highly statistically significant using several common statistical
tests, even after removal of potential outliers. Schelegle et al.
(2009) reported that, compared to filtered air, the largest change
in FEV1 for the 60 ppb protocol occurred after the sixth
(and final) exercise period.
---------------------------------------------------------------------------

    3. Prolonged exposure to an average O3 concentration of
72 ppb results in a statistically significant group mean decrement in
FEV1 of about 6% (Schelegle et al., 2009).\34\
---------------------------------------------------------------------------

    \34\ As noted above, for the 70 ppb exposure group, Schelegle et
al. (2009) reported that the actual mean exposure concentration was
72 ppb.
---------------------------------------------------------------------------

    4. Prolonged square-wave exposure to average O3
concentrations of 80 ppb, 100 ppb, or 120 ppb O3 results in
statistically significant group mean decrements in FEV1
ranging from 6 to 8%, 8 to 14%, and 13 to 16%, respectively (Folinsbee
et al., 1988; Horstman et al., 1990; McDonnell et al., 1991; Adams,
2002; Adams, 2003; Adams, 2006).
    As illustrated in Figure 6-1 of the ISA, there is a smooth dose-
response

curve without evidence of a threshold for exposures between 40 and 120
ppb O3 (U.S. EPA, 2013a, Figure 6-1). When these data are
taken together, the ISA concludes that ``mean FEV1 is
clearly decreased by 6.6-hour exposures to 60 ppb O3 and
higher concentrations in [healthy, young adult] subjects performing
moderate exercise'' (U.S. EPA, 2013a, p. 6-9).
    With respect to interindividual variability in lung function, in an
individual with relatively ``normal'' lung function, with recognition
of the technical and biological variability in measurements, within-day
changes in FEV1 of >=5% are clinically meaningful
(Pellegrino et al., 2005; ATS, 1991). The ISA (U.S. EPA, 2013a, section
6.1.) focuses on individuals with >10% decrements in FEV1
for two reasons. A 10% FEV1 decrement is accepted by the
American Thoracic Society (ATS) as an abnormal response and a
reasonable criterion for assessing exercise-induced bronchoconstriction
(Dryden et al., 2010; ATS, 2000). (U.S. EPA, 2013a, section <IP_ADDRESS>).
Also, some individuals in the Schelegle et al. (2009) study experienced
5-10% FEV1 decrements following exposure to filtered air.
    In previous NAAQS reviews, the EPA has made judgments regarding the
potential implications for individuals experiencing FEV1
decrements of varying degrees of severity.\35\ For people with lung
disease, the EPA judged that moderate functional decrements (e.g.,
FEV1 decrements >10% but <20%, lasting up to 24 hours) would
likely interfere with normal activity for many individuals, and would
likely result in more frequent use of medication (75 FR 2973, January
19, 2010). In previous reviews CASAC has endorsed these conclusions. In
the context of standard setting, in the last review of the
O3 NAAQS CASAC indicated that it is appropriate to focus on
the lower end of the range of moderate functional responses (e.g.,
FEV1 decrements >=10%) when estimating potentially adverse
lung function decrements in people with lung disease, especially
children with asthma (Henderson, 2006c; transcript of CASAC meeting,
day 8/24/06, page 149). More specifically, CASAC stated that ``[a] 10%
decrement in FEV1 can lead to respiratory symptoms,
especially in individuals with pre-existing pulmonary or cardiac
disease. For example, people with chronic obstructive pulmonary disease
have decreased ventilatory reserve (i.e., decreased baseline
FEV1) such that a >=10% decrement could lead to moderate to
severe respiratory symptoms'' (Samet, 2011). In this review, CASAC
reiterated its support for this conclusion, stating that ``[a]n FEV1
decrement of >=10% is a scientifically relevant surrogate for adverse
health outcomes for people with asthma and lung disease'' (Frey, 2014c
p. 3). Therefore, in considering interindividual variability in
O3-induced lung function decrements in the current review,
the EPA also focuses on the extent to which individuals were reported
to experience FEV1 decrements of 10% or greater.\36\
---------------------------------------------------------------------------

    \35\ Such judgments have been made for decrements in
FEV1 as well as for increased airway responsiveness and
symptomatic responses (e.g., cough, chest pain, wheeze). Ranges of
pulmonary responses and their associated potential impacts are
presented in Tables 3-2 and 3-3 of the 2007 Staff Paper (U.S. EPA,
2007).
    \36\ The approach to using results from controlled human
exposure studies conducted in healthy adults to provide perspective
on the potential public health impacts of O3-related
respiratory health effects is discussed in section II.A above, and
in sections II.C.2 and II.C.3 below.
---------------------------------------------------------------------------

    New studies (Schelegle et al., 2009; Kim et al., 2011) add to the
previously available evidence for interindividual variability in the
responses of healthy adults following exposures to O3.
Following prolonged exposures to 80 ppb O3 while at moderate
exertion, the proportion of healthy adults experiencing FEV1
decrements greater than 10% was 17% by Adams (2006), 26% by McDonnell
(1996), and 29% by Schelegle et al. (2009). Following exposures to 60
ppb O3, that proportion was 20% by Adams (2002), 3% by Adams
(2006), 16% by Schelegle et al. (2009), and 5% by Kim et al. (2011).
Across these studies, the weighted average proportion (i.e., based on
numbers of subjects in each study) of young, healthy adults with >10%
FEV1 decrements is 25% following exposure to 80 ppb
O3 and 10% following exposure to 60 ppb O3, for
6.6 hours at moderate exertion (U.S. EPA, 2013a, page 6-18 and 6-
19).\37\ \38\ The ISA notes that responses within an individual tend to
be reproducible over a period of several months, indicating that
interindividual differences reflect differences in intrinsic
responsiveness. Given this, the ISA concludes that ``[t]hough group
mean decrements are biologically small and generally do not attain
statistical significance, a considerable fraction of exposed
individuals experience clinically meaningful decrements in lung
function'' when exposed for 6.6 hours to 60 ppb O3 during
quasi continuous, moderate exertion (U.S. EPA, 2013a, section <IP_ADDRESS>,
p. 6-20).
---------------------------------------------------------------------------

    \37\ The ISA notes that by considering responses uncorrected for
filtered air exposures, during which lung function typically
improves (which would increase the size of the change, pre-and post-
exposure), 10% is an underestimate of the proportion of healthy
individuals that are likely to experience clinically meaningful
changes in lung function following exposure for 6.6 hours to 60 ppb
O3 during intermittent moderate exertion (U.S. EPA, 2012,
section <IP_ADDRESS>).
    \38\ Based on the data available at 60 ppb, 1% of subjects
experienced decrements >20% (also uncorrected for filtered air
exposures).
---------------------------------------------------------------------------

    This review has marked an advance in the ability to make reliable
quantitative predictions of the potential lung function response to
ozone exposure, and thus to reasonably predict the degree of
interindividual response of lung function to that exposure. McDonnell
et al. (2012) and Schelegle et al. (2012) developed models using data
on O3 exposure concentrations, ventilation rates, duration
of exposures, and lung function responses from a number of controlled
human exposure studies. See section <IP_ADDRESS> of the ISA (U.S. EPA 2013a,
p. 6-15). The McDonnell et al. (2012) and Schelegle et al. (2012)
studies analyzed large datasets to fit compartmental models that
included the concept of a dose of onset in lung function response or a
response threshold based upon the inhaled O3 dose. The
McDonnell et al. (2012) model was fit to a dataset consisting of the
FEV1 responses of 741 young, healthy adults (18-35 years of
age) from 23 individual controlled exposure studies. Concentrations
across individual studies ranged from 40 ppb to 400 ppb,\39\ activity
level ranged from rest to heavy exercise, duration of exposure was from
2 to 7.6 hours. The extension of the McDonnell et al. (2012) model to
children and older adults is discussed in section 6.2.4 of the HREA
(U.S. EPA, 2014a). Schelegle et al. (2012) also analyzed a large
dataset with substantial overlap to that used by McDonnell et al.
(2012). The Schelegle et al. (2012) model was fit to the
FEV1 responses of 220 young healthy adults (taken from a
dataset of 704 individuals) from 21 individual controlled exposure
studies. The resulting empirical models can estimate the frequency
distribution of individual responses for any exposure scenario as well
as summary measures of the distribution such as the mean or median
response and the proportions of individuals with FEV1
decrements >10%, 15%, and 20%.
---------------------------------------------------------------------------

    \39\ Responses to O3 in these studies were adjusted
for responses observed following exposure to filtered air.
---------------------------------------------------------------------------

    The predictions of the McDonnell and Schelegle models are
consistent with the observed results from the individual studies of
O3-induced FEV1 decrements. Specifically,
McDonnell et al. (2012) estimated that 9% of healthy exercising adults
would experience FEV1 decrements greater than 10% following

6.6 hour exposure to 60 ppb O3, and that 22% would
experience such decrements following exposure to 80 ppb O3
(U.S. EPA, 2013a, p. 6-18 and Figure 6-3).\40\ Schelegle et al. (2012)
estimated that, for a prolonged (6.6 hours) O3 exposure with
moderate, quasi-continuous exercise, the average dose of onset for
FEV1 decrement would be reached following 4 to 5 hours of
exposure to 60 ppb, and following 3 to 4 hours of exposure to 80 ppb.
However, 14% of the individuals were estimated to have a dose of onset
that was less than 40% of the average. Those individuals were estimated
to reach their dose of onset following 1 to 2 hours of exposure to 50
to 80 ppb O3 (U.S. EPA, 2013a, p. 6-16), which is consistent
with the threshold FEV1 responses reported by McDonnell et
al. (2012).
---------------------------------------------------------------------------

    \40\ Also consistent with the data from published studies (see
above), this model predicts that 1% of people would experience
FEV1 decrements >20% following 6.6 hour exposure to 60
ppb O3.
---------------------------------------------------------------------------

    CASAC agreed that these models mark a significant technical advance
over the exposure-response modeling approach used in the last review
(Frey, 2014a), stating that ``the comparison of the MSS [McDonnell-
Stewart-Smith] model results to those obtained with the exposure-
response (E-R) model is of tremendous importance. Typically, the MSS
model gives results about a factor of three higher than the E-R model
for school-aged children, which is expected because the MSS model
includes responses for a wider range of exposure protocols (under
different levels of exertion, lengths of exposure, and patterns of
exposure concentrations) than the E-R model'' (Frey, 2014a, p. 7).
CASAC explicitly found ``the updated and expanded lung finds the MSS
model to be scientifically and biologically defensible.'' (Frey, 2014a,
pp. 2, 8).
    As discussed above and in the ISA (U.S EPA, 2013a, Section 5.3.2),
secondary oxidation products formed following O3 exposures
can activate neural reflexes leading to decreased lung function. The
McDonnell and Schelegle models included mathematical approaches to
simulate the potential protective effect of antioxidants in the ELF at
lower ambient O3 concentrations, and include a dose
threshold below which changes in lung function do not occur.
    Epidemiologic studies \41\ have consistently linked short-term
increases in ambient O3 concentrations with lung function
decrements in diverse populations and lifestages, including children
attending summer camps, adults exercising or working outdoors, and
groups with pre-existing respiratory diseases such as asthmatic
children (U.S. EPA, 2013a, section <IP_ADDRESS>). Some of these studies
reported O3-associated lung function decrements accompanied
by respiratory symptoms \42\ in asthmatic children (Just et al., 2002;
Mortimer et al., 2002; Ross et al., 2002; Gielen et al., 1997; Romieu
et al., 1997; Thurston et al., 1997; Romieu et al., 1996). In contrast,
studies of children in the general population have reported similar
O3-associated lung function decrements but without
accompanying respiratory symptoms (Ward et al., 2002; Gold et al.,
1999; Linn et al., 1996) (U.S. EPA, 2013a, section <IP_ADDRESS>).
---------------------------------------------------------------------------

    \41\ Unless otherwise specified, the epidemiologic studies
discussed in the PA evaluate only adults.
    \42\ Reversible loss of lung function in combination with the
presence of symptoms meets the ATS definition of adversity (ATS,
2000).
---------------------------------------------------------------------------

    Several epidemiologic panel studies \43\ reported statistically
significant associations with lung function decrements at relatively
low ambient O3 concentrations. For outdoor recreation or
exercise, associations were reported in analyses restricted to 1-hour
average O3 concentrations less than 80 ppb (Spektor et al.,
1988a; Spektor et al., 1988b), 60 ppb (Brunekreef et al., 1994; Spektor
et al., 1988a), and 50 ppb (Brunekreef et al., 1994). Among outdoor
workers, Brauer et al. (1996) found a robust association with daily 1-
hour max O3 concentrations less than 40 ppb. Ulmer et al.
(1997) found a robust association in schoolchildren with 30-minute
maximum O3 concentrations less than 60 ppb. For 8-hour
average O3 concentrations, associations with lung function
decrements in children with asthma were found to persist at
concentrations less than 80 ppb in a U.S. multicity study (Mortimer et
al., 2002) and less than 51 ppb in a study conducted in the Netherlands
(Gielen et al., 1997).
---------------------------------------------------------------------------

    \43\ Panel studies include repeated measurements of health
outcomes, such as respiratory symptoms, at the individual level
(U.S. EPA, 2013a, p. 1x).
---------------------------------------------------------------------------

