United States September 2009
Environmental Protection m \/sr\r\m nn/im
Agency EPA/600/R-09/101
Provisional Assessment of Recent
Studies on Health and Ecological Effects
of Ozone Exposure
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
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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.
September 2009
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Table of Contents
TABLE OF CONTENTS
TABLE OF FIGURES v
AUTHORS AND REVIEWERS vi
1. INTRODUCTION 1
2. CONTROLLED HUMAN EXPOSURE STUDIES 2
3. EPIDEMIOLOGIC STUDIES
3.1. Human Health Effects Associated with Short-Term Ozone Exposure 5
3.1.1. Mortality 5
3.1.2. Respiratory Morbidity 7
3.1.2.1. Respiratory Hospital Admissions and Emergency Department Visits.
3.1.3.
3.2. Health
3.2.1.
3.2.2.
3.2.3.
3.2.4.
3.2.5.
3.1.2.2. Lung Function
3.1.2.3. Airway Inflammation
3.1.2.4. Asthma Exacerbation
3.1.2.5. Other Respiratory Symptoms
Cardiovascular Morbidity
3.1.3.1. Hospital Admissions and Emergency Department Visits
Effects Associated with Long-Term Ozone Exposures
Mortality
Lung Function and Respiratory Symptoms
Lung Cancer
Reproductive and Developmental Outcomes
Neurobehavioral Effects
12
13
13
15
15
17
19
19
20
22
23
25
3.3. Vulnerability or Susceptibility 25
4. TOXICOLOGICAL STUDIES 27
4.1.
4.2.
Respiratory Tract Effects of Ozone
4.1.1. Biochemical Effects
4.1.2. Effects on Immune Function
4. 1 .2. 1 . Lung Host Defenses
4.1.2.2. Allergic Responses
4.1.3. Inflammation and Lung Permeability Changes
4.1.4. Morphological Effects
4.1.5. Effects on Pulmonary Function
4.1.6. Genotoxicity Potential of Ozone
Systemic Effects of Ozone Exposure
4.2.1. Neurobehavioral Effects
4.2.2. Neuroendocrine Effects
4.2.3. Cardiovascular Effects
4.2.4. Reproductive and Developmental Effects
4.2.5. Effects on the Liver, Spleen, and Thymus
4.2.6. Effects on Cutaneous and Ocular Tissues
27
27
28
28
28
29
29
30
30
31
31
32
32
32
32
33
4.3. Interactions of Ozone with Other Co-Occurring Pollutants 33
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4.4. Susceptible and Vulnerable Populations 33
5. ECOLOGICAL AND VEGETATION STUDIES 35
5.1. Meta-Analyses of Vegetation Effects 35
5.2. Field Studies of Forest Ecosystems 36
5.3. Visible Foliar Injury 37
5.4. Agricultural Crops 37
5.5. Carbon Sequestration 37
6. SUMMARY 38
REFERENCES 39
September 2009
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Table of Figures
Figure 2-1. Cross-study comparison of mean 03-induced FE\A decrements following 6.6 h of constant,
square-wave exposure to varied 03 concentrations. 4
Figure 3-1. Association between short-term 03 exposure and hospital admissions and ED visits for all
respiratory diseases and asthma individually from recent studies and the 2006 AQCD. 9
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Authors and Reviewers
Authors
Dr. James S. Brown (O3 Team Leader)—National Center for Environmental Assessment, U.S.
Environmental Protection Agency, Research Triangle Park, NC
Dr. Christal Bowman—National Center for Environmental Assessment, U.S. Environmental
Protection Agency, Research Triangle Park, NC
Dr. Jeffrey Herrick—National Center for Environmental Assessment, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Dr. Thomas J. Luben—National Center for Environmental Assessment, U.S. Environmental
Protection Agency, Research Triangle Park, NC
Mr. Jason Sacks—National Center for Environmental Assessment, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Dr. Lisa Vinikoor—National Center for Environmental Assessment, U.S. Environmental Protection
Agency, Research Triangle Park, NC
Reviewers and Contributors
Dr. John J. Vandenberg (Division Director)—National Center for Environmental Assessment, U.S.
Environmental Protection Agency, Research Triangle Park, NC
Ms. Debra B. Walsh (Deputy Division Director)—National Center for Environmental Assessment,
U.S. Environmental Protection Agency, Research Triangle Park, NC
Dr. Mary A. Ross (Branch Chief)—National Center for Environmental Assessment, U.S.
Environmental Protection Agency, Research Triangle Park, NC
Dr. Christian Andersen—National Health and Environmental Effects Research Laboratory, U.S.
Environmental Protection Agency, Corvallis, OR
Dr. Dan Costa—Office of Research and Development, U.S. Environmental Protection Agency,
Research Triangle Park, NC 27711
Dr. Andy Ohio—National Health and Environmental Effects Research Laboratory, U.S.
Environmental Protection Agency, Chapel Hill, NC
Dr. Ian Gilmour—National Health and Environmental Effects Research Laboratory, U.S.
Environmental Protection Agency, Research Triangle Park, NC
Dr. Barbara Glenn—National Center for Environmental Research, U.S. Environmental Protection
Agency, Washington, DC
Dr. Deborah Mangis—National Exposure Research Laboratory, U.S. Environmental Protection
Agency, Research Triangle Park, NC
September 2009
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1. INTRODUCTION
In March 2008, EPA announced its final rule on the national ambient air quality standards
(NAAQS) for ozone (O3)(73 FR 16436). The scientific basis for this O3 NAAQS was the 2006 Air
Quality Criteria for Ozone and Related Photochemical Oxidants, hereafter 2006 O3 AQCD (U.S.
EPA, 2006). The 2006 O3 AQCD included a rigorous and thorough review of the pertinent literature
accepted for publication through December 2004. A limited number of papers accepted for
publication in 2005 and 2006 were also included in the 2006 O3 AQCD. These papers were
identified by EPA staff, by public comments, or by the Clean Air Scientific Advisory Committee
(CASAC) as adding significantly to the existing body of data on critically important topics.
Typically, these studies examined effects at lower O3 levels than previously reported or discussed
epidemiologic methodological issues.
The EPA has provisionally assessed the recent literature related to health and ecological effects
of O3 to identify pertinent new studies that were not included in the 2006 O3 AQCD. This effort
should not be considered a complete literature review. This provisional assessment has been through
an internal EPA peer review process; however, it has not been subjected to review by the CASAC or
open to the public comment process, as was done in the development of the 2006 O3 AQCD. The
intent of this provisional assessment is to determine if studies published since the 2006 O3 AQCD
materially change the conclusions of that document. Overall, EPA's provisional assessment of recent
studies, as discussed below, concludes that, taken in context, the new information and findings do
not materially change any of the broad scientific conclusions regarding the health and ecological
effects of ozone exposure made in the 2006 O3 AQCD. This new evidence strengthens conclusions
in the 2006 O3 AQCD related to the potential for health effects at exposure concentrations of less
than 80 ppb. The following sections highlight findings of recent studies from four scientific
disciplines that are the major focus of this provisional assessment: (1) controlled human exposure
studies, (2) epidemiology, (3) toxicology, and (4) ecology.
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2. CONTROLLED HUMAN EXPOSURE
STUDIES
In this provisional assessment, EPA has generally limited its consideration to those studies
conducted at or below 80 ppb O3; unlike studies included in the 2006 O3 AQCD, these studies have
not been subjected to rigorous review and as such this review is not intended to supplement the 2006
document.
Numerous controlled human exposure studies, reviewed in the 2006 O3 AQCD, showed that
young healthy nonsmoking adults exposed to > 80 ppb O3 developed transient, reversible decrements
in lung function; increased respiratory symptoms; increased nonspecific airway responsiveness; and
inflammatory responses compared to filtered air as a control exposure. Two studies evaluated the
effects of exposure to concentrations less than 80 ppb (i.e., 40 and 60 ppb) in healthy subjects
exposed for 6.6 hours during quasi continuous exercise (Adams, 2002, 2006). Exposure to 40 ppb
O3 produced responses similar to filtered air exposure (Adams, 2002, 2006). However, a statistically
significant increase in respiratory symptoms was reported following 5.6 and 6.6 hours of exposure to
60 ppb. Although not found to be statistically significant by Adams (2006), the group mean forced
expiratory volume in one second (FEVi) response during exposure to 60 ppb diverged from
responses for filtered-air after 5.6 h of exposure. Some individuals had FEVi decrements of >10%
after 6.6 h of exposure to 60 ppb. Thus, at the time the 2006 O3 AQCD was completed, there was
limited evidence of decreased pulmonary function and increased respiratory symptoms occurring
with O3 exposure below 80 ppb. Three new studies provide evidence of effects occurring in healthy
young adults at O3 concentrations below 80 ppb: Brown et al. (2008); McDonnell et al. (2007); and
Schelegle et al. (2009).
McDonnell et al. (2007) provided an empirical model for predicting average FEVi responses
as a function of O3 concentration, exposure time, minute ventilation, and age of the exposed
individual. This model was based on response data of healthy, nonsmoking, white males (n=541)
between the ages of 18-35 yr from 15 studies conducted at the U.S. EPA Human Studies Facility in
Chapel Hill, North Carolina. The model predicts temporal dynamics of FEVi change in response to
any set of O3 exposure conditions that might reasonably be experienced in the ambient environment.
McDonnell et al. (2009) tested the predictive ability of this model against independent data (i.e., data
that were not used to fit the model) of Adams (2000, 2002, 2003, 2006a, 2006b), Hazucha et al.
(1992), and Schelegle et al. (2009). The model generally captured the dynamics of FEVi responses
within about a one percentage point of the experimental data. Consistent with Bennett et al. (2007),
an increased body mass index (BMI) was found to be associated with enhanced FEVi responses by
September 2009 2
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McDonnell et al. (2009). The BMI effect is of the same order of magnitude but in the opposite
direction of the age effect where by FEVi responses diminish with increasing age. Although the
effects of age and BMI are relatively strong, these characteristics account for only a small amount of
the observed variability in individual responses.
Brown et al. (2008) show that the magnitude of the FEVi responses observed at 40 and 60 ppb
by Adams (2002, 2006) were consistent with a smooth dose-response curve for exposures between
40 and 120 ppb O3 (Figure 2-1). All studies in Figure 2-1 used the same 6.6 h exposure protocol in
which volunteers alternated between 50 min of exercise (VE~ 20 L/min/m2 body surface area) and
10 min of rest with an additional 35 min of rest after the third hour. Note that the Adams (2002,
2003, 2006) data illustrated on Figure 2-1 were not used in fitting the model developed by
McDonnell et al. (2007). In the reanalysis of the Adams (2006) data, Brown et al. (2008) also
showed that exposure to 60 ppb O3 causes a biologically small but highly statistically significant
(p < 0.002) decrease in mean FEVi responses of young healthy adults.
Schelegle et al. (2009) conducted a controlled human exposure study investigating the effects
of 6.6 hour exposures to O3 at mean concentrations of 60, 70, 80, and 87 ppb on respiratory
symptoms and pulmonary function in 31 young healthy adults. The mean percent change in FEVi
(istandard error) at the end of each protocol were 0.80 ± 0.90%, -2.72 ± 1.48%, -5.34 ± 1.42%, -7.02
± 1.60%, and -11.42 ± 2.20% for exposure to filtered air, 60, 70, 80, and 87 ppb O3, respectively.
