 (1.032, 1.160)Manchester:Total respiratory:0.970 (0.915, 1.029)Asthma:0.970 (0.863, 1.092)Cassino et al. (1999)New York CityJul 1992-Dec 1995Daily 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 ppbIQR 2824-h avg O3:17.5 ppbIQR 14CO, NO2,SO20, 1, 2, 3 Used Poisson GAM withdefault convergence criteria.No warm-season resultspresented. Significant O3effects 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-h max O3(per 100 ppb):Never smokers:Lag 2: 0.80 (0.58, 1.14)Light smokers:Lag 2: 0.89 (0.62, 1.16)Heavy smokers:Lag 2: 1.59 (1.08, 2.36)24-h avg O3(per 50 ppb):All subjects:Lag 2: 1.22 (0.98, 1.53)Never smokers:Lag 2: 0.88 (0.57, 1.12)Light smokers:Lag 2: 0.88 (0.60, 1.28)Heavy smokers:Lag 2: 1.72 (1.13, 2.62)



### AX7-41Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Weisel et al. (2002)New JerseyMay-Aug 1995Daily 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, butauthors report noautocorrelation, whichalleviates concerns about lackof control. Significant O3effects reported, even afteradjusting for potentialconfounding by pollen. Allthree O3indices gaveessentially same results.Slope estimate(visits/day/ppb):Excluding data from Maywhen pollen levels are high:O3only model:Lag 0: 0.039, p = 0.049O3with pollen model:Lag 0: 0.040, p = 0.014Friedman et al. (2001)Atlanta, GAJun-Sep 1996Emergencydepartment 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,mold0, 0-1, 0-2 Analysis using Poisson GEEmodels addressing serialautocorrelation. An overalldecrease was observed whencomparing the number of visitsand hospitalizations during theOlympic Games to the baselineperiod. However, significantassociations between O3andasthma events were foundduring the Olympic Games.1-h max O3(per 50 ppb):Pediatric emergencydepartments:Lag 0: 1.2 (0.99, 1.56)Lag 0-1: 1.4 (1.04, 1.79)Lag 0-2: 1.4 (1.03, 1.86)



### AX7-42Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Metzger et al. (2004)Atlanta, GA1993-2000Emergencydepartment visits fortotal and causespecificcardiovasculardiseases by age groups19+ years and 65+years. Time-seriesstudy.8-h max O3:Mar-Nov:Median 53.9 ppb10th %-90th %13.2-44.7NO2, SO2,CO, PM2.5,PM10,PM10-2.5,ultrafine PMcount, SO42!,H+, EC, OC,metals,oxygenatedhydrocarbons0-2 Poisson GLM regression usedfor 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, butnot O3.8-h max O3(per 25 ppb):All ages:Total cardiovascular:1.008 (0.987, 1.030)Dysrhythmia:1.008 (0.967, 1.051)Congestive heart failure:0.965 (0.918, 1.014)Ischemic heart disease:1.019 (0.981, 1.059)Peripheral vascular andcerebrovascular disease:1.028 (0.985, 1.073)Peel et al. (2005)Atlanta, GA1993-2000Emergencydepartment 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 23.8NO2, SO2,CO, PM2.5,PM10, PM10-2.5, ultrafinePM count,SO42!, H+,EC, OC,metals,oxygenatedhydrocarbons0-2 Poisson GEE and GLMregression 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-h max O3(per 25 ppb):All ages:All available data:Total respiratory:1.024 (1.008, 1.039)Upper respiratory infections:1.027 (1.009, 1.045)Asthma:1.022 (0.996, 1.049)Pneumonia:1.015 (0.981, 1.050)COPD:1.029 (0.977, 1.084)Warm season (Apr-Oct):Asthma:1.026 (1.002, 1.051)



### AX7-43Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Tolbert et al. (2000)Atlanta, GAJun-Aug 1993-1995Pediatric (aged0-16 years) asthmaemergency departmentvisits over threesummers in Atlanta.A unique feature ofthe study wasassignment of O3exposures 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 ppbSD 19.1PM10, NO2,mold, pollen1 A priori specification ofmodel, 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 withO3and PM10in 1-, but not in2-pollutant models (correlationbetween O3and PM10:r = 0.75). Secondary analysisindicated nonlinearity, with O3effects clearly significant onlyfor days$100 ppb vs. days<50 ppb.8-h max O3(per 20 ppb):Poisson regression:O3only model:1.040 (1.008, 1.074)Logistic regression:O3only model:1.042 (1.017, 1.068)O3with PM10model:1.024 (0.982, 1.069)Zhu et al. (2003)Atlanta, GAJun-Aug 1993-1995Asthma emergencydepartment visits inchildren (age 0-16years) over threesummers in Atlanta.Time-series study.8-h max O3:Levels notreported.None 1 Used Bayseian hierarchicalmodeling to address modelvariability and spatialassociations. Data wereanalyzed at the zip code levelto account for spatiallymisaligned longitudinal data.A positive, but nonsignificantrelationship between O3andemergency room visits forasthma.8-h max O3(per 20 ppb):Posterior median:1.016 (0.984, 1.049)



### AX7-44Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)CanadaDelfino et al. (1997b)Montreal, Quebec,CanadaJun-Sep 1992-1993Daily 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 11.5PM10, 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 O3in 1993 only forage >64 years. This O3effectreported to be robust in twopollutant models. Low O3levels raise plausibilityconcerns. Short data series,multiple tests performed, andinconsistent results acrossyears and age groups raisepossibility of chance findings.1993 (age >64 years):1-h max O3(per 36.2 ppb):Lag 1: 1.214 (1.084, 1.343)8-h max O3(per 30.7 ppb):Lag 1: 1.222 (1.091, 1.354)No significant O3effects in1992 or in other age groups atthe p < 0.02 level (chosen totake into account multipletesting bias).



### AX7-45Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Canada(cont’d)Delfino et al. (1998b)Montreal, Quebec,CanadaJun-Aug 1989-1990Daily 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 11.2EstimatedPM2.50, 1, 2 Same analytical approach usedin Delfino et al., 1997. Resultspresented only for 1989.Significant effects reported for1-day lag O3in 1989 only forage >64 years. This O3effectreported to be robust in2-pollutant models. Ozoneconcentrations weresignificantly higher in 1989than 1990 (p < 0.001).1989 (age >64 years):1-h max O3(per 44.1 ppb):Lag 1: 1.187 (0.969, 1.281)8-h max O3(per 37.5 ppb):Lag 1: 1.218 (1.097, 1.338)No significant O3effects in1990 or in other age groups atthe p < 0.05 level.Stieb et al. (1996)Saint John, NewBrunswick, CanadaMay-Sep 1984-1992Daily emergencydepartment visits forasthma in all ages,age <15 years and15+ years. Timeseries study.1-h max O3:41.6 ppbRange 0-16095th % 75SO2, NO2,SO42!, TSP0, 1, 2, 3 Poisson analysis with controlof 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.All ages:1-h max O3(per 40 ppb):Lag 2: 1.09 (1.00, 1.19)1-h max O3>75 ppb vs.#75ppb:Lag 2: 1.33 (1.10, 1.56)



### AX7-46Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)EuropeSunyer et al. (1997)Four European cities:Barcelona, Helsinki,London, and Paris1986-1992Emergencyadmissions 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 1-230BS, SO2, NO20, 1, 2, 3 Poisson analysis using APHEAmethodology. Significant O3effects on emergencyadmissions for asthmaobserved among 15-64 yearolds in Barcelona and London.Across all cities, there was nostrong evidence forassociations involving O3.1-h max O3(per 50 μg/m3):Weighted mean effect (bestlag selected for each city):Age <15 years:3-city pooled estimate(Barcelona data notavailable):1.006 (0.976, 1.037)Age 15-64 years:4-city pooled estimate:1.015 (0.955, 1.078)Atkinson et al. (1999a)London, England1992-1994Emergencydepartment visitsfor respiratorycomplaints, asthma forall ages and age 0-14,15-64, and 65+ years.Time-series study.8-h max O3:17.5 ppbSD 11.5NO2, SO2,CO, PM100, 1, 2, 30-1, 0-2, 0-3Poisson GLM regression usedfor analysis. No warm-seasonanalysis attempted. PM10positively associated.8-h max O3(per 25.7 ppb):All ages:Total respiratory:Lag 1: 1.017 (0.991, 1.043)Asthma:Lag 1: 1.027 (0.983, 1.072)Hajat et al. (1999;2002)London, England1992-1994Daily 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 11.5Warm season:22.7 ppbSD 12.2Cold season:12.1 ppbSD 7.6BS, SO2,NO2, CO,PM10, pollen0-3 Used Poisson GAM withdefault 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.Upper respiratory diseases,age$65 years:All year:8-h max O3(per 25.7 ppb)Lag 2:!8.3% (!13.3,!3.0)Warm season:8-h max O3(per 28.5 ppb)Lag 2:!0.6% (!6.1, 5.1)Cool season:8-h max O3(per 19.8 ppb)Lag 2:!7.9% (!12.9, 2.7)



### AX7-47Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Europe(cont’d)Thompson et al. (2001)Belfast, N Ireland1993-1995Asthma emergencydepartmentadmissions in children(age unspecified).Time-series study.24-h avg O3:Warm season:18.7 ppbIQR 9Cold season:17.1 ppbIQR 12PM10, SO2,NO2, CO,benzene0, 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 modelO3was no longer negativelyassociated with asthma visits.24-h avg O3(per 10 ppb):All year:O3only model:Lag 0-1: 0.93 (0.87, 1.00)O3with benzene model:Lag 0-1: 1.08 (0.97, 1.21)Warm season:O3only model:Lag 0-1: 0.99 (0.89, 1.10)Cold season:O3only model:Lag 0-1: 0.89 (0.82, 0.97)Bourcier et al. (2003)Paris, FranceJan 1999-Dec 1999Ophthalmologicalemergencyexamination;conjunctivitis andrelated ocular surfaceproblems. Timeseries study.24-h avg O3:35.7 μg/m3Range 1-97PM10, SO2,NO20, 1, 2, 3 Logistic Regression Results indicate a strongrelation to NO2and NO.24-h avg O3(per 69 μg/m3):Conjunctivitis:Lag 0: 1.13 (0.90, 1.42)Castellsague et al.(1995)Barcelona, Spain1985-1989Daily emergencydepartment visits forasthma in personsaged$14 years.Time-series study.1-h max O3:Summer:43 ppbIQR 22Winter:29 ppbIQR 16BS, SO2, NO2Not specified. Poisson regression with yearand month dummy variablesand extensive control forweather factors (minimum,maximum, mean temperature,relative humidity, dewpointtemperature; continuous andcategorical parameterizations)1-h max O3(per 12.7 ppb):Summer:0.991 (0.939, 1.045)Winter:1.055 (0.998, 1.116)



### AX7-48Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Europe(cont’d)Tobías et al. (1999)Barcelona, Spain1986-1989Daily asthmaemergency departmentvisits. Investigatedsensitivity of resultsto four alternativemethods forcontrolling asthmaepidemics. Timeseries study.Levels notreported.BS, NO2, SO2Not specified. Poisson analysis usingAPHEA methodology.Asthma epidemics eithernot controlled, or controlledwith one, six, or individualepidemic dummy variables.O3results were sensitive tomethod used to controlasthma epidemics, withregression coefficientsranging over 5-folddepending on the model.Only 1 of 8 models reportedhad a significant O3effect.Tenías et al.(1998; 2002)Valencia, Spain1994-1995Daily 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/m3BS, NO2,SO2, CO0, 1, 2, 3, 4, 5 Poisson analysis using APHEAmethodology. Comparedwarm and cold season effects.GAM explored in sensitivityanalysis. For asthma, both O3and NO2significant in singleand two-pollutant models, andO3effect larger in warmseason. For COPD, both O3and CO significant in bothsingle- and two-pollutantmodels and no difference in O3effects by season.1-h max O3(per 10 μg/m3):Asthma:All year:Lag 1: 1.06 (1.01, 1.11)Warm season:Lag 1: 1.08 (1.02, 1.05)Cold season:Lag 1: 1.04 (0.97, 1.11)COPD:All year:Lag 5: 1.06 (1.02, 1.10)Latin AmericaHernández-Garduñoet al. (1997)Mexico CityMay 1992-Jan 1993Visits to clinics forrespiratory diseases inpersons aged 1 monthto 92 years. Timeseries study.Percent timeexceeding 1-hmax O3of 120ppb:6.1-13.2% bylocationSO2, NO2,CO0, 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 O3nor NO2significantin two-pollutant model.1-h max O3(per maximumless average, value notgiven):Lag 0: 1.19 (SE 0.08),p < 0.05Lag 5: 1.19 (SE 0.08),p < 0.05



### AX7-49Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Latin America(cont’d)Lin et al. (1999)São Paulo, BrazilMay 1991-Apr 1993Daily pediatric (ageunspecified)respiratory emergencydepartment visits.Time-series study.1-h max O3:34 ppbSD 22SO2, CO,PM10, NO20, 1, 0-1, 0-2,0-3, 0-4, 0-5Seasonal control using monthdummy variables. Alsocontrolled day of week,temperature. Both O3andPM10associated with outcomealone and together.1-h max O3(per 5 ppb):O3only model:Lag 0-4: 1.022 (1.016, 1.028)O3with PM10model:Lag 0-4: 1.015 (1.009, 1.021)Martins et al. (2002)São Paulo, BrazilMay 1996-Sep 1998Daily emergencydepartment visitsfor chronic lowerrespiratory diseasesin personsaged >64 years.Time-series study.1-h max O3:34 ppbSD 21IQR 21CO, NO2,SO2, PM100-1, 0-2, 0-3,0-4, 0-5, 0-6.Analyzed using Poisson GAMwith default convergencecriteria. Only O3and SO2significant in single-pollutantmodels. Ozone effectremained significant when SO2included in two-pollutantmodel.1-h max O3(per 18.26 ppb):Lag 0-3: 1.14 (1.04, 1.23)Ilabaca et al. (1999)Santiago, ChileFeb 1995-Aug 1996The associationbetween pollutantlevels and emergencyvisits for pneumoniaand other respiratoryillnesses amongchildren. Time-seriesstudy.1-h max O3:Warm season:66.6 μg/m3SD 25.2Cold season:27.6 μg/m3SD 20.2PM10, PM2.5,SO2, NO21, 2, 3, 1-7 Poisson regression analysis. Warm season:1-h max O3(per 30 μg/m3):Lag 2: 1.019 (1.003, 1.035)Cold season:1-h max O3(per 24 μg/m3):Lag 2: 0.995 (0.978, 1.011)AsiaHwang and Chan(2002)50 communitiesin Taiwan1998Daily clinic visits forlower respiratoryillnesses for all ages.Time-series study.1-h max O3:Means for50 communities:54.2 ppbSD 10.2Range 38.9-78.3NO2, SO2,PM10, CO0, 1 Analysis using general linearregressions withmoving-average residualprocesses and Bayesianhierarchical modeling. Allpollutants except O3wereassociated with daily clinicvisits.1-h max O3(per 40 ppb):Bayesian hierarchical model:1.003 (0.983, 1.023)



### AX7-50Table AX7-3 (cont’d). Effects of O3on Daily Emergency Department VisitsReference, StudyLocation and PeriodOutcomes andDesign Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Asia(cont’d)Chew et al. (1999)SingaporeJan 1990-Dec 1994Emergencydepartment visits forasthma in personsaged 3-21 years.Time-series study.1-h max O3:23 ppbSD 15TSP, PM10,SO2, NO20, 1, 2 Simplistic but probablyadequate control for time byincluding 1-day laggedoutcome as covariate.In adjusted models thatincluded covariates, O3had no significant effect.No quantitative resultspresented for O3.