    Epidemiologic panel studies investigating the effects of short-term
exposure to O3 provided information on potential confounding
by copollutants such as particulate matter with a median aerodynamic
diameter less than or equal to 2.5 microns (PM2.5),
particulate matter with a median aerodynamic diameter less than or
equal to 10 microns (PM10), nitrogen dioxide
(NO2), or sulfur dioxide (SO2). These studies
varied in how they evaluated confounding. Some studies of subjects
exercising outdoors indicated that ambient concentrations of
copollutants such as NO2, SO2, or acid aerosol
were low, and thus not likely to confound associations observed for
O3 (Hoppe et al., 2003; Brunekreef et al., 1994; Hoek et
al., 1993). In other studies of children with increased outdoor
exposures, O3 was consistently associated with decreases in
lung function, whereas other pollutants such as PM2.5,
sulfate, and acid aerosol individually showed variable associations
across studies (Thurston et al., 1997; Castillejos et al., 1995; Berry
et al., 1991; Avol et al., 1990; Spektor et al., 1988a). Studies that
conducted copollutant modeling generally found O3-associated
lung function decrements to be robust (i.e., most copollutant-adjusted
effect estimates fell within the 95% confidence interval (CI) of the
single-pollutant effect estimates) (U.S. EPA, 2013a, Figure 6-10 and
Table 6-14). Most O3 effect estimates for lung function were
robust to adjustment for temperature, humidity, and copollutants such
as PM2.5, PM10, NO2, or
SO2. Although examined in only a few epidemiologic studies,
O3 also remained associated with decreases in lung function
with adjustment for pollen or acid aerosols (U.S. EPA, 2013a, section
<IP_ADDRESS>).
    Several epidemiologic studies demonstrated the protective effects
of vitamin E and vitamin C supplementation, and increased dietary
antioxidant intake, on O3-induced lung function decrements
(Romieu et al., 2002) (U.S. EPA, 2013a, Figure 6-7 and Table 6-8).\44\
These results provide support for the new, quantitative models
(McDonnell et al., 2012; Schelegle et al., 2012), discussed above,
which make use of the concept of oxidant stress to estimate the
occurrence of lung function decrements following exposures to
relatively low O3 concentrations.
---------------------------------------------------------------------------

    \44\ Evidence from controlled human exposure studies is mixed,
suggesting that supplementation may be ineffective in the absence of
antioxidant deficiency (U.S. EPA, 2013a, p. 5-63).
---------------------------------------------------------------------------

    In conclusion, new information from controlled human exposure
studies considerably strengthens the evidence and reduces the
uncertainties, relative to the evidence that was available at the time
of the 2008 review, regarding the presence and magnitude of lung
function decrements in healthy adults following prolonged exposures to
O3 concentrations below 80 ppb. As discussed in Section
<IP_ADDRESS> in the ISA (U.S. EPA, 2013, p. 6-12), there is information
available from four separate studies that evaluated exposures to 60 ppb
O3 (Kim et al., 2011; Schelegle et al., 2009; Adams 2002;
2006). Although not consistently statistically significant, group mean
FEV1 decrements following exposures to 60 ppb O3
are consistent

among these studies. Moreover, as is illustrated in Figure 6-1 of the
ISA (U.S. EPA, 2013a), the group mean FEV1 responses at 60
ppb fall on a smooth intake dose-response curve for exposures between
40 and 120 ppb O3. Based on the data in these studies, 10%
of young, healthy adults experience clinically meaningful decrements in
lung function when exposed for 6.6 hours to 60 ppb O3 during
intermittent, moderate exertion. One recent study has also reported
statistically significant decrements following exposures to 72 ppb
O3 (Schelegle et al., 2009). Predictions from newly
developed quantitative models are consistent with these experimental
results. Additionally, as discussed in more detail in section II.B.4
below, epidemiologic studies continue to provide evidence of lung
function decrements in people who are active outdoors, including people
engaged in outdoor recreation or exercise, children, and outdoor
workers, at low ambient O3 concentrations. While few new
epidemiologic studies of O3-associated lung function
decrements are available in this review, previously available studies
have reported associations with decrements, including at relatively low
ambient O3 concentrations.
ii. Pulmonary Inflammation, Injury, and Oxidative Stress
    Ozone exposures result in increased respiratory tract inflammation
and epithelial permeability. Inflammation is a host response to injury,
and the induction of inflammation is evidence that injury has occurred.
Oxidative stress has been shown to play a key role in initiating and
sustaining O3-induced inflammation. Secondary oxidation
products formed as a result of reactions between O3 and
components of the ELF can increase the expression of molecules (i.e.,
cytokines, chemokines, and adhesion molecules) that can enhance airway
epithelium permeability (U.S. EPA, 2013a, sections 5.3.3 and 5.3.4). As
discussed in detail in the ISA (U.S. EPA, 2013a, section 6.2.3),
O3 exposures can initiate an acute inflammatory response
throughout the respiratory tract that has been reported to persist for
at least 18-24 hours after exposure.
    Inflammation induced by exposure of humans to O3 can
have several potential outcomes: (1) Inflammation induced by a single
exposure (or several exposures over the course of a summer) can resolve
entirely; (2) continued acute inflammation can evolve into a chronic
inflammatory state; (3) continued inflammation can alter the structure
and function of other pulmonary tissue, leading to diseases such as
asthma; (4) inflammation can alter the body's host defense response to
inhaled microorganisms, particularly in potentially at-risk populations
or lifestages such as the very young and old; and (5) inflammation can
alter the lung's response to other agents such as allergens or toxins
(U.S. EPA, 2013a, section 6.2.3). Thus, lung injury and the resulting
inflammation provide a mechanism by which O3 may cause other
more serious morbidity effects (e.g., asthma exacerbations).\45\
---------------------------------------------------------------------------

    \45\ CASAC also addressed this issue: ``The CASAC believes that
these modest changes in FEV1 are usually associated with
inflammatory changes, such as more neutrophils in the
bronchoalveolar lavage fluid. Such changes may be linked to the
pathogenesis of chronic lung disease'' (Frey, 2014a p. 2).
---------------------------------------------------------------------------

    In the last review, controlled human exposure studies reported
O3-induced airway inflammation following exposures at or
above 80 ppb and animal toxicological studies provided evidence for
increases in inflammation and permeability in rabbits at levels as low
as 100 ppb O3. In the current review, the link between
O3 exposures and airway inflammation and injury has been
evaluated in additional controlled human exposure studies, as well as
in recent epidemiologic studies. Controlled human exposure studies have
generally been conducted in young, healthy adults or in adults with
asthma using lavage (proximal airway and bronchoalveolar), bronchial
biopsy, and more recently, induced sputum. These studies have evaluated
one or more indicators of inflammation, including neutrophil \46\ (PMN)
influx, markers of eosinophilic inflammation, increased permeability of
the respiratory epithelium, and/or prevalence of proinflammatory
molecules (U.S. EPA, 2013a, section <IP_ADDRESS>). Epidemiologic studies
have generally evaluated associations between ambient O3 and
markers of inflammation and/or oxidative stress, which plays a key role
in initiating and sustaining inflammation (U.S. EPA, 2013a, section
<IP_ADDRESS>).
---------------------------------------------------------------------------

    \46\ Referred to as either neutrophils or polymorphonuclear
neutrophils (or PMNs), these are the most abundant type of white
blood cells in mammals. PMNs are recruited to the site of injury
following trauma and are the hallmark of acute inflammation. The
presence of PMNs in the lung has long been accepted as a hallmark of
inflammation and is an important indicator that O3 causes
inflammation in the lungs. Neutrophilic inflammation of tissues
indicates activation of the innate immune system and requires a
complex series of events, that then are normally followed by
processes that clear the evidence of acute inflammation.
---------------------------------------------------------------------------

    There is an extensive body of evidence from controlled human
exposure studies indicating that short-term exposures to O3
can cause pulmonary inflammation. A single acute exposure (1-4 hours)
of humans to moderate concentrations of O3 (200-600 ppb)
while exercising at moderate to heavy intensities resulted in a number
of cellular and biochemical changes in the lung, including inflammation
characterized by increased numbers of PMNs, increased permeability of
the epithelial lining of the respiratory tract, cell damage, and
production of proinflammatory molecules (i.e., cytokines and
prostaglandins, U.S. EPA, 2006a). A meta-analysis of 21 controlled
human exposure studies (Mudway and Kelly, 2004) using varied
experimental protocols (80-600 ppb O3 exposures; 1-6.6 hours
exposure duration; light to heavy exercise; bronchoscopy at 0-24 hours
post-O3 exposure) reported that PMN influx in healthy
subjects is linearly associated with total O3 dose.
    Several studies, including one published since the last review
(Alexis et al., 2010), have reported O3-induced increases in
PMN influx and permeability following exposures at or above 80 ppb
(Alexis et al., 2010; Peden et al., 1997; Devlin et al., 1991), and
eosinophilic inflammation following exposures at or above 160 ppb
(Scannell et al., 1996; Peden et al., 1997; Hiltermann et al., 1999;
Vagaggini et al., 2002). In addition, one recent controlled human
exposure study has reported O3-induced PMN influx following
exposures of healthy adults to 60 ppb O3 (Kim et al., 2011),
the lowest concentration at which inflammatory responses have been
evaluated in human studies.
    As with FEV1 responses to O3, inflammatory
responses to O3 are generally reproducible within
individuals, with some individuals experiencing more severe
O3-induced airway inflammation than indicated by group
averages (Holz et al., 2005; Holz et al., 1999). Unlike O3-
induced decrements in lung function, which are attenuated following
repeated exposures over several days (U.S. EPA, 2013a, section
<IP_ADDRESS>), some markers of O3-induced inflammation and tissue
damage remain elevated during repeated exposures, indicating ongoing
damage to the respiratory system (U.S. EPA, 2013a, section <IP_ADDRESS>).
    Most controlled human exposure studies have reported that
asthmatics experience larger O3-induced inflammatory
responses than non-asthmatics.\47\ Specifically, asthmatics

exposed to 200 ppb O3 for 4-6 hours with exercise show
significantly more neutrophils in bronchoalveolar lavage fluid (BALF)
than similarly exposed healthy individuals (Scannell et al., 1996;
Basha et al., 1994). Bosson et al. (2003) reported significantly
greater expression of a variety of pro-inflammatory cytokines in
asthmatics, compared to healthy subjects, following exposure to 200 ppb
O3 for 2 hours. In addition, research available in the last
review, combined with a recent study newly available in this review,
indicates that pretreatment of asthmatics with corticosteroids can
prevent the O3-induced inflammatory response in induced
sputum, though pretreatment did not prevent FEV1 decrements
(Vagaggini et al., 2001; 2007). In contrast, Stenfors et al. (2002) did
not detect a difference in the O3-induced increases in
neutrophil numbers between 15 subjects with mild asthma and 15 healthy
subjects by bronchial wash at the 6 hours postexposure time point,
although the neutrophil increase in the asthmatic group was on top of
an elevated baseline.
---------------------------------------------------------------------------

    \47\ When evaluated, these studies have also reported
O3-induced respiratory symptoms in asthmatics.
Specifically, Scannell et al. (1996), Basha et al. (1994), and
Vagaggini et al. (2001, 2007) reported increased symptoms in
addition to inflammation.
---------------------------------------------------------------------------

    In people with allergic airway disease, including people with
rhinitis and asthma, evidence available in the last review indicated
that proinflammatory mediators also cause accumulation of eosinophils
in the airways (Jorres et al., 1996; Peden et al., 1995 and 1997;
Frampton et al., 1997; Hiltermann et al., 1999; Holz et al., 2002;
Vagaggini et al., 2002). The eosinophil, which increases inflammation
and allergic responses, is the cell most frequently associated with
exacerbations of asthma (72 FR 37846, July 11, 2007).
    Studies reporting inflammatory responses and markers of lung injury
have clearly demonstrated that there is important variation in the
responses of exposed subjects (72 FR 37831, July 11, 2007). Some
individuals also appear to be intrinsically more susceptible to
increased inflammatory responses from O3 exposure (Holz et
al., 2005). In healthy adults exposed to each 80 and 100 ppb
O3, Devlin et al. (1991) observed group average increases in
neutrophilic inflammation of 2.1- and 3.8-fold, respectively. However,
there was a 20-fold range in inflammatory responses between individuals
at both concentrations. Relative to an earlier, similar study conducted
at 400 ppb (Koren et al., 1989), Devlin et al. (1991) noted that
although some of the study population showed little or no increase in
inflammatory and cellular injury indicators analyzed after exposures to
lower levels of O3 (i.e., 80 and 100 ppb), others had
changes that were as large as those seen when subjects were exposed to
400 ppb O3. The study authors concluded that, ``while the
population as a whole may have a small inflammatory response to near-
ambient levels of ozone, there may be a significant subpopulation that
is very sensitive to these low levels'' (Devlin et al., 1991).
    A number of studies report that O3 exposures increase
epithelial permeability. Increased BALF protein, suggesting
O3-induced changes in epithelial permeability, has been
reported at 1 hour and 18 hours postexposure (Devlin et al., 1997;
Balmes et al., 1996). A meta-analysis of results from 21 publications
(Mudway and Kelly, 2004) for varied experimental protocols (80-600 ppb
O3; 1-6.6 hours duration; light to heavy exercise;
bronchoscopy at 0-24 hours post-O3 exposure; healthy
subjects), showed that increased BALF protein is associated with total
inhaled O3 dose. As noted in the 2009 PM ISA (U.S. EPA,
2009a), it has been postulated that changes in permeability associated
with acute inflammation may provide increased access of inhaled
antigens, particles, and other inhaled substances deposited on lung
surfaces to the smooth muscle, interstitial cells, immune cells
underlying the epithelium, and the blood (U.S. EPA, 2013a, sections
5.3.4, 5.3.5). As has been observed with FEV1 responses,
within individual changes in permeability are correlated with changes
following sequential O3 exposures (Que et al., 2011).
Changes in permeability and AHR apear to be mediated by different
pathways. Animal toxicology studies have provided some support for this
hypothesis (Adamson and Prieditis, 1995; Chen et al., 2006), though
these studies did not specifically evaluate O3 exposures
(U.S. EPA, 2009a).
    The limited epidemiologic evidence reviewed in the 2006
O3 AQCD (U.S. EPA, 2006a) reported associations between
short-term increases in ambient O3 concentrations and
airways inflammation in children (1-hour max O3 of
approximately 100 ppb). In the 2006 O3 AQCD (U.S. EPA,
2006a), there was limited evidence for increases in nasal lavage levels
of inflammatory cell counts and molecules released by inflammatory
cells (i.e., eosinophilic cationic protein, and myeloperoxidases).
Since 2006, as a result of the development of less invasive methods,
there has been a large increase in the number of studies assessing
ambient O3-associated changes in airway inflammation and
oxidative stress, the types of biological samples collected, and the
types of indicators. Most of these recent studies have evaluated
biomarkers of inflammation or oxidative stress in exhaled breath, nasal
lavage fluid, or induced sputum (U.S. EPA, 2013a, section <IP_ADDRESS>).
These recent studies form a larger database to establish coherence with
findings from controlled human exposure and animal studies that have
measured the same or related biological markers. Additionally, results
from these studies provide further biological plausibility for the
associations observed between ambient O3 concentrations and
respiratory symptoms and asthma exacerbations.
    A number of epidemiologic studies provide evidence that short-term
increases in ambient O3 exposure increase pulmonary
inflammation and oxidative stress in children, including those with
asthma (Sienra-Monge et al., 2004; Barraza-Villarreal et al., 2008;
Romieu et al., 2008; Berhane et al., 2011). Multiple studies examined
and found increases in exhaled nitric oxide (eNO)\48\ (Berhane et al.,
2011; Khatri et al., 2009; Barraza-Villarreal et al., 2008). In some
studies of subjects with asthma, increases in ambient O3
concentration at the same lag were associated with both increases in
pulmonary inflammation and respiratory symptoms (Khatri et al., 2009;
Barraza-Villarreal et al., 2008). Although more limited in number,
epidemiologic studies also found associations with cytokines such as
IL-6 or IL-8 (Barraza-Villarreal et al., 2008; Sienra-Monge et al.,
2004), eosinophils (Khatri et al., 2009), antioxidants (Sienra-Monge et
al., 2004), and indicators of oxidative stress (Romieu et al., 2008)
(U.S. EPA, 2013a, section <IP_ADDRESS>). Because associations with
inflammation were attenuated with higher antioxidant intake in the
study by Sienra-Monge et al. (2004), this study provides additional
evidence that inhaled O3 is likely to be an important source
of reactive oxygen species in airways and/or may increase pulmonary
inflammation via oxidative stress-mediated mechanisms among all age
groups. Limitations in some recent studies have contributed to
inconsistent results in adults (U.S. EPA, 2013a, section <IP_ADDRESS>).
---------------------------------------------------------------------------