Compared to filtered air, statistically significant decrements in FEVi and increases in total subjective
symptoms scores (p < 0.05) were found following exposure to mean concentrations of 70, 80 and
87 ppb O3. Although not statistically significant, the magnitude of the mean FEVi responses (3.5%
corrected for filtered air) at 60 ppb was about the same as reported by Adams (2006). This further
supports a smooth dose-response curve without evidence of a threshold for exposures between 40
and 120 ppb O3. Schelegle et al. (2009) also considered intersubject variability in FEVi responses.
Sixteen percent of individuals had > 10% FEVi decrements at 60 ppb and this fraction increased to
18, 29, and 42% at 70, 80, and 87 ppb, respectively. Combined with the data from Adams (2006),
Schelegle et al. (2009) confirm notable interindividual variability for O3 exposure concentrations
below 80 ppm.
September 2009
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20 -i
TJ S^ 15 -
Q) ifcMP
o c
3 CU
-o E
C m
u
10 -
c
O '
N •«-
°s
U. 5
0
* Adams (2006)
A Adams (2003)
X- Adams (2002)
Folinsbee etal
Horstman eta!. (1990)
McDonnell eta . (1991)
McDonnell etal. (2007)
(1988)
0.02 0.04 0.06 0.08 0.1
Ozone (ppm)
0.12
0.14
Source: Brown et al. (20
Figure 2-1. Cross-study comparison of mean (^-induced FEV1 decrements following 6.6 h of
constant, square-wave exposure to varied 03 concentrations. The McDonnell et al. (2007) curve
illustrates the predicted FEVi decrement at 6.6 h as a function of Os concentration for a 23-yr old
(the average age of subjects that participated in the illustrated studies). Error bars (where
available) are the standard error of responses. The data at 0.08 and 0.12 ppm have been offset
for illustrative purposes.
September 2009
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3. EPIDEMIOLOGIC STUDIES
EPA has screened and surveyed the recent epidemiologic literature and identified a number of
recent studies on the health effects associated with O3 exposure. This process has identified slightly
over 100 epidemiologic studies that encompass the majority of health outcomes addressed in the
2006 O3 AQCD. The following sections summarize the results of EPA's provisional assessment of
these epidemiologic studies for a range of health outcomes; the overall conclusions from the 2006 O3
AQCD are presented at the beginning of each section.
3.1. Human Health Effects Associated with Short-Term
Ozone Exposure
3.1.1.Mortality
The analysis of several large multicity studies, single-city studies, and additional meta-
analyses of these studies in the 2006 O3 AQCD found a "positive association between increasing
ambient O3 concentrations and excess risk for non-accidental and cardiopulmonary-related daily
mortality" (U.S. EPA, 2006). The 2006 O3 AQCD, therefore, concluded that the literature is "highly
suggestive that O3 directly or indirectly contributes to non-accidental and cardiopulmonary-related
mortality," but the underlying mechanisms by which such effects occur are not entirely clear (U.S.
EPA, 2006). An independent review of that literature by the National Research Council (NRC) also
concluded, "short-term exposure to ambient ozone is likely to contribute to premature deaths" (NRC,
2008).
This provisional assessment identified a number of recent short-term O3 exposure mortality
studies. Overall the studies are consistent with the conclusions of the 2006 O3 AQCD, supporting an
association between O3 and mortality (Bell et al., 2008; Burnett et al., 2004; Franklin et al., 2008;
Knowlton et al., 2004; Kolb et al., 2007; Ren et al., 2008a, 2008b; Zanobetti and Schwartz, 2008a,
2008b). Some studies did not find a statistically significant association but showed elevated risk
estimates (Dominici et al., 2005; Goldberg et al., 2006).
All studies that examined the association by season reported the association between O3
exposure and mortality is strongest in the summer (Dominici et al., 2005; Franklin et al., 2008; Kolb
et al., 2007; Zanobetti and Schwartz, 2008a, 2008b) but was null in the winter months (Kolb et al.,
2008; Zanobetti and Schwartz, 2008b). A study of 48 cities in the U.S. found the effect of O3 on all-
September 2009
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cause mortality increased in the early spring and summer and decreased to no association by
September (Zanobetti and Schwartz, 2008b).
Additionally, some studies went further than examining simply the overall association between
short-term exposure to O3 and mortality. These studies are summarized below:
• Bell et al. (2008) utilized data from the National Morbidity, Mortality, and Air Pollution
Study (NMMAPS), which included 98 urban communities from around the U.S. and
found the association between O3 (mean concentration: 26.8 ppb) and mortality was
greater among areas of high unemployment, higher proportion of African-American
residents, higher public transportation use, and a lower prevalence of central air
conditioning.
• Dominici et al. (2005) also used NMMAPS data to examine the association between O3
exposure (no concentration given) and mortality and observed a non-statistically
significant positive association with lag of 0 days. The association became more
pronounced when using only data from summer seasons.
• Although most of the point estimates were elevated, in their study population of
individuals 65 yr and older who lived and died in Montreal, Goldberg et al. (2006) found
no association between O3 exposure (mean daily O3 concentration: 15ppb) and mortality
except among those who died during the warm season and were diagnosed with diabetes
before their death.
• Kolb et al. (2007) identified a positive association between O3 (mean daily concentration:
15 ppb) and mortality during the warm season in Montreal among individuals at least
65 yr of age who had been previously diagnosed with congestive heart failure for at least
1 yr prior to death. This association was not observed during the cold season.
• In addition to observing a positive association between O3 (mean 8-h concentration
ranged by city from 15.1 to 62.8 ppb) and all-cause mortality during the summer months,
Zanobetti and Schwartz (2008a) reported a positive association between O3 and
cardiovascular disease mortality, respiratory mortality, and stroke mortality in their study
of 48 cities in the U.S.
• Franklin et al. (2008) reported an association between summertime O3 levels (mean daily
O3 concentration ranged by community from 21.4 to 48.7 ppb) and non-accidental
mortality. These authors found no confounding of the association when including PM2.s
September 2009
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in a copollutant model but the association between O3 and mortality decreased to null
when sulfate was included in the model.
The remaining short-term exposure mortality studies analyzed the potential modification and
confounding of the association between O3 and mortality due to various weather variables, including
temperature. In two separate studies, Ren et al. (2008a, 2008b) analyzed whether temperature
modified the O3-mortality effect and whether O3 modified the temperature-mortality effect,
respectively. Ren et al. (2008a) found in a study of 60 large eastern U.S. communities, temperature
synergistically modifies the O3-mortality effect, but the modification varies depending on the
geographic location. Specifically, the association was modified by high temperatures in the
northeastern U.S. but not in the Southeast. In contrast, Ren et al. (2008b) found in a study of
95 large U.S. communities, using the NMMAPS data, that O3 modified the temperature effect on
cardiovascular mortality across all regions of the U.S. Rainham et al. (2005) analyzed the overall
effect of weather on the air pollution-mortality association in a study in Toronto, Canada, and did not
find a systematic pattern of modification, but a modification effect seemed dependent on the type of
synoptic climatology category1 analyzed. An additional study examined potential confounding of
the O3-mortality relationship by PM using NMMAPS data. In Bell et al. (2007), confounding was
investigated by analyzing the effect of PM on the association between short-term exposure to O3 and
mortality using data from 98 U.S. communities. By estimating the correlation between daily PM and
O3 concentrations, along with including PM as a covariate in various models, Bell et al. (2007)
concluded that neither PMi0 nor PM2.5 is a likely confounder of the observed relationship between
O3 and mortality.
3.1.2.Respiratory Morbidity
Results from controlled human exposure studies and animal toxicological studies analyzed
during the completion of the 2006 O3 AQCD "provide clear evidence of causality for the
associations observed between acute (< 24 h) O3 exposure and relatively small, but statistically
significant declines in lung function observed in numerous recent epidemiologic studies. Declines in
lung function were particularly noted in children, asthmatics, and adults who work or exercise
outdoors" (U.S. EPA, 2006).
Since the 2006 O3 AQCD, many studies have been published examining the association
between short-term exposure to O3 (i.e., over a period of a few days) and respiratory morbidity.
These studies have examined multiple respiratory outcomes, including lung function, airway
inflammation, and asthma. Overall, the findings reported in the new studies of respiratory morbidity
1 Synoptic categories, which are also referred to as air mass categories were derived through a complex statistical approach that classifies
various meteorological components (i.e., temperature, dew point, components of wind, cloud cover, and sea level pressure) into six
categories.
September 2009
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are consistent with those in the 2006 O3 AQCD conclusions, particularly the numerous new studies
of hospital admissions and emergency department visits.
3.1.2.1. Respiratory Hospital Admissions and Emergency Department Visits
The 2006 O3 AQCD reported that numerous population time-series studies have "observed that
ambient O3 concentrations are positively and robustly associated with respiratory-related
hospitalization and asthma emergency department (ED) visits during the warm season. These
observations are strongly supported by the human clinical, animal toxicological, and epidemiologic
evidence for lung function decrements, increased respiratory symptoms, airway inflammation, and
airway hyperreactivity. Taken together, the overall evidence supports a causal relationship between
acute ambient O3 exposures and increased respiratory morbidity resulting in increased ED visits and
hospitalizations during the warm season" (U.S. EPA, 2006).
This provisional assessment identified numerous studies that focus on respiratory
hospitalization and ED visits conducted in the U.S. (Babin et al., 2007; Ito et al., 2007; Letz et al.,
2005; Lin et al., 2008; Magas et al., 2007; Medina-Ramon et al., 2006; Moore et al., 2008; Tolbert
et al., 2007) and Canada (Cakmak et al., 2006a; Fung et al., 2006; Lin et al., 2005; Szyskowicz et al.,
2008; Villeneuve et al., 2007; Yang et al., 2005). Results from recent studies on hospitalization
admissions and ED visits for all respiratory diseases and asthma individually, along with results of
similar studies from the 2006 O3 ACQD are included in Figure 3-1. A limited number of studies are
not illustrated where authors did not provide quantitative results that allowed for presentation in a
manner consistent with those studies in Figure 3-1. This figure does not include hospital admissions
or ED visits exclusively for chronic obstructive pulmonary disease (COPD) or respiratory infections.
Overall, the results of the recent studies are consistent with the 2006 O3 AQCD in reporting
associations during the warm season, but not during cool seasons or in all-year analyses.
September 2009
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Reference
Location
All Respiratory: 2006 AQCD Studies
Peel et al., 2005§
Yang etal., 2003*
Yang etal., 2003*
Wilson etal.,2005§
Schwartz etal., 1996 f
Burnett etal., 1997f
Wilson etal.,2005§
Burnett etal., 1997f
Delfino et al., 1998§
Delfino et al., 1997§
Linn et al., 2000*
Jones etal., 1995f
Atlanta, GA
Vancouver, CAN
Vancouver, CAN
Portland, ME
Cleveland
16 Canadian cities
Manchester, ME
Toronto, CAN
Montreal, CAN
Montreal, CAN
Los Angeles, CA
Baton Rouge, LA
All >»
£5+ yr — •——
All 4
65+yrJ.*.
All »-*-
All -•!.