### AX7-51Table AX7-4. Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United StatesNeidell (2004)California1992-1998Asthma hospitaladmissions within fiveage strata (0-1, 1-3,3-6, 6-12, and12-18 years).Time-series study.O3(index notspecified):38.9 ppbSD 17.8Low SES:40.1 ppbHigh SES:38.3 ppbCO, NO2, PM10;multipollutantmodelsNot specified. Statistical analysis usingnaturally occurring seasonalvariations in pollutantconcentrations within zipcodes. Linear regressionanalyses. Consistentsignificant positive effectsonly observed for CO.Negative O3effect observedin all age groups. Number ofsmog alerts was negativelyassociated with asthmahospitalizations, indicatingavoidance behavior on highO3days. Interaction termwith indicator variable forlow SES was positive in allage groups and statisticallysignificant in age 3-6 yearsand 12-18 years, afteradjusting for number of smogalerts.Slope estimate (adjusting fornumber of smog alerts):O3with CO, NO2, and PM10models:Age 3-6 years:!0.038 (SE 0.014)Age 6-12 years:!0.044 (SE 0.013)Age 12-18 years:!0.022 (SE 0.011)O3× low SES interactionterm:Age 3-6 years:0.092 (SE 0.026)Age 6-12 years:0.024 (SE 0.024)Age 12-18 years:0.042 (SE 0.019)Mann et al. (2002)South Coast air basin,CA1988-1995Ischemic heart diseaseadmissions for age40+ years. Time-seriesstudy.8-h max O3:50.3 ppbSD 30.1IQR 39.6PM10, CO, NO20, 1, 2, 3, 4, 5,0-1, 0-2, 0-3,0-4Poisson GAM with cubicB-splines; co-adjustment.No significant O3effectsobserved overall or in warmseason. CO and NO2significant in full-yearanalyses.O3coefficients all negative,but no consistent, significanteffect.



### AX7-52Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Linn et al. (2000)Los Angeles, CA1992-1995Total respiratory andtotal cardiovascularadmissions for age30+ years. Time-seriesstudy.24-h avg O3:Winter:14 ppbSD 7Spring:32 ppbSD 10Summer:33 ppbSD 8Fall:15 ppbSD 9PM10, CO, NO20 Poisson GLM;co-adjustment. Onlysignificant O3effectsobserved were inverseassociations with totalcardiac admission in full-yearand winter season, suggestingresidual confounding.No significant effects of O3on respiratory admissions.24-h avg O3(per 10 ppb):All year:Respiratory:1.008 (1.000, 1.016)Cardiovascular:0.993 (0.987, 0.999)Summer:Respiratory:1.006 (0.992, 1.020)Cardiovascular:1.001 (0.991, 1.011)Nauenberg and Basu(1999)Los Angeles, CA1991-1994Unscheduled asthmaadmissions for all ages.Time-series study.24-h avg O3:All year:19.88 ppbSD 11.13Nov-Mar:7.52 ppbSD 4.34PM100, 0-7 Poisson GLM with preadjustment. No significanteffects of O3. Nowarm-season resultspresented.24-h avg O3(per 20 ppb):Nov-Mar:Lag 0: 1.01 (0.93, 1.08)Sheppard et al.(1999; reanalysisSheppard, 2003)Seattle, WA1987-1994Asthma admissions forage <65 years.Time-series study.8-h max O3:30.4 ppbIQR 20PM2.5, PM10,PM10-2.5, SO2,CO1, 2, 3 Poisson GAM, reanalyzedwith stringent convergencecriteria; Poisson GLM.Results stratified by season.Ozone significant predictorof outcome. No twopollutant model resultsreported for O3.8-h max O3(per 20 ppb):GLM with natural splines:Lag 2: 1.07 (1.01, 1.13)



### AX7-53Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Schwartz (1996)Spokane, WAApr-Oct 1988-1990Total respiratoryadmissions in personsaged 65+ years.1-h max O3:79 μg/m3IQR 2324-h avg O3:56 μg/m3IQR 17PM102 Poisson GAM with defaultconvergence criteria. Resultsavailable only for warmseason. Ozone and PM10both significant predictors ofoutcome. No two-pollutantmodels reported. Ozoneeffects robust to moreextensive temperaturespecification.1-h max O3(per 50 μg/m3):Lag 2: 1.244 (1.002, 1.544)24-h avg O3(per 50 μg/m3):Lag 2: 1.284 (0.926, 1.778)Koken et al. (2003)Denver, COJul-Aug 1993-1997Cause-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 5.4-40.2PM10, NO2,SO2, CO0, 1, 2, 3, 4 Analysis using PoissonGLM. Results suggest thatO3increases the risk ofhospitalization for coronaryatherosclerosis andpulmonary heart disease.No association was found forPM10. Strong O3effectsobserved 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-h avg O3(per 9.7 ppb):Acute MI:0.824 (0.733, 0.925)Coronary atherosclerosis:1.123 (1.040, 1.214)Pulmonary heart disease:1.214 (1.040, 1.418)



### AX7-54Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Moolgavkar et al.(1997)Minneapolis/St. Paul,MN and Birmingham,AL1986-1991Pneumonia and COPDadmissions for age65+ years. Time-seriesstudy.24-h avg O3:Minneapolis/St. Paul:26.2 ppbIQR 15.3Birmingham:25.1 ppbIQR 12.7PM10, SO2, NO20, 1, 2, 3 Poisson GLM with coadjustment. Both O3andPM10significant in MN; notin AL. Ozone, but not PM10,effects were robust to NO2and SO2.24-h avg O3(per 15 ppb):Minneapolis/St. Paul:Pneumonia and COPD:Lag 1: 1.060 (1.033, 1.087)Pneumonia:Lag 1: 1.066 (1.034, 1.098)COPD:Lag 0: 1.045 (0.995, 1.067)Birmingham:Pneumonia and COPD:Lag 2: 1.006 (0.971, 1.042)Lippmann et al. (2000;reanalysis Ito, 2003,2004)Detroit, MI1992-1994Pneumonia, COPD,ischemic heart disease,dysrhythmias, heartfailure, and strokeadmissions for age65+ years. Time-seriesstudy.24-h avg O3:25 ppbMaximum 55PM10, PM2.5,PM10-2.5, SO42!,H+, NO2, SO2,CO0, 1, 2, 3, 0-1,0-2, 0-3Poisson GAM, reanalyzedwith stringent convergencecriteria; Poisson GLM. Atvarious lags, no consistent O3effect observed for anycause-specific hospitaladmission. No two-pollutantmodels reported.24-h avg O3(per 28 ppb):Poisson GLM:Pneumonia:Lag 0: 0.93 (0.83, 1.05)COPD:Lag 0: 0.94 (0.83, 1.08)Ischemic heart disease:Lag 0: 1.01 (0.94, 1.09)Dysrhythmias:Lag 0: 0.98 (0.86, 1.12)Heart failure:Lag 0: 1.00 (0.91, 1.09)Stroke:Lag 0: 0.99 (0.90, 1.09)Schwartz et al. (1996)Cleveland, OHApr-Oct 1988-1990Total respiratoryadmissions for age65+ years. Time-seriesstudy.1-h max O3:56 ppbIQR 28PM10, SO21-2 Poisson GLM with sinusoids;co-adjustment. Resultsavailable only for warmseason. Ozone and PM10both significant predictors ofoutcome. No two-pollutantmodels reported.1-h max O3(per 100 μg/m3):1.09 (1.02, 1.16)



### AX7-55Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)United States(cont’d)Gwynn and Thurston(2001)New York City1988-1990Respiratory admissionsfor all ages, stratifiedby race and insurancestatus. Time-seriesstudy.24-h avg O3:22.1 ppbIQR 14.1Maximum 80.7H+, SO42!, PM101 GLM with high-pass filter.Ozone associated withrespiratory admissions;effects larger for nonwhitesand for those uninsured or onmedicaid.24-h avg O3(per 58.6 ppb):White:1.032 (0.987, 1.079)Non-white:1.122 (1.074, 1.172)Uninsured:1.138 (1.084, 1.194)Gwynn et al. (2000)Buffalo, NYMay 1988-Oct 1990Total respiratoryadmissions for all ages.Time-series study.24-h avg O3:26.2 ppbIQR 14.8PM10, SO42–,H+, COH, CO,NO2, SO20, 1, 2, 3 Used Poisson with GAMdefault convergence criteriafor control of temperature;moving average control fortime. Ozone significantpredictor of outcome. Notwo-pollutant modelsreported.24-h avg O3(per 14.8 ppb):Lag 1: 1.029 (1.013, 1.045)Weisel et al. (2002)New JerseyMay-Aug 1995Asthma 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, butauthors report noautocorrelation, whichalleviates concerns aboutlack of control. SignificantO3effects reported afteradjusting for potentialconfounding by pollen.Slope estimate(admissions/day/ppb):5-h avg O3and 8-h avg O3:O3only model:Lag 2: 0.099, p = 0.057All three O3indices:O3with pollen model:Lag 2: 0.11, p = 0.033



### AX7-56Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)CanadaBurnett et al. (1997a)16 Canadian cities1981-1991Total 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 O3datamissing.SO2, NO2,CO, coefficientof haze0, 1, 2, 0-1, 0-2,1-2Poisson GLM with coadjustment. Results stratifiedby season. Significant O3effect observed in warmseason only. No O3effectson control outcomes. Resultsconsistent across cities.1-h max O3(per 30 ppb):All ages:Jan-Mar:Lag 1: 0.994 (0.964, 1.025)Apr-Jun:Lag 1: 1.042 (1.012, 1.073)Jul-Sep:Lag 1: 1.050 (1.026, 1.074)Oct-Dec:Lag 1: 1.028 (0.998, 1.059)Burnett et al. (1995)168 Hospitals inOntario, Canada1983-1988Respiratory andcardiovascularadmissions for allages and within agestrata. Study focusedmainly on testing forsulfate effects. Timeseries study.1-h max O3:36.3 ppbSO42!1 GLM with pre-adjustment ofoutcome variables. Resultsstratified by season. Authorsreport that O3associated withrespiratory admission inwarm season only.No quantitative resultspresented for O3.



### AX7-57Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Canada(cont’d)Burnett et al. (1997b)Toronto, Ontario,CanadaSummers 1992-1994Unscheduledrespiratory andcardiovascularadmissions for all ages.Time-series study.1-h max O3:41.2 ppbIQR 22PM2.5, PM10,H+, SO42!, SO2,NO2, CO,coefficientof haze0, 1, 2, 3, 4,2 to 5 multidayperiods lagged1 to 4 daysPoisson 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-h avg O3(8 a.m.-8 p.m.)(per 11.5 ppb):Models adjusted fortemperature and dewpoint:Respiratory :Lag 1-3: 1.064 (1.039, 1.090)Cardiovascular:Lag 2-4: 1.074 (1.035, 1.115)Burnett et al. (1999)Toronto, Ontario,Canada1980-1994Cause-specificrespiratory andcardiovascularadmissions for all ages.Cause categoriesincluded asthma,COPD, respiratoryinfections, heart failure,ischemic heart disease,and cerebrovasculardisease. Time-seriesstudy.24-h avg O3:19.5 ppbIQR 19EstimatedPM2.5, PM10,PM10-2.5, CO,NO2, SO20, 1, 2, 0-1, 0-2,1-2, 1-3, 2-3,2-4Poisson 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-h avg O3(per 19.5 ppb):Asthma:Lag 1-3: 1.063 (1.036, 1.091)COPD:Lag 2-4: 1.073 (1.038, 1.107)Respiratory infection:Lag 1-2: 1.044 (1.024, 1.065)Burnett et al. (2001)Toronto, Ontario,Canada1980-1994Acute respiratorydisease admissions forage <2 years. Timeseries study.1-h max O3:Summer:45.2 ppbIQR 25EstimatedPM2.5, PM10,PM10-2.5, CO,NO2, SO20, 1, 2, 3, 4,5, 0-4Poisson 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-h max O3(per 45.2 ppb):Summer:O3only model:Lag 0-4: 1.348 (1.193, 1.524)O3with PM2.5model:Lag 0-4: 1.330 (1.131, 1.565)



### AX7-58Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Canada(cont’d)Lin et al. (2003)Toronto, Ontario,Canada1981-1993Asthma admission forage 6-12 years.Case-crossover design.1-h max O3:30 ppbIQR 20CO, SO2, NO20, 0-1, 0-2, 0-3,0-4, 0-5, 0-6Conditional logisticregression model analysis.No O3effects observed.Positive relations to CO, SO2and NO2observed.1-h max O3(per 20 ppb):Odds ratios:Males:Lag 0: 0.96 (0.88, 1.04)Females:Lag 0: 0.86 (0.78, 1.04)Fung et al. (2005)Windsor, Ontario,CanadaApr 1995-Dec 2000Cardiovascular hospitaladmissions for age<65 and$65 years.Time-series study.1-h max O3:39.3 ppbSD 21.4Range 1-129NO2, SO2, CO,PM10,coefficientof haze, totalreduced sulfurcompounds0, 0-1, 0-2 Conducted both time-seriesanalysis using Poisson GLMwith natural splines.Strongest effect observed forSO2in individuals aged$65 years. No associationswere found any otherpollutant, including O3.1-h max O3(per 29 ppb):Age <65 years:Lag 0: 0.999 (0.913, 1.093)Lag 0-2: 1.042 (0.923, 1.177)Age$65 years:Lag 0: 0.974 (0.924, 1.027)Lag 0-2: 1.014 (0.941, 1.092)Luginaah et al. (2005)Windsor, Ontario,CanadaApr 1995-Dec 2000Respiratory hospitaladmissions by genderfor all ages and age0-14, 15-64, and65+ years. Time-seriesstudy.1-h max O3:39.3 ppbSD 21.4Range 1-129NO2, SO2, CO,PM10,coefficientof haze, totalreduced sulfurcompounds0, 0-1, 0-2 Conducted both time-seriesanalysis 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 O3and total reducedsulfur compounds.1-h max O3(per 29 ppb):All ages:Time-series analysis:Males:Lag 0: 1.04 (0.92, 1.17)Females:Lag 0: 0.95 (0.82, 1.10)Case-crossover analysis:Males:Lag 0: 1.06 (0.93, 1.22)Females:Lag 0: 1.01 (0.77, 1.34)



### AX7-59Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Canada(cont’d)Lin et al. (2004)Vancouver, BritishColumbia, Canada1987-1998Asthma admissions forage 6-12 years. Timeseries study.1-h max O3:28.02 ppbSD 11.54IQR 14.81CO, SO2, NO20, 0-1, 0-2, 0-3,0-4, 0-5, 0-6Poisson GAM with LOESS(using default convergencecriteria). Repeated analysiswith natural cubic splinesusing 1,000 iterations withconvergence criteria 10-15.Results were similar for bothanalyses. NO2exposureassociated for males in lowSES but not high. Noassociation for CO and O3ineither SES group.1-h max O3(per 14.8 ppb):Males:Low SES:Lag 1: 0.85 (0.76, 0.94)High SES:Lag 1: 0.93 (0.83, 1.04)Females:Low SES:Lag 1: 1.11 (0.97, 1.28)High SES:Lag 1: 0.91 (0.78, 1.05)Yang et al. (2003)Vancouver, BritishColumbia, CanadaJan 1986-Dec 1998Daily respiratoryadmissions in childrenaged <3 years andadults aged 65+ years.Bidirectionalcase-crossover.Conditional logisticregression.24-h avg O3:13.41 ppbSD 6.61IQR 9.74CO, NO2, SO2,coefficientof haze1, 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-h avg O3(per 9.74 ppb):Odds ratios:Age <3 years:Lag 4: 1.22 (1.15, 1.30)Age 65+ years:Lag 4: 1.13 (1.09, 1.18)



### AX7-60Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)EuropeAnderson et al. (1997)Five European cities:London, Paris,Amsterdam,Rotterdam, BarcelonaStudy periods vary bycity, ranging from1977-1992Emergency 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/m3Warm season:48-91 μg/m3Cool season:20-64 μg/m3TSP, SO2, NO2,BS0, 1, 2, 3, 4, 5 Poisson GLM using APHEAmethodology. Resultsstratified by season.Ozone most consistent andsignificant predictor ofadmissions. Warm-seasoneffect larger.1-h max O3(per 50 μg/m3):Weighted mean effect acrossfive cities (best lag selectedfor each city):All year:1.03 (1.01, 1.05)Warm season:1.03 (1.01, 1.05)Cool season:1.01 (0.98, 1.05)Atkinson et al. (2001)Eight European cities:Barcelona,Birmingham, LondonMilan, Netherlands,Paris, Rome, andStockholmStudy periods vary bycity, ranging fromearly to middle 1990sTotal 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, CON/A Study focused on PM10effects. Copollutantsincluded only as effectmodifiers. No direct O3results shown. Ozoneappeared to modify the PM10effect on respiratoryadmissions for persons overage 64 years of age.No results presented for O3.



