allergic disease (Vagaggini et al., 2002; Peden et al., 1995). Taken
together, these results point to several mechanistic pathways which
could account for the enhanced sensitivity to O3 in subjects
with asthma (U.S. EPA, 2013a, section <IP_ADDRESS>).
    As noted in the previous review (72 FR 37846, July 11, 2007)
asthmatics present a differential response profile for cellular,
molecular, and biochemical parameters (U.S. EPA, 2006a, Figure 8-1)
that are altered in response to acute O3 exposure. Ozone-
induced increases in neutrophils, IL-8 and protein were found to be
significantly higher in the BAL fluid from asthmatics compared to
healthy subjects, suggesting mechanisms for the increased sensitivity
of asthmatics (Basha et al., 1994; McBride et al., 1994; Scannell et
al., 1996; Hiltermann et al., 1999; Holz et al., 1999; Bosson et al.,
2003). Neutrophils, or PMNs, are the white blood cell most associated
with inflammation. IL-8 is an inflammatory cytokine with a number of
biological effects, primarily on neutrophils. The major role of this
cytokine is to attract and activate neutrophils. Protein in the airways
is leaked from the circulatory system, and is a marker for increased
cellular permeability.
    Bronchial constriction following provocation with O3
and/or allergens presents a two-phase response. The early response is
mediated by release of histamine and leukotrienes that leads to
contraction of smooth muscle cells in the bronchi, narrowing the lumen
and decreasing the airflow. In people with allergic airway disease,
including people with rhinitis and asthma, these mediators also cause
accumulation of eosinophils in the airways (Bascom et al., 1990; Jorres
et al., 1996; Peden et al., 1995 and 1997; Frampton et al., 1997a;
Michelson et al., 1999; Hiltermann et al., 1999; Holz et al., 2002;
Vagaggini et al., 2002). In asthma, the eosinophil, which increases
inflammation and allergic responses, is the cell most frequently
associated with exacerbations of the disease. A study by Bosson et al.
(2003) evaluated the difference in O3-induced bronchial
epithelial cytokine expression between healthy and asthmatic subjects.
After O3 exposure the epithelial expression of IL-5 and GM-
CSF increased significantly in asthmatics, compared to healthy
subjects. Asthma is associated with Th2-related airway response
(allergic response), and IL-5 is an important Th2-related cytokine. The
O3-induced increase in IL-5, and also in GM-CSF, which
affects the growth, activation and survival of eosinophils, may
indicate an effect on the Th2-related airway response and on airway
eosinophils. The authors reported that the O3-induced Th2-
related cytokine responses that were found within the asthmatic group
may indicate a worsening of their asthmatic airway inflammation and
thus suggest a plausible link to epidemiological data indicating
O3-associated increases in bronchial reactivity and hospital
admissions.
    The accumulation of eosinophils in the airways of asthmatics is
followed by production of mucus and a late-phase bronchial constriction
and reduced airflow. 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 change in PC20, the
concentration of methacholine causing a 20% decrease in
FEV1. Characteristic O3-induced inflammatory
airway neutrophilia at one time was considered a leading mechanism of
airway hyperresponsiveness. However, Hiltermann et al. (1999)
determined that the O3-induced change in percentage
neutrophils in sputum was not significantly related to the change in
PC20. These results are consistent with the results of Zhang et al.
(1995), which found neutrophilia in a murine model to be only
coincidentally associated with airway hyperresponsiveness, i.e., there
was no cause and effect relationship (U.S. EPA, 2006a, AX 6-26).
Hiltermann et al. (1999) concluded that the results point to the role
of eosinophils in O3-induced airway hyperresponsiveness.
Increases in O3-induced nonspecific airway responsiveness
incidence and duration could have important clinical implications for
asthmatics.
    Toxicological studies provide additional evidence of the biological
basis for the greater effects of O3 among those with asthma
or AHR (U.S. EPA, 2013a, section 8.2.2). In animal toxicological
studies, an asthmatic phenotype is modeled by allergic sensitization of
the respiratory tract. Many of the studies that provide evidence that
O3 exposure is an inducer of AHR and remodeling utilize
these types of animal models. For example, a series of experiments in
infant rhesus monkeys have shown these effects, but only in monkeys
sensitized to house dust mite allergen. Similarly, adverse changes in
pulmonary function were demonstrated in mice exposed to O3;
enhanced inflammatory responses were in rats exposed to O3,
but only in animals sensitized to allergen. In general, it is the
combined effects of O3 and allergic sensitization which
result in measurable effects on pulmonary function. In a pulmonary
fibrosis model, exposure to O3 for 5 days increased
pulmonary inflammation and fibrosis, along with the frequency of
bronchopneumonia in rats. Thus, short-term exposure to O3
may enhance damage in a previously injured lung (U.S. EPA, 2013a,
section 8.2.2).
    In the 2006 O3 AQCD, the potential for individuals with
asthma to have greater risk of O3-related health effects was
supported by a number of controlled human exposure studies, evidence
from toxicological studies, and a limited number of epidemiologic
studies. In section 8.2.2, the ISA reports that in the recent
epidemiologic literature some, but not all, studies report greater risk
of health effects among individuals with asthma. Studies examining
effect measure modification of the relationship between short-term
O3 exposure and altered lung function by corticosteroid use
provided limited evidence of O3-related health effects.
However, recent studies of behavioral responses have found that studies
do not take into account individual behavioral adaptations to
forecasted air pollution levels (such as avoidance and reduced time
outdoors), which may underestimate the observed associations in studies
that examined the effect of O3 exposure on respiratory
health (Neidell and Kinney, 2010). This could explain some
inconsistency observed among recent epidemiologic studies. The evidence
from controlled human exposure studies provides support for increased
detriments in FEV1 and greater inflammatory responses to
O3 in individuals with asthma than in healthy individuals
without a history of asthma. The collective evidence for increased risk
of O3-related health effects among individuals with asthma
from controlled human exposure studies is supported by recent
toxicological studies which provide biological plausibility for
heightened risk of asthmatics to respiratory effects due to
O3 exposure. Overall, the ISA finds there is adequate
evidence for asthmatics to be an at-risk population.
iii. Children
    Children are considered to be at greater risk from O3
exposure because their respiratory systems undergo lung