• All— •—
>64|yr •
1860yr' •
I All Respiratory: Recent Studies
Lin et al., 2008§
Cakmak etal., 2006*
Fung et al., 2006*
Tolbert et al., 2007§
New York, NY
10 Canadian cities
Vancouver, CAN
Atlanta, GA
0-1 7 yr i»
All!*
65+ yr -£
:•
I Asthma: 2006 AQCD Studies
Stiebetal, 1996t
Jaffe et al., 2003§
Cassinoetal., 1999|
Lin et al., 2004|
Linetal.,2004t
Lin et al., 2004|
Lin et al., 2004|
Tolbert et al., 2000§
Peel etal., 2005§
Zhuetal., 2003§
Wilson etal.,2005§
Wilson etal.,2005§
Burnett etal., 2001 f
Friedman etal., 2001 f
Babin et al., 2007§
Szyszkowicz., 2008a*
ltoetal.,2007§
Szyszkowicz., 2008a*
Villeneuveetal.,2007f
St. Johns, CAN
3 Ohio cities
New York, NY
Vancouver, CAN
Vancouver, CAN
Vancouver, CAN
Vancouver, CAN
Atlanta, GA
Atlanta, GA
Atlanta, GA
Portland, ME
Manchester, ME
Toronto, CAN
Atlanta, GA
Washington, DC
Edmonton, CAN
New York, NY
Edmonton, CAN
Alberta, CAN
18-84yr ! •
612yr • Boys Low SES
61°yr • \ Boyo High SES
6 1°yr • * Girls High SES
6 1°yr ' • Girb Low SES
0-1 6 yr »*-
All n-
0-1 6 yr 4-
All J-»-
AII-4-
*'2vr •
, ^y »
1 16yr ' i
> Asthma: Recent Studies
1-17yr »«-
10+ yr I— *—
i
1 1
as 1.0 is 2.0
Effect Estimate
Figure 3-1. Association between short-term 03 exposure and hospital admissions and ED
visits for all respiratory diseases and asthma individually from recent studies and the 2006
AQCD. Bolded studies considered warm season only. Entries arranged by period evaluated (all
year then warm season) and then by effect estimate precision. Effect estimates standardized
depending on the averaging time in study: 20 ppb for 24-h avg (*); 30 ppb for 8-h max (§); 40 ppb
for1-h max(t).
September 2009
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Two multicity studies reported associations between O3 and respiratory admissions:
• Medina-Ramon et al. (2006) evaluated the effect of ambient O3 (mean concentration
ranged by city from 15.0 to 63.0 ppb for the 35 cities with information during the warm
season and 19.3 to 34.5 ppb for the 16 cities with information on the cold season) on
respiratory hospital admissions among individuals 65 yr of age and older in 36 U.S.
cities. The authors found an association between O3 exposure and COPD and pneumonia
hospital admissions during the warm season.
• Cakmak et al. (2006a) examined whether community income and education modified the
effect of gaseous pollutants, including O3, on respiratory hospitalizations in 10 large
Canadian cities. Although the analysis focused on income and education variables, the
study did find an association between O3 exposure (mean daily O3 concentration ranged
by city from 17.0 to 23.7 ppb) and respiratory hospital admissions in both single and
multipollutant models, which excluded variables for income and education. The
association persisted within all categories for neighborhood-level income, but among
neighborhood-level education categories, the association was only observed in the lowest
education group.
Several single-city studies have also been conducted:
• A study of hospital admissions due to respiratory disease among children aged 0-17 yr
performed in New York City found a positive association with ambient O3 concentration
in five of the eleven regions included in the study (mean 8h maximum O3 concentration
44.1 ppb) (Lin et al., 2008a).
• Fung et al. (2006) performed an analysis of respiratory illness-related hospital
admissions in Vancouver, Canada among individuals 65 yr of age and older and found no
association with ambient levels of O3 (mean daily concentration 14.3 ppb).
• A study performed in the U.S. by Tolbert et al. (2007) found a positive association
between short-term O3 exposure (mean 8-h O3 concentration 53.0 ppb) and respiratory
disease-related ED visits during non-winter months. This association remained robust in
multipollutant models.
In addition, a number of single-city studies have reported generally positive associations with
hospitalization for asthma, but provide little new evidence for associations with COPD or respiratory
infection admissions.
September 2009 10
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• Babin et al. (2007) examined the association between O3 exposure (no concentration
given) and asthma-related pediatric ED visits among children age 1-17 yr. They
observed a positive association of same-day O3 exposure and ED visits. They also found
a positive association between same-day exposure and subsequent hospital admission.
These associations were strongest among children aged 5-12 yr. The authors found a
positive association between O3 exposure lagged for up to 4 days and ED visits for the
5-12-yr group.
• Moore et al. (2008) performed a study in California and reported that O3 (mean daily
maximum O3 concentration Apr-Sep of 87.8 ppb) had a positive association with hospital
discharge rates for asthma among children aged 0-19 yr. This study was not included in
Figure 3-1 because results were not provided in a form that could be utilized in a manner
consistent with other studies.
• Ito et al. (2007) examined the association between O3 and asthma-related ED visits using
3 different models in order to analyze different methods to account for temporality and
multicollinearity among pollutants and weather variables. The authors report a positive
association during the warm months (mean 8-h maximum O3 concentration 42.7 ppb),
but an inverse association between O3 concentrations and asthma-related ED visits
during the cold months (mean 8-h maximum O3 concentration 18.0 ppb). The positive
association observed in the warm season remained in multipollutant models; robust
results were observed for all 3 models.
• Villeneuve et al. (2007) reported an association between O3 exposure and ED visits for
asthma to be positive during the period of April-September (mean daily maximum O3
concentration 38.0 ppb); however, the association did not persist during the winter
months (October-March; mean daily maximum O3 concentration 24.3 ppb). Overall, the
association for the full year was positive, but when broken down into age groups, there
was no association for individuals under the age of 5 or over the age of 65 yr.
• Another study of asthma-related ED visits conducted in Edmonton, Canada (Szyskowicz,
2008) found a positive association with same-day and one day lag in O3 concentrations
(mean daily O3 concentration 18.6 ppb) among both individuals less than and older than
10 yr of age. The authors found an association persisted using a 2-day lag for those
under 10 yr old; no difference in the association was observed for warm or cold months.
• A study among children in Oklahoma City, OK detected no association between short-
term exposure to O3 and pediatric hospital admissions for asthma. The authors state that
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this is likely due to low levels of O3 in that area (mean 1-h O3 concentration 48.2 ppb)
(Magas et al., 2007). This study was not included in Figure 3-1 because results were not
provided in a form that could be utilized in a manner consistent with other studies.
• Yang et al. (2005) detected no association between short-term exposure to O3 (mean
daily concentration 14.1 ppb) and emergency or urgent hospitalizations for COPD among
individuals 65 yr of age and older. The authors attempted to look at multiple periods of
acute exposure by varying the lag days from 1-7 but there were no associations present
with any lag period.
• Lin et al. (2005) conducted a study in Toronto, Canada and found no association for
either boys or girls under the age of 15 yr for O3 exposure (mean daily O3 concentration
38.1 ppb) and hospital admissions for respiratory infections.
3.1.2.2. Lung Function
• In an observational study of healthy hikers, Girardot et al. (2006) found no association
between exposure to ambient O3 concentrations (mean of hikers' time weighted average
O3 concentration: 48.1 ppbv) and a decrease in lung function (i.e., FEVi or FVC).
• Another study (Thaller et al., 2008) conducted of individuals spending a large amount of
time outdoors (i.e., lifeguards) in Texas demonstrated an inverse relationship between O3
(median daily maximum concentration 35 ppb) and FEVi/FVC ratio. However, the
authors observed no change in FEVi or FVC alone in response to O3 levels. No measures
of exertion were included in this analysis; however, a separate analysis did show slight
changes in lung function after 1 hr of exercise.
• A study by Alexeeff et al. (2007) reported an overall association between O3 (mean 48-h
concentration 24.4 ppb) and FEVi and FVC. For FVC, the association was stronger
among those with airway hyperresponsiveness and among obese individuals.
• Lagorio et al. (2006) performed a panel study of individuals with co-morbid conditions
(COPD, asthma, or ischemic heart disease), and found no association between exposure
to ambient O3 concentrations and a decrease in lung function (i.e., FEVi or FVC).
Lung function has been assessed among elderly and young populations. A study of elderly
individuals from the Normative Aging Study determined O3 exposure was associated with a decrease
in FEVi and FVC, which was strongest when examining the 2-day average of O3 concentration
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(mean O3 concentration 24.4 ppb) (Alexeeff et al, 2008). The authors also determined that some
antioxidant genes polymorphisms may modify the effect of O3 exposure on lung function. In a study
of 86 school age children in Detroit, MI, Lewis et al. (2005), found an association between
increasing ambient O3 concentrations (mean daily O3 concentration 27 ppb) and reduced lung
function (FEVi), but greater than 75% of the children included in the study were classified as having
persistent asthma. Also, in a study of high school athletes, no association was observed between
post-exercise lung function and ambient O3 (mean 1-h maximum O3 concentration 71 ppb)
(Ferdinands et al., 2008). In addition, Liu et al. (2009) examined O3 exposure (median 2-day
average concentration 14.1 ppb) and FEVi and forced expiratory flow (FEF)25_75% among asthmatic
children aged 9-14 yr, living in nonsmoking households and found no association.
3.1.2.3. Airway Inflammation
Three studies measuring the association between short-term exposure to O3 and airway
inflammation have been performed recently:
• Adamkiewicz et al. (2004) conducted a study in a group of elderly individuals from Ohio
and found no association between O3 (mean daily concentration 15.3 ppb) and the
fraction of exhaled nitric oxide (FENO), a marker for airway inflammation.
• Ferdinands et al. (2008) observed no association between O3 (mean 1-h maximum
concentration 71 ppb) and breath pH, another marker of airway inflammation, among a
group of nonsmoking high school athletes after they completed their exercise.
• Liu et al. (2009) observed an inverse association between the average 2-day O3
concentration (median 2-day average concentration 14.1 ppb) and FENO. The
association was robust in the multipollutant analysis. The authors called the association
"counterintuitive" and were not able to identify a reason for this inverse association. An
oxidative stress marker, thiobarbituric acid reactive substances (TEARS), was positively
associated with O3 in the multipollutant model, although the results were not statistically
significant.
3.1.2.4. Asthma Exacerbation
Respiratory morbidity studies analyzed in the 2006 O3 AQCD found "significant associations
between acute exposure to ambient O3 and increases in a wide variety of respiratory symptoms ... in
asthmatic children." Epidemiologic studies also indicate that acute O3 exposure is likely associated
with increased asthma medication use in asthmatic children" (U.S. EPA, 2006). The present
evaluation identified three studies that analyzed the effect of ambient O3 concentrations on asthma
September 2009 13
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symptoms (Babin et al, 2008; Rabinovitch et al., 2004; Schildcrout et al., 2006) and one study on
physician visits (Burra et al., 2009). Although a few studies did not find an association between O3
concentrations and asthma exacerbation, this does not imply the results are inconsistent with those
previously found. A thorough evaluation of study populations, uncertainty in parameter estimates,
precise scientific questions, season in which the study was performed, and additional comparisons
between studies that examined the effect of O3 exposure on asthma exacerbations has not been
conducted and is necessary to interpret and compare the studies.