### AX7-61Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)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 1990sTotal 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, CON/A Main focus on PM10and BS.Gaseous copollutantsevaluated as effect modifiers.Greater PM10effects seen incities with lower annual O3levels. No risk estimatespresented for O3.No results presented for O3.Wong et al. (2002)London, England1992-1994Hong Kong1995-1997Total 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/m3SD 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/m3PM10, NO2, SO20, 1, 2, 30-1Poisson 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-h max O3(per 10 μg/m3):Total respiratory:London:All year:Lag 0-1: 1.008 (1.002, 1.014)Warm season:Lag 0-1: 1.010 (1.003, 1.017)Cool season:Lag 0-1: 1.002 (0.993, 1.012)Hong Kong:All year:Lag 0-1: 1.008 (1.003,1.013)Warm season:Lag 0-1: 1.008 (1.002, 1.014)Cool season:Lag 0-1: 1.010 (1.002, 1.017)



### AX7-62Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Europe(cont’d)Anderson et al. (1998)London, England1987-1992Admissions 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 16SO2, NO2,BS, pollens0, 1, 2, 0-1,0-2Poisson GLM using APHEAmethod; co-adjustment.Ozone significantlyassociated with asthmaadmissions in the warmseason for all ages and forage 15-64 years. Warmseason O3effect robust intwo-pollutant models.Inverse associations observedin the cool season for someage groups.8-h max O3(per 10 ppb):All ages:Warm season:Lag 1: 1.022 (1.006, 1.038)Cool season:Lag 1: 0.968 (0.946, 0.992)Atkinson et al. (1999b)London, England1992-1994Total 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 11.5NO2, SO2, CO,PM10, BS0, 1, 2, 3, 0-1,0-2, 0-3Poisson GLM using APHEAmethodology. No significantassociations seen between O3and respiratory admissions.Ozone was positivelyassociated with totalcardiovascular admissions inage 65+ years. Seasonalanalyses were not conducted.8-h max O3(per 25.7 ppb):All ages:Total respiratory:Lag 1: 1.012 (0.990, 1.035)Total cardiovascular:Lag 2: 1.023 (1.002, 1.046)Ponce de Leon et al.(1996)London, EnglandApr 1987-Feb 1992Total 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 14BS, SO2, NO20, 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.All ages:All year:8-h avg O3(per 26 ppb):Lag 1: 1.029 (1.011, 1.048)Warm season:8-h avg O3(per 29 ppb):Lag 1: 1.048 (1.025, 1.073)Cool season:8-h avg O3(per 20 ppb):Lag 1: 0.996 (0.972, 1.021)



### AX7-63Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Europe(cont’d)Poloniecki et al.(1997)London, EnglandApr 1987-Mar 1994Cause-specific and totalcirculatory admissionsfor all ages. Timeseries study.8-h avg O3(9 a.m.-5 p.m.):Median 13 ppbRange 0-94BS, NO2,SO2, CO0 Poisson regression usingAPHEA methodology. Noassociation was foundbetween O3and circulatorydiseases in all-year analyses.Results from acute MIsuggest potential seasonaleffect.8-h avg O3(per 25 ppb):Total circulatory:All year:0.9726 (0.9436, 1.0046)Acute MI:All year:0.9825 (0.9534, 1.0142)Warm season:1.0126 (0.9560, 1.0228)Cool season:0.9680 (0.9208, 1.0202)Prescott et al. (1998)Edinburgh, Scotland1992-1995Total respiratory andcardiovascularadmissions for age<65 years and65+ years. Time-seriesstudy.24-h avg O3:14.5 ppbRange 1-37BS, PM10, NO2,SO2, CO0, 1, 1-3 Poisson GLM, month dummyvariables; co-adjustment. NoO3or other pollution effectson respiratory admissions.Significant inverseassociation of O3withcardiac admissions in olderage group. Very low O3concentrations.24-h avg O3(per 10 ppb):Respiratory:Age <65 years:Lag 1-3: 0.971 (0.885, 1.068)Age 65+ years:Lag 1-3: 1.009 (0.916, 1.111)Cardiovascular:Age <65 years:Lag 1-3: 1.041 (0.946, 1.144)Age 65+ years:Lag 1-3: 0.941 (0.886, 0.999)



### AX7-64Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Europe(cont’d)Schouten et al. (1996)Amsterdam andRotterdam,the Netherlands1977-1989Unscheduled totalrespiratory, asthma, andCOPD admissions inall ages. Time-seriesstudy.8-h max O3:Amsterdam:Summer:86 μg/m35th % to 95th %28-152Winter:53 μg/m35th % to 95th %3-104Rotterdam:Summer:81 μg/m35th % to 95th %25-199Winter:45 μg/m35th % to 95th %3-96SO2, NO2, BS 0, 1, 2, 0-1, 0-2,0-3, 0-4, 0-5Poisson GLM using APHEAmethodology; co-adjustment.No consistent O3effects.Concern regarding multiplecomparisons.1-h max O3(per 100 μg/m3):Amsterdam and Rotterdam:Total respiratory, all ages:Summer:Lag 2: 1.051 (1.029, 1.073)Winter:Lag 2: 0.976 (0.951, 1.002)Hagen et al. (2000)Drammen, NorwayNov 1994-Dec 1997Total respiratoryadmissions for all ages.Time-series study.24-h avg O3:44.48 μg/m3SD 18.40IQR 26.29PM10, NO2,SO2, benzene,toluene,formaldehyde0 Poisson GAM with partialsplines; co-adjustment.Single and multipollutantmodels evaluated. No O3effects. Ozone levels lowand cycles may not havebeen adequately controlled.24-h avg O3(per 26.29 μg/m3):Lag 0: 0.964 (0.899, 1.033)Oftedal et al. (2003)Drammen, Norway1995-2000Admissions forrespiratory disease.Time-series study.24-h avg O3:44.6 μg/m3SD 19.2IQR 26.9Benzene,formaldehyde,toluene, PM10,NO2, SO20 Benzene had the strongestassociation.24-h avg O3(per 26.9 μg/m3):0.996 (0.942, 1.053)



### AX7-65Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Europe(cont’d)Pönkä and Virtanen(1996)Helsinki, Finland1987-1989Asthma admissions forage 0-14 years and15-64 years. Timeseries study.8-h max O3:All year:22 μg/m3Winter:20 μg/m3Spring:30 μg/m3Summer:23 μg/m3Fall:15 μg/m3TSP, SO2, NO20, 1, 2, 3, 4, 5 Poisson GLM using APHEAmethodology. Reportedsignificant O3effect for age0-14 years, but also forcontrol (digestive disease)conditions. Ozone levelsvery low.Not quantitatively useful.Ballester et al. (2001)Valencia, Spain1994-1996Emergency totalcardiovascularadmissions for all ages.Time-series study.8-h max O3:23 ppbRange 5-64SO2, NO2,CO, BS0, 1, 2, 3, 4, 5 Poisson GLM using APHEAmethodology. Resultsstratified by season. No O3effects.8-h max O3(per 5 ppb):Lag 2: 0.99 (0.97, 1.01)Latin AmericaGouveia and Fletcher(2000a)São Paulo, BrazilNov 1992-Sep 1994Total respiratory,pneumonia, and asthmaadmissions for age<5 years. Time-seriesstudy.1-h max O3:63.4 μg/m3SD 38.1IQR 50.3PM10, NO2,SO2, CO0, 1, 2 Poisson GLM with coadjustment using sine/cosinewaves. Significant O3effectson total respiratory andpneumonia admissions.Ozone effects fairly robustto NO2and PM10.1-h max O3(per 119.6 μg/m3):Total respiratory:Lag 0: 1.054 (1.003, 1.107)Pneumonia:Lag 0: 1.076 (1.014, 1.142)Asthma:Lag 2: 1.011 (0.899, 1.136)



### AX7-66Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)AustraliaMorgan et al. (1998a)Sydney, Australia1990-1994Admissions 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 11Bscatter, NO20, 1, 2, 0-1,0-2Poisson with GEE.No significant effects of O3in single or multipollutantmodels.1-h max O3(per 28 ppb):Asthma, age 1-14 years:Lag 1: 0.975 (0.932, 1.019)Asthma, age 15-64 years:Lag 0: 1.025 (0.975, 1.078)COPD, age 65+ years:Lag 0: 1.010 (0.960, 1.062)Heart disease, all ages:Lag 0: 1.012 (0.990, 1.035)Petroeschevsky et al.(2001)Brisbane, Australia1987-1994Unscheduled 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 1.7-64.7Winter:16.1 ppbSpring:23.3 ppbSummer:19.9 ppbFall:16.7 ppbBscatter, SO2,NO20, 1, 2, 3, 0-2,0-4Poisson GLM using APHEAco-adjustment methodology.Seasonal variations in O3effects also investigated.Only a few significantinteractions observed betweenO3and 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-h avg O3(per 10 ppb):All year, all ages:Total respiratory:Lag 2: 1.023 (1.003, 1.043)Asthma:Lag 0-4: 1.090 (1.042, 1.141)Total cardiovascular:Lag 3: 0.987 (0.971, 1.002)AsiaLee et al. (2002)Seoul, KoreaDec 1997-Dec 1999Asthma admissionsfor age <15 years.Time-series study.1-h max O3:36.0 ppbSD 18.6IQR 21.7SO2, NO2, CO,PM100, 1, 2, 3, 4,0-1, 1-2, 2-3,3-4Poisson GAM using defaultconvergence criteria. Ozoneassociated with asthmaadmissions in single- andtwo-pollutant models.1-h max O3(per 21.7 ppb):O3only model:Lag 1: 1.12 (1.07, 1.16)O3with PM10model:Lag 1: 1.10 (1.05, 1.15)



### AX7-67Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Asia(cont’d)Chang et al. (2005)Taipei, Taiwan1997-2001Total cardiovascularhospital admissions forall ages. Cool days(<20 °C) and warmdays ($20 °C) wereevaluated. Casecrossover approach.24-h avg O3:19.74 ppbIQR 10.87Range 2.30-53.93PM10, SO2,NO2, CO0-2 Conditional logisticregression. 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 exceptSO2were associated withcardiovascular admissions.Ozone effect slightlydiminished in two-pollutantmodel adjusting for PM10.24-h avg O3(per 10.87 ppb):Odds ratios:O3only models:Warm: 1.189 (1.154, 1.225)Cool: 1.073 (1.022, 1.127)O3with PM10models:Warm: 1.066 (1.038, 1.094)Cool: 0.980 (0.924, 1.039)Yang et al. (2004a)Kaohsiung, Taiwan1997-2000Total cardiovascularhospital admissions forall ages. Cool days(<25 °C) and warmdays ($25 °C) wereevaluated. Casecrossover approach.24-h avg O3:25.02 ppbIQR 21.20Range 1.25-83.00PM10, SO2,NO2, CO0-2 Conditional logisticregression. All pollutantsexcept SO2associated withcardiovascular admissions onwarm days. On cool days, O3effect was diminished.Ozone effect was robust toadjustment to copollutants.Results from tropical citymay restrict generalization toother locations.24-h avg O3(per 21.20 ppb):Odds ratios:O3only models:Warm: 1.351 (1.279, 1.427)Cool: 1.057 (0.962, 1.162)O3with PM10models:Warm: 1.308 (1.219, 1.404)Cool: 0.820 (0.732, 0.912)



### AX7-68Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Asia(cont’d)Tsai et al. (2003a)Kaohsiung, Taiwan1997-2000Stroke admissions(subarachnoidhemorrhagic stroke,primary intracerebralhemorrhage, ischemicstroke, and others) forall ages. Cool days(<20 °C) and warmdays ($20 °C) wereevaluated. Casecrossover approach.24-h avg O3:25.02 ppbIQR 21.20Range 1.25-83.00PM10, SO2,NO2, CO0-2 Conditional logisticregression. Warm dayassociations were positivewhile cool days weregenerally negative with somepositive associations. Ozoneeffect was robust toadjustment for SO2and CO,but not PM10.24-h avg O3(per 21.20 ppb):Odds ratios:O3only models:Primary intracerebralhemorrhage:Warm: 1.20 (1.06, 1.35)Cool: 0.57 (0.24, 1.34)Ischemic stroke:Warm: 1.15 (1.07, 1.23)Cool: 0.88 (0.50, 1.53)O3with PM10models:Primary intracerebralhemorrhage:Warm: 0.98 (0.85, 1.14)Ischemic stroke:Warm: 0.96 (0.88, 1.05)Wong et al. (1999a)Hong Kong1994-1995Total 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 24.15IQR 31.63NO2, SO2,PM100, 1, 2, 3, 4, 5,0-1, 0-2, 0-3,0-4, 0-5Poisson GLM using APHEAmethodology. Ozonesignificantly associated withtotal and cause specificrespiratory and cardiacoutcomes. Ozone resultsrobust to adjustment for highPM10, but not high NO2.Effects of O3persisted incold season.8-h max O3(per 10 μg/m3):All ages:Total respiratory:Lag 0-3: 1.022 (1.015, 1.029)Total cardiovascular:Lag 0-5: 1.013 (1.005, 1.021)



### AX7-69Table AX7-4 (cont’d). Effects of O3on Daily Hospital AdmissionsReference, StudyLocation and Period Outcomes and Design Mean O3LevelsCopollutantsConsideredLag StructureExaminedMethod, Findings,InterpretationEffects(Relative Risk and 95% CI)Asia(cont’d)Wong et al. (1999b)Hong KongJan 1995-Jun 1997Cause-specificcardiovascularadmissions for age$65 years. Time-seriesstudy.8-h avg O3:Warm season:31.2 μg/m3Cool season:34.8 μg/m3NO2, SO2,respirable PM0, 1, 2, 3, 4, 5,0-1, 0-2, 0-3,0-4, 0-5GLM with sinusoids;co-adjustment. Ozonesignificantly associated withtotal and cause-specificcardiovascular admissions incool season only, when O3levels are higher in HongKong. Details missing inbrief report.O3(per 50 μg/m3):O3with NO2models:Total cardiovascular:All year:Lag 0-1: 1.03 (1.00, 1.07)Warm season:Lag 0-1: 1.01 (0.95, 1.07)Cool season:Lag 0-1: 1.08 (1.02, 1.14)



### AX7-70Table AX7-5. Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesMeta-analysisBell et al. (2005)Various U.S. andnon-U.S. citiesVarying study periodsAll cause;cardiovascular;respiratory; allages; age 64+ or65+ years.Not applicable. Various PMindices0, 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).24-h avg O3(per 10 ppb):Posterior means:All cause:All year: 0.87% (0.55, 1.18)Warm: 1.50% (0.72, 2.29)Cardiovascular:All year: 1.11% (0.68, 1.53)Warm: 2.45% (0.88, 4.10)Respiratory:All year: 0.47% (!0.51,1.47)O3with PM model:All cause:All year: 0.97% (!0.03,1.98)Meta-analysis results wereconsistently larger than thosefrom NMMAPS. In addition,heterogeneity of city-specificestimatesin the meta-analysis werelarger compared toNMMAPS. These findingsindicate possible publicationbias.