growth until about 18-20 years of age and are therefore thought to be
intrinsically more at risk for O3-induced damage (U.S. EPA,
2006a). It is generally recognized that children spend more time
outdoors than adults, and, therefore, would be expected to have higher
exposure to O3 than adults. Children aged 11 years and older
and adults have higher absolute ventilation rates than younger children
aged 1-11 years. However, younger children have higher ventilation
rates relative to their lung volumes, which tends to increase dose
normalized to lung surface area. In all ages, exercise intensity has a
substantial effect on ventilation rate, high intensity activity results
in nearly double the ventilation rate for moderate activity. For more
information on time spent outdoors and ventilation rate differences by
age group, see section 4.4.1 in the ISA (U.S. EPA, 2013a).
    The 1996 O3 AQCD reported clinical evidence that
children, adolescents, and young adults (<18 years of age) appear, on
average, to have nearly equivalent spirometric responses to
O3 exposure, but have greater responses than middle-aged and
older adults (U.S. EPA, 1996). Symptomatic responses (e.g., cough,
shortness of breath, pain on deep inspiration) to O3
exposure, however, appear to increase with age until early adulthood
and then gradually decrease with increasing age (U.S. EPA, 1996).
Complete lung growth and development is not achieved until 18-20 years
of age in women and the early 20s for men; pulmonary function is at its
maximum during this time as well.
    Recent epidemiologic studies have examined different age groups and
their risk to O3-related respiratory hospital admissions and
emergency department visits. Evidence for greater risk in children was
reported in several studies. A study in Cyprus of short-term
O3 concentrations and respiratory hospital admissions
detected possible effect measure modification by age with a larger
association among individuals <15 years of age compared with those >15
years of age; the effect was apparent only with a 2-day lag (Middleton
et al., 2008). Similarly, a Canadian study of asthma-related emergency
department visits reported the strongest O3-related
associations among 5- to 14-year olds compared to the other age groups
(ages examined 0-75+) (Villeneuve et al., 2007). Greater O3-
associated risk in asthma-related emergency department visits were also
reported among children (<15 years) as compared to adults (15 to 64
years) in a study from Finland (Halonen et al., 2009). A study of New
York City hospital admissions demonstrated an increase in the
association between O3 exposure and asthma-related hospital
admissions for 6- to 18-year olds compared to those <6 years old and
those >18 years old (Silverman and Ito, 2010). When examining long-term
O3 exposure and asthma-related hospital admissions among
children, associations were determined to be larger among children 1 to
2 years old compared to children 2 to 6 years old (Lin et al., 2008). A
few studies reported positive associations among both children and
adults and no modification of the effect by age.
    The evidence reported in epidemiologic studies is supported by
recent toxicological studies which observed O3-induced
health effects in immature animals. Early life exposures of multiple
species of laboratory animals, including infant monkeys, resulted in
changes in conducting airways at the cellular, functional, ultra-
structural, and morphological levels. The studies conducted on infant
monkeys are most relevant for assessing effects in children. Carey et
al. (2007) conducted a study of O3 exposure in infant rhesus
macaques, whose respiratory tract closely resemble that of humans.
Monkeys were exposed either acutely or in episodes designed to mimic
human exposure. All monkeys acutely exposed to O3 had
moderate to marked necrotizing rhinitis, with focal regions of
epithelial exfoliation, numerous infiltrating neutrophils, and some
eosinophils. The distribution, character, and severity of lesions in
episodically exposed infant monkeys were similar to that of acutely
exposed animals. Neither exposure protocol for the infant monkeys
produced mucous cell metaplasia proximal to the lesions, an adaptation
observed in adult monkeys exposed in another study (Harkema et al.,
1987). Functional and cellular changes in conducting airways were
common manifestations of exposure to O3 among both the adult
and infant monkeys (Plopper et al., 2007). In addition, the lung growth
of the distal conducting airways in the infant monkeys was
significantly stunted by O3 and this aberrant development
was persistent 6 months postexposure (Fanucchi et al., 2006).
    Age may also affect the inflammatory response to O3
exposure. Toxicological studies reported that the difference in effects
among younger lifestage test animals may be due to age-related changes
in antioxidants levels and sensitivity to oxidative stress. Further
discussion of these studies may be found in section <IP_ADDRESS> of the ISA
(U.S. EPA, 2013a, p. 8-18).
    The previous and recent human clinical and toxicological studies
reported evidence of increased risk from O3 exposure for
younger ages, which provides coherence and biological plausibility for
the findings from epidemiologic studies. Although there was some
inconsistency, generally, the epidemiologic studies reported positive
associations among both children and adults or just among children. The
interpretation of these studies is limited by the lack of consistency
in comparison age groups and outcomes examined. However, overall, the
epidemiologic, controlled human exposure, and toxicological studies
provide adequate evidence that children are potentially at increased
risk of O3-related health effects.
iv. Older adults
    The ISA notes that older adults are at greater risk of health
effects associated with O3 exposure through a variety of
intrinsic pathways (U.S. EPA, 2013a, section <IP_ADDRESS>). In addition,
older adults may differ in their exposure and internal dose. Older
adults were outdoors for a slightly longer proportion of the day than
adults aged 18-64 years. For more information on time spent outdoors by
age group, see Section 4.4 in the ISA (U.S. EPA, 2013a). The gradual
decline in physiological processes that occurs with aging may lead to
increased risk of O3-related health effects (U.S. EPA,
2006a). Respiratory symptom responses to O3 exposure appears
to increase with age until early adulthood and then gradually decrease
with increasing age (U.S. EPA, 1996); lung function responses to
O3 exposure also decline from early adulthood (U.S. EPA,
1996). The reductions of these responses with age may put older adults
at increased risk for continued O3 exposure. In addition,
older adults, in general, have a higher prevalence of preexisting
diseases compared to younger age groups and this may also lead to
increased risk of O3-related health effects (U.S. EPA,
2013a, section <IP_ADDRESS>). With the number of older Americans increasing
in upcoming years (estimated to increase from 12.4% of the U.S.
population to 19.7% between 2000 to 2030, which is approximately 35
million and 71.5 million individuals, respectively) this group
represents a large population potentially at risk of O3-
related health effects (SSDAN CensusScope, 2010a; U.S. Census Bureau,
2010).
    The majority of recent studies reported greater effects of short-
term O3 exposure and mortality among older adults, which is
consistent with the findings of the 2006 O3 AQCD. A study
(Medina-Ram[oacute]n and Schwartz, 2008)