    \48\ Exhaled NO has been shown to be a useful biomarker for
airway inflammation in large population-based studies (Linn et al.,
2009) (U.S. EPA, 2013a, section 7.2.4).
---------------------------------------------------------------------------

    Exposure to ambient O3 on multiple days can result in
larger increases in pulmonary inflammation and oxidative stress, as
discussed in section <IP_ADDRESS> of the ISA (U.S. EPA, 2013a). In studies
that examined multiple O3 lags,

multiday averages of 8-hour maximum or 8-hour average concentrations
were associated with larger increases in pulmonary inflammation and
oxidative stress (Berhane et al., 2011; Delfino et al., 2010; Sienra-
Monge et al., 2004), consistent with controlled human exposure (U.S.
EPA, 2013a, section <IP_ADDRESS>) and animal studies (U.S. EPA, 2013a,
section <IP_ADDRESS>) reporting that some markers of pulmonary inflammation
remain elevated with O3 exposures repeated over multiple
days. Evidence from animal toxicological studies also clearly indicates
that O3 exposures result in damage and inflammation in the
lung (U.S. EPA, 2013a, section 5.3). In the few studies that evaluated
the potential for confounding, O3 effect estimates were not
confounded by temperature or humidity, and were robust to adjustment
for PM2.5 or PM10 (Barraza-Villarreal et al.,
2008; Romieu et al., 2008; Sienra-Monge et al., 2004).
    In conclusion, a relatively small number of controlled human
exposure studies evaluating O3-induced airway inflammation
have become available since the last review. For purposes of reviewing
the current O3 NAAQS, the most important of these recent
studies reported a statistically significant increase in airway
inflammation in healthy adults at moderate exertion following exposures
to 60 ppb O3, the lowest concentration that has been
evaluated for inflammation. In addition, a number of recent
epidemiologic studies report O3-associated increases in
markers of pulmonary inflammation, particularly in children. Thus,
recent studies continue to support the evidence for airway inflammation
and injury that was available in previous reviews, with new evidence
for such effects following exposures to lower concentrations than had
been evaluated previously.
iii. Airway Hyperresponsiveness
    Airway hyperresponsiveness (AHR) refers to a condition in which the
conducting airways undergo enhanced bronchoconstriction in response to
a variety of stimuli. Airway hyperresponsiveness is an important
consequence of exposure to ambient O3 because its presence
reflects a change in airway smooth muscle reactivity, and indicates
that the airways are predisposed to narrowing upon inhalation of a
variety of ambient stimuli including specific triggers (i.e.,
allergens) and nonspecific triggers (e.g., SO2, and cold
air). People with asthma are generally more sensitive to
bronchoconstricting agents than those without asthma, and the use of an
airway challenge to inhaled bronchoconstricting agents is a diagnostic
test in asthma (U.S. EPA, 2013, section 6.2.2). Standards for airway
responsiveness testing have been developed for the clinical laboratory
(ATS, 2000), although variation in the methodology for administering
the bronchoconstricting agent may affect the results (Cockcroft et al.,
2005). There is a wide range of airway responsiveness in people without
asthma, and responsiveness is influenced by a number of factors,
including cigarette smoke, pollutant exposures, respiratory infections,
occupational exposures, and respiratory irritants. Dietary antioxidants
have been reported to attenuate O3-induced bronchial
hyperresponsiveness in people with asthma (Trenga et al., 2001).
    Evidence for airway hyperresponsiveness (AHR) following
O3 exposures is derived primarily from controlled human
exposure and toxicological studies (U.S. EPA, 2013a, section 6.2.2).
Airway responsiveness is often quantified by measuring changes in
pulmonary function following the inhalation of an aerosolized allergen
or a nonspecific bronchoconstricting agent (e.g., methacholine), or
following exposure to a bronchoconstricting stimulus such as cold air.
In the last review, controlled human exposure studies of mostly adults
(>=18 years of age) had shown that exposures to O3
concentrations at or above 80 ppb increase airway responsiveness, as
indicated by a reduction in the concentration of specific (e.g.,
ragweed) and non-specific (e.g., methacholine) agents required to
produce a given reduction in lung function (e.g., as measured by
FEV1 or specific airway resistance) (U.S. EPA, 2013a,
section <IP_ADDRESS>). This O3-induced AHR has been reported to
be dose-dependent (Horstman et al., 1990). Animal toxicology studies
have reported O3-induced AHR in a number of species, with
some rat strains exhibiting hyperresponsiveness following 4-hour
exposures to O3 concentrations as low as 50 ppb (Depuydt et
al., 1999). Since the last review, there have been relatively few new
controlled human exposure and animal toxicology studies of
O3 and AHR, and no new studies have evaluated exposures to
O3 concentrations at or below 80 ppb (U.S. EPA, 2013a,
section <IP_ADDRESS>).
    Airway hyperresponsiveness is linked with the accumulation and/or
activation of eosinophils in the airways of asthmatics, which is
followed by production of mucus and a late-phase asthmatic response
(section II.B.4.a.ii). In a study of 16 intermittent asthmatics,
Hiltermann et al. (1999) found that there was a significant inverse
correlation between the O3-induced change in the percentage
of eosinophils in induced sputum and the concentration of methacholine
causing a 20% decrease in FEV1. Hiltermann et al. (1999)
concluded that the results point to the role of eosinophils in
O3-induced AHR. Increases in O3-induced
nonspecific airway responsiveness incidence and duration could have
important clinical implications for children and adults with asthma,
such as exacerbations of their disease.
    Airway hyperresponsiveness after O3 exposure appears to
resolve more slowly than changes in FEV1 or respiratory
symptoms (Folinsbee and Hazucha, 2000). Studies suggest that
O3-induced AHR usually resolves 18 to 24 hours after
exposure, but may persist in some individuals for longer periods
(Folinsbee and Hazucha, 1989). Furthermore, in studies of repeated
exposure to O3, changes in AHR tend to be somewhat less
susceptible to attenuation with consecutive exposures than changes in
FEV1 (Gong et al., 1997; Folinsbee et al., 1994; Kulle et
al., 1982; Dimeo et al., 1981) (U.S. EPA, 2013a, section 6.2.2). In
animal studies a 3-day continuous exposure resulted in attenuation of
O3-induced AHR (Johnston et al., 2005) while repeated
exposures for 2 hours per day over 10 days did not (Chhabra et al.,
2010), suggesting that attenuation could be lost when repeated
exposures are interspersed with periods of rest (U.S. EPA, 2013a,
section <IP_ADDRESS>).
    As mentioned above, in addition to human subjects a number of
species, including nonhuman primates, dogs, cats, rabbits, and rodents,
have been used to examine the effect of O3 exposure on AHR,
(U.S. EPA, 1996, Table 6-14; and U.S. EPA, 2006a, Annex Table AX5-12,
p. AX5-36). A body of animal toxicology studies, including some recent
studies conducted since the last review, provides support for the
O3-induced AHR reported in humans (U.S. EPA, 2013a, section
<IP_ADDRESS>). Although most of these studies evaluated O3
concentrations above those typically found in ambient air in cities in
the United States (i.e., most studies evaluated O3
concentrations of 100 ppb or greater), one study reported that a very
low exposure concentration (50 ppb for 4 hours) induced AHR in some rat
strains (Depuydt et al., 1999). Additional recent rodent studies
reported O3-induced AHR following exposures to O3
concentrations from 100 to 500 ppb (Johnston et al., 2005; Chhabra et
al., 2010; Larsen et al., 2010).

In characterizing the relevance of these exposure concentrations, the
ISA noted that a study using radiolabeled O3 suggests that
even very high O3 exposure concentrations in rodents could
be equivalent to much lower exposure concentrations in humans.
Specifically, a 2000 ppb (2 ppm) O3 exposure concentration
in resting rats was reported to be roughly equivalent to a 400 ppb
exposure concentration in exercising humans (Hatch et al., 1994). Given
this relationship, the ISA noted that animal data obtained in resting
conditions could underestimate the risk of effects for humans (U.S.
EPA, 2013a, section 2.4, p. 2-14).
    The 2006 AQCD (U.S. EPA, 2006a, p. 6-34) concluded that spirometric
responses to O3 are independent of inflammatory responses
and markers of epithelial injury (Balmes et al., 1996; Blomberg et al.,
1999; Torres et al., 1997). Significant inflammatory responses to
O3 exposures that did not elicit significant spirometric
responses have been reported (Holz et al., 2005). A recent study (Que
et al., 2011) indicates that AHR also appears to be mediated by a
differing physiologic pathway. These results from controlled human
exposure studies indicate that O3-induced lung function
decrements, inflammatory responses and pulmonary injury (leading to
increased epithelial permeability), and AHR, are mediated by apparently
different physiologic pathways. Except for lung function decrements, we
do not have concentration or exposure response information about the
other, potentially more sensitive,\49\ clinical endpoints (i.e.,
inflammation, increased epithelial permeability, AHR) that would allow
us to quantitatively estimate the size of the population affected and
the magnitude of their responses.
---------------------------------------------------------------------------

    \49\ CASAC noted that ``while measures of FEV1 are quantitative
and readily obtainable in humans, they are not the only measures--
and perhaps not the most sensitive measures--of the adverse health
effects induced by ozone exposure.'' (Henderson, 2006).
---------------------------------------------------------------------------