The following observations were made from the studies of children:
• Schildcrout et al. (2006) investigated the relation between ambient criteria pollutant
concentrations and asthma exacerbations (defined as having any asthma episode ranging
from a mild episode for less than 2 h to an episode greater than 2 h that resulted in the
shortening of normal activity and/or hospitalization/doctor visits) in a cohort of children
in 8 U.S. cities (median Ih maximum O3 concentration ranged by city from 43.0 to
65.8 ppb). The authors included a population of children in which the severity of their
asthma was not clearly identified. However, the overall study included 990 children
with, on average, 12 children being examined every day. The O3 analysis included the
months May through September, which resulted in the study population being less than
the 990 children observed during the course of the full study. As a result, the total
number of children observed is not comparable to other large multicity studies that
examined the effect of O3 concentrations on asthma exacerbation. In this study,
Schildcrout et al. (2006) reported no association between O3 concentrations and asthma
exacerbation.
• Rabinovitch et al. (2004), in a study that examined the association between asthma
symptoms and O3 during the winter months (mean daily 1-h maximum O3 concentration
28.2 ppb), reported no association between O3 levels and FEVi or bronchodilator use
among children. However, a positive association was observed between daily O3
concentration and current day symptoms.
• Burra et al. (2009) conducted a study of children and adults in Toronto, Canada. Slightly
inverse associations were found between short-term O3 exposure (mean daily 1-h
maximum O3 concentration 33.3 ppb) and asthma-related physician visits for both
children (1-17 yr old) and adults (18-64 yr old). Babin et al. (2008) examined asthma
exacerbations among a Medicaid population (0-65+ yr old) in the Washington, D.C. area.
Overall, no association was observed between short-term exposure to O3 (concentration
not provided) and asthma exacerbations, but when restricting the analysis to include only
September 2009 14
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the spring and summer months, the authors found a positive association between O3 and
general acute care for asthma exacerbations.
3.1.2.5. Other Respiratory Symptoms
Finally, a study was conducted examining building related symptoms (heath symptoms present
when an individual is in a building but are absent or decreased when the individual is not in the
building) and found outdoor levels of O3 (during the regular workday, the late workday, and the 24-h
mean) were associated with reports of upper respiratory (nose/sinus congestion, sore throat, sneeze)
and lower respiratory (wheeze, shortness of breath, chest tightness) building-related symptoms
(Apte et al., 2008).
3.1.3.Cardiovascular Morbidity
The 2006 O3 AQCD concluded that the "generally limited body of evidence is highly
suggestive that O3 directly and/or indirectly contributes to cardiovascular-related morbidity,"
including physiologic effects (i.e., release of platelet activating factor [PAF]), heart rate variability
(HRV), arrhythmias, and myocardial infarctions (U.S. EPA, 2006). However, the available body of
evidence reviewed during the 2006 O3 AQCD does not "fully substantiate links between ambient O3
exposure and adverse cardiovascular outcomes" (U.S. EPA, 2006). The results of the more recent
studies presented here are consistent with those of the 2006 O3 AQCD.
Four studies were identified (Metzger et al., 2007; Rich et al., 2006a; Rich et al., 2006b;
Sarnat et al., 2006) that investigated the effect of O3 on arrhythmias. Each study used different
cardiac episodes to identify an arrhythmia event: Sarnat et al. (2006) (mean daily O3 concentration
22 ppb) used supraventricular and ventricular ectopy; Rich et al. (2006a) (mean daily O3
concentration 22.6 ppb) used paroxysmal atrial fibrillation episodes; Rich et al. (2006b) (mean daily
O3 concentration 27.5 ppb) used ventricular arrhythmias; and Metzger et al. (2007) (mean 8-h O3
concentration 53.9 ppb) used tachyarrhythmic events. Of these studies, Sarnat et al. (2006) and Rich
et al. (2006a) found an association between O3 concentrations and the onset of arrhythmias in a study
of non-smoking older adults, and in a study of patients with implantable cardiac devices (ICDs) in
Boston, MA, respectively. The Sarnat et al. (2006) study was performed from June to December.
The study by Rich et al. (2006a) was conducted throughout the year but when the researchers
compared the results for warm versus cold seasons, they observed them to be similar. Rich et al.
(2006b) in a study of 56 patients with ICD in St. Louis, MO observed a weak association between O3
concentrations and arrhythmias although the researchers did not assess seasonal variation. Metzger
et al. (2007) did not find any association for the warm season in a study of 518 patients with
tachyarrhythmia that had ICDs in Atlanta, GA.
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In addition, numerous studies were identified that examined physiologic effects in response to
O3 exposure (Goldberg et al., 2008; Liao et al., 2005; Lisabeth et al, 2008; Park et al, 2007;
Wellenius et al., 2007; Wheeler et al., 2006; Zanobetti et al., 2004). None of these studies assessed
seasonal effects. These studies include:
• A study of 50-85 yr olds with limited physical function and ejection fraction no greater
than 35% (lower ejection fraction indicates poor efficiency of the heart; ejection fraction
of a normal heart is about 55%) were examined at a McGill University Heart Failure and
Transplant Center to determine the effect of O3 on oxygen saturation and pulse rate
(Goldberg et al., 2008). There was a moderate, positive association between O3 exposure
(concentration not provided) and oxygen saturation. No association was present between
O3 exposure and pulse rate.
• The Atherosclerosis Risk in Communities (ARIC) cohort found O3 exposure (mean daily
8-h O3 concentration 0.04 ppm) was associated with some but not all markers of
hemostasis and inflammation. Instead of a strictly concentration-dependent association,
the association between O3 exposure and the markers was relatively small or absent at
low levels of O3 exposure but much greater at higher levels (approximately 70 ppb and
higher). Fibrinogen was associated only among those with a history of cardiovascular
disease (Liao et al., 2005).
• Wellenius et al. (2007) did not observe any fluctuations in B-type natriuretic peptide
(BNP), a marker of congestive heart failure severity, with O3 exposure (mean daily O3
concentration 25.1 ppb).
• A study by Park et al. (2007) assessed the effect of O3 concentrations (mean daily O3
concentration ranged by location from 17 to 29 ppb) and the origin of the ambient air on
HRV in a cohort of men in Boston, MA. An association was detected but only when the
air originated from the west.
• Wheeler et al. (2006) conducted a study on individuals living in Atlanta, GA who either
had a myocardial infarction 3-12 mo before the start of the study or who had self-
reported a physician's diagnosis of moderate to severe COPD. In this study O3 exposure
(mean 4-h O3 concentration ranged by community from 8.0 to 33.8 ppb) was not
associated with the standard deviation of normal R-R intervals (a marker of HRV).
• A study of outpatients with cardiac disease conducted in Boston, MA reported an
association between short-term exposure to O3 (mean 120-h concentration 24 ppb) and
September 2009 16
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higher resting diastolic blood pressure in a single-pollutant model. However, in a
multipollutant model no association with O3 was observed (Zanobetti et al., 2004).
• Lisabeth et al. (2008) performed a study in Texas to assess the association between
exposure to O3 (median 24-h concentration 25.6 ppb) and stroke/transient ischemic
attacks, and found a positive but not statistically significant association.
3.1.3.1. Hospital Admissions and Emergency Department Visits
Highly suggestive evidence for O3-induced cardiovascular effects [has been] provided by a
few population studies of cardiovascular hospital admissions, which reported positive O3
associations during the warm season between ambient O3 concentrations and cardiovascular
hospitalizations [and ED visits]" (U.S. EPA, 2006). The O3 AQCD, therefore, concluded, that the
"generally limited body of evidence is highly suggestive that O3 directly and/or indirectly contributes
to cardiovascular morbidity, but more research is needed to further substantiate the links between
ambient O3 exposure and adverse cardiovascular outcomes" (U.S. EPA, 2006).
Six recent cardiovascular hospital admission and ED visit studies were identified from the
U.S. and Canada (Cakmak et al., 2006b; Peel et al., 2007; Symons et al., 2006; Szyszkowicz, 2008b;
Villeneuve et al., 2006; Wellenius et al., 2005), four of which found no association between ambient
O3 concentrations and either hospital admissions or ED visits, one which found a positive association
among younger men, and one which overall found a positive association but found no association for
some cities. Comparison between recent studies and those in the 2006 O3 AQCD is difficult because
the majority of recent studies included all seasons unlike previous studies that concentrated on the
warm season when levels of O3 are greater and the likelihood of exposure is increased. Individual
observations for these studies are presented below:
• Peel et al. (2007) examined the effect of ambient O3 concentrations (mean 8-h O3
concentration 55.6 ppb) on cardiovascular ED visits in 31 Atlanta, GA hospitals for
individuals inflicted with chronic conditions (e.g., hypertension, diabetes, COPD). The
authors observed no overall association between O3 and cardiovascular disease ED visits.
ED visits for peripheral and cerebrovascular disease increased with ambient O3 levels
among individuals who had COPD. These results add to the evidence that individuals
having various co-morbid conditions, including COPD, have an increased susceptibility
to ambient O3 air pollution. Seasonal variation in the association was not assessed.
• Cakmak et al. (2006b) examined the relationship between O3 exposure and hospital
admissions for cardiac disease in 10 large Canadian cities (mean O3 concentration ranged
by city from 13.5 to 23.7 ppb). Overall the authors found a positive association,
September 2009 17
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although the association varied between cities, with some cities showing no association.
In addition, they reported the association between O3 and hospital admissions was not
modified by sex, neighborhood-level income, or neighborhood-level education. Seasonal
variation in the association was not assessed.
• A study of five hospitals in Edmonton, Canada found a positive association between ED
visits for acute ischemic stroke and one day lagged O3 concentration (mean daily
concentration 18.6 ppb) among men aged 20-64 yr during the warm season
(Szyszkowicz 2008b). A similar association was not seen for men 65-100 yr of age or
for women. Also, no association was seen with same-day O3 levels.
• A study performed from April to December of 2002 reported no association between O3
(mean 8-h concentration 31 ppb) and hospital admissions for symptom exacerbation
among individuals already diagnosed with congestive heart failure (Symons et al., 2006).
• Villeneuve et al. (2006) did not detect an association between O3 levels and ED visits for
hemorrhagic and acute ischemic strokes during either the summer (mean daily O3
concentration 21.8 ppb) or winter (mean daily O3 concentration 12.2 ppb) months.
• Wellenius et al. (2005) reported no association between O3 (mean daily concentration
24.3 ppb) and rate of hospital admissions for congestive heart failure among Medicare
recipients performed a study in the Pittsburgh, PA area. Seasonal variation in the
association was not assessed.
In addition to the respiratory and cardiovascular specific hospital admission and ED visit
studies already presented, two U.S. studies examined the effect of ambient O3 concentrations on both
respiratory and cardiovascular hospital admissions and ED visits (Tolbert et al., 2007; Zanobetti and
Schwartz 2006). Zanobetti and Schwartz (2006) found that O3 concentration (median O3
concentration 22.4 ppb) was not associated with an increase in myocardial infarction and pneumonia
hospital admissions. Similarly, Tolbert et al. (2007) found no association (mean 8-h O3
concentration 53.0 ppb) with ED visits for cardiovascular disease during non-winter months.