### AX7-71Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesMeta-analysis(cont’d)Ito et al. (2005)Various U.S. andnon-U.S. citiesVarying study periodsAll cause Not applicable. Various PMindicesReported lagsup to 3-day lagsMeta-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.24-h avg O3(per 20 ppb):O3only model:All year: 1.6% (1.1, 2.0)Warm: 3.5% (2.1, 4.9)O3with PM model:All year: 1.5% (0.8, 2.2)Non-GAM-affected:All year: 1.4% (0.8, 2.0)GAM-affected:All year: 1.9% (1.0, 2.8)Correction for funnel plotasymmetry:All year: 1.4% (0.9, 1.9)Seven U.S. cities analysisfound that including PMin the model did notsubstantially reduce the O3risk estimates. However,differences in the weatheradjustment model couldresult in a 2-fold difference inrisk estimates.



### AX7-72Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesMeta-analysis(cont’d)Levy et al. (2005)Various U.S., Canadianand European citiesVarying study periodsAll cause Not applicable. PM10, PM2.5, SO2,NO2, CO0, 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.1-h max O3(per 10 μg/m3):O3only model:All year: 0.21% (0.16, 0.26)Warm: 0.43% (0.29, 0.56)Cool:!0.02 (!0.17, 0.14)Non-GAM-affected:All year: 0.23% (0.15, 0.31)GAM-affected:All year: 0.20% (0.13, 0.27)Nonlinear specification oftemperature:All year: 0.20% (0.13, 0.27)Linear specification oftemperature:All year: 0.06 (!0.03, 0.16)In the metaregression,air-conditioning prevalenceand lag time were thestrongest predictorsof between-study variability.



### AX7-73Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited StatesBell et al. (2004)95 U.S. communities1987-2000All cause;cardiopulmonary;all ages; age<65 years;age 65-74 years;age$75 years24-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 models0, 1, 2, 3, 0-6 Poisson GLM;Bayesian hierarchicalmodel. Time-seriesstudy.24-h avg O3(per 10 ppb):Posterior means:All cause, all ages:All-available data:Lag 0: 0.25% (0.12, 0.39)Lag 0-6: 0.52% (0.27, 0.77)Warm season:Lag 0: 0.22% (0.08, 0.38)Lag 0-6: 0.39% (0.13, 0.65)All cause:All-available data:Age <65 years:Lag 0-6: 0.50% (0.10, 0.92)Age 65-74 years:Lag 0-6: 0.70% (0.28, 1.12)Age$75 years:Lag 0-6: 0.52% (0.18, 0.87)Cardiopulmonary, all ages:All-available data:Lag 0-6: 0.64% (0.31, 0.98)



### AX7-74Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Samet et al. (2000;reanalysis Dominici et al.,2003)90 U.S. cities (80 U.S.cities with O3data)1987-1994All cause;cardiopulmonary24-h avg O3:Mean range:Approximately12 ppb(Des Moines, IA)to 36 ppb(San Bernardino,CA)PM10, NO2, SO2,CO; two-pollutantmodels0, 1, 2 Poisson GAM,reanalyzed withstringent convergencecriteria; Poisson GLM.Time-series study.24-h avg O3(per 10 ppb):Posterior means:All cause:All available data:Lag 0: 0.42% (0.22, 0.62)Lag 1: 0.19% (0.03, 0.35)Summer:Lag 1: 0.51% (0.23, 0.78)Winter:Lag 1:!0.53% (!1.10, 0.05)Huang et al. (2005)19 large U.S. citiesJun-Sept 1987-1994Cardiopulmonary 24-h avg O3:Mean range:Approximately18 ppb (Oakland,CA) to 56 ppb(San Bernardino,CA)Daily range across19 U.S. cities:0-100 ppbPM10, PM2.5; twopollutant models0, 1, 2, 0-6 Poisson GLM;Bayesian hierarchicalmodel. Time-seriesstudy.24-h avg O3(per 10 ppb):Posterior means:Single-day lag models:O3only model:Lag 0: 0.73% (0.27, 1.19)O3with PM10model:Lag 0: 0.74% (!0.33, 1.72)Cumulative lag models:O3only model:Lag 0-6: 1.25% (0.47, 2.03)Model adjusted for heatwaves:Lag 0-6: 1.11% (0.38, 1.86)



### AX7-75Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Schwartz (2005)14 U.S. cities1986-1993All cause 1-h max O3:Median range:35.1 ppb (Chicago,IL) to 60.0 ppb(Provo, UT)PM10; twopollutant models0 Case-crossoveranalysis; conditionallogical regressioncontrolled fortemperature usingnonlinear regressionsplines and matching1-h max O3(per 10 ppb):Analysis with temperatureregression splines:All year:0.19% (0.03, 0.35)Warm season:0.26% (0.07, 0.44)Cold season:0% (!0.27, 0.27)Analysis with temperaturematched controls:All year:0.23% (0.01, 0.44)Warm season:0.37% (0.11, 0.62)Cold season:!0.13% (!0.53, 0.28)Kinney and Özkaynak(1991)Los Angeles County, CA1970-1979All cause;respiratory;circulatory1-h max totaloxidants (Ox):75 ppbSD 45KM (particleopticalreflectance), NO2,SO2, CO;multipollutantmodels1 OLS (ordinary leastsquares) on high-passfiltered variables.Time-series study.All cause:Multipollutant model:Slope estimate:0.030 deaths/ppb (SE 0.009),p = 0.0005Cardiovascular:O3only model:Slope estimate:0.023 deaths/ppb (SE 0.006),p < 0.0001Kinney et al. (1995)Los Angeles County, CA1985-1990All cause 1-h max O3:70 ppbSD 41PM10, NO2, SO2,CO; two-pollutantmodels1 Linear, log-linear, andPoisson. Time-seriesstudy.1-h max O3(per 143 ppb):O3only model:2% (0, 5)O3with PM10model:0% (!6, 6)



### AX7-76Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Ostro (1995)San Bernardino County andRiverside County, CA1980-1986All cause 1-h max O3:140 ppbRange 20-370PM2.50 Autoregressive linear;Poisson. Time-seriesstudy.1-h max O3(per 100 ppb):Warm season:2.0% (0.0, 5.0)Ostro et al. (2000)Coachella Valley, CA1989-1998All cause;respiratory;cardiovascular1-h max O3:Palm Springs:67 ppbRange 0-190Indio:62 ppbRange 0-180PM10, PM2.5,PM10-2.5, NO2, CO0 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.1-h max O3(per 40 ppb):All cause:!1% (!4, 3)Respiratory:3% (!9, 16)Cardiovascular:!4% (!9, 1)Fairley (1999; reanalysisFairley, 2003)Santa Clara County, CA1989-1996All cause;respiratory;cardiovascular8-h max O3:29 ppbSD 1524-h avg O3:16 ppbSD 9O3ppb-h >60 ppb:Levels not reported.PM10, PM2.5,PM10-2.5, SO42!,coefficient ofhaze, NO3-, NO2,SO2; two-pollutantmodels0 Poisson GAM,reanalyzed withstringent convergencecriteria; Poisson GLM.Time-series study.GAM with stringentconvergence criteria:All cause:8-h max O3(per 33 ppb):3.1% (!0.3, 6.6)O3ppb-h >60 ppb(increment not reported):3.8% (1.4, 6.3)Cardiovascular:8-h max O3(per 33 ppb):2.6% (!2.3, 7.8)O3ppb-h >60 ppb(increment not reported):4.3% (0.4, 8.3)



### AX7-77Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Gamble (1998)Dallas, TX1990-1994All cause;respiratory;cardiovascular;cancer; other24-h avg O3:All year:22 ppbRange 0-160Summer:30 ppbRange 0-160Winter:12 ppbRange 0-75PM10, NO2, SO2,CO; two-pollutantmodels1-2 Poisson GLM. Timeseries study.All year:24-h avg O3(per 14.7 ppb):All cause:2.7% (0.6, 4.8)Cardiovascular:2.4% (!1.1, 6.0)Summer:24-h avg O3(per 13.1 ppb):All cause:3.5% (p < 0.05)Cardiovascular:3.3% (p > 0.05)Winter:24-h avg O3(per 7.7 ppb):All cause:2.4% (p > 0.05)Cardiovascular:1.5% (p > 0.05)Dockery et al. (1992)St. Louis, MO and EasternTennessee1985-1986All cause 24-h avg O3:St. Louis, MO:22.5 ppbSD 18.5Eastern Tennessee:23.0 ppbSD 11.4PM10, PM2.5,SO42!, H+, NO2,SO21 Poisson with GEE.Time-series study.24-h avg O3(per 20 μg/m3):St. Louis, MO:0.6% (t = 0.38)Eastern Tennessee:!1.3% (t =!0.37)



### AX7-78Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Ito and Thurston (1996)Cook County, IL1985-1990All cause;respiratory;circulatory; cancer;race/gendersubcategories1-h max O3:38.1 ppbSD 19.9PM10, NO2, SO2,CO; two-pollutantmodels0-1 Poisson GLM. Timeseries study.1-h max O3(per 100 ppb):All cause:O3only model:10% (6, 15)O3with PM10model:7% (1, 12)Circulatory (results given ingraphic format):O3only model:12% (6, 20)Moolgavkar (2003)Cook County, IL and LosAngeles County, CA1987-1995All cause;cardiovascular24-h avg O3:Cook County:Median 18 ppbRange 0.2-67Los AngelesCounty:Median 24 ppbRange 0.6-77PM2.5, PM10, NO2,SO2, CO; twopollutant models0, 1, 2, 3, 4, 5 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.24-h avg O3(per 100 ppb):All cause, all year:Cook County:Lag 0: 1.4% (t = 6.3)Los Angeles CountyLag 0: 0.4% (t = 2.3)All cause, summer:Cook County:Lag 0: 2.9% (t = 7.2)Los Angeles CountyLag 0: 1.0% (t = 2.8)Cardiovascular, all year:Cook County:Lag 0: 1.8% (t = 5.5)Los Angeles CountyLag 0: 0.2% (t = 0.9)Cardiovascular, summer:Cook County:Lag 0: 3.3% (t = 5.6)Los Angeles CountyLag 0: 0.8% (t = 1.7)



### AX7-79Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Moolgavkar (2000)Cook County, IL; LosAngeles County, CA; andMaricopa County, AZ1987-1995Cardiovascular;cerebrovascular;COPD24-h avg O3:Cook County:Median 18 ppbRange 0.2-67Los AngelesCounty:Median 24 ppbRange 0.6-77Maricopa County:Median 25 ppbRange 1-50PM2.5, PM10, NO2,SO2, CO; two- andthree-pollutantmodels0, 1, 2, 3, 4, 5 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.24-h avg O3(per 100 ppb):Cook County:Cardiovascular, all year:Lag 0: 1.51% (0.78, 2.24)COPD, all year:Lag 0: 1.53% (!0.49, 3.55)Los Angeles County andMaricopa County:O3results not presented.Noted as negative or smalland nonsignificant in all-yearand warm-season analyses.Lippmann et al. (2000;reanalysis Ito, 2003, 2004)Detroit, MI1985-19901992-1994All cause;respiratory;circulatory;cause-specific24-h avg O3:1985-1990:20.9 ppbIQR 12.0-27.51992-1994:25 ppbIQR 18-30PM10, PM2.5,PM10-2.5, SO42!, H+,NO2, SO2, CO;two-pollutantmodels0, 1, 2, 3, 0-1,0-2, 0-3Poisson GAM,reanalyzed withstringent convergencecriteria; Poisson GLM.Time-series study.Poisson GLM:All lags and outcomes duringboth study periods (n = 140):24-h avg O3(per 5th to95th % increment):Median 1.6%Range!1.8-2.61985-1990:24-h avg O3(per 36 ppb):All cause:Lag 0: 1.08% (!1.08, 3.30)Circulatory:Lag 0: 1.84% (!1.26, 5.04)1992-199424-h avg O3(per 28 ppb):All cause:Lag 0: 2.58% (!2.41, 7.82)Circulatory:Lag 0: 2.13% (!5.04, 9.85)



### AX7-80Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Lipfert et al. (2000a)Seven counties inPhiladelphia, PA area1991-1995All cause;respiratory;cardiovascular;all ages; age65+ years; age<65 years; varioussubregionalboundaries1-h max O3:44.76 ppbSD 25.6824-h avg O3:23.44 ppbSD 13.86PM10, PM2.5,PM10-2.5, SO42!,NO3-, other PMindices, NO2, SO2,CO; two-pollutantmodels0-1 Linear with 19-dayweighted averageShumway filters.Time-series study.1-h max O3(per 45 ppb lessbackground, not reported):All cause, all ages:O3only model:3.19%, p < 0.055O3with PM2.5model:3.34%, p < 0.055Cardiovascular, all ages:O3only model:3.98%, p < 0.055O3with PM2.5model:5.35%, p < 0.055Moolgavkar et al. (1995)Philadelphia, PA1973-1988All 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 0.0-32.9TSP, SO2;multipollutantmodels1 Poisson; GEE andnonparametricbootstrap methods.Time-series study.24-h avg O3(per 100 ppb):O3with TSP and SO2models:Spring:2.0% (!6.7, 11.5)Summer:14.9% (6.8, 23.6)Fall:!4.5% (!13.9, 5.9)Winter:0.4% (!15.6, 19.4)



### AX7-81Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and PeriodOutcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Chock et al. (2000)Pittsburgh, PA1989-1991All cause; age<74 years;age 75+ years1-h max O3:Levels not reported.PM10, NO2, SO2,CO; two-, five-,and six-pollutantmodels0 Poisson GLM. Timeseries study.1-h max O3(per 40 ppb):Age <74 years:O3only model:!1.5% (t =!0.68)O3with PM10model:!2.0% (t =!0.93)Age 75+ years:O3only model:!1.8% (t =!0.82)O3with PM10model:!2.2% (t =!0.98)De Leon et al. (2003)New York City1985-1994Circulatory andcancer with andwithoutcontributingrespiratory causes24-h avg O3:21.59 ppb5th %-95th %7.00-44.97PM10, NO2, SO2,CO; two-pollutantmodels0 or 1 Poisson GAM withstringent convergencecriteria; Poisson GLM.Time-series study.Quantitative results not given.Circulatory deaths:Larger O3effect estimateswith contributing respiratorycauses than without(RR nonsignificant).Cancer deaths:Smaller O3effect estimateswith contributing respiratorycauses than without(RR nonsignificant).