    In summary, a strong body of controlled human exposure and animal
toxicological studies, most of which were available in the last review
of the O3 NAAQS, report O3-induced AHR after
either acute or repeated exposures (U.S. EPA, 2013a, section <IP_ADDRESS>).
People with asthma often exhibit increased airway responsiveness at
baseline relative to healthy controls, and they can experience further
increases in responsiveness following exposures to O3.
Studies reporting increased airway responsiveness after O3
exposure contribute to a plausible link between ambient O3
exposures and increased respiratory symptoms in asthmatics, and
increased hospital admissions and emergency department visits for
asthma (U.S. EPA, 2013a, section <IP_ADDRESS>).
iv. Respiratory Symptoms and Medication Use
    Respiratory symptoms are associated with adverse outcomes such as
limitations in activity, and are the primary reason for people with
asthma to use quick relief medication and seek medical care. Studies
evaluating the link between O3 exposures and such symptoms
allow a direct characterization of the clinical and public health
significance of ambient O3 exposure. Controlled human
exposure and toxicological studies have described modes of action
through which short-term O3 exposures may increase
respiratory symptoms by demonstrating O3-induced AHR (U.S.
EPA, 2013a, section 6.2.2) and pulmonary inflammation (U.S. EPA, 2013a,
section 6.2.3).
    The link between subjective respiratory symptoms and O3
exposures has been evaluated in both controlled human exposure and
epidemiologic studies, and the link with medication use has been
evaluated in epidemiologic studies. In the last review, several
controlled human exposure studies reported respiratory symptoms
following exposures to O3 concentrations at or above 80 ppb.
In addition, one study reported such symptoms following exposures to 60
ppb O3, though the increase was not statistically different
from filtered air controls. Epidemiologic studies reported associations
between ambient O3 and respiratory symptoms and medication
use in a variety of locations and populations, including asthmatic
children living in U.S. cities. In the current review, additional
controlled human exposure studies have evaluated respiratory symptoms
following exposures to O3 concentrations below 80 ppb and
recent epidemiologic studies have evaluated associations with
respiratory symptoms and medication use (U.S. EPA, 2013a, sections
6.2.1, 6.2.4).
    In controlled human exposure studies available in the last review
as well as newly available studies, statistically significant increases
in respiratory symptoms have been reported in healthy adult volunteers
engaged in intermittent, moderate exertion following 6.6 hour exposures
to average O3 concentrations of 80 ppb (Adams, 2003; Adams,
2006; Schelegle et al., 2009) and 72 ppb (Schelegle et al., 2009). Such
symptoms have been reported to increase with increasing O3
exposure concentrations, duration of exposure, and activity level
(McDonnell et al., 1999).
    Results have been less consistent for lower exposure
concentrations. A recent study by Schelegle et al. (2009) reported a
statistically significant increase in respiratory symptoms in healthy
adults following 6.6 hour exposures to an average O3
concentration of 72 ppb, but not 60 ppb. Kim et al. (2011) also did not
find statistically significant increases in respiratory symptoms
following exposures of healthy adults to 60 ppb O3. Adams
(2006) reported an increase in respiratory symptoms in healthy adults
during a 6.6 hour exposure protocol with an average O3
exposure concentration of 60 ppb. This increase was significantly
different from initial respiratory symptoms, but not from filtered air
controls. The findings for O3-induced respiratory symptoms
in controlled human exposure studies, and the evidence integrated
across disciplines describing underlying modes of action, provide
biological plausibility for epidemiologic associations observed between
short-term increases in ambient O3 concentration and
increases in respiratory symptoms (U.S. EPA, 2013a, section 6.2.4).
    In epidemiologic panel studies of respiratory symptoms, data
typically are collected by having subjects (or their parents) record
symptoms and medication use in a diary without direct supervision by
study staff. Several limitations of symptom reports are well
recognized, as described in the ISA (U.S. EPA, 2013a, section 6.2.4).
Nonetheless, symptom diaries remain a convenient tool to collect
individual-level data from a large number of subjects and allow
modeling of associations between daily changes in O3
concentration and daily changes in respiratory morbidity over multiple
weeks or months. Importantly, many of the limitations in these studies
are sources of random measurement error that can bias effect estimates
to the null or increase the uncertainty around effect estimates (U.S.
EPA, 2013a, section 6.2.4). Because respiratory symptoms are associated
with limitations in activity and daily function and are the primary
reason for using medication and seeking medical care, the evidence is
directly coherent with the associations consistently observed between
increases in ambient O3 concentration and increases in
asthma emergency department visits, discussed below (U.S. EPA, 2013a,
section 6.2.4).
    Most epidemiologic studies of O3 and respiratory
symptoms and medication use have been conducted in children

and/or adults with asthma, with fewer studies, and less consistent
results, in non-asthmatic populations (U.S. EPA, 2013a, section 6.2.4).
The 2006 AQCD (U.S. EPA, 2006a, U.S. EPA, 2013a, section 6.2.4)
concluded that the collective body of epidemiologic evidence indicated
that short-term increases in ambient O3 concentrations are
associated with increases in respiratory symptoms in children with
asthma. A large body of single-city and single-region studies of
asthmatic children provides consistent evidence for associations
between short-term increases in ambient O3 concentrations
and increased respiratory symptoms and asthma medication use in
children with asthma (U.S. EPA, 2013a, Figure 6-12, Table 6-20, p. 79).
    Methodological differences among studies make comparisons across
recent multicity studies of respiratory symptoms difficult. Because of
fewer person-days of data (Schildcrout et al., 2006) or examination of
19-day averages of ambient O3 concentrations (O'Connor et
al., 2008), the ISA did not give greater weight to results from recent
multicity studies than results from single-city studies (U.S. EPA,
2013a, section <IP_ADDRESS>).\50\ While evidence from the few available U.S.
multicity studies is less consistent (O'Connor et al., 2008;
Schildcrout et al., 2006; Mortimer et al., 2002), the overall body of
epidemiologic evidence with respect to the association betweeen
exposure to O3 and respiratory symptoms in asthmatic
children remains compelling (U.S. EPA, 2013a, section <IP_ADDRESS>).
Findings from a small body of studies indicate that O3 is
also associated with increased respiratory symptoms in adults with
asthma (Khatri et al., 2009; Feo Brito et al., 2007; Ross et al., 2002)
(U.S. EPA, 2013a, section <IP_ADDRESS>).
---------------------------------------------------------------------------

    \50\ Though, as discussed below, for other endpoints (e.g.,
hospital admissions, emergency department visits) the ISA focused
primarily on multicity studies.
---------------------------------------------------------------------------

    Available evidence indicates that O3-associated
increases in respiratory symptoms are not confounded by temperature,
pollen, or copollutants (primarily PM) (U.S. EPA, 2013a, section
<IP_ADDRESS>; Table 6-25; Romieu et al., 1996; Romieu et al., 1997; Thurston
et al., 1997; Gent et al., 2003). However, identifying the independent
effects of O3 in some studies was complicated due to the
high correlations observed between O3 and PM or different
lags and averaging times examined for copollutants. Nonetheless, the
ISA noted that the robustness of associations in some studies of
individuals with asthma, combined with findings from controlled human
exposure studies for the direct effects of O3 exposure,
provide substantial evidence supporting the independent effects of
short-term ambient O3 exposure on respiratory symptoms (U.S.
EPA, 2013a, section <IP_ADDRESS>).
    Epidemiologic studies of medication use have reported associations
with 1-hour maximum O3 concentrations and with multiday
average O3 concentrations (Romieu et al., 2006; Just et al.,
2002). Some studies reported O3 associations for both
respiratory symptoms and asthma medication use (Escamilla-Nu[ntilde]ez
et al., 2008; Romieu et al., 2006; Schildcrout et al., 2006; Jalaludin
et al., 2004; Romieu et al., 1997; Thurston et al., 1997) while others
reported associations for either respiratory symptoms or medication use
(Romieu et al., 1996; Rabinovitch et al., 2004; Just et al., 2002;
Ostro et al., 2001).
    In summary, both controlled human exposure and epidemiologic
studies have reported respiratory symptoms attributable to short-term
O3 exposures. In the last review, the majority of the
evidence from controlled human exposure studies in young, healthy
adults was for symptoms following exposures to O3
concentrations at or above 80 ppb. Although studies that have become
available since the last review have not reported increased respiratory
symptoms in young, healthy adults following exposures with moderate
exertion to 60 ppb, one recent study did report increased symptoms
following exposure to 72 ppb O3. As was concluded in the
2006 O3 AQCD (U.S. EPA, 2006a; U.S. EPA, 1996), the
collective body of epidemiologic evidence indicates that short-term
increases in ambient O3 concentration are associated with
increases in respiratory symptoms in children with asthma (U.S. EPA,
2013a, section 6.2.4). Recent studies of respiratory symptoms and
medication use, primarily in asthmatic children, add to this evidence.
In a smaller body of studies, increases in ambient O3
concentration were associated with increases in respiratory symptoms in
adults with asthma.
v. Lung Host Defense
    The mammalian respiratory tract has a number of closely integrated
defense mechanisms that, when functioning normally, provide protection
from the potential health effects of exposures to a wide variety of
inhaled particles and microbes. These defense mechanisms include
mucociliary clearance, alveolobronchiolar transport mechanism, alveolar
macrophages,\51\ and adaptive immunity \52\ (U.S. EPA, 2013a, section
6.2.5). The previous O3 AQCD (U.S. EPA, 2006a) concluded
that animal toxicological studies provided evidence that acute exposure
to O3 concentrations as low as 100 to 500 ppb can increase
susceptibility to infectious diseases due to modulation of these lung
host defenses. This conclusion was based, in large part, on animal
studies of alveolar macrophage function and mucociliary clearance (U.S.
EPA, 2013a, section 6.2.5).
---------------------------------------------------------------------------

    \51\ Phagocytic white blood cells within the alveoli of the
lungs that ingest inhaled particles.
    \52\ The adaptive immune system, is also known as the acquired
immune system. Acquired immunity creates immunological memory after
an initial response to a specific pathogen, leading to an enhanced
response to subsequent encounters with that same pathogen.
---------------------------------------------------------------------------

    Integrating animal study results with human exposure evidence, the
2006 Criteria Document concluded that available evidence indicates that
short-term O3 exposures have the potential to impair host
defenses in humans, primarily by interfering with alveolar macrophage
function. Any impairment in alveolar macrophage function may lead to
decreased clearance of microorganisms or nonviable particles.
Compromised alveolar macrophage functions in asthmatics may increase
their susceptibility to other O3 effects, the effects of
particles, and respiratory infections (U.S. EPA, 2006a, p. 8-26). These
conclusions were based largely on studies conducted in animals exposed
for several hours up to several weeks to O3 concentrations
from 100 to 250 ppb (Hurst et al., 1970; Driscoll et al., 1987; Cohen
et al., 2002). Consistent with the animal evidence, a controlled human
exposure study available in the last review had reported decrements in
the ability of alveolar macrophages to phagocytize yeast following
exposures of healthy volunteers to O3 concentrations of 80
and 100 ppb for 6.6 hours during moderate exercise (Devlin et al.,
1991).
    Alveolobronchiolar transport mechanisms refers to the transport of
particles deposited in the deep lung (alveoli) which may be removed
either up through the respiratory tract (bronchi) by alveolobronchiolar
transport or through the lymphatic system. The pivotal mechanism of
alveolobronchiolar transport involves the movement of alveolar
macrophages with ingested particles to the bottom of the conducting
airways. These airways are lined with ciliated epithelial cells and
cells that produce mucous, which surrounds the macrophages. The
ciliated epithelial cells move the

mucous packets up the resiratory tract, hence the term ``mucociliary
escalator.'' Although some studies show reduced tracheobronchial
clearance after O3 exposure (U.S. EPA, 2013a, section
<IP_ADDRESS>), alveolar clearance of deposited material is accelerated,
presumably due to macrophage influx, which in itself can be damaging.
    With regard to adaptive immunity, a limited number of epidemiologic
studies have examined associations between O3 exposure and
hospital admissions or emergency department visits for respiratory
infection, pneumonia, or influenza. Results have been mixed, and in
some cases conflicting (U.S. EPA, 2013a, sections <IP_ADDRESS> and <IP_ADDRESS>).
With the exception of influenza, it is difficult to ascertain whether
cases of respiratory infection or pneumonia are of viral or bacterial
etiology. A recent study that examined the association between
O3 exposure and respiratory hospital admissions in response
to an increase in influenza intensity observed an increase in
respiratory hospital admissions (Wong et al., 2009), but information
from toxicological studies of O3 and viral infections is
ambiguous.
    In summary, relatively few studies conducted since the last review
have evaluated the effects of O3 exposures on lung host
defense. When the available evidence is taken as a whole, the ISA
concludes that acute O3 exposures impair the host defense
capability of animals, primarily by depressing alveolar macrophage
function and perhaps also by decreasing mucociliary clearance of
inhaled particles and microorganisms. Coupled with limited evidence
from controlled human exposure studies, this suggests that humans
exposed to O3 could be predisposed to bacterial infections
in the lower respiratory tract (U.S. EPA, 2013a, section <IP_ADDRESS>).
vi. Allergic and Asthma-Related Responses
    Effects resulting from combined exposures to O3 and
allergens have been studied in a variety of animal species, generally
as models of experimental asthma. Pulmonary function and AHR in animal
models of asthma are discussed in detail in Section <IP_ADDRESS> and Section
<IP_ADDRESS>, respectively, in the ISA (U.S. EPA, 2013a). Studies of
allergic and asthma-related responses are discussed in detail in
sections 5.3.6 and 6.2.6 of the ISA (U.S. EPA, 2013a).
    Evidence available in the last review indicates that O3
exposure skews immune responses toward an allergic phenotype and could
also make airborne allergens more allergenic. In humans, allergic
rhinoconjunctivitis symptoms are associated with increases in ambient
O3 concentrations (Riediker et al., 2001). Controlled human
exposure studies have observed O3-induced changes indicating
allergic skewing. Airway eosinophils, which are white blood cells that
participate in allergic disease and inflammation, were observed to
increase in volunteers with atopy \53\ and mild asthma (Peden et al.,
1997). In a more recent study, expression of IL-5, a cytokine involved
in eosinophil recruitment and activation, was increased in subjects
with atopy but not in healthy subjects (Hernandez et al., 2010).
Epidemiologic studies describe associations between eosinophils in both
short- (U.S. EPA, 2013a, section <IP_ADDRESS>) and long-term (U.S. EPA,
2013a, section 7.2.5) O3 exposure, as do chronic exposure
studies in non-human primates. Collectively, findings from these
studies suggest that O3 can induce or enhance certain
components of allergic inflammation in individuals with allergy or
allergic asthma.
---------------------------------------------------------------------------

    \53\ Atopy is a predisposition toward developing certain
allergic hypersensitivity reactions. A person with atopy typically
presents with one or more of the following: eczema (atopic
dermatitis), allergic rhinitis (hay fever), allergic conjunctivitis,
or allergic asthma.
---------------------------------------------------------------------------