conducted in 48 cities across the U.S. reported larger effects among
adults >=65 years old compared to those <65 years. Further
investigation of this study population revealed a trend of
O3-related mortality risk that gets larger with increasing
age starting at age 51 (Zanobetti and Schwartz, 2008a). Another study
conducted in 7 urban centers in Chile reported similar results, with
greater effects in adults >=65 years old (Cakmak et al., 2007). More
recently, a study conducted in the same area reported similar
associations between O3 exposure and mortality in adults
aged <64 years old and 65 to 74 years old, but the risk was increased
among the older age group (Cakmak et al., 2011). A study performed in
China reported greater effects in populations >=45 years old (compared
to 5 to 44 year olds), with statistically significant effects present
only among those >=65 years old (Kan et al., 2008). An Italian study
reported higher risk of all-cause mortality associated with increased
O3 concentrations among individuals >=85 year old as
compared to those 35 to 84 years old (Stafoggia et al., 2010). The Air
Pollution and Health: A European and North American Approach (APHENA)
project examined the association between O3 exposure and
mortality for those <75 and >=75 years of age. In Canada, the
associations for all-cause and cardiovascular mortality were greater
among those >=75 years old. In the U.S., the association for all-cause
mortality was slightly greater for those <75 years of age compared to
those >=75 years old in summer-only analyses. No consistent pattern was
observed for CVD mortality. In Europe, slightly larger associations for
all-cause mortality were observed in those <75 years old in all-year
and summer-only analyses. Larger associations were reported among those
<75years for CVD mortality in all-year analyses, but the reverse was
true for summer-only analyses (Katsouyanni et al., 2009).
    With respect to epidemiologic studies of O3 exposure and
hospital admissions, a positive association was reported between short-
term O3 exposure and respiratory hospital admissions for
adults >=65 years old but not for those adults aged 15 to 64 years
(Halonen et al., 2009). In the same study, no association was observed
between O3 concentration and respiratory mortality among
those >=65 years old or those 15 to 64 years old. No modification by
age (40 to 64 year olds versus >64 year olds) was observed in a study
from Brazil examining O3 levels and COPD-related emergency
department visits.
    Although some outcomes reported mixed findings regarding an
increase in risk for older adults, recent epidemiologic studies report
consistent positive associations between short-term O3
exposure and mortality in older adults. The evidence from mortality
studies is consistent with the results reported in the 2006
O3 AQCD and is supported by toxicological studies providing
biological plausibility for increased risk of effects in older adults.
Also, older adults may be experiencing increased exposure compared to
younger adults. Overall, the ISA (U.S. EPA, 2013a) concludes adequate
evidence is available indicating that older adults are at increased
risk of O3-related health effects.
v. People With Diets Lower in Vitamins C and E
    Diet was not examined as a factor potentially affecting risk in
previous O3 AQCDs, but recent studies have examined
modification of the association between O3 and health
effects by dietary factors. Because O3 mediates some of its
toxic effects through oxidative stress, the antioxidant status of an
individual is an important factor that may contribute to increased risk
of O3-related health effects. Supplementation with vitamins
C and E has been investigated in a number of studies as a means of
inhibiting O3-mediated damage.
    Two epidemiologic studies have examined effect modification by diet
and found evidence that certain dietary components are related to the
effect O3 has on respiratory outcomes. In one recent study,
the effects of fruit/vegetable intake and Mediterranean diet were
examined. Increases in these food patterns, which have been noted for
their high vitamins C and E and omega-3 fatty acid content, were
positively related to lung function in asthmatic children living in
Mexico City, and modified by O3 exposure (Romieu et al.,
2009). Another study examined supplementation of the diets of asthmatic
children in Mexico with vitamins C and E (Sienra-Monge et al., 2004).
Associations were detected between short-term O3 exposure
and nasal airway inflammation among children in the placebo group but
not in those receiving the supplementation.
    The epidemiologic evidence is supported by controlled human
exposure studies, discussed in section 8.4.1 of the ISA (U.S. EPA,
2013a), that have shown that the first line of defense against
oxidative stress is antioxidants-rich extracellular lining fluid (ELF)
which scavenges free radicals and limit lipid peroxidation. Exposure to
O3 depletes antioxidant levels in nasal ELF probably due to
scrubbing of O3; however, the concentration and the activity
of antioxidant enzymes either in ELF or plasma do not appear to be
related to O3 responsiveness. Controlled studies of dietary
antioxidant supplementation have demonstrated some protective effects
of [alpha]-tocopherol (a form of vitamin E) and ascorbate (vitamin C)
on spirometric measures of lung function after O3 exposure
but not on the intensity of subjective symptoms and inflammatory
responses. Dietary antioxidants have also afforded partial protection
to asthmatics by attenuating postexposure bronchial
hyperresponsiveness. Toxicological studies discussed in section 8.4.1
of the ISA (U.S. EPA, 2013a) provide evidence of biological
plausibility to the epidemiologic and controlled human exposure
studies.
    Overall, the ISA (U.S. EPA, 2013a) concludes adequate evidence is
available indicating that individuals with diets lower in vitamins C
and E are at risk for O3-related health effects. The
evidence from epidemiologic studies is supported by controlled human
exposure and toxicological studies.
vi. Outdoor Workers
    Studies included in the 2006 O3 AQCD reported that
individuals who participate in outdoor activities or work outside to be
a population at increased risk based on consistently reported
associations between O3 exposure and respiratory health
outcomes in these groups (U.S. EPA, 2006a). Outdoor workers are exposed
to ambient O3 concentrations for a greater period of time
than individuals who spend their days indoors. As discussed in section
4.7 of the ISA (U.S. EPA, 2013a) outdoor workers sampled during the
work shift had a higher ratio of personal exposure to fixed-site
monitor concentrations than health clinic workers who spent most of
their time indoors. Additionally, an increase in dose to the lower
airways is possible during outdoor exercise due to both increases in
the amount of air breathed (i.e., minute ventilation) and a shift from
nasal to oronasal breathing. The association between FEV1
responses to O3 exposure and minute ventilation is discussed
more fully in section <IP_ADDRESS> of the 2006 O3 AQCD (U.S. EPA,
2006a).
    Previous studies have shown that increased exposure to
O3 due to outdoor work leads to increased risk of
O3-related health effects, specifically decrements in lung
function (U.S. EPA, 2006a). The strong evidence from the 2006
O3 AQCD, which demonstrated increased exposure, dose, and
ultimately risk of O3-related health effects in this
population, supports the

conclusion that there is adequate evidence to indicate that increased
exposure to O3 through outdoor work increases the risk of
O3-related health effects.
    In some cases, it is difficult to determine a factor that results
in increased risk of effects. For example, previous assessments have
included controlled human exposure studies in which some healthy
individuals demonstrate greater O3-related health effects
compared to other healthy individuals. Interindividual variability has
been observed for lung function decrements, symptomatic responses,
pulmonary inflammation, AHR, and altered epithelial permeability in
healthy adults exposed to O3, and these results tend to be
reproducible within a given individual over a period of several months
indicating differences in the intrinsic responsiveness. In many cases
the reasons for the variability is not clear. This may be because one
or some of the factors described above have not been evaluated in
studies, or it may be that additional, unidentified factors influence
individual responses to O3 (U.S. EPA, 2013a, section 8.5).
    As discussed in chapter 8 of the ISA (U.S. EPA, 2013a), there is a
lack of information regarding the extent to which some factors may
increase risk from O3 exposures. Due to this lack of
information, the ISA concluded that for some factors, such as sex, SES,
and obesity, there is only ``suggestive'' evidence of increased risk,
or that for a number of factors the evidence is inadequate to draw
conclusions about potential increase in risk of effects. Overall, the
factors for which the ISA concludes there is adequate evidence of
increased risk for experiencing O3-related effects were
related to asthma, lifestage (children and older adults), genetic
variability, dietary factors, and working outdoors.
b. Size of At-Risk Populations
    One consideration in the assessment of potential public health
impacts is the size of various population groups for which there is
adequate evidence of increased risk for health effects associated with
O3-related air pollution exposure (U.S. EPA, 2014c, section
<IP_ADDRESS>). The factors for which the ISA judged the evidence to be
``adequate'' with respect to contributing to increased risk of
O3-related effects among various populations and lifestages
included: asthma; childhood and older adulthood; diets lower in
vitamins C and E; certain genetic variants; and working outdoors (U.S.
EPA, 2013a, section 8.5). No statistics are available to estimate the
size of an at-risk population based on nutritional status or genetic
variability.
    With regard to asthma, Table 3-7 in the PA (U.S. EPA, 2014c,
section <IP_ADDRESS>) summarizes information on the prevalence of current
asthma by age in the U.S. adult population in 2010 (Schiller et al.
2012; children--Bloom et al., 2011). Individuals with current asthma
constitute a fairly large proportion of the population, including more
than 25 million people. Asthma prevalence tends to be higher in
children than adults. Within the U.S., approximately 8.2% of adults
have reported currently having asthma (Schiller et al., 2012) and 9.5%
of children have reported currently having asthma (Bloom et al.,
2011).\59\
---------------------------------------------------------------------------

    \59\ As noted below (II.C.3.a.ii), asthmatics can experience
larger O3-induced respiratory effects than non-asthmatic,
healthy adults. The responsiveness of asthmatics to O3
exposures could depend on factors that have not been well-evaluated
such as asthma severity, the effectiveness of asthma control, or the
prevalence of medication use.
---------------------------------------------------------------------------