### AX7-82Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and PeriodOutcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesUnited States(cont’d)Klemm and Mason (2000);Klemm et al. (2004)Atlanta, GAAug 1998-July 2000All cause;respiratory;cardiovascular;cancer; other; age<65 years; age65+ years8-h max O3:47.03 ppbSD 24.71PM2.5, PM10-2.5,EC, OC, NO2,SO42!,NO3-, SO2, CO0-1 Poisson GLM usingquarterly, monthly, orbiweekly knots fortemporal smoothing.Time-series study.All cause, age 65+ years:Quarterly knots:Slope estimate:0.00079 (SE 0.00099),t = 0.80Monthly knots:Slope estimate:0.00136 (SE 0.00111),t = 1.22CanadaVedal et al. (2003)Vancouver, BritishColumbia, Canada1994-1996All cause;respiratory;cardiovascular1-h max O3:27.3 ppbSD 10.2PM10, NO2, SO2,CO0, 1, 2 Poisson GAM withstringent convergencecriteria. Time-seriesstudy.1-h max O3(per 10.2 ppb):Summer:All cause:Lag 0: 4.0% (1.4, 6.7)Respiratory:Lag 0: 1.5% (!6.6, 9.6)Cardiovascular:Lag 0: 3.9% (!0.3, 8.0)Villeneuve et al. (2003)Vancouver, BritishColumbia, Canada1986-1999All cause;respiratory;cardiovascular;cancer;socioeconomicstatus24-h avg O3:13.4 ppbRange 0.6-38.6PM2.5, PM10,PM2.5-10, TSP,coefficient ofhaze, SO42!, SO2,NO2, CO0, 1, 0-2 Poisson GLM withnatural splines. Timeseries study.24-h avg O3(per 13.7 ppb):All year:All cause:Lag 0: 1.4% (!0.9, 3.6)Respiratory:Lag 0: 1.6% (!4.5, 8.1)Cardiovascular:Lag 0: 0.7% (!2.7, 4.3)Cancer:Lag 0: 2.6% (!1.2, 6.5)No effect modification of O3-mortality effects bysocioeconomic status.



### AX7-83Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesCanada(cont’d)Goldberg et al. (2003)Montreal, Quebec, Canada1984-1993Congestive heartfailure asunderlying cause ofdeath vs. thoseclassified as havingcongestive heartfailure 1 year priorto death24-h avg O3:29.0 μg/m3SD 17.1PM2.5, coefficientof haze, SO42!,SO2, NO2, CO0, 1, 0-2 Poisson GLM withnatural splines. Timeseries study.24-h avg O3(per 21.3 μg/m3):Congestive heart failure asunderlying cause of death:Lag 0-2: 4.54% (!5.64,15.81)Having congestive heartfailure 1 year prior to death:Lag 0-2: 2.34% (!1.78, 6.63)Goldberg et al. (2001)Montreal, Quebec, Canada1984-1993All cause; causespecific; all ages;age <65 years; age$65 years24-h avg O3:29.0 μg/m3SD 17.1PM2.5, coefficientof haze, SO2, NO2,NO, CO0, 1, 0-2 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.24-h avg O3(per 21.3 μg/m3):All cause, all year:All ages:Lag 0-2: 2.26% (1.23, 3.29)Age <65 years:Lag 0-2: 0.18% (!1.79, 2.20)Age$65 years:Lag 0-2: 2.84% (1.66, 4.04)Cardiovascular, all year:All ages:Lag 0-2: 3.00% (1.44, 4.59)Age <65 years:Lag 0-2: 1.33% (!2.30, 5.09)Age$65 years:Lag 0-2: 3.33% (1.62, 5.08)



### AX7-84Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEuropeGryparis et al. (2004)23 European citiesStudy periods vary by city,ranging from 1990-1997All cause;respiratory;cardiovascular1-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-pollutantmodels0-1 Poisson GAM withstringent convergencecriteria; Bayesianhierarchical model.Time-series study.8-h max O3(per 10 μg/m3):Weighted mean effect across21 cities with 8-h max O3concentrations:Random effects model:All cause:All year:0.03% (!0.18, 0.21)Warm season:O3only model:0.31% (0.17, 0.52)O3with PM10model:0.27% (0.08, 0.49)Cold season:O3only model:0.12% (!0.12, 0.37)O3with PM10model:0.22% (!0.08, 0.51)Respiratory:Warm season:1.13% (0.74, 0.51)Cold season:0.26% (!0.50, 0.84)Cardiovascular:Warm season:0.46% (0.22, 0.73)Cold season:0.07% (!0.28, 0.41)



### AX7-85Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Touloumi et al. (1997)Four European cities:London, ParisBarcelona, AthensStudy periods vary by city,ranging from 1986-1992All 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 42.8BS, NO2; twopollutant models0, 1, 2, 3, 0-1,0-2, 0-3Poisson autoregressive.Time-series study.1-h max O3(per 50 μg/m3):Weighted mean effect acrossfour cities (best lag selectedfor each city):Single-day lag, randomeffects models:O3only model:2.9% (1.0, 4.9)O3with BS model:2.8% (0.5, 5.0)Cumulative lag, fixed effectsmodel:O3only model:2.4% (1.2, 3.7)Zmirou et al. (1998)Four European cities:London, Paris, Lyon,BarcelonaStudy periods vary by city,ranging from 1985-1992Respiratory;cardiovascular8-h avg O3(9 a.m.-5 p.m.):London:Cold: 21.0 μg/m3Warm: 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/m3BS, TSP, SO2,NO20, 1, 2, 3, 0-1,0-2, 0-3Poisson GLM. Timeseries study.8-h avg O3(per 50 μg/m3):Weighted mean effect acrossfour cities (best lag selectedfor each city):Random effects models:Respiratory:5% (2, 8)Cardiovascular:2% (0, 3)



### AX7-86Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Anderson et al. (1996)London, England1987-1992All cause;respiratory;cardiovascular1-h max O3:20.6 ppbSD 13.28-h avg O3(9 a.m.-5 p.m.):15.5 ppbSD 10.9BS, NO2, SO2;two-pollutantmodels0 Poisson GLM. Timeseries study.All year:8-h avg O3(per 26 ppb):All cause:2.43% (1.11, 3.76)Respiratory:6.03% (2.22, 9.99)Cardiovascular:1.44% (!0.45, 3.36)Warm season:8-h avg O3(per 29 ppb):All cause:3.48% (1.73, 5.26)Respiratory:5.41% (0.35, 10.73)Cardiovascular:3.55% (1.04, 6.13)Cool season:8-h avg O3(per 20 ppb):All cause:0.77% (!0.88, 2.44)Respiratory:6.20 (1.67, 10.94)Cardiovascular:!1.69% (!3.99, 0.68)Bremner et al. (1999)London, England1992-1994All 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 11.5BS, PM10, NO2,SO2, CO; twopollutant modelsSelected bestfrom 0, 1, 2, 3,(all cause);0, 1, 2, 3, 0-1,0-2, 0-3(respiratory,cardiovascular)Poisson GLM. Timeseries study.8-h max O3(per 26 ppb):All ages:All cause:Lag 2:!0.7% (!2.3, 0.9)Respiratory:Lag 2:!3.6% (!7.7, 0.8)Cardiovascular:Lag 2: 3.5% (0.5, 6.7)



### AX7-87Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Anderson et al. (2001)West Midlands region,England1994-1996All cause;respiratory;cardiovascular; allages; age 0-14years; age 15-64years; age 65+years8-h max Ox:24.0 ppbSD 13.8PM10, PM2.5,PM2.5-10, BS, SO42-,NO2, SO2, CO0-1 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.8-h max O3(per 30.8 ppb):All ages:All cause:2.9% (!0.1, 6.0)Respiratory:2.2% (!5.4, 10.4)Cardiovascular:0.9% (!3.4, 5.4)Prescott et al. (1998)Edinburgh, Scotland1992-1995All cause;respiratory;cardiovascular; allages; age <65years; age$65years24-h avg O3:14.5 ppbSD 2.3BS, PM10, NO2,SO2, CO; twopollutant models0 Poisson GLM. Timeseries study.24-h avg O3(per 10 ppb):All cause, all ages:!4.2% (!8.1,!0.1)Cardiovascular, age$65years:2.2% (!5.1, 10.3)Le Tertre et al. (2002a)Le Havre, Lyon, Paris,Rouen, Strasbourg, andToulouse, FranceStudy periods vary by city,ranging from 1990-1995All cause;respiratory;cardiovascular8-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/m3BS, NO2, SO20-1 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.8-h max O3(per 50 μg/m3):Six-city pooled estimates:All cause:2.7% (1.3, 4.1)Respiratory:0.8% (!4.8, 6.2)Cardiovascular:2.4% (!0.3, 5.1)



### AX7-88Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Dab et al. (1996)Paris, France1987-1992Respiratory 1-h max O3:43.9 μg/m35th %-99th %6.0-147.08-h max O3:27.7 μg/m35th %-99th %3-110BS, PM13, NO2,SO2, CO0 Poisson autoregressive.Time-series study.1-h max O3(per 100 μg/m3):1.074 (0.934, 1.235)8-h max O3(per 100 μg/m3):1.040 (0.934, 1.157)Zmirou et al. (1996)Lyon, France1985-1990All cause;respiratory;cardiovascular;digestive1-h max O3:15.23 μg/m3Range 0-1528-h avg O3(9 a.m.-5 p.m.):9.94 μg/m3Range 0-78.92PM13, SO2, NO2Selected bestfrom 0, 1, 2, 3Poisson GLM. Timeseries study.8-h avg O3(per 50 μg/m3):All cause:Lag 0: 3% (!5, 12)Respiratory:Lag 1: 1% (!8, 10)Cardiovascular:Lag 1: 0% (!11, 12)Sartor et al. (1995)BelgiumSummer 1994All cause; age<65 years;age 65+ years24-h avg O3:Geometric mean:During heat wave(42-day period):72.4 μg/m3Range 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 18.8-64.9TSP, NO, NO2,SO20, 1, 2 Log-linear regression.Time-series study.No individual regressioncoefficient for O3alone;interaction with temperaturesuggested.24-h avg O3(from 18.8 to111.5 μg/m3) and temperature(from 10.0 to 27.5oC):Age <65 years:Lag 1: 16% increase inmortality (5.3% expected)Age 65+ years:Lag 1: 36.5% increase inmortality (4% expected)



### AX7-89Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Hoek et al. (2000;reanalysis Hoek, 2003)The Netherlands: entirecountry, four urban areas1986-1994All cause; COPD;pneumonia;cardiovascular8-h avg O3(12 p.m.-8 p.m.):Median: 47 μg/m3Range 1-226PM10, BS, SO42!,NO3-, NO2, SO2,CO; two-pollutantmodels1, 0-6 Poisson GAM,reanalyzed withstringent convergencecriteria; Poisson GLM.Time-series study.Poisson GLM:All cause:8-h avg O3(per 150 μg/m3):Lag 1: 4.3% (2.4, 6.2)8-h avg O3(per 120 μg/m3):Lag 0-6: 5.9% (3.1, 8.7)Hoek et al. (2001;reanalysis Hoek, 2003)The Netherlands1986-1994Totalcardiovascular;myocardialinfarction;arrhythmia; heartfailure;cerebrovascular;thrombosis-related8-h avg O3(12 p.m.-8 p.m.):Median: 47 μg/m3Range 1-226PM10, NO2, SO2,CO1 Poisson GAM,reanalyzed withstringent convergencecriteria; Poisson GLM.Time-series study.8-h avg O3(per 150 μg/m3):Poisson GLM:Total cardiovascular:6.2% (3.3, 9.2)Myocardial infarction:4.3% (0.1, 8.6)Arrhythmia:11.4% (!1.2, 25.5)Heart failure:10.2% (1.2, 19.9)Cerebrovascular:9.1% (2.9, 15.7)Thrombosis-related:16.6% (2.8, 32.2)Roemer and van Wijinen(2001)Amsterdam, theNetherlands1987-1998All cause 8-h max O3:Background sites:43 μg/m3Maximum 221Traffic sites:36 μg/m3Maximum 213BS, PM10, NO2,SO2, CO1, 2, 0-6 Poisson GAM withdefault convergencecriteria (only onesmoother). Time-seriesstudy.8-h max O3(per 100 μg/m3):Total population usingbackground sites:Lag 1:!0.3% (!4.1, 3.7)Total population using trafficsites:Lag 1: 0.2% (!3.6, 4.2)



### AX7-90Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Verhoeff et al. (1996)Amsterdam, theNetherlands1986-1992All cause; all ages;age 65+ years1-h max O3:43 μg/m3Maximum 301PM10, NO2, SO2,CO; multipollutantmodels0, 1, 2 Poisson. Time-seriesstudy.1-h max O3(per 100 μg/m3)All ages:Lag 0: 1.8% (!3.8, 7.8)Lag 1: 0.1% (!4.7, 5.1)Lag 2: 4.9% (0.1, 10.0)Peters et al. (2000b)NE Bavaria, Germany1982-1994Coal basin in CzechRepublic1993-1994All cause;respiratory;cardiovascular;cancer24-h avg O3:Czech Republic:40.3 μg/m3SD 25.0Bavaria, Germany:38.2 μg/m3SD 21.9TSP, PM10, NO2,SO2, CO0, 1, 2, 3 Poisson GLM.Time-series study.24-h avg O3(per 100 μg/m3):Czech Republic:All cause:Lag 2: 7.8% (!1.8, 18.4)Bavaria, Germany:All cause:Lag 0: 8.2% (0.4, 16.7)Cardiovascular:Lag 0: 6.1% (!3.7, 17.0)Pönkä et al. (1998)Helsinki, Finland1987-1993All cause;cardiovascular; age<65 years, age 65+years24-h avg O3:Median 18 μg/m35th %-95th % 3-51TSP, PM10, NO2,SO20, 1, 2, 3, 4, 5,6, 7Poisson GLM. Timeseries study.24-h avg O3(per 20 μg/m3):All cause:Age <65 years:Not significant, values notreported.Age 65+ years:Not significant, values notreported.Cardiovascular:Age <65 years:Lag 0:!2.0% (!9.5, 6.1)Lag 1: 6.2% (!2.2, 15.5)Age 65+ years:Not significant, values notreported.