    Evidence available in the last review indicates that O3
may also increase AHR to specific allergen triggers (75 FR 2970,
January 19, 2010). Two studies (J[ouml]rres et al., 1996; Holz et al.,
2002) observed increased airway responsiveness to O3
exposure with bronchial allergen challenge in subjects with preexisting
allergic airway disease. Ozone-induced exacerbation of airway
responsiveness persists longer and attenuates more slowly than
O3-induced lung function decrements and respiratory symptom
responses and can have important clinical implications for asthmatics.
Animal toxicology studies indicate that O3 enhances
inflammatory and allergic responses to allergen challenge in sensitized
animals. In addition to exacerbating existing allergic responses,
toxicology studies indicate that O3 can also act as an
adjuvant to produce sensitization in the respiratory tract. Along with
its pro-allergic effects (inducing or enhancing certain components of
allergic inflammation in individuals with allergy or allergic asthma),
O3 could also make airborne allergens more allergenic. When
combined with NO2, O3 has been shown to enhance
nitration of common protein allergens, which may increase their
allergenicity (Franze et al., 2005).
vii. Hospital Admissions and Emergency Department Visits
    The 2006 O3 AQCD evaluated numerous studies of
respiratory-related emergency department visits and hospital
admissions. These were primarily time-series studies conducted in the
U.S., Canada, Europe, South America, Australia, and Asia. Based on such
studies, the 2006 O3 AQCD concluded that ``the overall
evidence supports a causal relationship between acute ambient
O3 exposures and increased respiratory morbidity resulting
in increased emergency department visits and [hospital admissions]
during the warm season'' \54\ (U.S. EPA, 2006a). This conclusion was
``strongly supported by the human clinical, animal toxicologic[al], and
epidemiologic evidence for [O3-induced] lung function
decrements, increased respiratory symptoms, airway inflammation, and
airway hyperreactivity'' (U.S. EPA, 2006a).
---------------------------------------------------------------------------

    \54\ Epidemiologic associations for O3 are more
robust during the warm season than during cooler months (e.g.,
smaller measurement error, less potential confounding by
copollutants). Rationale for focusing on warm season epidemiologic
studies for O3 can be found at 72 FR 37838-37840.
---------------------------------------------------------------------------

    The results of recent studies largely support the conclusions of
the 2006 O3 AQCD (U.S. EPA, 2013a, section 6.2.7). Since the
completion of the 2006 O3 AQCD, relatively fewer studies
conducted in the U.S., Canada, and Europe have evaluated associations
between short-term O3 concentrations and respiratory
hospital admissions and emergency department visits, with a growing
number of studies conducted in Asia. This epidemiologic evidence is
discussed in detail in the ISA (U.S. EPA, 2013a, section 6.2.7).\55\
---------------------------------------------------------------------------

    \55\ The consideration of ambient O3 concentrations
in the locations of these epidemiologic studies are discussed in
sections II.D.1.b and II.E.4.a below, for the current standard and
alternative standards, respectively.
---------------------------------------------------------------------------

    In considering this body of evidence, the ISA focused primarily on
multicity studies because they examine associations with respiratory-
related hospital admissions and emergency department visits over large
geographic areas using consistent statistical methodologies (U.S. EPA,
2013a, section <IP_ADDRESS>). The ISA also focused on single-city studies
that encompassed a large number of daily hospital admissions or
emergency department visits, included long study-durations, were
conducted in locations not represented by the larger studies, or
examined population-specific characteristics that may impact the risk
of O3-related health effects but were not evaluated in the
larger studies (U.S. EPA, 2013a, section <IP_ADDRESS>). When

examining the association between short-term O3 exposure and
respiratory health effects that require medical attention, the ISA
distinguishes between hospital admissions and emergency department
visits because it is likely that a small percentage of respiratory
emergency department visits will be admitted to the hospital;
therefore, respiratory emergency department visits may represent
potentially less serious, but more common outcomes (U.S. EPA, 2013a,
section <IP_ADDRESS>).
    Several recent multicity studies (e.g., Cakmak et al., 2006; Dales
et al., 2006) and a multi-continent study (Katsouyanni et al., 2009)
report associations between short-term O3 concentrations and
increased respiratory-related hospital admissions and emergency
department visits. These multicity studies are supported by results
from single-city studies also reporting consistent positive
associations using different exposure assignment approaches (i.e.,
average of multiple monitors, single monitor, population-weighted
average) and averaging times (i.e., 1-hour max and 8-hour max) (U.S.
EPA, 2013a, sections <IP_ADDRESS> to <IP_ADDRESS>). When examining cause-specific
respiratory outcomes, recent studies report positive associations with
hospital admissions and emergency department visits for asthma
(Strickland et al., 2010; Stieb et al., 2009) and chronic obstructive
pulmonary disease (COPD) (Stieb et al., 2009; Medina-Ramon et al.,
2006), with more limited evidence for pneumonia (Medina-Ramon et al.,
2006; Zanobetti and Schwartz, 2006). In seasonal analyses (U.S. EPA,
2013a, Figure 6-19, Table 6-28), stronger associations were reported in
the warm season or summer months, when O3 concentrations are
higher, compared to the cold season, particularly for asthma
(Strickland et al., 2010; Ito et al., 2007) and COPD (Medina-Ramon et
al., 2006). The available evidence indicates that children are at
greatest risk for effects leading to O3-associated hospital
admissions and emergency department visits (Silverman and Ito, 2010;
Mar and Koenig, 2009; Villeneuve et al., 2007).
    Although the collective evidence across studies indicates a mostly
consistent positive association between O3 exposure and
respiratory-related hospital admissions and emergency department
visits, the magnitude of these associations may be underestimated to
the extent members of study populations modify their behavior in
response to air quality forecasts, and to the extent such behavior
modification increases exposure misclassification (U.S. EPA, 2013,
Section 4.6.6). Studies examining the potential confounding effects of
copollutants have reported that O3 effect estimates remained
relatively robust upon the inclusion of PM and gaseous pollutants in
two-pollutant models (U.S. EPA, 2013a, Figure 6-20, Table 6-29).
Additional studies that conducted copollutant analyses, but did not
present quantitative results, also support these conclusions
(Strickland et al., 2010; Tolbert et al., 2007; Medina-Ramon et al.,
2006) (U.S. EPA, 2013a, section <IP_ADDRESS>).
    In the last review, studies had not evaluated the concentration-
response relationship between short-term O3 exposure and
respiratory-related hospital admissions and emergency department
visits. A preliminary examination of this relationship in studies that
have become available since the last review found no evidence of a
deviation from linearity when examining the association between short-
term O3 exposure and asthma hospital admissions (U.S. EPA,
2013a, page 6-157; Silverman and Ito, 2010). In addition, an
examination of the concentration-response relationship for
O3 exposure and pediatric asthma emergency department visits
found no evidence of a threshold at O3 concentrations as low
as 30 ppb (for daily maximum 8-hour concentrations) (Strickland et al.,
2010). However, in both studies there is uncertainty in the shape of
the concentration-response curve at the lower end of the distribution
of O3 concentrations due to the low density of data in this
range (U.S. EPA, 2013a, page 6-157).
viii. Respiratory Mortality
    The controlled human exposure, epidemiologic, and toxicological
studies discussed in section 6.2 of the ISA (U.S. EPA, 2013a) provide
evidence for respiratory morbidity effects, including emergency
department visits and hospital admissions, in response to short-term
O3 exposures. Moreover, evidence from experimental studies
indicates multiple potential pathways of respiratory effects from
short-term O3 exposures, which support the continuum of
respiratory effects that could potentially result in respiratory-
related mortality in adults (U.S. EPA, 2013a, section 6.2.8). The 2006
O3 AQCD found inconsistent evidence for associations between
short-term O3 concentrations and respiratory mortality (U.S.
EPA, 2006a). Although some studies reported a strong positive
association between O3 and respiratory mortality, additional
studies reported small associations or no associations. New
epidemiologic evidence for respiratory mortality is discussed in detail
in section 6.2.8 of the ISA (U.S. EPA, 2013a). The majority of recent
multicity studies have reported positive associations between short-
term O3 exposures and respiratory mortality, particularly
during the summer months (U.S. EPA, 2013a, Figure 6-36).
    Specifically, recent multicity studies from the U.S. (Zanobetti and
Schwartz, 2008b), Europe (Samoli et al., 2009), Italy (Stafoggia et
al., 2010), and Asia (Wong et al., 2010), as well as a multi-continent
study (Katsouyanni et al., 2009), reported associations between short-
term O3 concentrations and respiratory mortality (U.S. EPA,
2013a, Figure 6-37, page 6-259). With respect to respiratory mortality,
summer-only analyses were consistently positive and most were
statistically significant. All-year analyses had more mixed results,
but most were positive.
    Of the studies evaluated, only the studies by Katsouyanni et al.
(2009) and by Stafoggia et al. (2010) analyzed the potential for
copollutant confounding of the O3-respiratory mortality
relationship. Based on the results of these analyses, the ISA concluded
that O3 respiratory mortality risk estimates appear to be
moderately to substantially sensitive (e.g., increased or attenuated)
to inclusion of PM10. However, in the APHENA study
(Katsouyanni et al., 2009), the mostly every-6th-day sampling schedule
for PM10 in the Canadian and U.S. datasets greatly reduced
their sample size and limits the interpretation of these results (U.S.
EPA, 2013a, section 6.2.8).
    In summary, recent epidemiologic studies support and reinforce the
epidemiologic evidence for O3-associated respiratory
hospital admissions and emergency department visits from the last
review. In addition, the evidence for associations with respiratory
mortality has been strengthened since the last review, with the
addition of several large multicity studies. The biological
plausibility of the associations reported in these studies is supported
by the experimental evidence for respiratory effects.
b. Respiratory Effects--Long-Term
    Since the last review, the body of evidence indicating the
occurrence of respiratory effects due to long-term O3
exposure has been strengthened. This evidence is discussed in detail in
the ISA (U.S. EPA, 2013a, Chapter 7) and summarized below for new-onset
asthma and asthma prevalence, asthma hospital admissions, pulmonary
structure and function, and respiratory mortality.

i. New-Onset Asthma and Asthma Prevalence
    Asthma is a heterogeneous disease with a high degree of temporal
variability. The on-set, progression, and symptoms can vary within an
individual's lifetime, and the course of asthma may vary markedly in
young children, older children, adolescents, and adults. In the
previous review, longitudinal cohort studies that examined associations
between long-term O3 exposures and the onset of asthma in
adults and children indicated a direct effect of long-term
O3 exposures on asthma risk in adults (McDonnell et al.,
1999, 15-year follow-up; Greer et al., 1993, 10-year follow-up) and
effect modification by O3 in children (McConnell et al.,
2002). Since that review, additional studies have evaluated
associations with new onset asthma, further informing our understanding
of the potential gene-environment interactions, mechanisms, and
biological pathways associated with incident asthma.
    In children, the relationship between long-term O3
exposure and new-onset asthma has been extensively studied in the
Children's Health Study (CHS), a long-term study that was initiated in
the early 1990's which has evaluated effects in several cohorts of
children. The CHS was initially designed to examine whether long-term
exposure to ambient pollution was related to chronic respiratory
outcomes in children in 12 communities in southern California. In the
CHS, new-onset asthma was classified as having no prior history of
asthma at study entry with subsequent report of physician-diagnosed
asthma at follow-up, with the date of onset assigned to be the midpoint
of the interval between the interview date when asthma diagnosis was
first reported and the previous interview date. The results of one
study (McConnell et al., 2002) available in the previous review
indicated that within high O3 communities, asthma risk was
3.3 times greater for children who played three or more outdoor sports
as compared with children who played no sports.
    For this review, as discussed in section <IP_ADDRESS> of the ISA (U.S.
EPA, 2013a), recent studies from the CHS provide evidence for gene-
environment interactions in effects on new-onset asthma by indicating
that the lower risks associated with specific genetic variants are
found in children who live in lower O3 communities. These
studies indicate that the risk for new-onset asthma is related in part
to genetic susceptibility, as well as behavioral factors and
environmental exposure. The onset of a chronic disease, such as asthma,
is partially the result of a sequence of biochemical reactions
involving exposures to various environmental agents metabolized by
enzymes related to a number of different genes. Oxidative stress has
been proposed to underlie the mechanistic hypotheses related to
O3 exposure. Genetic variants may impact disease risk
directly, or modify disease risk by affecting internal dose of
pollutants and other environmental agents and/or their reaction
products, or by altering cellular and molecular modes of action.
Understanding the relation between genetic polymorphisms and
environmental exposure can help identify high-risk subgroups in the
population and provide better insight into pathway mechanisms for these
complex diseases.
    The CHS analyses (Islam et al., 2008; Islam et al., 2009; Salam et
al., 2009) have found that asthma risk is related to interactions
between O3 and variants in genes for enzymes such as heme-
oxygenase (HO-1), arginases (ARG1 and 2), and glutathione S transferase
P1 (GSTP1). Biological plausibility for these findings is provided by
evidence that these enzymes have antioxidant and/or anti-inflammatory
activity and participate in well-recognized modes of action in asthma
pathogenesis. As O3 is a source of oxidants in the airways,
oxidative stress serves as the link among O3 exposure,
enzyme activity, and asthma. Further, several lines of evidence
demonstrate that secondary oxidation products of O3 initiate
the key modes of action that mediate downstream health effects (U.S.
EPA, 2013a, section 5.3). For example, HO-1 responds rapidly to
oxidants, has anti-inflammatory and antioxidant effects, relaxes airway
smooth muscle, and is induced in the airways during asthma. Cross-
sectional studies by Akinbami et al. (2010) and Hwang et al. (2005)
provide further evidence relating O3 exposures with asthma
prevalence. Gene-environment interactions are discussed in detail in
Section <IP_ADDRESS> in the ISA (U.S. EPA, 2013a).
ii. Asthma Hospital Admissions
    In the 2006 AQCD, studies on O3-related hospital
discharges and emergency department visits for asthma and respiratory
disease mainly looked at short-term (daily) metrics. The short-term
O3 studies presented in section <IP_ADDRESS> of the ISA (U.S.
EPA, 2013a) and discussed above in section <IP_ADDRESS> continue to indicate
that there is evidence for increases in both hospital admissions and
emergency department visits in children and adults related to all
respiratory outcomes, including asthma, with stronger associations in
the warm months. New studies, discussed in section 7.2.2 of the ISA
(U.S. EPA, 2013a) also evaluated long-term O3 exposure
metrics, providing a new line of evidence that suggests a positive
exposure-response relationship between the first hospital admission for
asthma and long-term O3 exposure, although the ISA cautions
in attributing the associations in that study to long-term exposures
since there is potential for short-term exposures to contribute to the
observed associations.
    Evidence associating long-term O3 exposure to first
asthma hospital admission in a positive concentration-response
relationship is provided in a retrospective cohort study (Lin et al.,
2008b). This study investigated the association between chronic
exposure to O3 and childhood asthma admissions by following
a birth cohort of more than 1.2 million babies born in New York State
(1995-1999) to first asthma admission or until December 31, 2000. Three
annual indicators (all 8-hour maximum from 10:00 a.m. to 6:00 p.m.)
were used to define chronic O3 exposure: (1) Mean
concentration during the follow-up period (41.06 ppb); (2) mean
concentration during the O3 season (50.62 ppb); and (3)
proportion of follow-up days with O3 levels >70 ppb. The
effects of copollutants were controlled, and interaction terms were
used to assess potential effect modifications. A positive association
between chronic exposure to O3 and childhood asthma hospital
admissions was observed, indicating that children exposed to high
O3 levels over time are more likely to develop asthma severe
enough to be admitted to the hospital. The various factors were
examined and differences were found for younger children (1-2 years),
poor neighborhoods, Medicaid/self-paid births, geographic region and
others. As shown in the ISA, Figure 7-3 (U.S. EPA, 2013a, p. 7-16),
positive concentration-response relationships were observed. Asthma
admissions were significantly associated with increased O3
levels for all chronic exposure indicators.
    In considering the relationship between long-term pollutant
exposures and chronic disease health endpoints, where chronic
pathologies are found with acute expression of chronic disease,
K[uuml]nzli (2012) hypothesizes that if the associations of pollution
with events are much larger in the long-term studies, it provides some
indirect evidence that air pollution increases the pool of subjects
with chronic disease, and that more acute events are to be