    With regard to lifestages, based on U.S. census data from 2010
(Howden and Meyer, 2011), about 74 million people, or 24% of the U.S.
population, are under 18 years of age and more than 40 million people,
or about 13% of the U.S. population, are 65 years of age or older.
Hence, a large proportion of the U.S. population (i.e., more than a
third) is included in age groups that are considered likely to be at
increased risk for health effects from ambient O3 exposure.
    With regard to outdoor workers, in 2010, approximately 11.7% of the
total number of people (143 million people) employed, or about 16.8
million people, worked outdoors one or more days per week (based on
worker surveys).\60\ Of these, approximately 7.4% of the workforce, or
about 7.8 million people, worked outdoors three or more days per week.
---------------------------------------------------------------------------

    \60\ The O*NET program is the nation's primary source of
occupational information. Central to the project is the O*NET
database, containing information on hundreds of standardized and
occupation-specific descriptors. The database, which is available to
the public at no cost, is continually updated by surveying a broad
range of workers from each occupation. http://www.onetcenter.org/overview.html. http://www.onetonline.org/find/descriptor/browse/Work_Context/4.C.2/.
---------------------------------------------------------------------------

    The health statistics data illustrate what is known as the
``pyramid'' of effects. At the top of the pyramid, there are
approximately 2.5 million deaths from all causes per year in the U.S.
population, with about 250 thousand respiratory-related deaths (CDC-
WONDER, 2008). For respiratory health diseases, there are nearly 3.3
million hospital discharges per year (HCUP, 2007), 8.7 million
respiratory emergency department visits (HCUP, 2007), 112 million
ambulatory care visits (Woodwell and Cherry, 2004), and an estimated
700 million restricted activity days per year due to respiratory
conditions (Adams et al., 1999). Combining small risk estimates with
relatively large baseline levels of health outcomes can result in quite
large public health impacts. Thus, even a small percentage reduction in
O3 health impacts on cardiopulmonary diseases would reflect
a large number of avoided cases.
c. Impacts of Averting Behavior
    The activity pattern of individuals is an important determinant of
their exposure (U.S. EPA, 2013a, section 4.4.1). Variation in
O3 concentrations among various microenvironments means that
the amount of time spent in each location, as well as the level of
activity, will influence an individual's exposure to ambient
O3. Activity patterns vary both among and within
individuals, resulting in corresponding variations in exposure across a
population and over time. Individuals can reduce their exposure to
O3 by altering their behaviors, such as by staying indoors,
being active outdoors when air quality is better, and by reducing their
activity levels or reducing the time being active outdoors on high-
O3 days (U.S. EPA, 2013a, section 4.4.2).
    The widely reported Air Quality Index (AQI) conveys advice to the
public, and particularly at-risk populations, on reducing short- or
prolonged-exposures on days when ambient levels of common, criteria air
pollutants (except lead), are elevated (www.airnow.gov). Information
communicated by the AQI is based on the evidence and exposure/risk
information assessed in the review of the NAAQS; it is updated and
revised as necessary during the review of each standard. Proposed
changes to the AQI sub-index for O3, based on evidence and
exposure/risk information assessed in this review, are discussed in
section III below.
    The AQI describes the potential for health effects from
O3 (and other individual pollutants) in six color-coded
categories of air-quality, ranging from Good (green), Moderate
(yellow), Unhealthy for Sensitive Groups (orange), Unhealthy (red), and
Very Unhealthy (purple), and Hazardous (maroon). Levels in the
unhealthy ranges (i.e., Unhealthy for Sensitive Groups and above) come
with recommendations about reducing exposure. Forecasted and actual AQI
values for O3 are reported to the public

during the O3 season. The AQI advisories explicitly state
that children, older adults, people with lung disease, and people who
are active outdoors, may be at greater risk from exposure to
O3. People are advised to reduce exposure depending on the
predicted O3 levels and the likelihood of risk. This advice
includes being active outdoors when air quality is better, and reducing
activity levels or reducing the time being active outdoors on high-
O3 days. Staying indoors to reduce exposure is not
recommended until air quality reaches the Very Unhealthy or Hazardous
categories.
    Evidence of individual averting behaviors in response to AQI
advisories has been found in several studies, including activity
pattern and epidemiologic studies, especially for the at-risk
populations, such as children, older adults, and people with asthma,
who are targeted by the advisories. Such effects are less pronounced in
the general population, possibly due to the opportunity cost of
behavior modification. Epidemiologic evidence from a study (Neidell and
Kinney, 2010) conducted in the 1990's in Los Angeles, CA reports
increased asthma hospital admissions among children and older adults
when O3 alert days (1-hour max O3 concentration
>200 ppb) were excluded from the analysis of daily hospital admissions
and O3 concentrations (presumably thereby eliminating
averting behavior based on high O3 forecasts). If averting
behavior reduces exposure to ambient O3, then epidemiologic
studies that do not account for averting behavior may produce effect
estimates that are biased toward the null due to exposure
misclassification (U.S. EPA, 2013, section 4.6.6).

C. Human Exposure and Health Risk Assessments

    To put judgments about health effects that are adverse for
individuals into a broader public health context, the EPA has developed
and applied models to estimate human exposures to O3 and
O3-associated health risks. Exposure and risk estimates
based on such models are presented and assessed in the HREA (U.S. EPA,
2014a). In reviewing the draft HREA, CASAC expressed the view that the
document is ``well-written, founded based upon comprehensive analyses
and adequate for its intended purpose'' (Frey, 2014a, p. 1). Analyses
in the HREA inform consideration of the O3 exposures and
health risks that could be allowed by the current standard and
alternative standards, and consideration of the kind and degree of
uncertainties inherent in estimates of O3 exposures and
health risks.
    The following sections discuss the air quality adjustment approach
used in the HREA for exposure and health risk estimates (II.C.1); the
approach taken to estimate exposures, key exposure results, and
important uncertainties (II.C.2); and the approaches taken to estimate
O3 health risks, key risk results, and important
uncertainties (II.C.3).
1. Air Quality Adjustment
    As discussed above (section I.E), O3 is formed near the
Earth's surface due to chemical interactions involving solar radiation
and precursor pollutants including VOCs, NOX, CH4
and CO. The response of O3 to changes in precursor
concentrations is nonlinear. In particular, NOX causes both
the formation and destruction of O3. The net impact of
NOX emissions on O3 concentrations depends on the
local quantities of NOX, VOC, and sunlight, which interact
in a set of complex chemical reactions. In some areas, such as urban
centers where NOX emissions typically are high,
NOX leads to the net destruction of O3,
decreasing O3 concentrations in the immediate vicinity. This
phenomenon is particularly pronounced under conditions that lead to low
ambient O3 concentrations (i.e. during cool, cloudy weather
and at night when photochemical activity is limited or nonexistent).
However, while NOX can initially destroy O3 near
emission sources, these same NOX emissions eventually react
to form O3 downwind of those sources. Photochemical model
simulations suggest that reductions in NOX emissions will
slightly increase O3 concentrations near NOX
sources on days with lower O3 concentrations, while at the
same time decreasing the highest O3 concentrations in
outlying areas. The atmospheric chemistry that influences ambient
O3 concentrations is discussed in more detail in the ISA
(U.S. EPA, 2013a, Chapter 3) and the PA (U.S. EPA, 2014c, Chapter 2)
(see also Frey, 2014a, pp. 10 and 11).
    The HREA uses a photochemical model to estimate sensitivities of
O3 to changes in precursor emissions in order to estimate
ambient O3 concentrations that would just meet the current
and alternative standards (U.S. EPA, 2014a, Chapter 4).\61\ For the 15
urban study areas evaluated in the HREA,\62\ this model-based
adjustment approach estimates hourly O3 concentrations at
each monitor location when modeled U.S. anthropogenic precursor
emissions (i.e., NOX, VOC) \63\ are reduced. The HREA
estimates air quality that just meets the current and alternative
standards for the 2006-2008 and 2008-2010 periods.\64\
---------------------------------------------------------------------------