### AX7-91Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Saez et al. (2002)Barcelona, Spain1991-1995Madrid, Spain1992-1995Valenica, Spain1994-1996All cause;respiratory;cardiovascular8-h max O3:Barcelona:67.5 μg/m3SD 32.2Madrid:42.1 μg/m3SD 27.8Valencia:45.5 μg/m3SD 19.7NO2, PM, SO2,CO; multipollutantmodels0-5 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.8-h max O3(per 10 μg/m3):Three-city pooled estimates:All cause:0.23% (!0.15, 0.61)Respiratory:0.29% (!0.05, 0.63)Cardiovascular:0.60% (0.08, 1.13)Garcia-Aymerich et al.(2000)Barcelona, Spain1985-1989All cause;respiratory;cardiovascular;general population;patients with COPD1-h max O3:Levels not reported.BS, NO2, SO2, Selected bestsingle-day lagPoisson GLM.Time-series study.1-h max O3(per 50 μg/m3):All cause:General population:Lag 5: 2.4% (0.6, 4.2)COPD patients:Lag 3: 4.0% (!4.7, 13.4)Respiratory:General population:Lag 5: 3.5% (!1.9, 9.2)COPD patients:Lag 3: 5.7% (!7.9, 21.4)Cardiovascular:General population:Lag 1: 2.9% (0.4, 5.4)COPD patients:Lag 3: 1.1% (!14.2, 19.2)Saez et al. (1999)Barcelona, Spain1986-1989Asthma mortality;age 2-45 years1-h max O3:Levels not reported.BS, NO2, SO2, 0-2 Poisson with GEE.Time-series study.Slope estimate:0.021 (SE 0.011), p = 0.054



### AX7-92Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Sunyer et al. (1996)Barcelona, Spain1985!1991All cause;respiratory;cardiovascular;all ages;age 70+ years1-h max O3:Summer:86.5 μg/m3Range 9.5-283.5Winter:55.2 μg/m3Range 7-189.2BS, SO2, NO2Selected bestsingle-day lagAutoregressivePoisson. Time-seriesstudy.1-h max O3(per 100 μg/m3):All cause, all ages:All year:Lag 0: 4.8% (1.2, 8.6)Summer:Lag 0: 5.8% (1.7, 10.1)Winter:Lag 0: 2.6% (!3.5, 9.1)Respiratory, all ages:All year:Lag 5: 7.1% (!3.8, 19.2)Summer:Lag 5: 5.0% (!7.3, 18.8)Winter:Lag 5: 14.0% (!7.6, 40.6)Cardiovascular, all ages:All year:Lag 1: 5.8% (0.9, 11.1)Summer:Lag 1: 8.8% (2.8, 15.2)Winter:Lag 1:!0.8% (!8.9, 7.9)Sunyer and Basagana(2001)Barcelona, Spain1990-1995Mortality in acohort of patientswith COPD1-h max O3:Mean not reportedIQR 21 μg/m3PM10, NO2, CO 0-2 Conditional logistic(case-crossover)1-h max O3(per 21 μg/m3):Odds ratio:0.979 (0.919, 1.065)



### AX7-93Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesEurope(cont’d)Sunyer et al. (2002)Barcelona, Spain1986-1995All cause,respiratory, andcardiovascularmortality in acohort of patientswith severe asthma1-h max O3:Median 69.3 μg/m3Range 6.6-283.08-h max O3:Median 54.4 μg/m3Range 3.9-244.5PM10, BS, SO2,NO2, CO, pollen0-2 Conditional logistic(case-crossover)1-h max O3(per 48 μg/m3):Odds ratios:Patients with only oneadmission:All cause:1.096 (0.820, 1.466)Cardiovascular:1.397 (0.854, 2.285)Patients with more thanone admission:All cause:1.688 (0.978, 2.643)Cardiovascular:1.331 (0.529, 3.344)Patients admitted for bothasthma and COPD:All cause:0.946 (0.674, 1.326)Cardiovascular:0.985 (0.521, 1.861)Díaz et al. (1999)Madrid, Spain1990-1992All cause;respiratory;cardiovascular24-h avg O3:Levels not reported.TSP, NO2, SO2,CO1, 4, 10 Autoregressive linear.Time-series study.24-h avg O3(per 25 μg/m3):For O3levels higher than 35μg/m3:All cause:Lag 4: 12% (p < 0.01)U-shaped (quadratic) O3-mortality relationship with aminimum of 35 μg/m3.



### AX7-94Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesLatin AmericaBorja-Aburto et al. (1997)Mexico City1990-1992All cause;respiratory;cardiovascular; allages; age <5 years;age >65 years1-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 ppbTSP, SO2, CO;two-pollutantmodels0, 1, 2 Poisson iterativelyweighted and filteredleast-squares method.Time-series study.1-h max O3(per 100 ppb):All ages:O3only model:All cause:Lag 0: 2.4% (1.1, 3.9)Respiratory:Lag 0: 2.3% (!1.9, 6.7)Cardiovascular:Lag 0: 3.6% (0.6, 6.6)O3with TSP model:All cause:Lag 0:!1.8% (!10.0, 6.4)Respiratory:Lag 0:!1.9% (!11.0, 8.2)Cardiovascular:Lag 0: 2.4 (!4.4, 9.6)Borja-Aburto et al. (1998)SW Mexico City1993-1995All cause;respiratory;cardiovascular;other; all ages;age >65 years1-h max O3:163 ppbSD 5724-h avg O3:44.0 ppbSD 15.7PM2.5, NO2, SO2;two-pollutantmodels0, 1, 2, 3, 4, 5,1-2Poisson GAM withdefault convergencecriteria (only onesmoother). Time seriesstudy.24-h avg O3(per 10 ppb):All cause, all ages:Lag 1-2: 0.6% (!0.3, 1.5)All cause, age > 65 years:Lag 1-2: 0.8% (!0.4, 2.0)Respiratory, all ages:Lag 1-2:!0.7% (!3.6, 2.1)Cardiovascular, all ages:Lag 1-2: 1.8% (0.1, 3.5)Other noninjury, all ages:Lag 1-2: 0.3% (!0.9, 1.4)



### AX7-95Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesLatin America(cont’d)O’Neill et al. (2004)Mexico City1996-1998All cause; all ages;age 65+ years;SES gradient24-h avg O3:35.3 ppbSD 11.0PM100-1 Poisson GAM withstringent convergencecriteria. Time-seriesstudy.24-h avg O3(per 10 ppb):All ages:0.65% (0.02, 1.28)Age 65+ years:1.39% (0.51, 2.28)SES gradient did not showany consistent pattern.Téllez-Rojo et al. (2000)Mexico City1994Respiratory;COPD mortality;age 65+ years;within medicalunit; outside ofmedical unit1-h max O3:134.5 ppbSD 33.4PM10, NO2, SO21, 2, 3, 4, 5, 1-3,1-5, 1-7Poisson, iterativelyweighted and filteredleast-squares method.Time-series study.1-h max O3(per 40 ppb):Outside medical unit:Respiratory:Lag 1-5: 14.0% (4.1, 24.9)COPD mortality:Lag 1-5: 15.6% (4.0, 28.4)Loomis et al. (1999)Mexico City1993-1995Infant mortality 24-h avg O3:44.1 ppbSD 15.7PM2.5, NO20, 1, 2, 3, 4, 5,2-3Poisson GAM withdefault convergencecriteria. Time-seriesstudy.24-h avg O3(per 10 ppb):O3only model:2.45% (!0.54, 5.43)O3with PM2.5model:1.40% (!1.92, 4.72)Gouveia and Fletcher(2000b)São Paulo, Brazil1991-1993All 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 42.1PM10, NO2, SO2,CO0, 1, 2 Poisson GLM. Timeseries study.1-h max O3(per 106 μg/m3):All ages:All cause:Lag 0: 0.8% (!1.1, 2.7)Age 65+ years:All cause:Lag 2: 2.3% (0, 4.6)Respiratory:Lag 2: 5.1% (!0.6, 11.1)Cardiovascular:Lag 0: 3.1% (!0.4, 6.7)



### AX7-96Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesLatin America(cont’d)Pereira et al. (1998)São Paulo, Brazil1991-1992Intrauterinemortality1-h max O3:67.5 μg/m3SD 45.0PM10, NO2, SO2,CO0 Poisson, linear withM-estimation. Timeseries study.Slope estimate:0.0000 (SE 0.0004)Saldiva et al. (1994)São Paulo, Brazil1990-1991Respiratory; age<5 years24-h avg O3:12.14 ppbSD 9.94PM10, NO2, SO2,CO; multipollutantmodels0-2 OLS of transformeddata. Time-seriesstudy.Slope estimate:0.01048 deaths/day/ppb(SE 0.02481), p = 0.673Saldiva et al. (1995)São Paulo, Brazil1990-1991All cause;age 65+ years1-h max O3:38.3 ppbSD 29.724-h avg O3:12.5 ppbSD 11.5PM10, NO2, SO2,CO; two-pollutantmodels0-1 OLS; Poisson withGEE. Time-seriesstudy.Slope estimate:1-h max O3:0.0280 deaths/day/ppb(SE 0.0213), p > 0.0524-h avg O3:0.0093 deaths/day/ppb(SE 0.0813), p > 0.05Cifuentes et al. (2000)Santiago, Chile1988-1966All cause 1-h max O3:Summer:108.2 ppbIQR 48.0PM2.5, PM10-2.5,CO, SO2, NO20, 1, 2, 3, 4, 5,1-2, 1-3, 1-4,1-5Poisson GAM withdefault convergencecriteria; Poisson GLM.Time-series study.1-h max O3per (108.2 ppb):Poisson GLM:Summer:O3only model:Lag 1-2: 0.3% (t = 0.3)Multipollutant model:Lag 1-2:!0.1% (t =!0.1)Ostro et al. (1996)Santiago, Chile1989-1991All cause 1-h max O3:52.8 ppbRange 11-264PM10, NO2, SO2;two-pollutantmodels1 OLS, several othermethods. Time-seriesstudy.All year:1-h max O3(per 52.8 ppb):!3% (!4,!2)Summer:1-h max O3(per 100 ppb):4% (0, 9)



### AX7-97Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesAustraliaMorgan et al. (1998b)Sydney, Australia1989-1993All cause;respiratory;cardiovascular1-h max O3:24 ppbSD 13PM bynephelometer,NO2;multipollutantmodels0 Poisson with GEE.Time-series study.1-h max O3(per 28 ppb):All cause:2.04% (0.37, 3.73)Respiratory:!0.84% (!7.16, 5.91)Cardiovascular:2.52% (!0.25, 5.38)Simpson et al. (1997)Brisbane, Australia1987-1993All cause;respiratory;cardiovascular;all ages; age<65 years;age 65+ years8-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 1.7-56.9PM10, PM bynephelometer,NO2, SO2, CO0 Autoregressive Poissonwith GEE. Time-seriesstudy.8-h avg O3(per 10 ppb):All cause, all ages:All year:2.4% (0.8, 4.0)Summer:3.0% (1.0, 5.0)Winter:1.3% (!1.4, 4.1)AsiaKim et al. (2004)Seoul, Korea1995-1999All cause 1-h max O3:All year:35.16 ppbSD 18.31Summer:46.87 ppbSD 22.46Winter:21.26 ppbSD 6.92PM10, NO2, SO2,CO; two-pollutantmodels1 Poisson GAM withstringent convergencecriteria (linear model);GLM with cubicnatural spline; GLMwith B-mode spline(threshold model).Time-series study.1-h max O3(per 21.5 ppb):All year:Linear model:2.6% (1.7, 3.5)Threshold model:3.4% (2.3, 4.4)Summer:Linear model:1.9% (0.5, 3.3)Threshold model:3.8% (2.0, 5.7)



### AX7-98Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesAsia(cont’d)Lee et al. (1999)Seoul and Ulsan, Korea1991-1995All cause 1-h max O3:Seoul:32.4 ppb10th %-90th %14-55Ulsan:26.0 ppb10th %-90th %16-39TSP, SO20 Poisson with GEE.Time-series study.1-h max O3(per 50 ppb):Seoul:1.5% (0.5, 2.5)Ulsan:2.0% (!11.1, 17.0)Lee and Schwartz (1999)Seoul, Korea1991-1995All cause 1-h max O3:Seoul:32.4 ppb10th %-90th %14-55TSP, SO20 Conditional logisticregression. Casecrossover withbidirectional controlsampling.1-h max O3(per 50 ppb):Two controls, plus and minus1 week:1.5% (!1.2, 4.2)Four controls, plus and minus2 weeks:2.3% (!0.1, 4.8)Kwon et al. (2001)Seoul, Korea1994-1998Mortality in acohort of patientswith congestiveheart failure1-h max O3:31.8 ppbIQR 20.5Range 4.3-102.8PM10, NO2, SO2,CO0 Time-series analysisusing Poisson GAMwith defaultconvergence criteria;case-crossover analysisusing conditionallogistic regression.1-h max O3(per 20.5 ppb):Odds ratios from casecrossover study design:General population:1.9% (1.0, 2.9)Congestive heart failurecohort:5.1% (!3.6, 14.7)



### AX7-99Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesAsia(cont’d)Ha et al. (2003)Seoul, Korea1995-1999All cause;respiratory;postneonatal(1 month to 1 year);age 2-64 years; age$65 years8-h avg O3:21.2 ppbSD 11.6Range 2.9-69.1PM10, NO2, SO2,CO0 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.8-h avg O3(per 16.1 ppb):Respiratory:Postneonatal:22.6% (!41.2, 155.8)Age 2-64 years:9.8% (6.8, 13.0)Age$65 years:3.7% (2.6, 4.8)Hong et al. (2002)Seoul, Korea1995-1998Acute strokemortality8-h avg O3:22.6 ppbSD 12.4IQR 9.3PM10, NO2, SO2,CO0 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.8-h avg O3(per 9.3 ppb):O3only model:2.9% (0.3, 5.5)PM10< median: 5.5%PM10$median:!2.5%Tsai et al. (2003b)Kaohsiung, Taiwan1994-2000All cause;respiratory;cardiovascular;tropical area24-h avg O3:23.6 ppbRange 1.2-83.0PM10, SO2, NO2,CO0-2 Conditional logisticregression. Casecrossover analysis.24-h avg O3(per 19.2 ppb):Odds ratios:All cause:0.994 (0.995, 1.035)Respiratory:0.996 (0.848, 1.169)Cardiovascular:1.005 (0.919, 1.098)Yang et al. (2004b)Taipei, Taiwan1994-1998All cause;respiratory;cardiovascular;subtropical area24-h avg O3:17.18 ppbRange 2.3-43.47PM10, SO2, NO2,CO0-2 Conditional logisticregression. Casecrossover analysis.24-h avg O3(per 9.34 ppb):Odds ratios:All cause:0.999 (0.972, 1.026)Respiratory:0.991 (0.897, 1.094)Cardiovascular:1.004 (0.952, 1.058)



### AX7-100Table AX7-5 (cont’d). Effects of Acute O3Exposure on MortalityReference, StudyLocation and Period Outcome Measure Mean O3LevelsCopollutantsConsideredLag StructureReported Method/Design Effect EstimatesAsia(cont’d)Wong et al. (2001)Hong Kong1995-1997All cause;respiratory;cardiovascular8-h avg O3(9 a.m.-5 p.m.):Warm:32.0 ppbSD 24.5Range 0-168.9Cool:35.1 ppbSD 21.3Range 0-101.6PM10, NO2, SO2;two-pollutantmodels3, 4, 5 Poisson GAM withdefault convergencecriteria. Time-seriesstudy.8-h avg O3(per 16.1 ppb):All cause:Warm:Lag 5:!1% (!3, 2)Cool:Lag 5: 4% (1, 6)Respiratory:Warm:Lag 4:!1% (!6, 5)Cool:Lag 4: 8% (2, 15)Cardiovascular:Warm:Lag 3:!2% (!6, 3)Cool:Lag 3: 5% (0, 11)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+ yearsAverage monthlyO3:Baseline:18.5 μg/m3SD 7.51 year afterintervention:21.3 μg/m3SD 9.12-5 years afterintervention:22.1 μg/m3SD 10.2SO2(mainpollutant ofinterest, 45%reduction observed5 years afterintervention),PM10, SO42-, NO2Monthlyaveragesconsideredwithout lagsPoisson regression ofmonthly averages toestimate changes in theincrease in deaths fromwarm to cool season.Annual proportionalchange in death ratebefore and after theintervention was alsoexamined.Declines observed in allcause (2.1%, p = 0.001),respiratory (3.9%, p = 0.001),and cardiovascular (2.0%, p =0.020) mortality after theintervention.Analysis not specific for O3effects. As O3levels did notchange before and after theintervention, O3likely did notplay a role in the decline inobserved mortality.