expected to be seen for higher exposures. The results of Lin et al
(2008a) for first asthma hospital admission, presented in Figure 7-3
(U.S. EPA, 2013a, p. 7-16), show effects estimates that are larger than
those reported in a study of childhood asthma hospital admission in New
York State (Silverman and Ito, 2010), discussed above. The ISA (U.S.
EPA, 2013a, p. 7-16) notes that this provides some support for the
hypothesis that O3 exposure may not only have triggered the
events but also increased the pool of asthmatic children, but cautions
in attributing the associations in the Lin et al. (2008) study to long-
term exposures since there is potential for short-term exposures to
contribute to the observed associations.
iii. Pulmonary Structure and Function
    In the 2006 O3 AQCD, few epidemiologic studies had
investigated the effect of chronic O3 exposure on pulmonary
function. The definitive 8-year follow-up analysis of the first cohort
of the CHS (U.S. EPA, 2013a, section <IP_ADDRESS>) provided little evidence
that long-term exposure to ambient O3 was associated with
significant deficits in the growth rate of lung function in children.
The strongest evidence was for medium-term effects of extended
O3 exposures over several summer months on lung function
(FEV1) in children, i.e., reduced lung function growth being
associated with higher ambient O3 levels. Short-term
O3 exposure studies presented in the ISA (U.S. EPA, 2013a,
section <IP_ADDRESS>) provide a cumulative body of epidemiologic evidence
that strongly supports associations between ambient O3
exposure and decrements in lung function among children. A later CHS
study (Islam et al., 2007) included in this review (U.S. EPA, 2013a,
section <IP_ADDRESS>) also reported no substantial differences in the effect
of O3 on lung function. However, in a more recent CHS study,
Breton et al. (2011) hypothesized that genetic variation in genes on
the glutathione metabolic pathway may influence the association between
ambient air pollutant exposures and lung function growth in children,
and found that variation in the GSS locus was associated with
differences in risk of children for lung function growth deficits
associated ambient air pollutants, including O3. A recent
study (Rojas-Martinez et al., 2007) of long-term exposure to
O3, described in section <IP_ADDRESS> of the ISA (U.S. EPA,
2013a, p. 7-19), observed a relationship with pulmonary function
declines in school-aged children where O3 and other
pollutant levels were higher (90 ppb at high end of the range) than
those in the CHS. Two studies of adult cohorts provide mixed results
where long-term exposures were at the high end of the range.
    Long-term studies in animals allow for greater insight into the
potential effects of prolonged exposure to O3 that may not
be easily measured in humans, such as structural changes in the
respiratory tract. Despite uncertainties, epidemiologic studies
observing associations of O3 exposure with functional
changes in humans can attain biological plausibility in conjunction
with long-term toxicological studies, particularly O3-
inhalation studies performed in non-human primates whose respiratory
systems most closely resemble that of the human. An important series of
studies, discussed in section <IP_ADDRESS> of the ISA (U.S. EPA, 2013a),
have used nonhuman primates to examine the effect of O3
alone, or in combination with an inhaled allergen, house dust mite
antigen (HDMA), on morphology and lung function. Animals exhibit the
hallmarks of allergic asthma defined for humans (NHLBI, 2007). These
studies and others have demonstrated changes in pulmonary function and
airway morphology in adult and infant nonhuman primates repeatedly
exposed to environmentally relevant concentrations of O3
(U.S. EPA, 2013a, section <IP_ADDRESS>).
    The initial observations in adult nonhuman primates have been
expanded in a series of experiments using infant rhesus monkeys
repeatedly exposed to 0.5 ppm O3 starting at 1 month of age
(Plopper et al., 2007; Schelegle et al. 2003). The purpose of these
studies was to determine if a cyclic regimen of O3
inhalation would amplify the allergic responses and structural
remodeling associated with allergic sensitization and inhalation in the
infant rhesus monkey; they provide evidence of an O3-induced
change in airway resistance and responsiveness provides biological
plausibility of long-term exposure, or repeated short-term exposures,
to O3 contributing to the effects of asthma in children.
    In addition, significant structural changes in the respiratory
tract development, during which conducting airways increase in diameter
and length, have been observed in infant rhesus monkeys after cyclic
exposure to O3 (Fanucchi et al., 2006). These effects are
noteworthy because of their potential contribution to airway
obstruction and AHR which are central features of asthma. A number of
studies in both non-human primates and rodents demonstrate that
O3 exposure can increase collagen synthesis and deposition,
including fibrotic-like changes in the lung (U.S. EPA, 2013a, section
<IP_ADDRESS>).
    Collectively, evidence from animal studies strongly suggests that
chronic O3 exposure is capable of damaging the distal
airways and proximal alveoli, resulting in lung tissue remodeling and
leading to apparent irreversible changes. Potentially, persistent
inflammation and interstitial remodeling play an important role in the
progression and development of chronic lung disease. Further discussion
of the modes of action that lead to O3-induced morphological
changes can be found in section 5.3.7 of the ISA (U.S. EPA, 2013a).
Discussion of mechanisms involved in lifestage susceptibility and
developmental effects can be found in section <IP_ADDRESS> of the ISA (U.S.
EPA, 2013a). The findings reported in chronic animal studies offer
insight into potential biological mechanisms for the suggested
association between seasonal O3 exposure and reduced lung
function development in children as observed in epidemiologic studies
(U.S. EPA, 2013a, section <IP_ADDRESS>).
iv. Respiratory Mortality
    A limited number of epidemiologic studies have assessed the
relationship between long-term exposure to O3 and mortality
in adults. The 2006 O3 AQCD concluded that an insufficient
amount of evidence existed ``to suggest a causal relationship between
chronic O3 exposure and increased risk for mortality in
humans'' (U.S. EPA, 2006a). Though total and cardio-pulmonary mortality
were considered in these studies, respiratory mortality was not
specifically considered.
    In the most recent follow-up analysis of the American Cancer
Society (ACS) cohort (Jerrett et al., 2009), cardiopulmonary deaths
were separately subdivided into respiratory and cardiovascular deaths,
rather than combined as in the Pope et al. (2002) work. Increased
O3 exposure was associated with the risk of death from
respiratory causes, and this effect was robust to the inclusion of
PM2.5. The association between increased O3
concentrations and increased risk of death from respiratory causes was
insensitive to the use of different models and to adjustment for
several ecologic variables considered individually. The authors
reported that when seasonal averages of 1-hour daily maximum
O3 concentrations ranged from 33 to 104 ppb, there was no
statistical deviation from a linear concentration-response relationship
between O3 and respiratory mortality across 96 U.S. cities
(U.S. EPA, 2013a, section 7.7). However, the authors also

evaluated the degree to which models incorporating thresholds provided
a better fit to the data. Based on these analyses, Jerrett et al.
(2009) reported ``limited evidence'' for an effect threshold at an
O3 concentration of 56 ppb (p=0.06).
    Additionally, a recent multicity time series study (Zanobetti and
Schwartz, 2011), which followed (from 1985 to 2006) four cohorts of
Medicare enrollees with chronic conditions that might predispose to
O3-related effects, observed an association between long-
term (warm season) exposure to O3 and elevated risk of
mortality in the cohort that had previously experienced an emergency
hospital admission due to COPD. A key limitation of this study is the
inability to control for PM2.5, because data were not
available in these cities until 1999.
c. Cardiovascular Effects
    A relatively small number of studies have examined the potential
effect of short-term O3 exposure on the cardiovascular
system. The 2006 O3 AQCD (U.S. EPA, 2006a, p. 8-77)
concluded that ``O3 directly and/or indirectly contributes
to cardiovascular-related morbidity,'' but added that the body of
evidence was limited. This conclusion was based on a controlled human
exposure study that included hypertensive adult males; a few
epidemiologic studies of physiologic effects, heart rate variability,
arrhythmias, myocardial infarctions, and hospital admissions; and
toxicological studies of heart rate, heart rhythm, and blood pressure.
    More recently, the body of scientific evidence available that has
examined the effect of O3 on the cardiovascular system has
expanded. There is an emerging body of animal toxicological evidence
demonstrating that short-term exposure to O3 can lead to
autonomic nervous system alterations (in heart rate and/or heart rate
variability) and suggesting that proinflammatory signals may mediate
cardiovascular effects. Interactions of O3 with respiratory
tract components result in secondary oxidation product formation and
subsequent production of inflammatory mediators, which have the
potential to penetrate the epithelial barrier and to initiate toxic
effects systemically. In addition, animal toxicological studies of
long-term exposure to O3 provide evidence of enhanced
atherosclerosis and ischemia/reperfusion (I/R) injury, corresponding
with development of a systemic oxidative, proinflammatory environment.
Recent experimental and epidemiologic studies have investigated
O3-related cardiovascular events and are summarized in
section 6.3 of the ISA (U.S. EPA, 2013a). Overall, the ISA summarized
the evidence in this review as follows (U.S. EPA, 2013a, p. 6-211).

    In conclusion, animal toxicological studies demonstrate
O3-induced cardiovascular effects, and support the strong
body of epidemiologic evidence indicating O3-induced
cardiovascular mortality. Animal toxicological and controlled human
exposure studies provide evidence for biologically plausible
mechanisms underlying these O3-induced cardiovascular
effects. However, a lack of coherence with epidemiologic studies of
cardiovascular morbidity remains an important uncertainty.

    Controlled human exposure studies discussed in previous AQCDs have
not demonstrated any consistent extrapulmonary effects. In this review,
evidence from controlled human exposure studies suggests cardiovascular
effects in response to short-term O3 exposure (U.S. EPA,
2013a, section 6.3.1) and provides some coherence with evidence from
animal toxicology studies. Controlled human exposure studies also
support the animal toxicological studies by demonstrating
O3-induced effects on blood biomarkers of systemic
inflammation and oxidative stress, as well as changes in biomarkers
that can indicate the potential for increased clotting following
O3 exposures. Increases and decreases in high frequency
heart rate variability (HRV) have been reported following relatively
low (120 ppb during rest) and high (300 ppb with exercise)
O3 exposures, respectively. These changes in cardiac
function observed in animal and human studies provide preliminary
evidence for O3-induced modulation of the autonomic nervous
system through the activation of neural reflexes in the lung (U.S. EPA
2013a, section 5.3.2).
    Overall, the ISA concludes that the available body of epidemiologic
evidence examining the relationship between short-term exposures to
O3 concentrations and cardiovascular morbidity is
inconsistent (U.S. EPA, 2013a, section <IP_ADDRESS>). Across studies,
different definitions (i.e., ICD-9 diagnostic codes) were used for both
all-cause and cause-specific cardiovascular morbidity (U.S. EPA, 2013a,
Tables 6-35 to 6-39), which may contribute to inconsistency in results.
However, within diagnostic categories, no consistent pattern of
association was found with O3. Generally, the epidemiologic
studies used nearest air monitors to assess O3
concentrations, with a few exceptions that used modeling or personal
exposure monitors. The inconsistencies in the associations observed
between short-term O3 and cardiovascular disease (CVD)
morbidities are unlikely to be explained by the different exposure
assignment methods used (U.S. EPA, 2013a, section 4.6). The wide
variety of biomarkers considered and the lack of consistency among
definitions used for specific cardiovascular disease endpoints (e.g.,
arrhythmias, HRV) make comparisons across studies difficult.
    Despite the inconsistent evidence for an association between
O3 concentration and CVD morbidity, mortality studies
indicate a consistent positive association between short-term
O3 exposure and cardiovascular mortality in multicity
studies and in a multi-continent study. When examining mortality due to
CVD, epidemiologic studies consistently observe positive associations
with short-term exposure to O3. Additionally, there is some
evidence for an association between long-term exposure to O3
and mortality, although the association between long-term ambient
O3 concentrations and cardiovascular mortality can be
confounded by other pollutants (U.S. EPA, 2013a). The ISA (U.S. EPA
2013a, section 6.3.4) states that taken together, the overall body of
evidence across the animal and human studies is sufficient to conclude
that there is likely to be a causal relationship between relevant
short-term exposures to O3 and cardiovascular system
effects.
d. Total Mortality
    The 2006 O3 AQCD concluded that the overall body of
evidence was highly suggestive that short-term exposure to
O3 directly or indirectly contributes to nonaccidental and
cardiopulmonary-related mortality in adults, but additional research
was needed to more fully establish underlying mechanisms by which such
effects occur (U.S. EPA, 2013a, p. 2-18). In building on the 2006
evidence for mortality, the ISA states the following (U.S. EPA, 2013a,
p. 6-261).