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3.2. Health Effects Associated with Long-Term Ozone
Exposures
3.2.1.Mortality
Few epidemiologic studies have assessed the relationship between long-term exposure to O3
and mortality. As a result, the 2006 O3 AQCD concluded that an insufficient amount of evidence
exists "to suggest a causal relationship between chronic O3 exposure and increased risk for mortality
in humans" (U.S. EPA, 2006).
This provisional assessment identified a few studies that examined the association between
long-term exposure to O3 and mortality. Two of these studies focused specifically on traffic density
(Lipfert et al., 2006a, 2006b), and therefore, were not addressed in this analysis.
Chen et al. (2005) utilized data from the AHSMOG study and reported no significant
associations between long-term O3 exposure (mean O3 concentration 26.2 ppb) and fatal coronary
heart disease. However, in 2-pollutant models, O3 strengthened the association between PM and
death from coronary heart disease.
One recent study that examined long-term exposure to O3 did report a positive association
between ambient O3 concentration and respiratory causes of death (Jerrett et al., 2009). Jerrett et al.
(2009) utilized the ACS cohort with data from 1977 through 2000 (mean O3 concentration ranged
from 33.3 to 104.0 ppb during this time period). The average O3 concentrations were determined
from April through September, which the authors state is because "O3 concentrations tend to be
elevated during the warmer seasons and because fewer data were available for the cooler seasons."
Exposure to O3 was positively associated with risk of death from respiratory causes, and this
association remained after controlling for PM2.s using copollutant models. Further examination of
the association between O3 exposure and respiratory-related mortality revealed the association was
modified by temperature, with the association being present at higher temperatures. There was also
geographic variation in the association. Jerrett et al. (2009) observed an association between long-
term O3 exposure and cardiopulmonary, cardiovascular, and ischemic heart disease mortality in
single pollutant models as well, but the associations were not present when PM2.5 was included in the
model.
Another recent study also utilized data from the ACS cohort (Krewski et al., 2009) and
observed a positive association between O3 exposure between April through September 1980 and all-
cause and cardiopulmonary disease mortality. This association was robust to control for ecologic
variables. No association was observed between summer O3 exposure (mean individual O3
concentration 30.2 ppb) and deaths related to ischemic heart disease or lung cancer. In addition,
September 2009 19
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Krewski et al. (2009) found no association with mortality when examining year-round O3 exposure
(mean individual O3 concentration 22.9 ppb).
3.2.2.Lung Function and Respiratory Symptoms
The 2006 O3 AQCD concluded that, "the epidemiologic data, collectively, indicates that the
current evidence is suggestive, but inconclusive for respiratory health effects from long-term O3
exposure" (U.S. EPA, 2006). This provisional review identified multiple studies that assessed the
effect of long-term exposure to O3 on lung function and its development (Gauderman et al., 2007;
Islam et al., 2007; Karr et al., 2007; Li et al., 2006; Lin, 2008b; Meng et al., 2007; Millstein et al.,
2004; Mortimer et al., 2008; Parker et al., 2009; Qian et al., 2005; Tager et al., 2005; Wilhelm et al.,
2008). The results of recent studies are generally mixed. A description of each of the
aforementioned studies and their findings are presented below:
• A study of infants aged 3 wk to 1 yr of age found no association between either chronic
or subchronic O3 exposure (both chronic and subchronic: mean 8-h maximum O3
concentration 23 ppb) and hospital admissions for acute bronchiolitis when controlling
for PM2.5 exposure (Karr et al., 2007). In single pollutant models, O3 had a slightly
negative association with hospital admissions.
• A study of asthmatic children 6-11 yr of age conducted in Fresno, CA examined if
prenatal exposure to high ambient O3 concentrations was predictive of current lung
function (Mortimer et al., 2008). Prenatal exposure was evaluated for each trimester and
the entire pregnancy. The authors found no association between O3 exposure (median 8-h
O3 concentration almost 50 ppb) and lung function among asthmatic children. There was
also no association with exposure during 0-3 yr of life (median 8-h O3 concentration
50 ppb).
• Islam et al. (2007) investigated the relationship between air pollution, lung function, and
the subsequent development of asthma in a cohort of 9-10 yr old children without asthma
or wheeze from the Children's Health Study. The authors found long-term O3 exposure
(concentration not provided) did not have any observable effect on FEF, and, therefore,
was not associated with lung damage or asthma development.
• Asthmatic children from the Children's Health Study in California were assessed and no
association was found between O3 and asthma or wheezing outcomes (Li et al., 2006).
However, a protective effect from a certain genotype (TNF-308GG genotype) was
observed for wheezing outcomes but only in communities with low-O3 levels (mean
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annual O3 concentration 37.5 ppb). In addition, the TNF-308GG genotype was less
protective in high O3 areas (mean annual O3 concentration 57.8 ppb) among individuals
with the GSTM1 null or GSTP1 105 Val alleles.
• Gauderman et al. (2007) utilized the Children's Health Study to examine lung function
growth among adolescents during an 8-yr study period. They found no association
between O3 exposure (concentration not provided) and lung function development.
• Other researchers (Millstein et al., 2004) using the Children's Health Study reported an
association between monthly average O3 concentrations (mean monthly O3
concentration ranged by communities from 15 to 40 ppb for winter months and 30 to
105 ppb for summer months) and use of asthma medication among asthmatic children
approximately 9 yr of age. The association was stronger among children who spent more
time outdoors. Overall, no association was observed between O3 and the presence of
wheeze; however the association was positive among children who spent the most time
outdoors. O3 exposure appeared to have a protective effect for wheeze during the fall
and winter months. The authors report that this may be due to "... an artifact created by
correlated exposures, meteorology, or behavioral responses to meteorological
conditions."
• Tager et al. (2005) examined the effect of O3 exposure (mean 8-h "time outdoors"
monthly O3 concentration 36 ppb for men and 33 ppb for women) on individuals who
had grown-up in either the Los Angeles or San Francisco, CA area. Tager et al. (2005)
estimated lifetime exposure to O3 and found it to be associated with decreased lung
function among college freshman.
• Parker et al. (2009) conducted a study examining summer exposure to O3 (median
concentration 31.5 ppb) and report of respiratory allergy/hay fever among children aged
3-17 yr old. The authors observed a positive association in both single and
multipollutant models. This association was robust to adjustment for demographic and
geographic variables. In addition, the authors observed a positive association for annual
O3 exposure and respiratory allergy/hay fever among children.
• A study of asthmatic children (age 0-17 yr old) living in California was conducted to
examine the association between annual-average O3 concentrations (mean hourly O3
concentration 21 ppb) and asthma exacerbations/hospital admissions (Wilhelm et al.,
2008). Wilhelm et al. (2008) found a positive association between annual-average O3
concentrations and both daily/weekly asthma symptoms and ED visits/hospital
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admissions. The association persisted after inclusion of PM, race/ethnicity, and poverty-
level as covariates.
• Lin et al. (2008b) followed children (1-6 yr) born in New York until their first asthma
hospitalization (those without a hospitalization reported were followed until the end of
the study). The authors observed a positive dose-response association between O3
exposure (mean 8-h concentration 41.1 ppb) and asthma hospitalizations. The
association was strongest in New York City (compared to other regions of New York
state) and among children 1-2 yr of age (compared to those older than 2 yr).
• Meng et al. (2007) reported that among their study population (those ever diagnosed by a
physician as having asthma) continuous O3 (concentration not provided) was positively
associated with poorly controlled asthma among men but no association was present for
women. Poorly controlled asthma was defined as having daily or weekly asthma
symptoms or having at least one hospital or ED visit due to asthma during the previous
year. In addition, O3 exposure above the 90 percentile (based on the distribution of
exposure among the study population) was associated with poorly controlled asthma
among individuals 65 yr of age and older. This study did not examine categories of older
men versus younger men to determine if one of these groups was driving the association.
• A study conducted in three communities across the U.S. detected an association between
lung function and O3 (mean concentration ranged by community from 29.6 to 49.5 ppb)
(Qian et al., 2005). The association remained among groups of individuals, such as those
with current respiratory symptoms and those with chronic lung diseases. The authors
concluded, "... Our results suggest negative effects of long-term exposure to ... O3 on
pulmonary function, even at levels below current national standards."
In addition, one study examined the association between O3 exposure and oxidative stress.
Among individuals living in California, a positive association was observed between 2-wk, 1-mo,
and lifetime O3 exposure (mean monthly O3 concentration 30.5 ppb) and 8-isoprostane (8-iso-PGF),
a measure of lipid peroxidation (Chen et al., 2007a). However, no association was found between O3
and a biomarker for ferric reducing ability of plasma (FRAP), a biomarker for antioxidant capacity.
3.2.3.Lung Cancer
The 2006 O3 AQCD concluded that, "the weight of evidence from recent animal toxicological
studies and a very limited number of epidemiologic studies do not support ambient O3 as a
pulmonary carcinogen" (U.S. EPA, 2006). This provisional assessment identifies two studies (Chen
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et al., 2006; Huen et al., 2006), which both observed cytogenic damage (i.e., micronuclei formation
and degenerated cells) in response to an increase in O3 exposure (Huen et al: mean 8-h monthly O3
concentrations ranged from about 0.03 ppm in April to 0.014 ppm in November; Chen et al:
concentrations not provided). These studies included children, college students, and adult women.
Although cytogenic damage could potentially lead to cancer development, neither study concluded
that O3 is a pulmonary carcinogen. No studies were identified that directly examined the association
between exposure to O3 and lung cancer incidence. One study, discussed in the section reviewing
long-term exposure to ozone and mortality (Section 3.2.1), observed no association between O3
exposure and lung cancer mortality.
3.2.4.Reproductive and Developmental Outcomes
A limited number of studies have examined the relationship between O3 exposure and birth-
related outcomes, including mortality, premature births, low birth weight (LEW), and birth defects.
The 2006 O3 AQCD concluded that "O3 [is] not an important predictor of several birth-related
outcomes including intrauterine and infant mortality, premature births, and low birth weight" (U.S.
EPA, 2006).
This provisional assessment identifies recent studies that analyzed the effect of O3 exposure on
various birth outcomes, including preterm birth (Currie et al., 2008; Wilhelm et al., 2005); fetal
growth (Brauer et al., 2008; Dugandzic et al., 2006; Liu et al., 2007; Salam et al., 2005; Wilhelm
et al., 2005); respiratory effects/hospitalizations (Dales et al., 2006; Triche et al., 2006); mortality
(Dales et al., 2004; Ritz et al., 2006; Woodruff et al., 2008) and birth defects (Gilboa et al., 2005;
Strickland et al., 2009). Although some of these studies show a positive association, overall, the
results are inconsistent. Future studies examining the relationship between O3 and reproductive and
developmental outcomes will be important in understanding more about these associations. A
synopsis of the findings for each birth outcome given in recent studies is presented below:
• Preterit! Birth: Wilhelm et al. (2005) analyzed the association between O3 exposure
during varying periods of pregnancy (mean O3 concentration of about 21-22 ppb for all
periods) and preterm birth in California from 1994-2000. The authors found a positive
association between O3 levels in both the first trimester of pregnancy and the first month
of pregnancy and preterm birth. No association was observed between O3 in the 6 weeks
before birth and preterm delivery. Currie et al (2008) performed a study in New Jersey
and observed a negative association between O3 (mean 8-h concentration 36.0 ppb) in the
second trimester and the number of weeks of gestation. When CO was included in the
models, this association was no longer present although there was an association between
O3 during the third trimester and gestational period in this multipollutant model.