### AX7-101Table AX7-6. Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited StatesGalizia and Kinney(1999; exposure dataKinney et al., 1998)U.S. nationwide19951-h max O3:10-year mean Jun-Aug:61.2 ppbSD 15.5Range 13-185Cross-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 O3exposure was treated as ahigh/low dichotomous variable, with subjectsassigned to the high O3category if they lived for4+ years in counties with 10-year summer mean O3levels greater than 80 ppb. Four lung functionvariables (FVC, FEV1, FEF25-75, FEF75) wereregressed on O3exposure, 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 O3exposure, controlling for sex, race,parental education, and maternal smoking.Significant decrements in FEV1and FEF25-75in relation to O3exposure were observed for allsubjects and for males alone, butnot for females alone. Similar patterns observed for FVC andFEF75, but not with statistical significance.Percent difference in lung function for high vs. low O3exposuregroups: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 index were significantly elevatedfor high O3exposure group.Odds ratios for symptoms:Wheeze: 1.97 (1.06, 3.66)Respiratory symptom index: 2.00 (1.15, 3.46)Goss et al. (2004)U.S. nationwide1999-20001-h max O3:51.0 ppbSD 7.3Cohort 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 AerometricInformation Retrieval System with patients’ homezip code. Studied exacerbation and lung function.Mortality was also of interest, but study wasunderpowered to examinethis outcome. Logisticregression models were used to analyze theexacerbations and multiple linear regression wasused to study lung function. O3monitoring seasonand regional effects also were examined.Ozone may increase the risk for pulmonary exacerbations in cysticfibrosis patients.Odds ratios for two or more exacerbations (per 10 ppb increase in1-h max O3):O3only model: 1.10 (1.03, 1.17)O3with PM2.5model: 1.08 (1.01, 1.15)PM2.5, but not O3, was significantly associated with declines inlung function in these patients.



### AX7-102Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Kinney and Lippmann(2000)Fort Sill, OK;Fort Leonard Wood,MO; Fort Dix, NJ;Fort Benning, GA;West Point, NYApr-Sep 19901-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 O3levels duringsummer training.Mean FEV1declined significantly over the two measurementpoints for all subjects combined, which may reflect combinedeffects of O3with exposures to dust,vehicle exhaust, andenvironmental tobacco smoke as reported by subjects from all fourlocations in the post-summer questionnaire. However, a largermean decline was seen at the higher O3site, Fort Dix, than at theremaining three sites, suggesting an influence of O3exposures.A larger decline was observed in subjects with post-summermeasurements in the 1st and 2nd weeks after returning fromtraining vs. those measured inthe 3rd and 4th weeks, which isconsistent with the lung functioneffects being somewhat transient.Change in lung function over the summer:FEV1:All locations:!44 mL (SE 21), p = 0.035Fort Dix:!78 mL (SE 41), p = 0.07Forts Sill, Leonard Wood, and Benning combined:!31 mL (SE 24), p = 0.21Greer et al. (1993)California1973-1987Annual 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 casesof asthma among 1,305 males and51 incident cases among 2,272 females. In logistic regressionanalyses, long-term O3exposures were associated with increasedrisk of incident asthmaamong males but not females.Relative risks for incident casesof asthma (per 10 ppb increasein annual mean O3):Males: 3.12 (1.61, 5.85)Females: 0.94 (0.65, 1.34)



### AX7-103Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)McDonnell et al.(1999)California1973-19928-h avg O3(9 a.m.-5 p.m):20-year mean:46.5 ppbSD 15.3This 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 asthmacases 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 asthma among 972 males and79 incident cases among 1,786 females. In logistic regressionanalyses, long-term O3exposures were associated with increasedrisk of incident asthma amongmales but not females. Otherpollutants were neither associated with asthma incidence norwere confounders of the O3association in males.Relative risks for incident casesof asthma (per 27 ppb increasein 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 SouthernCaliforniacommunities1993-19941-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 from1986-1990 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 associated significantly withprevalence of wheeze. No associations of O3with any of therespiratory diseases or symptoms.Decreased lung function was associated with multiple pollutantsamong females but not males. For O3exposure in females, all fourlung function variables declined with increasing exposure.Associations were stronger for current (1994) exposure comparedto previous (1986-1990) exposure. In males who spent more timeoutdoors, FVC and FEV1declined significantly with higher currentexposure to O3.Change in lung function (per 40 ppb 1-h max O3from 1986-1990):Females:PEF:!187.2 mL/s (SE 50.1), p < 0.005FEF25-75:!102.2 mL/s (SE 28.8), p < 0.01Males:PEF: 31.1 mL/s (SE 48.8), p > 0.05FEF25-75: 11.7 mL/s (SE 26.7), p > 0.05



### AX7-104Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Gauderman et al.(2000; 2004a,b)12 SouthernCaliforniacommunities1993-20018-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, difference in lung functiongrowth from the least to the most polluted community was notassociated with any of the air pollutants, including O3. Among the4th graders, decreased lung growthwas associated with exposuresto PM2.5, NO2, acid vapor, and elemental carbon, but not with O3.It should be noted, however, that there was only about a 2- to2.5-fold difference in O3concentrations from the least to mostpolluted communities, compared to the other pollutants which hada 4- to 8-fold difference in concentrations. In addition, theseresults should be interpreted with caution given the potential forsubstantial misclassification of O3exposure.Gauderman et al.(2002)12 SouthernCaliforniacommunities1996-19998-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, inorganicacid, elemental carbon, and organic carbon.Adjusted linear regression model was used.In this cohort, a significant association between O3and PEF andFVC was noted in children spending more time outdoors.Percent difference in annual increases in lung function from leastto most polluted community (per36.6 ppb increase in annual mean8-h avg O3):PEF:All children:!1.21% (!2.06,!0.36)Children more outdoors:!1.62% (!2.93,!0.29)Children less outdoors:!0.87% (!2.09, 0.37)McConnell et al.(1999)12 SouthernCaliforniacommunities19931-h max O3:Estimated annual mean:65.6 ppbRange 35.5-97.5First cohort of the Children’s Health Study.Association of O3with prevalence of chronic lowerrespiratory tract symptoms among children with ahistory of asthma was examined in a cross-sectionalstudy in 12 communities. Questionnaires werecompleted by parents of3,676 4th, 7th, and 10thgraders, of which 493 had asthma. Exposure data(O3NO2, PM10, PM2.5, and inorganic acid vapors)collected in 1994 usedto estimate exposure.Analysis using logistic regression method.Children with asthma were muchmore likely to have bronchitis orrelated symptoms than children without such history. Among theasthmatic children, significant relationship were observed betweenphlegm and all pollutants studied, with the exception of O3.



### AX7-105Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)McConnell et al.(2003)12 SouthernCaliforniacommunities1996-19998-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 1.7-13.2A 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 with the various airpollutants. Within-community effects were greater than thebetween-community effects. Authors note that if the larger withincommunity effect estimates are correct, then other cross-sectional(between-community) studies may have underestimated the trueeffect of air pollution on respiratory symptoms in children. Thesedifferences may be attributable to confounding by poorly measuredor unmeasured risk factors that vary between communities. Ozoneeffect estimates were markedlyreduced in two-pollutant models(odds ratios not provided).Odds ratios for bronchitic symptoms (per ppb O3):Within-community effects: 1.06 (1.00, 1.12)Between-community effects: 0.99 (0.98, 1.01)McConnell et al.(2002)12 SouthernCaliforniacommunities1993-19981-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 69.3-87.2Prospective 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, andinorganic acid vapors. Asthma incidence wasexamined as a function ofnumber of sports playedin high- and low-pollution communities, controllingfor age, sex, and ethnic origin.Asthma incidence was not higher in the high-pollutioncommunities as compared with the low-pollution communities,regardless of the pollutant used to define high/low. In fact,the high-O3communities had generally lower asthma incidence.However, in high-O3communities, there was an increased risk ofasthma in children playing three ormore sports vs. those playingno sports; no such increase was observed in the low-O3communities. No other pollutant showed this association. Theseresults suggest that high levelsof physical activity is associatedwith risk of new asthma development for children livingin communities with high O3levels.Relative risk of developing asthma in children playing three ormore sports vs. those playing no sports:Low-pollution communities: 0.8 (0.4, 1.6)High-pollution communities: 3.3 (1.9, 5.9)



### AX7-106Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Avol et al. (2001)12 SouthernCaliforniacommunities and sixwestern statesBaseline 1994Follow-up 19988-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 inO3levels110 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 tochange in exposures toPM10, NO2, and O3.Negative but nonsignificant associations were found between lungfunction parameters and changes in O3. The relationship wasstrongest with PM10. Subjects who moved to areas of lower PM10showed greater increases in FEV1 compared subjects who movedto areas with higher PM10.Change in lung function (per 10 ppb increase in changes in annualmean 8-h avg O3):FEV1: 0.1 mL (!8.7, 8.9)FVC:!1.4 mL (!10.8, 8.0)MMEF (maximal midexpiratory flow):!3.4 mL/s (!23.6, 16.8)PEF:!8.9 mL/s (!41.6, 23.8)Ritz and Yu (1999)Southern California1989-1993Last trimester average:20.9 ppbRange 3.0-49.4125,573 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 CO during the last trimesterwas associated with a significantly increased risk for low birthweight. Effects of CO appeared more pronounced after adjustmentfor concurrent exposures to NO2, PM10, and O3. Ozone effectestimates were not reported.Ritz et al. (2000)Southern California1989-19938-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 3.3-117Data 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 regressionanalysis used, controlling for maternal age, race,education, parity, and other factors.Both PM10and CO during early or late pregnancy were associatedwith increased risk for preterm birth. No associations observedwith O3.



### AX7-107Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Ritz et al. (2002)Southern California1987-199324-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 ppbThe 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!aorticdefects, 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 observed for O3concentrations during the 2nd month of gestation on aortic arteryand valve defects, pulmonary artery and valve anomalies, andconotruncal defects. CO during the 2nd gestational month wasfound to be associated with ventricular septal defects. The resultswere inconclusive for NO2and PM10. Findings from this studysuggest that there may be a vulnerable window of development tohuman malformations.Odds ratios for birth defects (per 10 ppb O3during 2nd month ofgestation):Aortic defects: 1.56 (1.16, 2.09)Pulmonary valve defects: 1.34 (0.96, 1.87)Conotruncal defects: 1.36 (0.91, 2.03)Künzli et al. (1997);Tager et al. (1998)Los Angeles and SanFrancisco, CA;Berkeley, CA19958-h avg O3(10 a.m.-6 p.m.):Lifetime monthlyaverage:Los Angeles:Median 51.5 ppbRange 25-74San Francisco:Median 22.5 ppbRange 16-33A 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. Bydesign, students hadpreviously resided in one of two metropolitan areasthat differed greatly in O3concentrations,San Francisco or Los Angeles. A key goal was totest whether measures of small airways function(e.g., nitrogen washout, FEF25-75, FEF75) weresensitive measures of long-term O3impacts.Lifetime exposures to O3, PM10and NO2assignedby interpolation to sequence of residence locationsfrom available monitoring stations. Multipleexposure measures werederived with varyingdegrees of incorporation of time-activityinformation, going from ecological concentrationto individual time-activity weighted exposure.Performed linear regression analysis of lungfunction on O3exposures, controlling for height,ethnicity, gender, and region.Decreased FEF25-75and FEF75were associated with long-term O3exposures. Results were similar whether O3exposure was purelyecologic or incorporated time-activity information. FVC, FEV1,and nitrogen washout were generally not associated with O3levels.No evidence for PM10or NO2main effects or confounding of O3.Similar patterns results using O3hours >60 ppb as exposure metricinstead of daily 8-h avg O3. Surprisingly, region of residence wasa major negative confounder as lung function was lower onaverage among students from the low O3city, San Francisco, thanamong those who had lived in Los Angeles. Ozone exposureswere significant predictors only after controlling the regionaleffect.Change in lung function (per20 ppb increase in lifetime mean8-h avg O3):FEF25-75:!420 mL/s (!886, 46); 7.2% of population meanFEF75:!334 mL/s (!657,!11); 14% decline of population mean



### AX7-108Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Tager et al. (2005)Los Angeles andSan Francisco, CA;Berkeley, CA2000-20028-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 ppbSimilar 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 airwaysize) was also examined.In the models examining only the main effects of O3, noassociations were observed between lifetime exposure to O3andlung function parameters in eithermen or women. However, afterincluding an interaction term for FEF25-75/FVC ratio, consistentinverse associations between increasing lifetime exposure to O3and FEF25-75and FEF75were observed for both men and women.The adverse impact of increased lifetime exposure to O3was foundto decrease with increasing FEF25-75/FVC ratio. Comparableregressions with PM10and NO2showed similar results. WhenPM10and NO2were added to the O3model for FEF75, there were nomeaningful changes in the effectestimates for lifetime exposure toO3or the interaction term while the effect parameters for PM10andNO2were reduced substantially. The potential effect ofmeasurement error from the useof questionnaire responses toestimate exposure to O3was assessed. The measurement errorcorrection did not have a meaningful effect on the magnitude ofthe association with O3.Change in lung function (per 17ppb increase in lifetime mean 8-havg O3), after including interaction term for FEF25-75/FVC ratio:FEV1:!19% (!39, 1)FEF75:!37% (!41,!32)FEF25-75:!29% (!33, 24)Gong et al. (1998b)Glendora, CA1977-19871-h max O3:Annual means range(1983-1987):109-134 ppbLongitudinal cohort study of 164 adults (mean age45 years; 34% males) from a high O3communityunderwent 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 O3over 2 h withintermittent exercise. 45 subjects agreed toparticipate. Investigators hypothesized that acutelyresponsive subjects would show more rapid declinesin function over the study period.Mean FVC and FEV1showed nonsignificant increase from T2 toT3, whereas an earlier analysis ofthe T1 to T2 change had found asignificant decline in function (Detels et al., 1987). There wasevidence for “regression to the mean,” in that subject with largerdeclines in function from T1 to T2tended to have larger increasesin function from T2 to T3. A consistent decline in FEV1/FVC ratiowas observed at all three time points (p < 0.0001 by ANOVA).Acute changes in lung function,determined using controlled O3exposures, were not associated with chronic lung function changes.



### AX7-109Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Chen et al. (2002)Washoe County, NV1991-19998-h max O3:27.23 ppbSD 10.62Range 2.76-62.44Birth weight for 36,305 single births analyzedin relation to mean PM10, O3, and CO levels in 1st,2nd, and 3rd trimesters.PM10was the only air pollutant associated with decreased birthweights. Ozone levels quite low throughout study.Kinney et al. (1996b)New York City1992-19931-h max O3:Summer(Jul-Sep 1992):58 ppbMaximum 100Winter(Jan-Mar 1992):32 ppbMaximum 64Summer(Jul-Sep 1993):69 ppbMaximum 142Study 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 O3levels, six subjects underwent a thirdbronchoalveolar lavage in the summer of 1993.Study tested whether inflammatory markers inbronchoalveolar lavage fluid were elevated duringthe summer O3season among adults who regularlyexercised outdoors. Outcomes included celldifferentials, release of IL-8 and TNF-"inbronchoalveolar lavage cellssupernatants, releaseof reactive oxygen species by macrophages, andconcentrations of protein, lactate dehydrogenase,IL-8, fibronectin, a1-antitrypsin (a1-AT),complement fragments (C3a), and PGE2inbronchoalveolar lavage fluids.There was no evidence of acute inflammation in the summer of1992 compared to the winter; i.e., neutrophil differentials, IL-8 andTNF-"showed no significant differences. However, a measure ofcell damage, lactate dehydrogenase, was elevated in the summer,suggesting possible O3-mediated damage to the lung epitheliumwith repeated exposures to O3while exercising. O3levels duringthe summer of 1992 were atypically low for New York City.Among six subjects who agreed to undergo a third bronchoalveolarlavage test in the summer of1993, lactate dehydrogenase wasagain elevated compared to winter. In addition, IL-8 was elevatedin the summer of 1993, suggesting acute inflammation.