    \61\ The HREA uses the Community Multi-scale Air Quality (CMAQ)
photochemical model instrumented with the higher order direct
decoupled method (HDDM) to estimate O3 concentrations
that would occur with the achievement of the current and alternative
O3 standards (U.S. EPA, 2014a, Chapter 4).
    \62\ The urban study areas assessed are Atlanta, Baltimore,
Boston, Chicago, Cleveland, Dallas, Denver, Detroit, Houston, Los
Angeles, New York, Philadelphia, Sacramento, St. Louis, and
Washington, DC.
    \63\ Exposure and risk analyses for most urban study areas focus
on reducing U.S. anthropogenic NOX emissions alone. The
exceptions are Chicago and Denver. Exposure and risk analyses for
Chicago and Denver are based on reductions in emissions of both
NOX and VOC (U.S. EPA, 2014a, section <IP_ADDRESS>; Appendix
4D).
    \64\ These simulations are illustrative and do not reflect any
consideration of specific control programs designed to achieve the
reductions in emissions required to meet the specified standards.
Further, these simulations do not represent predictions of when,
whether, or how areas might meet the specified standards.
---------------------------------------------------------------------------

    As discussed in Chapter 4 of the HREA (U.S. EPA, 2014a), this
approach to adjusting air quality models the physical and chemical
atmospheric processes that influence ambient O3
concentrations. Compared to the quadratic rollback approach used in
previous reviews, it provides more realistic estimates of the spatial
and temporal responses of O3 to reductions in precursor
emissions. Because ambient NOX can contribute both to the
formation and destruction of O3 (U.S. EPA, 2014a, Chapter
4), as discussed above, the response of ambient O3
concentrations to reductions in NOX emissions is more
variable than indicated by the quadratic rollback approach. This
improved approach to adjusting O3 air quality is consistent
with recommendations from the National Research Council of the National
Academies (NRC, 2008). In addition, CASAC strongly supported the
improved approach, stating that ``the quadratic rollback approach has
been replaced by a scientifically more valid Higher-order Decoupled
Direct Method (HDDM)'' and that ``[t]he replacement of the quadratic
rollback procedure by the HDDM procedure is important and supported by
the CASAC'' (Frey, 2014a, pp.1 and 3).
    Consistent with the O3 chemistry summarized above, in
locations and time periods when NOX is predominantly
contributing to O3 formation (e.g., downwind of important
NOX sources, where the highest O3 concentrations
often occur), model-based adjustment to the current and alternative
standards decreases

estimated ambient O3 concentrations compared to recent
monitored concentrations (U.S. EPA, 2014a, section <IP_ADDRESS>). In
contrast, in locations and time periods when NOX is
predominantly contributing to O3 titration (e.g., in urban
centers with high concentrations of NOX emissions, where
ambient O3 concentrations are often suppressed and thus
relatively low \65\), model-based adjustment increases ambient
O3 concentrations compared to recent monitored
concentrations (U.S. EPA, 2014a, section <IP_ADDRESS>; Frey, 2014a, p. 10).
---------------------------------------------------------------------------

    \65\ Titration is also prominent during time periods when
photochemistry is limited, and ambient O3 concentrations
are relatively low, such as at night and on cool, cloudy days (U.S.
EPA, 2014a, Chapter 4).
---------------------------------------------------------------------------

    Within urban study areas, the overall impacts of model-based air
quality adjustment are to reduce the O3 concentrations at
the upper ends of ambient distributions and to increase the
O3 concentrations at the lower ends of those distributions
(U.S. EPA, 2014a, section <IP_ADDRESS>, Figures 4-9 and 4-10).\66\ Seasonal
means of daily O3 concentrations generally exhibit only
modest changes upon model adjustment, reflecting the seasonal balance
between daily decreases in relatively higher concentrations and
increases in relatively lower concentrations (U.S. EPA, 2014a, Figures
4-9 and 4-10). The resulting compression in the seasonal distributions
of ambient O3 concentrations is evident in all of the urban
study areas evaluated, though the degree of compression varies
considerably across areas (U.S. EPA, 2014a, Figures 4-9 and 4-10).
---------------------------------------------------------------------------

    \66\ It is important to note that sensitivity analyses in the
HREA indicate that the increases in low O3 concentrations
are smaller when NOX and VOC emissions are reduced than
when only NOX emissions are reduced (U.S. EPA, 2014a,
Appendix 4-D, section 4.7).
---------------------------------------------------------------------------

    This compression in the distributions of ambient O3
concentrations has important implications for exposure and risk
estimates in urban study areas. Estimates influenced largely by the
upper ends of the distribution of ambient concentrations (i.e.,
exposures of concern and lung function risk estimates, as discussed in
sections 3.2.2 and <IP_ADDRESS> of the PA (U.S. EPA, 2014c)) decrease with
adjustment of air quality to the current and alternative standards. In
contrast, seasonal risk estimates influenced by the full distribution
of ambient O3 concentrations (i.e., epidemiology-based risk
estimates, as discussed in section <IP_ADDRESS> of the PA) either decrease
or increase in response to air quality adjustment, depending on the
balance between the daily decreases in high O3
concentrations and increases in low O3 concentrations.\67\
---------------------------------------------------------------------------

    \67\ In addition, because epidemiology-based risk estimates use
``area-wide'' average O3 concentrations, calculated by
averaging concentrations across multiple monitors in urban study
areas (U.S. EPA, 2014c, section <IP_ADDRESS>), risk estimates on a given
day depend on the daily balance between increasing and decreasing
O3 concentrations at the individual monitors that are
averaged together to calculate the ``area-wide'' concentration.
---------------------------------------------------------------------------

    In their review of the second draft HREA, CASAC considered this
issue, in particular noting that ``reductions in nitrogen oxides
emissions can lead to less scavenging of ozone and free radicals,
resulting in locally higher levels of ozone'' (Frey, 2014a, p. 10).
CASAC recommended that ``the EPA should identify and discuss whether
and to what extent health risks in the urban core may be affected by
NOX reductions or other possible strategies'' and, in
particular, concluded that it would ``be of interest to learn if there
would be any children or outdoor workers in the more urban areas who
would experience significantly higher exposures to ozone as a result of
possible changes in the ozone NAAQS'' (Frey, 2014a, p. 10). Consistent
with this advice, the exposure and risk implications of the spatial and
temporal patterns of ambient O3 following air quality
adjustment in urban study areas are discussed in the final HREA (U.S.
EPA, 2014a, Chapter 9) and the final PA (U.S. EPA, 2014c, sections
3.2.2, 3.2.3), and are summarized below within the context of the PA's
consideration of exposure estimates (II.D.2.a) and risk estimates
(II.D.2.b and II.D.2.c).
2. Exposure Assessment
    This section discusses the HREA assessment of human exposures to
O3. Section II.C.2.a provides an overview of the approach
used in the HREA to assessing exposures and the approach in the PA to
considering exposure estimates, and summarizes key results. Section
II.C.2.b summarizes the important uncertainties in exposure estimates.
a. Overview and Summary of Key Results
    The exposure assessment presented in the HREA (U.S. EPA, 2014a,
Chapter 5) provides estimates of the number and percent of people
exposed to various concentrations of ambient O3, while at
specified exertion levels. The HREA estimates exposures in the 15 urban
study areas for four study groups, all school-age children (ages 5 to
18), asthmatic school-age children, asthmatic adults (ages 19 to 95),
and all older adults (ages 65 to 95), reflecting the evidence
indicating that these populations are at increased risk for
O3-attributable effects (U.S. EPA, 2013a, Chapter 8). An
important purpose of these exposure estimates is to provide perspective
on the extent to which air quality adjusted to just meet the current
O3 NAAQS could be associated with exposures to O3
concentrations reported to result in respiratory effects.\68\ Estimates
of such ``exposures of concern'' provide perspective on the potential
public health impacts of O3-related effects, including
effects that cannot currently be evaluated in a quantitative risk
assessment.\69\
---------------------------------------------------------------------------