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Fetal Growth: Salam et al. (2005) assessed the effect of increasing O3 concentrations
on LEW in a population of infants born in California from 1975-1987. The authors
reported that a positive association exists between an increase in O3 concentrations and
LEW over the entire pregnancy (mean 8-h O3 concentration 50.6 ppb) with the
association being the strongest in the 2nd and 3rd trimesters. Two studies performed in
Canada (Dugandzic et al., 2006; Liu et al., 2007) and one study performed in California
(Wilhelm et al., 2005) also analyzed the effect of O3 on LBW/intrauterine growth
restriction and did not detect an association between O3 and LEW. The mean
concentrations reported in these studies were 21 ppb daily (Dugandzic et al., 2006),
16.5 ppb daily (Liu et al., 2007), and 2.2 ppb (Wilhelm et al., 2005). One study
performed in Vancouver, Canada reported an inverse association between O3 and small-
for-gestational age infants; however, the authors state that this was likely due to the high
negative correlation between traffic-related air pollutants and O3 (mean concentration
14 ppb) (Brauer et al., 2008).
Respiratory: Triche et al. (2006) examined respiratory effects of O3 in infants of
asthmatic mothers. The authors found for every interquartile range (IQR) increase in
24-h average O3 (mean concentration 35.2 ppb), infants of asthmatic mothers had a
greater likelihood of wheeze and difficulty breathing compared to infants whose mother
did not have asthma. An association was not observed for wheeze for an IQR increase in
8-h maximum or 1-h maximum O3 concentrations (mean O3 concentration 54.5 and
60.8 ppb, respectively). In addition, Dales et al. (2006) tested the association between
daily neonatal respiratory hospitalizations and ambient O3 concentrations in 11 large
Canadian cities (mean daily concentration ranged by city from 16.4 to 23.1 ppb). The
authors concluded current O3 levels are responsible for a significant proportion of
respiratory hospitalizations in neonates.
Mortality: Two studies have reported no association between ambient levels of O3 (Ritz
et al.: mean O3 concentration 22 ppb; Dales et al.: mean daily O3 concentration ranged by
city from 27.0 to 36.9 ppb) and sudden infant death syndrome (SIDS) (Dales et al., 2004;
Ritz et al., 2006) or between O3 and respiratory causes of postnatal death (Ritz et al.,
2006). Another study found no association between O3 exposure and deaths from
respiratory causes; however, the researchers did detect a positive association between O3
exposure (median O3 concentration approximately 27 ppb) and deaths from SIDS
(Woodruff etal, 2008).
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• Birth D0f6CtS Two studies have been conducted examining the relationship between
O3 exposure during pregnancy and birth defects. A recent study conducted in Atlanta,
GA examined O3 exposure during the third through seventh week of pregnancy and
reported no association with risk of cardiovascular malformations (mean 8-h O3
concentration excluding November through February ranged by 5-yr groups from 39.8 to
43.3 ppb) (Strickland et al., 2009). A study conducted in Texas (Gilboa et al., 2005)
looked at a similar period of exposure but reported no association with most of the birth
defects studied (O3 concentration was studied using quartiles with the lowest
representing <18 ppb and the highest representing > 31 ppb). The authors found slightly
elevated odds ratios for pulmonary artery and valve defects but the results were not
statistically significant. Gilboa et al. (2005) also detected an inverse association between
O3 exposure and isolated ventricular septal defects.
In addition to prenatal and neonatal outcomes, Sokol et al. (2006) conducted a study in Los
Angeles, CA to examine the association between air pollution and sperm quality and sperm count.
The authors found increased levels of O3 (mean daily concentration 21.7 ppb) were associated with a
decrease in sperm quality. No association was detected between O3 and sperm count.
3.2.5.Neurobehavioral Effects
The epidemiology section of the 2006 O3 AQCD did not include a summary statement on the
effect of O3 on neurobehavioral effects because, although multiple toxicological studies have been
performed examining the association between O3 exposure (mean O3 concentration 26.5 ppb) and
neurobehavioral effects, there were no epidemiologic studies published at the time. Only one
epidemiologic study has been conducted since then. Chen et al. (2009) utilized data from the
NHANES III cohort to study the relationship between O3 and neurobehavioral effects. The authors
observed an association between annual exposure to O3 and tests measuring coding ability and
attention/short-term memory. There was no association between O3 exposure and reaction time tests.
The authors conclude that overall, there is a positive association between annual O3 exposure and
reduced performance on neurobehavioral tests.
3.3. Vulnerability or Susceptibility
Epidemiologic studies reviewed in the 2006 O3 AQCD suggest that "exercising (moderate to
high physical exertion) children and adolescents appear to demonstrate increased responsiveness to
ambient concentrations of O3 and may be more likely to experience O3-induced health effects" (U.S.
EPA, 2006). Since the 2006 O3 AQCD, only one study in the U.S. or Canada has been identified that
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examined the role of exercising and responsiveness to O3. As previously discussed in the Short-term
Respiratory Morbidity section (Section 3.1.2), high school athletes were examined before and after
exercise but no association was found between O3 levels (mean 1-h maximum O3 concentration
71 ppb) and breath pH, an airway inflammation marker (Ferdinands et al., 2008). However, the
study had a small sample size of only 16 participants.
Human clinical and epidemiologic studies analyzed in the 2006 O3 AQCD demonstrated that
"genetic polymorphisms for antioxidant enzymes and inflammatory genes (GSTM1, NQO1, and
Tnf-a) may modulate the effect of O3 exposure on pulmonary function and airway inflammation"
(U.S. EPA, 2006). This provisional assessment identified three studies (Alexeeff et al., 2008; Chen
et al., 2007b; Islam et al., 2009) along with two review papers (London 2007; McCunney 2005),
which found that genetic polymorphisms in antioxidant genes can lead to a decrease in lung function
upon exposure to O3. (Islam et al.: mean 8-h O3 concentration varied by community from 46.5 to
64.9 ppb; Chen et al.: mean 8-h O3 concentration 37 ppb for males and 33 ppb for females; Alexeeff
et al.: mean O3 concentration 24.4 ppb).
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4. TOXICOLOGICAL STUDIES
A survey of the peer-reviewed literature published since the 2006 O3 AQCD has identified a
number of recent toxicological studies of health effects related to O3 exposure conducted at or below
1 ppm. Overall, the nearly 70 animal studies and 18 in vitro studies support and extend the findings
of the most recent assessment. EPA's provisional assessment of these studies is summarized in the
following sections for individual health outcomes in the context of the conclusions made in the 2006
O3AQCD.
4.1. Respiratory Tract Effects of Ozone
Based on the cumulative evidence from the animal and human studies, the 2006 O3 AQCD
concluded that acute O3 exposure is causally associated with respiratory effects, including
Os-induced pulmonary function decrements, respiratory symptoms, lung inflammation, increased
lung permeability, decreased host defenses against infectious lung disease, and airway
hyperresponsiveness. More recent evidence in these areas is presented under the headings outlined in
the 2006 document.
4.1.1.Biochemical Effects
Ozone has the potential to interact with a wide range of different cellular components, and the
resulting reaction products may act downstream to mediate toxicity. A number of new studies
examine the ability of O3 to exert oxidative stress and modify biological molecules (or other
pollutants as discussed in Section 4.3 below) (Doyle et al, 2007; Foucaud et al., 2006; Franze et al,
2005; Janic et al., 2005; Kafoury and Kelley, 2005; Stages et al., 2007; Valavanidis et al., 2009). One
of the major postulated molecular mechanisms of action of O3 is peroxidation of fatty acids and
lipids in the lung. The generation of oxidized lipids or lipoproteins is implicated in the pathogenesis
of atherosclerosis and neurodegenerative diseases. Stewart et al. (2005) have shown O3 treatment of
low-density lipoproteins induces amyloid-like structures that are recognized by macrophages.
Macrophages or similar cells containing these structures are a feature of both atherosclerotic and
neurodegenerative plaques.
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4.1.2.Effects on Immune Function
4.1.2.1. Lung Host Defenses
As described in the 2006 AQCD, O3 causes complex changes in the immune system, skewing
immune responses toward allergy while inhibiting responses required for defense against bacterial
and viral infection. Cumulative findings from previous assessments of O3 in models of infectious
lung disease included increased mortality and morbidity, decreased pathogen clearance, increased
bacterial growth, and increased severity of infection at exposure levels of 0.1-1 ppm. A few recent
studies further illustrate impaired innate and acquired immune function after O3 exposure in vitro
and in vivo. In mice, O3 exposure impaired natural killer cell activity, which is an innate defense
against viral infection and tumors. Antigen-specific reactivity also decreased, indicating a weakening
of the acquired immunity for subsequent memory responses (Feng et al, 2006). In vitro exposure to
0.03 ppm O3 for five minutes significantly decreased macrophage-like cell mobility in response to
pathogen-related chemotactic stimulation (Klestadt et al., 2005). O3 mediated oxidation of surfactant
proteins reduced their ability to enhance phagocytosis of both gram-positive and gram-negative
bacteria by macrophages (Mikerov et al., 2008). In addition, reduced phagocytic capacity was
observed in pulmonary macrophages recovered from O3 exposed marine toads (Dohm et al., 2005).
4.1.2.2. Allergic Responses
Effects resulting from combined exposures to O3 and allergens continue to be studied in a
variety of animal species, generally as models of experimental asthma. When combined with NO2,
O3 has been shown to enhance nitration of common protein allergens, which may increase their
allergenicity (Franze et al., 2005). Five weeks of continuous exposure to 0.4 ppm O3 (but not at 0.1
or 0.2 ppm O3) augmented sneezing and nasal secretions in a guinea pig model of nasal allergy.
Nasal eosinophils and allergic antibody levels in serum were also elevated by exposure to
concentrations as low as 0.2 ppm (lijima and Kobayashi, 2004). O3 exposure enhanced eosinophil
accumulation, along with IL-5 and IL-13, in allergic rats (Wagner et al., 2007). Long-term studies in
infant monkeys demonstrated reduced airway eosinophils with allergen and O3 compared to allergen
alone, although hyperresponsiveness after the combined exposure was still evident (Joad et al.,
2006). O3 alone or combined with allergen increased lymphocyte frequency in peripheral blood and
pulmonary lavage fluid. Exposure to O3 and allergen altered the distribution of lymphocytes in the
airways, but the implications of these results are not clear in the absence of further analysis of the
lymphocyte population (Miller et al., 2009).