    The evaluation of new multicity studies that examined the
association between short-term O3 exposures and mortality
found evidence that supports the conclusions of the 2006 AQCD. These
new studies reported consistent positive associations between short-
term O3 exposure and all-cause (nonaccidental) mortality,
with associations persisting or increasing in magnitude during the
warm season, and provide additional support for associations between
O3 exposure and cardiovascular and respiratory mortality.

    The 2006 O3 AQCD reviewed a large number of time-series
studies of associations between short-term O3 exposures and
total mortality including single- and multicity studies, and meta-
analyses. In the large U.S. multicity

studies that examined all-year data, effect estimates corresponding to
single-day lags ranged from a 0.5-1% increase in all-cause
(nonaccidental) total mortality per a 20 ppb (24-hour), 30 ppb (8-hour
maximum), or 40 ppb (1-hour maximum) increase in ambient O3
(U.S. EPA, 2013a, section 6.6.2). Available studies reported some
evidence for heterogeneity in O3 mortality risk estimates
across cities and across studies. Studies that conducted seasonal
analyses reported larger O3 mortality risk estimates during
the warm or summer season. Overall, the 2006 O3 AQCD
identified robust associations between various measures of daily
ambient O3 concentrations and all-cause mortality, which
could not be readily explained by confounding due to time, weather, or
copollutants. With regard to cause-specific mortality, consistent
positive associations were reported between short-term O3
exposure and cardiovascular mortality, with less consistent evidence
for associations with respiratory mortality. The majority of the
evidence for associations between O3 and cause-specific
mortality were from single-city studies, which had small daily
mortality counts and subsequently limited statistical power to detect
associations. The 2006 O3 AQCD concluded that ``the overall
body of evidence is highly suggestive that O3 directly or
indirectly contributes to nonaccidental and cardiopulmonary-related
mortality'' (U.S. EPA, 2013a, section 6.6.1).
    Recent studies have strengthened the body of evidence that supports
the association between short-term O3 concentrations and
mortality in adults. This evidence includes a number of studies
reporting associations with nonaccidental as well as cause-specific
mortality. Multi-continent and multicity studies have consistently
reported positive and statistically significant associations between
short-term O3 concentrations and all-cause mortality, with
evidence for larger mortality risk estimates during the warm or summer
months (U.S. EPA, 2013a, Figure 6-27; Table 6-42). Similarly,
evaluations of cause-specific mortality have reported consistently
positive associations with O3, particularly in analyses
restricted to the warm season (U.S. EPA, 2013a, Figure 6-37; Table 6-
53).\56\
---------------------------------------------------------------------------

    \56\ Respiratory mortality is discussed in more detail above.
---------------------------------------------------------------------------

    In assessing the evidence for O3-related mortality, the
2006 AQCD also noted that multiple uncertainties remained regarding the
relationship between short-term O3 concentrations and
mortality, including the extent of residual confounding by
copollutants; characterization of the factors that modify the
O3-mortality association; the appropriate lag structure for
identifying O3-mortality effects; and the shape of the
O3-mortality concentration-response function and whether a
threshold exists. Many of the studies, published since the last review,
have attempted to address one or more of these uncertainties. The ISA
(U.S. EPA, 2013a, section 6.6.2) discusses the extent to which recent
studies have evaluated these uncertainties in the relationship between
O3 and mortality.
    In particular, recent studies have evaluated different statistical
approaches to examine the shape of the O3-mortality
concentration-response relationship and to evaluate whether a threshold
exists for O3-related mortality. In an analysis of the
National Morbidity and Mortality Air Pollution Study (NMMAPS) data,
Bell et al. (2006) evaluated the potential for a threshold in the
O3-mortality relationship. The authors reported positive and
statistically significant associations with mortality in a variety of
restricted analyses, including analyses restricted to days with 24-hour
area-wide average O3 concentrations below 60, 55, 50, 45,
40, 35, and 30 ppb. In these restricted analyses O3 effect
estimates were of similar magnitude, were statistically significant,
and had similar statistical precision. In analyses restricted to days
with 24-hour average O3 concentrations below 25 ppb, the
O3 effect estimate was similar in magnitude to the effect
estimates resulting from analyses with the higher cutoffs, but had
somewhat lower statistical precision, with the estimate approaching
statistical significance (i.e., based on observation of Figure 2 in
Bell et al., 2006). In analyses restricted to days with lower 24-hour
average O3 concentrations (i.e., below 20 and 15 ppb),
effect estimates were similar in magnitude to analyses with higher
cutoffs, but with notably less statistical precision, and were not
statistically significant (i.e., confidence intervals included the
null, indicating no O3-associated mortality, based on
observation of Figure 2 in Bell et al., 2006). Ozone was no longer
positively associated with mortality when the analysis was restricted
to days with 24-hour O3 concentrations below 10 ppb. Given
the relatively small number of days included in these restricted
analyses, especially for cut points of 20 ppb and below,\57\
statistical uncertainty is increased.
---------------------------------------------------------------------------

    \57\ For example, Bell et al. (2006) reported that for analyses
restricted to 24-hour O3 concentrations at or below 20
ppb, 73% of days were excluded on average across the 98 communities.
---------------------------------------------------------------------------

    Bell et al. (2006) also evaluated the shape of the concentration-
response relationship between O3 and mortality. Although the
results of this analysis suggested the lack of threshold in the
O3-mortality relationship, the ISA noted that it is
difficult to interpret such a curve because: (1) There is uncertainty
around the shape of the concentration-response curve at 24-hour average
O3 concentrations generally below 20 ppb; and (2) the
concentration-response curve does not take into consideration the
heterogeneity in O3-mortality risk estimates across cities
(U.S. EPA, 2013a, section <IP_ADDRESS>).
    Several additional studies have used the NMMAPS dataset to evaluate
the concentration-response relationship between short-term
O3 concentrations and mortality. For example, using the same
data as Bell et al. (2006), Smith et al. (2009) conducted a subset
analysis, but instead of restricting the analysis to days with
O3 concentrations below a cutoff, the authors only included
days above a defined cutoff (cutoffs from 15 and 60 ppb). The results
of this analysis were consistent with those reported by Bell et al.
(2006). Specifically, the authors reported consistent positive
associations for all cutoff concentrations up to concentrations where
the total number of days available were so limited that the variability
around the central estimate was increased (i.e., cutoff values at or
above about 50 ppb) (U.S. EPA, 2013a, section <IP_ADDRESS>). In addition,
using NMMAPS data for 1987-1994 for Chicago, Pittsburgh, and El Paso,
Xia and Tong (2006) reported evidence for a threshold around a 24-hour
average O3 concentration of 25 ppb, though the threshold
values estimated in the analysis were sometimes in the range of where
data density was low (U.S. EPA, 2013a, section <IP_ADDRESS>). Stylianou and
Nicolich (2009) examined the existence of thresholds following an
approach similar to Xia and Tong (2006) using data from NMMAPS for nine
major U.S. cities (i.e., Baltimore, Chicago, Dallas/Fort Worth, Los
Angeles, Miami, New York, Philadelphia, Pittsburgh, and Seattle) for
the years 1987-2000. The authors reported that the estimated
O3-mortality risks varied across the nine cities, with the
models exhibiting apparent thresholds in the 10-45 ppb range for
O3 (24-hour average). However, given the city-to-city
variation in risk estimates, combining the city-specific estimates into
an overall estimate complicates the interpretation of the results.
Additional studies in

Europe, Canada, and Asia did not report the existence of a threshold
(Katsouyanni et al., 2009), with inconsistent and/or inconclusive
results across cities, or a non-linear relationship in the
O3-mortality concentration-response curve (Wong et al.,
2010).
3. Adversity of O3 Effects
    In making judgments as to when various O3-related
effects become regarded as adverse to the health of individuals, in
previous NAAQS reviews, the EPA has relied upon the guidelines
published by the American Thoracic Society (ATS) and the advice of
CASAC. In 2000, the ATS published an official statement on ``What
Constitutes an Adverse Health Effect of Air Pollution?'' (ATS, 2000),
which updated and built upon its earlier guidance (ATS, 1985). The
earlier guidance defined adverse respiratory health effects as
``medically significant physiologic changes generally evidenced by one
or more of the following: (1) Interference with the normal activity of
the affected person or persons, (2) episodic respiratory illness, (3)
incapacitating illness, (4) permanent respiratory injury, and/or (5)
progressive respiratory dysfunction,'' while recognizing that
perceptions of ``medical significance'' and ``normal activity'' may
differ among physicians, lung physiologists and experimental subjects
(ATS, 1985). The 2000 ATS guidance builds upon and expands the 1985
definition of adversity in several ways. The guidance concludes that
transient, reversible loss of lung function in combination with
respiratory symptoms should be considered adverse. There is also a more
specific consideration of population risk (ATS, 2000). Exposure to air
pollution that increases the risk of an adverse effect to the entire
population is adverse, even though it may not increase the risk of any
individual to an unacceptable level. For example, a population of
asthmatics could have a distribution of lung function such that no
individual has a level associated with clinically important impairment.
Exposure to air pollution could shift the distribution to lower levels
that still do not bring any individual to a level that is associated
with clinically relevant effects. However, this would be considered to
be adverse because individuals within the population would have
diminished reserve function, and therefore would be at increased risk
to further environmental insult (U.S. EPA, 2013a, p. lxxi; and 75 FR at
35526/2, June 22, 2010).
    The ATS also concluded that elevations of biomarkers such as cell
types, cytokines and reactive oxygen species may signal risk for
ongoing injury and more serious effects or may simply represent
transient responses, illustrating the lack of clear boundaries that
separate adverse from nonadverse events. More subtle health outcomes
also may be connected mechanistically to health effects that are
clearly adverse, so that small changes in physiological measures may
not appear clearly adverse when considered alone, but may be part of a
coherent and biologically plausible chain of related health outcomes
that include responses that are clearly adverse, such as mortality
(U.S. EPA, 2014c, section <IP_ADDRESS>).
    In this review, the new evidence provides further support for
relationships between O3 exposures and a spectrum of health
effects, including effects that meet the ATS criteria for being adverse
(ATS, 1985 and 2000). The ISA determination that there is a causal
relationship between short-term O3 exposure and a full range
of respiratory effects, including respiratory morbidity (e.g., lung
function decrements, respiratory symptoms, inflammation, hospital
admissions, and emergency department visits) and mortality, provides
support for concluding that short-term O3 exposure is
associated with adverse effects (U.S. EPA, 2013a, section 2.5.2).
Overall, including new evidence of cardiovascular system effects, the
evidence supporting an association between short-term O3
exposures and total (nonaccidental, cardiopulmonary) respiratory
mortality is stronger in this review (U.S. EPA, 2013a, section 2.5.2).
And the judgment of likely causal associations between long-term
measures of O3 exposure and respiratory effects such as new-
onset asthma, prevalence of asthma, asthma symptoms and control, and
asthma hospital admissions provides support for concluding that long-
term O3 exposure is associated with adverse effects ranging
from episodic respiratory illness to permanent respiratory injury or
progressive respiratory decline (U.S. EPA, 2013a, section 7.2.8).
    Application of the ATS guidelines to the least serious category of
effects related to ambient O3 exposures, which are also the
most numerous and, therefore, are also potentially important from a
public health perspective, involves judgments about which medical
experts on CASAC panels and public commenters have in the past
expressed diverse views. To help frame such judgments, in past reviews,
the EPA has defined gradations of individual functional responses
(e.g., decrements in FEV1 and airway responsiveness) and
symptomatic responses (e.g., cough, chest pain, wheeze), together with
judgments as to the potential impact on individuals experiencing
varying degrees of severity of these responses. These gradations were
used in the 1997 O3 NAAQS review and slightly revised in the
2008 review (U.S. EPA, 1996, p. 59; 2007, p. 3-72; 72 FR 37849, July
11, 2007). These gradations and impacts are summarized in Tables 3-2
and 3-3 in the 2007 O3 Staff Paper (U.S. EPA, 2007, pp. 3-74
to 3-75).
    For active healthy people, including children, moderate levels of
functional responses (e.g., FEV1 decrements of >=10% but
<20%, lasting 4 to 24 hours) and/or moderate symptomatic responses
(e.g., frequent spontaneous cough, marked discomfort on exercise or
deep breath, lasting 4 to 24 hours) would likely interfere with normal
activity for relatively few sensitive individuals (U.S. EPA, 2007, p.
3-72; 72 FR 37849, July 11, 2007); whereas large functional responses
(e.g., FEV1 decrements >=20%, lasting longer than 24 hours)
and/or severe symptomatic responses (e.g., persistent uncontrollable
cough, severe discomfort on exercise or deep breath, lasting longer
than 24 hours) would likely interfere with normal activities for many
sensitive individuals (U.S. EPA, 2007, p. 3-72; 72 FR 37849, July 11,
2007) and, therefore, would be considered adverse under ATS guidelines.
For the purpose of estimating potentially adverse lung function
decrements in active healthy people in the 2008 O3 NAAQS
review, the CASAC panel for that review indicated that a focus on the
mid to upper end of the range of moderate levels of functional
responses is most appropriate (e.g., FEV1 decrements >=15%
but <20%) (Henderson, 2006; U.S. EPA, 2007, p. 3-76). In this review,
CASAC concurred that the ``[e]stimation of FEV1 decrements
of >=15% is appropriate as a scientifically relevant surrogate for
adverse health outcomes in active healthy adults'' (Frey, 2014c, p. 3).
However, for children and adults with lung disease, even moderate
functional (e.g., FEV1 decrements >=10% but <20%, lasting up
to 24 hours) or symptomatic responses (e.g., frequent spontaneous
cough, marked discomfort on exercise or with deep breath, wheeze
accompanied by shortness of breath, lasting up to 24 hours) would
likely interfere with normal activity for many individuals, and would
likely result in additional and more frequent use of