    \68\ In addition, the range of modeled personal exposures to
ambient O3 provide an essential input to the portion of
the health risk assessment based on exposure-response functions (for
lung function decrements) from controlled human exposure studies.
The health risk assessment based on exposure-response information is
discussed below (II.C.3).
    \69\ In this review, the term ``exposure of concern'' is defined
as a personal exposure, while at moderate or greater exertion, to 8-
hour average ambient O3 concentrations at and above
specific benchmarks. As discussed below, benchmarks represent
exposure concentrations at which O3-induced health
effects are known to occur, or can reasonably be anticipated to
occur, in some individuals.
---------------------------------------------------------------------------

    In the absence of large scale exposure studies that encompass the
general population, as well as at-risk populations, modeling is the
preferred approach to estimating exposures to O3 (U.S. EPA,
2014a, Chapter 5). The use of exposure modeling also facilitates the
estimation of exposures resulting from ambient O3
concentrations differing from those present during exposure studies. In
the HREA, population exposures to ambient O3 concentrations
are estimated using the current version of the Air Pollutants Exposure
(APEX) model. The APEX model simulates the movement of individuals
through time and space and estimates their exposures to a given
pollutant in indoor, outdoor, and in-vehicle microenvironments (U.S.
EPA, 2014a, section 5.1.3). APEX takes into account important factors
that contribute to total human exposure to ambient O3,
including the temporal and spatial distributions of people and
O3 concentrations throughout an urban area, the variation of
O3 concentrations within various microenvironments, and the
effects of exertion on breathing rate in exposed individuals (U.S. EPA,
2014a, section 5.1.3). To the extent spatial and/or temporal patterns
of ambient O3 concentrations are altered upon model
adjustment, as discussed above, exposure estimates reflect population
exposures to those altered patterns.
    The HREA estimates 8-hour exposures at or above benchmark
concentrations of

60, 70, and 80 ppb for individuals engaged in moderate or greater
exertion (i.e., to approximate conditions in the controlled human
exposure studies on which benchmarks are based). Benchmarks reflect
exposure concentrations at which O3-induced respiratory
effects are known to occur in some healthy adults engaged in moderate,
intermittent exertion, based on evidence from controlled human exposure
studies (U.S. EPA, 2013a, section 6.2; U.S. EPA, 2014c, section
<IP_ADDRESS>). The amount of weight to place on the estimates of exposures
at or above specific benchmark concentrations depends in part on the
weight of the scientific evidence concerning health effects associated
with O3 exposures at those benchmark concentrations. It also
depends on judgments about the importance, from a public health
perspective, of the health effects that are known or can reasonably be
inferred to occur as a result of exposures at benchmark concentrations
(U.S. EPA, 2014c, sections 3.1.3, 3.1.5).
    As discussed in more detail above (II.B.2), the health evidence
that supports evaluating exposures of concern at or above benchmark
concentrations of 60, 70, and 80 ppb comes from a large body of
controlled human exposure studies reporting a variety of respiratory
effects in healthy adults. The lowest O3 exposure
concentration for which controlled human exposure studies have reported
respiratory effects in healthy adults is 60 ppb (based on changes in
group mean responses), with more evidence supporting this benchmark
concentration in the current review than in the last review. In healthy
adults, 6.6 hour exposures to 60 ppb O3 have been reported
to decrease lung function and to increase airway inflammation.
Exposures of healthy adults to 72 ppb O3 for 6.6 hours have
been reported to result in larger average lung function decrements,
compared to 60 ppb, as well as in increased respiratory symptoms.
Exposures of healthy adults to 80 ppb O3 for 6.6 hours have
been reported to result in larger average lung function decrements than
following exposures to 60 or 72 ppb and, depending on the study, to
increase airway inflammation, increase respiratory symptoms, increase
airways responsiveness, and decrease lung host defense (based on
changes in group means) (U.S. EPA, 2014c, section <IP_ADDRESS>). In
commenting on the evidence for benchmark concentrations, CASAC stated
the following (Frey, 2014c, p. 6):

The 80 ppb-8hr benchmark level represents an exposure level for
which there is substantial clinical evidence demonstrating a range
of ozone-related effects including lung inflammation and airway
responsiveness in healthy individuals. The 70 ppb-8hr benchmark
level reflects the fact that in healthy subjects, decreases in lung
function and respiratory symptoms occur at concentrations as low as
72 ppb and that these effects almost certainly occur in some people,
including asthmatics and others with low lung function who are less
tolerant of such effects, at levels of 70 ppb and below. The 60 ppb-
8hr benchmark level represents the lowest exposure level at which
ozone-related effects have been observed in clinical studies of
healthy individuals. Based on its scientific judgment, the CASAC
finds that the 60 ppb-8hr exposure benchmark is relevant for
consideration with respect to adverse effects on asthmatics.

    In considering estimates of O3 exposures of concern at
or above benchmarks of 60, 70, and 80 ppb, the PA focuses on modeled
exposures for school-age children (ages 5-18), including asthmatic
school-age children, which are key at-risk populations identified in
the ISA (U.S. EPA, 2014c, section 3.1.5). The percentages of children
estimated to experience exposures of concern are considerably larger
than the percentages estimated for adult populations (i.e.,
approximately 3-fold larger across urban study areas) (U.S. EPA, 2014a,
section 5.3.2 and Figures 5-5 to 5-8). The larger exposure estimates
for children are due primarily to the larger percentage of children
estimated to spend an extended period of time being physically active
outdoors when O3 concentrations are elevated (U.S. EPA,
2014a, sections 5.3.2 and 5.4.1).
    Although exposure estimates differ between children and adults, the
patterns of results across the urban study areas and years are similar
among all of the populations evaluated (U.S. EPA, 2014a, Figures 5-5 to
5-8). Therefore, while the PA highlights estimates in children,
including asthmatic school-age children, it also notes that the
patterns of exposures estimated for children represent the patterns
estimated for adult asthmatics and older adults.
    Table 1 below summarizes key results from the exposure assessment.
Table 1 presents estimates of the percentages and numbers of all
school-aged children estimated to experience exposures of concern when
air quality was adjusted to just meet the current and alternative 8-
hour O3 standards. The percentage of all school-age children
in the 15 urban study areas estimated to experience exposures of
concern declines when comparing just meeting the current standard to
just meeting alternative 8-hour O3 standards. Substantial
variability is evident across years and urban study areas, as indicated
by the ranges of averaged estimates and estimates for worst-case years
and study areas. As discussed below, the interindividual variability in
responsiveness following exposures of concern means that only a subset
of individuals who are exposed at and above a given benchmark
concentration would actually be expected to experience respiratory
effects.