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4.1.3.Inflammation and Lung Permeability Changes
The 2006 O3 AQCD states that the extensive human clinical and animal toxicological
evidence, together with the limited epidemiologic evidence available, suggests a causal role for O3 in
inflammatory responses in the airways. Numerous recent in vitro and in vivo studies add to these
observations of O3-induced inflammation and injury, and provide new information regarding the
underlying mechanisms (Carey et al., 2007; Castagna et al, 2009; Cho et al., 2007; Dahl et al, 2007;
Damera et al., 2009; Fakhrzadeh et al., 2008; Han et al., 2008; Huffman et al., 2006; Inoue et al.,
2008; Jang et al., 2005; Janic et al., 2005; Johnston et al., 2005a, 2005b, 2006, 2007; Kenyon et al.,
2006; Kooter et al., 2007; Manzer et al., 2006; Oslund et al., 2008; Oyarzun et al., 2005; Plopper
et al., 2006; Servais et al., 2005; Vancza et al., 2009; Voynow et al., 2008; Wagner et al., 2007; Wang
et al., 2007; Yoon et al., 2007). Protective roles have been identified for nitric oxide synthase
(Kenyon et al., 2006), metallothionein (Inoue et al., 2008), matrix metalloproteinases (Yoon et al.,
2007), Clara cell secretory protein (Plopper et al., 2006), and the recognition of oxidized lipids by
alveolar macrophages (Dahl et al., 2007). The molecular mechanisms of TNF receptor mediated lung
injury induced by O3 and associated signaling pathways have been examined (Cho et al., 2007;
Fakhrzadeh et al., 2008), along with the changes in gene expression which characterize O3 induced
stress and inflammation (Wang et al., 2007). Other contributors to injury and inflammation include
the IL-1 and neurokinin receptors (Johnston et al., 2007; Oslund et al., 2008), and NQO1 (Voynow
et al., 2008), an enzyme involved in oxidative stress. Studies indicate a role for oxidative stress in
mediating inflammation (Jang et al., 2005; Wagner et al., 2007).
4.1.4.Morphological Effects
The 2006 O3 AQCD reports the collective evidence from animal studies strongly suggests that
chronic O3 exposure causes damage leading to irreversible lung tissue remodeling. Compromised
pulmonary function and structural changes due to persistent inflammation may exacerbate the
progression and development of chronic lung disease, and may underlie the suggested association
between seasonal O3 exposure and reduced lung function development in children as observed in
epidemiologic studies. Further evidence of these effects is provided by several new studies which
expand on the findings of previously described studies in infant rhesus monkeys exposed
episodically to 0.5 ppm O3 alone or in combination with house dust mite antigen (HDMA) over 5 mo
(Evans et al., 2004; Fanucchi et al., 2006; Kajekar et al., 2007). Two of these studies examined
morphological changes after a 6 month recovery period. Kajekar et al. (2007) showed exposure to O3
and/or HDMA resulted in hyperinnervation and abnormal nerve distribution in pulmonary airways
consistent with that found in asthmatic lungs. O3 exposure alone resulted in these effects, more so
than HDMA alone but not to the same extent as O3 and HDMA combined. Evans et al. (2004)
September 2009 29
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demonstrated thickening of the basement membrane zone these monkeys immediately following
exposure to O3 alone compared to filtered air. When O3 was combined with HDMA, the basement
membrane zone exhibited atypical development. After a recovery period with intermittent allergen
challenge in the absence of O3 this atypical appearance resolved, but thickening was significantly
greater than that observed after filtered air exposure. In allergic rats, O3 exposure resulted in
thickening of the walls of the terminal bronchioles and proximal alveolar ducts (Wagner et al., 2007).
4.1.5.Effects on Pulmonary Function
Pulmonary function decrements occur in a number of species with acute exposures (< 1 week)
ranging from 0.25 to 0.4 ppm O3. Similar to humans, lung function responses in rodents become
attenuated with repeated daily exposures. The 2006 O3 AQCD did not specifically discuss pulmonary
function effects from chronic O3 exposure. The 1996 O3 AQCD characterized these effects as
difficult to summarize; ranging from none or minimal, to obstructive, or restrictive lung function
abnormalities. In the few cases where recovery was evaluated, physiological alterations resolved
over several months post O3 exposure. Information published more recently adds to the evidence of
ventilation defects induced by acute or subchronic exposure (Cremillieux et al., 2008), but only one
study in mice chronically exposed to a high (1 ppm) level of O3 was identified (Funabashi et al.,
2004). In this study, O3 alone had little effect on baseline pulmonary function parameters after 5 wk
of exposure (6 h/day, 5 days/wk). However, significantly increased respiratory resistance and
decreased dynamic compliance were observed during O3 exposure in allergic mice, consistent with
other studies indicating that preexisting allergic disease confers susceptibility.
The 2006 O3 AQCD concluded that evidence from human clinical and animal toxicological
studies clearly indicates that acute exposure to O3 can induce airway hyperresponsiveness (AHR). A
number of new studies build upon previous findings (Joad et al., 2006; Johnston et al., 2005a; Lotriet
et al., 2007; Pichavant et al., 2008; Voynow et al., 2008), including a study by Jang et al. (2005)
demonstrating significantly increased AHR in mice after a three hour exposure to 0.12 ppm O3. This
study is notable in that AHR is observed in a non-allergic animal model at a level considerably lower
than previously reported. As in the 2006 O3 AQCD, AHR with repeated or subchronic exposures is
not as evident, especially at lower levels. In a recent study by Johnston et al. (2005b), 3 h but not
72 h of exposure to 0.3 ppm O3 induced AHR in mice.
4.1.6.Genotoxicity Potential of Ozone
The 2006 O3 AQCD concluded that the weight of evidence from the new experimental animal
studies (using non-lifetime exposures) does not support ambient O3 as being a pulmonary
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carcinogen. One or two studies since then have observed O3-induced DNA damage, but as an
indicator of oxidative stress rather than carcinogenicity (Chuang et al., 2009; Servais et al., 2005).
4.2. Systemic Effects of Ozone Exposure
Ozone indirectly affects extrapulmonary sites through a number of proposed mechanisms,
including subsequent reactions induced by soluble mediators (induced or produced by O3) or cell
trafficking. More recent evidence of systemic effects is presented under the individual headings
outlined in the 2006 document.
4.2.1.Neurobehavioral Effects
The 2006 O3 AQCD included evidence that acute exposures to O3 are associated with
alterations in neurotransmitters, motor activity, short and long term memory, and sleep patterns.
Additionally, histological signs of neurodegeneration have been observed. Research in the area of
O3-induced neurotoxicity has notably increased over the past few years. A number of new studies
demonstrate various perturbations in neurologic function or histology, including changes consistent
with Parkinson's and Alzheimer's disease pathologies. Oxidative stress has been proposed as a major
contributor to premature death of substantia nigra dopamine neurons in Parkinson's disease. Angoa-
Perez et al. (2006) have shown lipoperoxidation in the substantia nigra and a decrease in nigral
dopamine neurons in rats exposed to 0.25 ppm, 4h/day, for 7, 15, 30, or 60 days. Estrogen attenuated
O3-induced oxidative stress and nigral neuronal death, consistent with the higher incidence of
Parkinson's disease in men and the amelioration of Parkinsonian symptoms by estrogen therapy.
Martinez-Canabal et al. (2008) showed exposure of rats to 0.25 ppm, 4h/day, for 7, 15, or 30 days
increased lipoperoxides in the hippocampus, a region of the brain which is important for higher
cognitive function including memory acquisition. This effect was observed at day 7 and continued to
increase with time, indicating cumulative oxidative damage. The study also observed a loss of
neurons and increased expression of COX-2, which has a role in neurodegenerative disease and is
observed in the tissues of Alzheimer's patients. Consistent with Alzheimer's incidence in the elderly,
the administration of growth hormone was protective.
Other neurobehavioral observations include disruption of the sleep-wake cycle (Alfaro-
Rodriguez and Gonzalez-Pina, 2005), overexpression of injury repair factors in the brain (Araneda
et al., 2008), altered cerebral reactivity to stress (Boussouar et al., 2009), inflammation and oxidative
stress in brain tissues (Calderon-Garciduenas et al., 2007; Calderon Guzman et al., 2005; Calderon
Guzman et al., 2006; Colin-Barenque et al., 2005; Escalante-Membrillo et al., 2005; Guevara-
Guzman et al., 2009; Pereyra-Munoz et al., 2006), altered neurotransmitter levels (Gonzalez-Pina
et al., 2008; Soulage et al., 2004), impaired olfactory perception and memory (Guevara-Guzman
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et al., 2009), increased defensive/submissive behavior and reduced social investigation (Santucci
et al., 2006), and altered vasoregulatory markers in the brain, indicating potential cerebrovascular
effects (Thomson et al., 2007).
4.2.2.Neuroendocrine Effects
No recent studies have become available to add to the limited evidence regarding
neuroendocrine effects presented in the 2006 assessment.
4.2.3.Cardiovascular Effects
It was concluded in the 2006 O3 AQCD that the generally limited body of evidence was highly
suggestive that O3 directly and/or indirectly contributes to cardiovascular-related morbidity. Five
new in vivo studies have been identified which show adverse cardiovascular effects of O3, either
alone or in combination with particles (Chuang et al., 2009; Hamade et al., 2008; Hamade and
Tankersley, 2009; Thomson et al., 2005, 2006). A recent study by Chuang et al. (2009) demonstrated
vascular mitochondrial damage in infant macaque monkeys after acute exposure to 0.5 ppm O3
(8 h/day for 5 days) and general vascular dysfunction in mice exposed from 6-14 wk of age
(0.5 ppm, 8 h/day, 5 days/wk). In apoE -/- mice, this cyclic intermittent exposure resulted in
significantly increased atherogenesis.
4.2.4.Reproductive and Developmental Effects
Very few reproductive or developmental effects at low O3 levels were evident at the time of
the 2006 O3 AQCD. Since then, a few additional studies of developmental outcomes have been
identified, predominantly in the area of neurobehavioral development. Santucci et al. (2006)
demonstrated behavioral alterations in male mice born to dams exposed continuously to 0.3 or
0.6 ppm O3 from 30 days prior to breeding through gestational day (GD)17. Gestational rat lung
development was altered by acute exposure to 1 ppm O3 (Lopez et al. 2008). Gonzalez-Pina et al.
(2008) showed disruptions in the cerebellar catecholamine system of male rats born to dams exposed
to 1 ppm O3 throughout pregnancy, and changes suggestive of disrupted neuronal plasticity were
observed in rats exposed gestationally to 0.5 ppm O3 from GD5-GD20 (Boussouar et al. 2009).
4.2.5.Effects on the Liver, Spleen, and Thymus
According to the 2006 O3 AQCD, most effects on the liver (NO production, protein synthesis)
and thymus (shrinkage, altered T cell mediated systemic immunity) occur only with high (1-2 ppm)
O3 exposures. Low levels (0.1 ppm) affect xenobiotic metabolism by the liver but this is species
specific. Only one additional study, conducted at a high 1 ppm O3 exposure, has been identified (Last
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et al., 2005) in which alterations in gene expression underlying O3-induced cachexia and
downregulation of xenobiotic metabolism were examined.
4.2.6.Effects on Cutaneous and Ocular Tissues
The 2006 O3 AQCD reported that although there is evidence of oxidative stress at near
ambient O3 levels, skin and eyes are only affected at high concentrations (greater than 1-5 ppm). A
recent study demonstrated that 0.25 ppm O3 differentially alters expression of metalloproteinases in
the skin of young and aged mice, indicating age-related susceptibility to oxidative stress (Fortino
etal.,2007).