medication (U.S. EPA, 2007, p. 3-72; 72 FR 37849, July 11, 2007). For
people with lung disease, large functional responses (e.g.,
FEV1 decrements >=20%, lasting longer than 24 hours) and/or
severe symptomatic responses (e.g., persistent uncontrollable cough,
severe discomfort on exercise or deep breath, persistent wheeze
accompanied by shortness of breath, lasting longer than 24 hours) would
likely interfere with normal activity for most individuals and would
increase the likelihood that these individuals would seek medical
treatment (U.S. EPA, 2007, p. 3-72; 72 FR 37849, July 11, 2007). In the
last O3 NAAQS review, for the purpose of estimating
potentially adverse lung function decrements in people with lung
disease the CASAC panel indicated that a focus on the lower end of the
range of moderate levels of functional responses is most appropriate
(e.g., FEV1 decrements >=10%) (Henderson, 2006; U.S. EPA,
2007, p. 3-76). In addition, in their letter advising the Administrator
on the reconsideration of the 2008 final decision, CASAC stated that
``[a] 10% decrement in FEV1 can lead to respiratory symptoms,
especially in individuals with pre-existing pulmonary or cardiac
disease. For example, people with chronic obstructive pulmonary disease
have decreased ventilatory reserve (i.e., decreased baseline
FEV1) such that a >=10% decrement could lead to moderate to
severe respiratory symptoms'' (Samet, 2011). In this review, CASAC
concurred that ``[a]n FEV1 decrement of >=10% is a scientifically
relevant surrogate for adverse health outcomes for people with asthma
and lung disease'' (Frey, 2014c, p. 3).
    In judging the extent to which these impacts represent effects that
should be regarded as adverse to the health status of individuals, in
previous NAAQS reviews, the EPA has also considered whether effects
were experienced repeatedly during the course of a year or only on a
single occasion (U.S. EPA, 2007). Although some experts would judge
single occurrences of moderate responses to be a nuisance, especially
for healthy individuals, a more general consensus view of the adversity
of such moderate responses emerges as the frequency of occurrence
increases. Thus it has been judged that repeated occurrences of
moderate responses, even in otherwise healthy individuals, may be
considered to be adverse since they could well set the stage for more
serious illness (61 FR 65723). The CASAC panel in the 1997 NAAQS review
expressed a consensus view that these ``criteria for the determination
of an adverse physiological response were reasonable'' (Wolff, 1995).
In the review completed in 2008, estimates of repeated occurrences
continued to be an important public health policy factor in judging the
adversity of moderate lung function decrements in healthy and asthmatic
people (72 FR 37850, July 11, 2007).
    Evidence new to this review indicates that 6.6-hour exposures to 60
ppb O3 during moderate exertion can result in pulmonary
inflammation in healthy adults (based on study mean). As discussed in
the ISA, the initiation of inflammation can be considered as evidence
that injury has occurred. Inflammation induced by a single
O3 exposure can resolve entirely but, as noted in the ISA
(U.S. EPA, 2013a, p. 6-76), ``continued acute inflammation can evolve
into a chronic inflammatory state,'' which would be adverse.
    Responses measured in controlled human exposure studies indicate
that the range of effects elicited in humans exposed to ambient
O3 concentrations include: Decreased inspiratory capacity;
mild bronchoconstriction; rapid, shallow breathing pattern during
exercise; and symptoms of cough and pain on deep inspiration (U.S. EPA,
2013a, section <IP_ADDRESS>). Young, healthy adults exposed for 6.6 hours to
O3 concentrations >=60 ppb, while engaged in intermittent
moderate exertion, develop reversible, transient decrements in lung
function. In addition, depending on the exposure concentration and the
duration of exposure, young healthy adults have been shown to
experience symptoms of breathing discomfort and inflammation if minute
ventilation or duration of exposure is increased sufficiently (U.S.
EPA, 2013a, section <IP_ADDRESS>). Among healthy subjects there is
considerable interindividual variability in the magnitude of the
FEV1 responses, but when data were combined across studies
at 60 ppb (U.S. EPA, 2013a, pp. 6-17 to 6-18), 10% of healthy subjects
had >10% FEV1 decrements. Moreover, consistent with the
findings of the ISA (U.S. EPA, 2013a, section <IP_ADDRESS>), CASAC concluded
that ``[a]sthmatic subjects appear to be at least as sensitive, if not
more sensitive, than non-asthmatic subjects in manifesting ozone-
induced pulmonary function decrements'' (Frey, 2014c, p. 4). The
combination of lung function decrements and respiratory symptoms, which
has been considered adverse in previous reviews, has been demonstrated
in healthy adults following prolonged (6.6 hour) exposures, while at
intermittent moderate exertion, to 72 ppb. For these types of effects,
information from controlled human exposure studies, which provides an
indication of the magnitude and thus adversity of effects at different
O3 concentrations, combined with estimates of occurrences in
the population from the HREA, provide information about their
importance from a policy perspective.
4. Ozone-Related Impacts on Public Health
    Setting standards to provide appropriate public health protection
requires consideration of the factors that put populations at greater
risk from O3 exposure. In order to estimate the potential
for public health impacts, it is important to consider not only the
adversity of the health effects, but also the populations at greater
risk and potential behaviors that may reduce exposures.
a. Identification of At-Risk Populations and Lifestages
    The currently available evidence expands the understanding of
populations that were identified to be at greater risk of
O3-related health effects at the time of the last review
(i.e., people who are active outdoors, people with lung disease,
children and older adults and people with increased responsiveness to
O3) and supports the identification of additional factors
that may lead to increased risk (U.S. EPA, 2006, section 3.6.2; U.S.
EPA, 2013a, Chapter 8). Populations and lifestages may be at greater
risk for O3-related health effects due to factors that
contribute to their susceptibility and/or vulnerability to
O3. The definitions of susceptibility and vulnerability have
been found to vary across studies, but in most instances
``susceptibility'' refers to biological or intrinsic factors (e.g.,
lifestage, sex, preexisting disease/conditions) while ``vulnerability''
refers to non-biological or extrinsic factors (e.g., socioeconomic
status [SES]) (U.S. EPA, 2013a, p. 8-1; U.S. EPA, 2010c, 2009d). In
some cases, the terms ``at-risk'' and ``sensitive'' have been used to
encompass these concepts more generally. In the ISA and PA, ``at-risk''
is the all-encompassing term used to define groups with specific
factors that increase their risk of O3-related health
effects.
    There are multiple avenues by which groups may experience increased
risk for O3-induced health effects. A population or
lifestage \58\ may exhibit greater effects than other populations or
lifestages exposed to the same

concentration or dose, or they may be at greater risk due to increased
exposure to an air pollutant (e.g., time spent outdoors). A group with
intrinsically increased risk would have some factor(s) that increases
risk through a biological mechanism and, in general, would have a
steeper concentration-risk relationship, compared to those not in the
group. Factors that are often considered intrinsic include pre-existing
asthma, genetic background, and lifestage. A group of people could also
have extrinsically increased risk, which would be through an external,
non-biological factor, such as socioeconomic status (SES) and diet.
Some groups are at risk of increased internal dose at a given exposure
concentration, for example, because of breathing patterns. This
category would include people who work or exercise outdoors. Finally,
there are those who might be placed at increased risk for experiencing
greater exposures by being exposed to higher O3
concentrations. This would include, for example, groups of people with
greater exposure to ambient O3 due to less availability or
use of home air conditioners such that they are more likely to be in
locations with open windows on high O3 days. Some groups may
be at increased risk of O3-related health effects through a
combination of factors. For example, children tend to spend more time
outdoors when O3 levels are high, and at higher levels of
activity than adults, which leads to increased exposure and dose, and
they also have biological, or intrinsic, risk factors (e.g., their
lungs are still developing) (U.S. EPA, 2013a, Chapter 8). An at-risk
population or lifestage is more likely to experience adverse health
effects related to O3 exposures and/or, develop more severe
effects from exposure than the general population.
---------------------------------------------------------------------------

    \58\ Lifestages, which in this case includes childhood and older
adulthood, are experienced by most people over the course of a
lifetime, unlike other factors associated with at-risk populations.
---------------------------------------------------------------------------

i. People With Specific Genetic Variants
    There is adequate evidence for populations with certain genotypes
being more at-risk than others to the effects of O3 exposure
on health (U.S. EPA, 2013a, section 8.1). Controlled human exposure and
epidemiologic studies have reported evidence of O3-related
increases in respiratory symptoms or decreases in lung function with
variants including GSTM1, GSTP1, HMOX1, and NQO1. NQO1 deficient mice
were found to be resistant to O3-induced AHR and
inflammation, providing biological plausibility for results of studies
in humans. Additionally, studies of rodents have identified a number of
other genes that may affect O3-related health outcomes,
including genes related to innate immune signaling and pro- and anti-
inflammatory genes, which have not been investigated in human studies.
ii. People With Asthma
    Previous O3 AQCDs identified individuals with asthma as
a population at increased risk of O3-related health effects.
Multiple new epidemiologic studies included in the ISA have evaluated
the potential for increased risk of O3-related health
effects in people with asthma, including: Lung function; symptoms;
medication use; AHR; and airway inflammation (also measured as exhaled
nitric oxide fraction, or FeNO). A study of lifeguards in Texas
reported decreased lung function with short-term O3 exposure
among both individuals with and without asthma; however, the decrease
was greater among those with asthma (Thaller et al., 2008). A Mexican
study of children ages 6-14 detected an association between short-term
O3 exposure and wheeze, cough, and bronchodilator use among
asthmatics but not non-asthmatics, although this may have been the
result of a small non-asthmatic population (Escamilla-Nu[ntilde]ez et
al., 2008). A study of modification by AHR (an obligate condition among
asthmatics) reported greater short-term O3-associated
decreases in lung function in elderly individuals with AHR, especially
among those who were obese (Alexeeff et al., 2007). With respect to
airway inflammation, in one study, a positive association was reported
for airway inflammation among asthmatic children following short-term
O3 exposure, but the observed association was similar in
magnitude to that of non-asthmatics (Barraza-Villarreal et al., 2008).
Similarly, another study of children in California reported an
association between O3 concentration and FeNO that persisted
both among children with and without asthma as well as those with and
without respiratory allergy (Berhane et al., 2011). Finally, Khatri et
al. (2009) found no association between short-term O3
exposure and altered lung function for either asthmatic or non-
asthmatic adults, but did note a decrease in lung function among
individuals with allergies.
    New evidence for difference in effects among asthmatics has been
observed in studies that examined the association between O3
exposure and altered lung function by asthma medication use. A study of
children with asthma living in Detroit reported a greater association
between short-term O3 and lung function (i.e.,
FEV1) for corticosteroid users compared with
noncorticosteroid users (Lewis et al., 2005). Conversely, another study
found decreased lung function among noncorticosteroid users compared to
users, although in this study, a large proportion of non-users were
considered to be persistent asthmatics (Hern[aacute]ndez-Cadena et al.,
2009). Lung function was not related to short-term O3
exposure among corticosteroid users and non-users in a study taking
place during the winter months in Canada (Liu et al., 2009).
Additionally, a study of airway inflammation reported a
counterintuitive inverse association with O3 of similar
magnitude for all groups of corticosteroid users and non-users (Qian et
al., 2009).
    Controlled human exposure studies that have examined the effects of
O3 on adults with asthma and healthy controls are limited.
Based on studies reviewed in the 1996 and 2006 O3 AQCDs,
subjects with asthma appeared to be more sensitive to acute effects of
O3 in terms of FEV1 and inflammatory responses
than healthy non-asthmatic subjects. For instance, Horstman et al.
(1995) observed that mild-to-moderate asthmatics, on average,
experienced double the O3-induced FEV1 decrement
of healthy subjects (19% versus 10%, respectively, p=0.04). Moreover, a
statistically significant positive correlation between FEV1
responses to O3 exposure and baseline lung function was
observed in individuals with asthma, i.e., responses increased with
severity of disease. Minimal evidence exists suggesting that
individuals with asthma have smaller O3-induced
FEV1 decrements than healthy subjects (3% versus 8%,
respectively) (Mudway et al., 2001). However, the asthmatics in that
study also tended to be older than the healthy subjects, which could
partially explain their lesser response since FEV1 responses
to O3 exposure diminish with age. Individuals with asthma
also had significantly more neutrophils in the BALF (18 hours
postexposure) than similarly exposed healthy individuals (Peden et al.,
1997; Scannell et al., 1996; Basha et al., 1994). Furthermore, a study
examining the effects of O3 on individuals with atopic
asthma and healthy controls reported that greater numbers of
neutrophils, higher levels of cytokines and hyaluronan, and greater
expression of macrophage cell-surface markers were observed in induced
sputum of atopic asthmatics compared with healthy controls (Hernandez
et al., 2010). Differences in O3-induced epithelial cytokine
expression were noted in bronchial biopsy samples from asthmatics and
healthy controls (Bosson et al., 2003). Cell-surface marker and
cytokine expression results, and the

presence of hyaluronan, are consistent with O3 having
greater effects on innate and adaptive immunity in these asthmatic
individuals. In addition, studies have demonstrated that O3
exposure leads to increased bronchial reactivity to inhaled allergens
in mild allergic asthmatics (Kehrl et al., 1999; Jorres et al., 1996)
and to the influx of eosinophils in individuals with pre-existing