Table 1--Summary of Estimated Exposures of Concern in All School-age Children for the Current and Alternative O3
                                         Standards in Urban Study Areas
----------------------------------------------------------------------------------------------------------------
                                                                                % Children--
                                   Standard level     Average %     Average number of children    worst year and
     Benchmark  concentration           (ppb)         children      exposed  [average number of     worst area
                                                    exposed \70\     asthmatic children] \71\
----------------------------------------------------------------------------------------------------------------
                                   One or more exposures of concern per season
----------------------------------------------------------------------------------------------------------------
>=80 ppb.........................              75           0-0.3  27,000 [3,000]..............              1.1
                                               70           0-0.1  3,700 [300].................              0.2
                                               65               0  300 [0].....................                0
                                               60               0  100 \72\ [0]................                0
>=70 ppb.........................              75         0.6-3.3  362,000 [40,000]............              8.1
                                               70         0.1-1.2  94,000 [10,000].............              3.2
                                               65           0-0.2  14,000 [2,000]..............              0.5
                                               60               0  1,400 [200].................              0.1
>=60 ppb.........................              75          9.5-17  2,316,000 [246,000].........             25.8
                                               70        3.3-10.2  1,176,000 [126,000].........             18.9
                                               65           0-4.2  392,000 [42,000]............              9.5

                                               60           0-1.2  70,000 [8,000]..............              2.2
----------------------------------------------------------------------------------------------------------------
                                   Two or more exposures of concern per season
----------------------------------------------------------------------------------------------------------------
>=80 ppb.........................              75               0  600 [100]...................              0.1
                                               70               0  0 [0].......................                0
                                               65               0  0 [0].......................                0
                                               60               0  0 [0].......................                0
>=70 ppb.........................              75         0.1-0.6  46,000 [5,000]..............              2.2
                                               70           0-0.1  5,400 [600].................              0.4
                                               65               0  300 [100]...................                0
                                               60               0  0 [0].......................                0
>=60 ppb.........................              75         3.1-7.6  865,000 [93,000]............             14.4
                                               70         0.5-3.5  320,000 [35,000]............              9.2
                                               65           0-0.8  67,000 [7,500]..............              2.8
                                               60           0-0.2  5,100 [700].................              0.3
----------------------------------------------------------------------------------------------------------------

b. Key Uncertainties
---------------------------------------------------------------------------

    \70\ Estimates for each urban case study area were averaged for
the years evaluated in the HREA (2006 to 2010). Ranges reflect the
ranges across urban study areas. Estimates smaller than 0.05% were
rounded downward to zero (from U.S. EPA, 2014a, Tables 5-11 and 5-
12).
    \71\ Numbers of children exposed in each urban case study area
were averaged over the years 2006 to 2010. These averages were then
summed across urban study areas. Numbers were rounded to nearest
thousand unless otherwise indicated. Estimates smaller than 50 were
rounded downward to zero (from U.S. EPA, 2014a, Appendix 5F Table
5F-5). See below for discussion of uncertainties in exposure
estimates.
    \72\ As discussed in section 4.3.3 of the HREA, the model-based
air quality adjustment approach used to estimate risks associated
with the current and alternative standards was unable to estimate
the distribution of ambient O3 concentrations in New York
City upon just meeting an alternative standard with a level of 60
ppb. Therefore, for the 60 ppb standard level the numbers of
children and asthmatic children reflect all of the urban study areas
except New York.
---------------------------------------------------------------------------

    In considering exposure estimates within the context of the current
and alternative O3 standards, the PA also notes important
uncertainties in these estimates. For example, due to variability in
responsiveness, only a subset of individuals who experience exposures
at or above a benchmark concentration can be expected to experience
health effects.\73\ Given the lack of sufficient exposure-response
information for most of the health effects that informed benchmark
concentrations, estimates of the number of people likely to experience
exposures at or above benchmark concentrations generally cannot be
translated into quantitative estimates of the number of people likely
to experience specific health effects.\74\ The PA views health-relevant
exposures as a continuum with greater confidence and less uncertainty
about the existence of adverse health effects at higher O3
exposure concentrations, and less confidence and greater uncertainty as
one considers lower exposure concentrations. This view draws from the
overall body of available health evidence, which indicates that as
exposure concentrations increase, the incidence, magnitude, and
severity of effects increases.
---------------------------------------------------------------------------

    \73\ As noted below (II.C.3.a.ii), in the case of asthmatics,
responsiveness to O3 could depend on factors that have
not been well-evaluated, such as asthma severity, the effectiveness
of asthma control, or the prevalence of medication use.
    \74\ The exception to this is lung function decrements, as
discussed below (and in U.S. EPA, 2014c, section <IP_ADDRESS>).
---------------------------------------------------------------------------

    Though the PA indicates less confidence in the likelihood of
adverse health effects as O3 exposure concentrations
decrease, it also notes that the controlled human exposure studies that
provided the basis for health benchmark concentrations have not
evaluated at-risk populations. Compared to the healthy individuals
included in controlled human exposure studies, members of at-risk
populations (e.g., asthmatics, children) could be more likely to
experience adverse effects, could experience larger and/or more serious
effects, and/or could experience effects following exposures to lower
O3 concentrations. The CASAC expressed similar views in
their advice to the Administrator (Frey, 2014a, pp. 7 and 14). In
considering estimated exposures of concern (U.S. EPA, 2014c, section
3.4), the PA notes that concerns about the potential for adverse health
effects, including effects in at-risk populations must be balanced
against the increasing uncertainty regarding the likelihood of such
effects following exposures to lower O3 concentrations.
    Uncertainties associated with the APEX exposure modeling also have
the potential to be important (U.S. EPA, 2014a, section 5.5.2, Table 5-
6). For example, the HREA concludes that exposures of concern could be
underestimated for some individuals who are frequently and routinely
active outdoors during the warm season (U.S. EPA, 2014a, section
5.5.2). This could include outdoor workers and children who are
frequently active outdoors. The HREA specifically notes that long-term
diary profiles (i.e., monthly, annual) do not exist for such
populations, limiting the extent to which APEX outputs reflect people
who follow similar daily routines resulting in high exposures, over
extended periods of time.
    In order to evaluate one dimension of the potential implications of
this uncertainty for exposure estimates, the HREA reports the results
of limited exposure model sensitivity analyses using subsets of
activity diaries specifically selected to reflect groups spending a
larger proportion of time being active outdoors during the
O3 season. When diaries were selected to mimic activity
patterns performed by outdoor workers, the percent of modeled
individuals estimated to experience exposures of concern was higher
than the other adult populations evaluated. The percentages of outdoor
workers estimated to experience exposures of concern were generally
similar to the percentages estimated for children (i.e., using the full
database of diary profiles) in the worst-case urban study area and year
(i.e., urban study area and year with the largest percent of children
estimated to experience exposures of concern) (U.S. EPA, 2014a, section
<IP_ADDRESS>, Figure 5-14). In