4.3. Interactions of Ozone with Other Co-Occurring
Pollutants
The importance of considering the contributions of O3 interactions with other co-occurring air
pollutants to health effects due to O3 containing pollutant mixes was highlighted in the 2006 O3
AQCD. The interaction of O3 with PM has been an area of continued focus since the 2006 O3
AQCD, which concluded that O3 may enhance PM formation and particle uptake, modify the
biological potency of certain types of ambient PM, and exacerbate PM-induced cardiovascular
effects. Approximately ten additional studies have investigated O3-PM interactions and combined
exposure effects. An in vitro study by Valavanidis et al. (2009) demonstrated that O3 substantially
increases the reactive oxygen species generating capacity of various samples of traffic-related PM,
particularly smaller particles (ambient PMi0 and PM2.5, lab-generated diesel and gasoline exhaust
particles were tested). In rats, the effects of combined particle and O3 exposures on production of
vasoactive endothelin peptides are mixed and may be additive or antagonistic depending on the
particular endothelin or tissue being examined (Thomson et al., 2005, 2006, 2007). Synergistic
toxicological effects between the copollutants O3 and 1-Nitronaphthalene (1-NN) have been
observed in the rat lung (Schmelzer et al., 2006; Wheelock et al., 2005), whereas a subsequent study
showed that pre-exposure to O3 actually protected against 1-NN mediated damage in certain areas of
the nose, particularly those in which O3 had caused goblet cell metaplasia and mild hyperplasia (Lee
etal.,2008).
4.4. Susceptible and Vulnerable Populations
Information concerning susceptibility and vulnerability gleaned from toxicological studies is
distributed throughout Chapters 4 and 5 in the 2006 O3 AQCD, which concluded that genetic factors,
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age, gender, pregnancy, preexisting pulmonary disease (allergic or otherwise), and copollutant
exposures can all contribute to susceptibility. More recent studies continue to show that a preexisting
asthmatic phenotype confers susceptibility to O3 in animals (Funabashi et al, 2004; Wagner et al.,
2007), as do preexisting fibrotic lung disease and hyperthyroidism (Huffman et al., 2006; Oyarzun
et al., 2005). New studies also support previous findings of greater susceptibility in immature and
senescent animals. Susceptible genotypes previously identified in humans have been examined in
two recent studies in mice. Voynow et al. (2008) have shown that NAD(P)H quinone oxidoreductase
1 (NQO1) deficient mice, like their human counterparts, are resistant to O3 induced AHR and
inflammation. In humans, an association between inflammatory conditions including asthma and
increased TNF-a production due to a TNF polymorphism has been observed. The role of TNF-a in
Os-induced responses has been previously established through depletion experiments, but a more
recent study investigated the effects of combined O3 and PM exposure in transgenic TNF
overexpressing mice. Kumarathasan et al. (2005) found that subtle effects of these pollutants were
difficult to identify in the midst of the severe pathological changes caused by constitutive TNF-a
overexpression. However, there was evidence that TNF transgenic mice were more susceptible to
Os/PM-induced oxidative stress, and they exhibited elevation of a serum creatine kinase after
pollutant exposure, which may suggest potential systemic or cardiac related effects.
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5. ECOLOGICAL AND VEGETATION
STUDIES
Numerous studies of the effects of O3 on vegetation and ecosystems were reviewed in the
2006 O3 AQCD. That document concluded that the effects of O3 on vegetation and ecosystems
appear to be widespread across the US, and experimental studies demonstrated plausible
mechanisms for these effects. Many exposure studies were conducted at the species level, in field
chambers. However, there were emerging studies at larger-scales, including ecosystem levels, which
supported the results of the field chamber studies. The 2006 O3 AQCD also concluded O3 effects in
plants are cumulative and metrics that accumulate hourly O3 concentrations while positively
weighting the higher concentrations have a better statistical fit to growth and yield response than do
mean or peak indices.
EPA has surveyed and screened the recent vegetation and ecological literature and identified a
number of studies on effects associated with O3 exposure that were published since the 2006 O3
AQCD. This provisional assessment is limited to studies of vegetation and ecosystems that occur in
the US and report endpoints most relevant to the review of the secondary standard. The following
section summarizes the results of the provisional review for a range of issues related to the effect of
O3 on vegetation and ecosystems.
5.1. Meta-Analyses of Vegetation Effects
Recently published meta-analyses have quantitatively compiled peer reviewed studies from
the past 40 yr on the effect of current and future O3 exposures on the physiology and growth of forest
and crop species (Feng et al, 2008; Wittig et al., 2007; Wittig et al., 2008). In compiling more than
55 studies, Wittig et al. (2007) reported that current O3 concentrations in the northern hemisphere are
decreasing photosynthesis (-11%) and stomatal conductance (-13%) across tree species. They also
found that younger trees (<4 yr) were affected less by O3 than older trees. Further, the authors also
found that damage to photosynthesis is consistent with the cumulative uptake of O3 into the leaf
(Wittig et al., 2007). In another meta-analysis, Wittig et al. (2008) reported that current ambient O3
concentrations (~40ppb) significantly decreased annual total biomass growth (-7%) across 263
studies. However, this effect could be greater (-11 to -17%) in areas that have higher O3
concentrations and as background O3 increases in the future (Wittig et al., 2008). In a meta-analysis
of 52 studies of wheat, Feng et al. (2008) reported that current ambient O3 concentrations may be
decreasing yield by an average of 17.5%. The authors also found that O3-induced decreases in yield
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were greater in wheat grown in the field than grown in the in pots. Together these meta-analyses
demonstrate the coherence of O3 effects across numerous studies and species using a variety of
experimental techniques.
5.2. Field Studies of Forest Ecosystems
Two companion papers (McLaughlin et al, 2007a, 2007b) investigated the effects of ambient
O3 on tree growth and hydrology at forest sites in the southern Appalachian Mountains. The authors
reported the cumulative effects of ambient levels of O3 decreased seasonal stem growth by 30-50%
for most trees species in a high O3 year in comparison to a low O3 year (McLaughlin et al., 2007a).
The authors also report that high ambient O3 concentrations can disrupt whole tree water use and in
turn reduce late-season stream-flow (McLaughlin et al., 2007b). The finding that O3 exposures
disrupt tree water use is consistent with several recent studies that report O3 exposure resulting in
loss of stomatal control, incomplete stomatal closure at night and a decoupling of photosynthesis and
stomatal conductance (Gregg et al., 2006; Grulke et al., 2007a, 2007b).
Since the 2006 O3 AQCD several new studies were published based on the Aspen FACE "free
air" O3 and carbon dioxide exposure experiment in a forest in Wisconsin (Darbah et al., 2007, 2008;
Hillstrom and Lindroth, 2008; Kubiske et al., 2006a, 2006b; Liu et al., 2007; Percy et al., 2007; Zak
et al., 2007). Kubiske et al. (2006b) reported that elevated O3 may change the intra- and inter-
species competition. For example, O3 treatments increased the rate of conversion from a mixed
aspen-birch community to a birch dominated community. Darbah et al. (2007, 2008) reported that
O3 treatments decreased paper birch seed weight and seed germination and that this would likely
lead to a negative impact of regeneration for that species. Hillstrom and Lindroth (2008) found that
elevated O3 treatments significantly affected insect community composition. In another study at this
site, Percy et al. (2007) showed that negative growth effects were seen below the previous 8-h O3
standard level of 0.084 ppm. The authors also attempted to compare different O3 metrics to predict
effects on tree growth by using trees repeatedly measured over 5 yr. The authors suggested that 4th
highest maximum metric was a strong predictor of effects, but they did not include the 3-mo 12-h
W126 in their analysis. Overall, the studies at the Aspen FACE experiment are consistent with many
of the open-top chamber studies that were the foundation of previous O3 NAAQS reviews. These
results strengthen our understanding of O3 effects on forests and demonstrate the relevance of the
knowledge gained from trees grown in open-top chamber studies.
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5.3. Visible Foliar Injury
Several new studies have been published on the incidence of foliar injury in the field due to
ambient O3 concentrations (Campbell et al, 2007; Chappelka et al, 2007; Davis, 2007a, 2007b;
Davis and Orendovici, 2006; Kohut, 2007). Kohut (2007) presented a foliar injury assessment for
244 National parks over 5 yr. The author reported that risk of foliar injury was high in 65 parks,
moderate in 46 parks, and low in 131 parks. Chappelka et al. (2007) reported that the average
incidence of O3-induced foliar injury was 73% on milkweed in the Great Smokey Mountain National
Park in the years 1992-1996. Three papers (Davis, 2007a, 2007b; Davis and Orendovici, 2006)
reported O3-induced foliar injury in several plants species in National Wildlife Refuges in Maine,
Michigan and New Jersey. In a study of the west coast of the U.S, Campbell et al. (2007) reported
ozone injury in 25-37% of biosites in California forested ecosystems from 2000-2005.
5.4. Agricultural Crops
The effect of O3 on crop health and productivity is an important area of research, and several
studies have been published on this topic since the 2006 AQCD. For example, in a study of peanuts
in North Carolina, near ambient and elevated exposures of O3 reduced photosynthesis and yield
compared to very low O3 conditions (Burkey et al., 2007; Booker et al., 2007). In another study,
Grantz and Vu (2009) reported that sugarcane biomass growth significantly declined under O3
exposure. This result is important because sugarcane is being considered as a bioenergy crop to be
grown in the San Joaquin Valley of California, an area with high levels of ambient O3.
5.5. Carbon Sequestration
In a large-scale modeling analysis, Sitch et al. (2007) suggested that increasing ambient O3
concentrations across the globe suppress the land carbon sink due to decreased plant productivity. A
consequence of the diminishing carbon sink would be increased CO2 accumulation in the
atmosphere. The authors suggest that the radiative forcing of this extra CO2 is greater than the direct
radiative forcing of O3 as a greenhouse gas alone.
Another modeling study considered how the changes in climate, CO2 concentration and O3
pollution have affected carbon storage in the Great Smokey Mountain National Park in the years
1971-2001 (Zhang et al., 2007). The authors reported that rising CO2 concentrations had
significantly stimulated carbon storage, but ambient O3 concentrations reduced the potential carbon
storage by approximately 50%.
September 2009 37
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6. SUMMARY
EPA emphasizes that this is a provisional evaluation of the recent literature, and it is not
intended to serve as a supplement to the 2006 O3 AQCD. This summary of recent studies has not
undergone the detailed and extensive review process entailed in the development of a Criteria
Document or Integrated Science Assessment, and it has not been reviewed by CASAC.
Overall, the recent study results support and expand upon findings in the 2006 O3 AQCD;
these results do not materially change any of the broad scientific conclusions regarding the health
effects of O3 exposure made in the 2006 O3 AQCD. Briefly:
Recent controlled human exposure studies strengthen evidence for lung function decrements in
healthy young adults during exposures to O3 concentrations below 80 ppb.
The epidemiologic evidence from recent publications provides further evidence that short-term
exposure to O3 is associated with effects on the respiratory system, and also report associations with
mortality.
Many new toxicological studies are available on respiratory or allergic effects; in addition,
some have suggested systemic effects of O3 on the cardiovascular or neurological systems.
New ecological analyses expand the already large body of evidence indicating that O3
exposure causes injury to plants.
September 2009 38
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