### AX7-110Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsEuropeCharpin et al. (1999)Seven towns inSE FranceJan-Feb 19938-h max O3:Range of means:30.2-52.1 μg/m324-h avg O3:Range of means:20.1-42.1 μg/m3Cross-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 ambientO3and other pollutant (NO2and SO2) levels. Testedhypothesis 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 differences in atopy levels wereseen across the seven towns.Authors concluded that long-termexposures to oxidant pollution do not favor increased allergy tocommon allergens. The very low winter O3levels monitored andlack of long-term exposure data make it impossible to reach thisconclusion in a definitive manner.Ramadour et al.(2000)Seven towns inSE FranceJan-Feb 19938-h max O3:Range of means:30.2-52.1 μg/m3Cross-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 O3levels in France. Subjects completedISAAC survey of asthma and respiratory symptoms.In addition to O3also collected data on SO2andNO2. Analyzed relationships between asthma andother respiratory conditionswith 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 associations seen between O3and 12-mo history of wheezing, history of asthma attack, exerciseinduced asthma and/or dry cough in last 12 months.In simple bivariate scatterplotsof respiratory outcomes vs. meanO3levels in the seven towns, there appeared to be strong positiverelationships (r = 0.71 for wheezing in last 12 months and r = 0.96for asthma attacks). No data onslope estimates given. Concernsabout potential confounding across towns limits the interpretationof this study.



### AX7-111Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsEurope(cont’d)Ihorst et al. (2004)Nine communities inLower AustriaApr 1994-Oct 1997Six communities inGermanyFeb 1996-Oct 19991⁄2-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 ppbLongitudinal cohort study of 2,153 children (medianage 7.6 years) were studied for the effects of semiannual and 31⁄2-year mean O3concentrations onFVC 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 O3exposure on lunggrowth 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 O3levels were associated withdiminished lung function growth during the summer, butincreased lung function growth in the winter.Change in lung function (4th quartile vs. 1st quartile semi-annualO3mean):Summer:FEV1(mL/100 days):!18.5 (!27.1,!9.8)FVC (mL/100 days):!19.2 (!27.8,!10.6)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 O3exposure (mean summerO3over a 31⁄2-year period) and lung function growth was found.Kopp et al. (2000)Ten communities inAustria and SWGermanyMar 1994-Nov 19951⁄2-h avg O3:Mean from Apr-Oct1994:Stratified by low,medium, highexposure:Low: 24-33 ppbMedium: 35-38 ppbHigh: 44-52 ppbLongitudinal 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 FEV1increases were observed in children exposedto high ambient O3levels vs. those exposed to lower O3levelsduring the summer. During the winter, children in higher O3areasshowed a slightly greater increase in FVC and FEV1than those inthe low O3areas, which might reflect that children make up forlung function deficits during the winter season.Change in lung function for high vs. low O3exposure groups (perppb O3):FEV1:Summer of 1994:!0.303 mL/day, p = 0.007Winter of 1994/1995: 0.158 mL/day, p = 0.006Summer of 1995:!0.322 mL/day, p = 0.001



### AX7-112Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsEurope(cont’d)Frischer et al. (1999)Nine communities inAustria1994-199624-h avg O3:Summer:34.8 ppbSD 8.7Winter:23.1 ppbSD 7.7Longitudinal cohort study of communities from twocounties chosen to represent a broad range of O3concentrations; 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 O3would 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 O3levelsand change in lung function (FVC, FEV1, andMEF50[maximal expiratoryflow at 50% of vitalcapacity]) 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 O3exposures were associated with reductions ingrowth in all three lung functionmeasures. Inconsistent resultsseen for other pollutants. Summer season lung function growthdecrements per unit O3were larger when data restricted to childrenwho spent whole summer in their community. No evidence fornonlinear O3effect. No confounding of O3effect by temperature,ETS, or acute respiratory illnesses.Change in lung function (per ppb O3):FEV1(mL/day):All subjects:Summer:!0.029 (SE 0.005), p < 0.001Winter:!0.024 (SE 0.006), p < 0.001Restricted to subjects who stayed in community:Summer:!0.034 (SE 0.009), p < 0.001FVC (mL/day):All subjects:Summer:!0.018 (SE 0.005), p < 0.001Winter:!0.010 (SE 0.006), p = 0.08Restricted to subjects who stayed in community:Summer:!0.033 (SE 0.007), p < 0.001Frischer et al. (2001)Nine communities inAustriaSep-Oct 19971⁄2-h avg O3:30-day mean:31.57 ppbIQR 20.61A 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 protein-X concentrations werefound to be significantly associated with O3levels, after adjustingfor gender, site, and atopy.Change in log urinary eosinophil protein-X (per ppb O3):0.007 μg/mmol creatinine (SE 0.02), p < 0.001



### AX7-113Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsEurope(cont’d)Horak et al. (2002a,b)Eight communities inAustria1994-1997Seasonal mean O3:Summer:31.8 ppbRange 18.7-49.3Winter:19.8 ppbRange 12.7-35.9This 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 O3showed a negative effect on lung functiongrowth, confirming the previous shorter study. Ozone effects wererobust to inclusion of PM10into the model. However, for FEV1inwinter, the O3effect slightly diminished after including PM10.Taking into account only children who stayed at home the wholesummer period did not affect the results.Change in lung function (per ppb O3):FEV1(mL/day):O3only models:Summer:!0.021, p < 0.001Winter:!0.020, p < 0.001O3with PM10models:Summer:!0.020, p < 0.001Winter:!0.012, p = 0.04Palli et al. (2004)Florence, Italy1993-199824-h avg O3:Range of monthlymeans from 1993-1998:Approximately25-125 ppbCohort 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 O3exposure.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 O3exposure timewindows were calculated after stratifying bysmoking history, area of residence, and populationtype (random sample or exposed workers).Consistent relationships between O3exposure and DNA adductlevels were observed only among never smokers. Correlationswere highest among never smokerswho resided in the urban areaand were not occupationally exposed to vehicle traffic pollution.Associations were significant up to a time window of 0-60 daysprior to the blood draw in the subgroup of never smokers, withstrongest relationships observed between 30-45 days prior.



### AX7-114Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsLatin AmericaCalderón-Garcidueñaset al. (1995)SW Mexico CityNov 1993Manzanillo, MexicoJan 19941-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 fourtimes 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 from Mexico City hadabnormal nasal mucosae, including mucosal atrophy, markeddecreases in the numbers of ciliated-type cells and goblet cells,and squamous metaplasia.Exposed children had significantly higher nasalpolymorphonuclear leukocyte counts (p < 0.001) and nasal CD11bexpression (p < 0.001) vs. controls. However, the inflammatoryresponse did not seem to correlate with the previous day’s O3exposure, suggesting that there might be a competinginflammatory mechanism at the bronchoalveolar level. Overall,these results suggest that ambient O3produces an inflammatoryresponse in chronically exposedchildren. However, it should benoted that urban children were exposed to a complex pollutionmix, making it difficult to attribute effects to O3specifically.Gouveia et al. (2004)São Paulo, Brazil19971-h max O3:63.0 ppbSD 33.5Birth weight for 179,460 single births analyzedin relation to PM10, SO2, CO, NO2, and O3levels in1st, 2nd, and 3rd trimesters. GAM and logisticregression models used for analysis.Exposures to PM10and CO during 1st trimester were found tohave significant negative associations with birth weight.No associations observed for theother air pollutants, including O3.



### AX7-115Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsAsiaHa et al. (2001)Seoul, Korea1996-19978-h avg O3:1st trimester:Median 22.4 ppbIQR 13.63rd trimester:Median 23.3 ppbIQR 16.1Examined 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 and3rd trimesters were initiallyexamined separately. For the1st trimester exposure estimates,positive associations with risk oflow birth weight were observedfor CO, NO2, SO2, and TSP, but not O3. For the 3rd trimesterexposure estimates, a positive association was observed for O3, butnot the other pollutants. When exposures from both trimesterswere examined simultaneously, the risk of low birth weightremained positive for CO, NO2, SO2, and TSP during the 1sttrimester. However for O3, the positive association with 3rdtrimester exposure was diminished. These results suggest thatexposures to CO, NO2, SO2, and TSP in the 1st trimester may berisk factors for low birth weight.Relative risk of low birth weight (per 13.6 ppb 8-h avg O3for 1sttrimester; per 16.1 ppb 8-h avg O3for 3rd trimester):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)



### AX7-116Table AX7-6 (cont’d). Effects of Chronic O3Exposure on Respiratory HealthReference, StudyLocation, and Period Mean O3Levels Study Description Results and CommentsAsia(cont’d)Kuo et al. (2002)Central Taiwan19961-h max O3:Annual mean rangeacross 7 of 8 schools:18.6-27.3 ppbCross-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 logisticregression. 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% to 14.5% across the 8schools. Based on simple Pearson correlations, mean O3(r = 0.51)and NO2(r = 0.63) levels were correlated with variations in asthmaprevalence. However, only NO2remained significant in multiplelogistic regression analyses after adjusting for various potentialconfounding factors.Longitudinal hospital admissions results are inconclusive dueto analytical limitations. Monthly correlations of hospitaladmissions for asthmatics yielded variable results, all of whichwould be confounded by temporal factors.



### AX7-117Table AX7-7. Effects of Chronic O3Exposure on Mortality and Incidence of CancerReference, Location,Study Period Mean O3Levels Study Description Results and CommentsUnited StatesPope et al. (2002)U.S. nationwide1982-19981-h max O3:Mean from Jul-Sep:59.7 ppbSD 12.8Prospective 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 O3on mortality risk, though theassociation of Jul-Sep O3concentrations with all causeand cardiopulmonary mortality were positive and nearlysignificant.Residential location was known only at enrollment tostudy in 1982. Thus, exposure misclassification islikely to be high.Lipfert et al. (2000b;2003)32 VeteransAdministration hospitalsnationwide in the U.S.1976-199695th % O3:1960-1974: 132 ppb1975-1981: 140 ppb1982-1988: 94 ppb1989-1996: 85 ppbCohort study of approximately 50,000 U.S. veterans(all males) diagnosed with hypertension. Mean age atrecruitment was 51 years. Exposure to O3during fourperiods (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 proportionalhazards regression, adjusting for race, smoking, age,systolic and diastolic blood pressure, body mass index,and socioeconomic factors.Positive average concurrent responses for TSP, SO42!,NO2, O3in individual period analyses, but only O3wassignificant for overall. Two-pollutants analyses indicatethat responses to peak O3are robust.Relative risks (per mean 95th % O3less estimatedbackground level, value not reported):Averaged over all four periods:Exposure concurrent with mortality:O3only model:9.4% (SE 4.6), p < 0.05O3with NO2model:12.2%, p < 0.05Exposure before mortality:O3only model:!0.2% (SE 6.3) p > 0.05Analyses were robust to the deletion of diastolic bloodpressure in the models, indicating that the associationbetween mortality and O3was not mediated throughblood pressure.



### AX7-118Table AX7-7 (cont’d). Effects of Chronic O3Exposure on Mortality and Incidence of CancerReference, Location,Study Period Mean O3Levels Study Description Results and CommentsUnited States(cont’d)Abbey et al. (1999)Three California airbasins: San Francisco,South Coast (Los Angelesand eastward), San Diego1977-199224-h avg O3:Monthly average from1973 to censor date:26.11 ppbSD 7.65IQR 12.0O3h/year >100 ppb:330 h/yearSD 295IQR 551Prospective 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, andbody mass index. Analyzedmortality from all natural causes, cardiopulmonary,nonmalignant respiratory, and lung cancer. Ozoneresults were presented for both metrics.Of 16 regressions involving O3exposures (two genders;four mortality causes; two O3metrics), 11 were positiveand one was statistically significant, for lung cancer inmales for O3h/year >100 ppb.Relative risks for lung cancer mortality in males:24-h avg O3(per 12.0 ppb):2.10 (0.99, 4.44)O3h/year >100 ppb (per 551 h/year):4.19 (1.81, 9.69)Inconsistency across outcomes and genders raisespossibility of spurious finding. The lack ofcardiopulmonary effects raises plausibility concerns.Beeson et al. (1998)Three California airbasins: San Francisco,South Coast (Los Angelesand eastward), San Diego1977-199224-h avg O3:Monthly average from1973 to 1992:26.2 ppbSD 7.7O3h/year >100 ppb:333 h/yearSD 297IQR 556Prospective 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, withassignment of individuallong-term exposures to O3, PM10, SO42-, and SO2, was aunique 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, showed moderate associationfor O3and incident lung cancer risk.Relative risks for lung cancer incident in males:O3h/year >100 ppb (per 556 h/year):All males: 3.56 (1.35, 9.42)Never smokers: 4.48 (1.25, 16.04)Past smokers: 2.15 (0.42, 10.89)



### AX7-119Table AX7-7 (cont’d). Effects of Chronic O3Exposure on Mortality and Incidence of CancerReference, Location,Study Period Mean O3Levels Study Description Results and CommentsLatin AmericaPereira et al. (2005)São Paulo, BrazilExposure period1981-1990Case period1997Mean avg of days/yearwhen O3levels exceededair quality standards (unitsnot provided):Lapa: 40.2Moema: 19.6Moóca: 67.1Sé: 28.2Annual 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 study provide limitedevaluation of the relationship between air pollution andcancer. There was a significant difference in theincidence of larynx and lung cancer among the SãoPaulo city districts.Of all the pollutants examined O3was best correlatedwith cases of larynx and lung cancer.Pearson correlation coefficient:Larynx cancer: 0.9929 (p = 0.007)Lung cancer: 0.7234 (p = 0.277)



### 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 inte rvals 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 d ecrease 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, μ i 

### 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 i th sample (effect estimate). In this case, the 

### $ σ

i 

### summary density is called a variable kernel density estimate, as h i 

### varies depending on the

standard error of each estimate. To extend the summary density to an optimal density consider h i 

### of the form

where k is a constant to be determined, F g 

### is the geometric mean of the estimated standard

errors and

where is the standard deviation and IQR i 

### is the interquartile range of the samples (effect 

### $ σ

i 

### estimates). Both and IQR i 

### / 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 extens ion of the summary density to an optimal kernel density will be referred to as the extension

. Next, the choice of the h i 

### 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 O 3 

### -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 Increment a

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 O 3 ; 30 ppb for 8-h max O 3 ; and 20 ppb for 24 h avg O 3 . b Indicates use of Poisson GAM w ith 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 μ i 

### and its standard error is

substituted for F i 

### . 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 O 3 

### 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 O 3 

### -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 di fferent 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 devi ation 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 effect s 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 bemade 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 clus ter 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 Concentrat ion-Response Model for Mortality Risk and Long-Term O 3 

## Concentrations
A three-parameter Gompertz concentration-response model was fit to examine the association between mortality risk from acute O 3 

### exposure and long-term O 3 

### concentrations using data from the U.S. 95 communities study (Be ll 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 O 3 

### 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 O 3 

### . 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 O 3 

### associated with a 0.05% excess risk in mortality (EC 0.05% 

### ). The EC 0.05% 

### is a risk that is believed to be low enough to be in the noise band. The upper 95% confidence limit on the EC 0.05% 

### 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 concentra tions 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 × b 1 

### 0.63 0.21 (0.20, 1.06)

EC 0.05% 

### 25.8 0.9 (24.0, 27.6)

b 2 

### 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 O 3 

### 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 O 3 

### plotted against communityspecific long-term average 24-h avg O 3 

### 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 EC 0.05% 

### would be to estimate the Gompertz model directly from the pooled data from all the communities. Some of the disadvantages of estimating

the EC 0.05% 

### 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 O 3 

### level, but rather have some other relationship; and (3) the data points represent a sampling of communities rather than individuals. To compare O 3 

### 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 O 3 

### corresponds to a 40 ppb increase in 1-h max O 3 

### ). Many researchers believe that short spike exposures are more toxic than longer averages. However, the 24-h avg

O 3 

### may be a more stable exposure estimate and still correlate with the shorter metrics of

exposure.

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