addition, when diaries were restricted to children who did not report
any time spent inside a school or performing paid work (i.e., to mimic
children spending large portions of their time outdoors during the
summer), the number experiencing exposures of concern increased by
approximately 30% (U.S. EPA, 2014a, section <IP_ADDRESS>). Though these
sensitivity analyses are limited to single urban study areas, and
though there is uncertainty associated with diary selection approaches
to mimic highly exposed populations, they suggest the possibility that
some at-risk groups could experience more frequent exposures of concern
than indicated by estimates made using the full database of activity
diary profiles.
    In further considering activity diaries, the HREA also notes that
growing evidence indicates that people can change their behavior in
response to high O3 concentrations, reducing the time spent
being active outdoors (U.S. EPA, 2014a, section <IP_ADDRESS>). Commonly
termed ``averting behaviors,'' these altered activity patterns could
reduce personal exposure concentrations. Therefore, the HREA also
performed limited sensitivity analyses to evaluate the potential
implications of averting behavior for estimated exposures of concern.
These analyses suggest that averting behavior could reduce the
percentages of children estimated to experience exposures of concern at
or above the 60 or 70 ppb benchmark concentrations by approximately 10
to 30%, with larger reductions possible for the 80 ppb benchmark (U.S.
EPA, 2014a, Figure 5-15). As discussed above for other sensitivity
analyses, these analyses are limited to a single urban case study area
and are subject to uncertainties associated with assumptions about the
prevalence and duration of averting behaviors. However, the results
suggest that exposures of concern could be overestimated, particularly
in children (Neidell, 2009; U.S. EPA, 2013, Figures 4-7 and 4-8), if
the possibility for averting behavior is not incorporated into
estimates.
3. Quantitative Health Risk Assessments
    For some health endpoints, there is sufficient scientific evidence
and information available to support the development of quantitative
estimates of O3-related health risks. In the last review of
the O3 NAAQS, the quantitative health risk assessment
estimated O3-related lung function decrements, respiratory
symptoms, respiratory-related hospital admissions, and nonaccidental
and cardiorespiratory-related mortality (U.S. EPA, 2007). In those
analyses, both controlled human exposure and epidemiologic studies were
used for the quantitative assessment of O3-related human
health risks.
    In the current review, for short-term O3 concentrations,
the HREA estimates lung function decrements; respiratory symptoms in
asthmatics; hospital admissions and emergency department visits for
respiratory causes; and all-cause mortality (U.S. EPA, 2014a). For
long-term O3 concentrations, the HREA estimates respiratory
mortality (U.S. EPA, 2014a).\75\ Estimates of O3-induced
lung function decrements are based on exposure modeling, combined with
exposure-response relationships from controlled human exposure studies
(U.S. EPA, 2014a, Chapter 6). Estimates of O3-associated
respiratory symptoms, hospital admissions and emergency department
visits, and mortality are based on concentration-response relationships
from epidemiologic studies (U.S. EPA, 2014a, Chapter 7). As with the
exposure assessment discussed above, O3-associated health
risks are estimated for recent air quality and for ambient
concentrations adjusted to just meet the current and alternative
O3 standards, based on 2006-2010 air quality and adjusted
precursor emissions. The following sections discuss the lung function
risk assessment (II.C.3.a) and the epidemiology-based morbidity and
mortality risk assessments (II.C.3.b) from the HREA, including
important sources of uncertainty in these estimates.
---------------------------------------------------------------------------

    \75\ Estimates of O3-associated respiratory mortality
are based on the study by Jerrett et al. (2009). This study used
seasonal averages of 1-hour daily maximum O3
concentrations to estimate long-term concentrations.
---------------------------------------------------------------------------

a. Lung Function Risk Assessment
    Section II.C.3.a.i provides an overview of the approach used in the
HREA to assessing lung function risks, an overview of the approach in
the PA to considering lung function risk estimates, and a summary of
key results. Section II.C.3.a.ii presents a summary of key
uncertainties in lung function risk estimates.
i. Overview and Summary of Key Results
    In the current review, the HREA estimates risks of lung function
decrements in school-aged children (ages 5 to 18), asthmatic school-
aged children, and the general adult population for the 15 urban study
areas. The results presented in the HREA are based on an updated dose-
threshold model that estimates FEV1 responses for
individuals following short-term exposures to O3 (McDonnell
et al., 2012), reflecting methodological improvements since the last
review (II.B.2.a.i, above; U.S. EPA, 2014a, section 6.2.4). The impact
of the dose threshold is that O3-induced FEV1
decrements result primarily from exposures on days with average ambient
O3 concentrations above about 40 ppb (U.S. EPA, 2014a,
section 6.3.1, Figure 6-9).\76\
---------------------------------------------------------------------------

    \76\ Analysis of this issue in the HREA is based on risk
estimates in Los Angeles for 2006 unadjusted air quality. The HREA
shows that more than 90% of daily instances of FEV1
decrements >=10% occur when 8-hr average ambient concentrations are
above 40 ppb for this modeled scenario. The HREA notes that the
distribution of responses will be different for different study
areas, years, and air quality scenarios (U.S. EPA, 2014c, Chapter
6).
---------------------------------------------------------------------------

    The HREA estimates risks of moderate to large lung function
decrements, defined as FEV1 decrements >=10%, 15%, or 20%.
In evaluating these lung function risk estimates within the context of
considering the current and alternative O3 standards, the PA
focuses on the percent of children estimated to experience one or more
and two or more decrements >=10, 15, and 20%, noting that the
percentage of asthmatic children estimated to experience such
decrements is virtually indistinguishable from the percentage estimated
for all children.\77\ Compared to children, a smaller percentage of
adults were estimated to experience O3-induced
FEV1 decrements (U.S. EPA, 2014a, section 6.3.1, Table 6-4).
As for exposures of concern (see above), the patterns of results across
urban study areas and over the years evaluated are similar in children
and adults. Therefore, while the PA highlights estimates in children,
it notes that these results are also representative of the patterns
estimated for adult populations.
---------------------------------------------------------------------------

    \77\ Though see below for discussion of uncertainty in lung
function responses of children and asthmatics.
---------------------------------------------------------------------------

    Table 2 below summarizes key results from the lung function risk
assessment. Table 2 presents estimates of the percentages of school-
aged children estimated to experience O3-induced
FEV1 decrements >=10, 15, or 20% when air quality was
adjusted to just meet the current and alternative 8-hour O3
standards. Table 2 also presents the numbers of children, including
children with asthma, estimated to experience such decrements. As shown
in these tables, the percentage of school-age children in the 15 urban
study areas estimated to experience O3-induced
FEV1 decrements declines when comparing just meeting the
current standard to just meeting alternative

8-hour O3 standards. Substantial variability is evident
across years and urban study areas, as indicated by the ranges of
averaged estimates and estimates for worst-case years and locations.

 Table 2--Summary of Estimated O3-Induced Lung Function Decrements for the Current and Potential Alternative O3
                                       Standards in Urban Case Study Areas
----------------------------------------------------------------------------------------------------------------
                                                                     Number of children (5 to 18    % Children
      Lung function decrement         Alternative      Average %    years)  [number of asthmatic  worst year and
                                    standard level   children \78\         children] \79\              area
----------------------------------------------------------------------------------------------------------------
                                        One or more decrements per season
----------------------------------------------------------------------------------------------------------------
>=10%.............................              75           14-19  3,007,000 [312,000].........              22
                                                70           11-17  2,527,000 [261,000].........              20
                                                65            3-15  1,896,000 [191,000].........              18
                                                60            5-11  1,404,000 [139,000] \80\....              13
>=15%.............................              75             3-5  766,000 [80,000]............               7
                                                70             2-4  562,000 [58,000]............               5
                                                65             0-3  356,000 [36,000]............               4
                                                60             1-2  225,000 [22,000]............               3
>=20%.............................              75             1-2  285,000 [30,000]............             2.8
                                                70             1-2  189,000 [20,000]............             2.1
                                                65             0-1  106,000 [11,000]............             1.4
                                                60             0-1  57,000 [6,000]..............             0.9
----------------------------------------------------------------------------------------------------------------
                                        Two or more decrements per season
----------------------------------------------------------------------------------------------------------------
>=10%.............................              75          7.5-12  1,730,000 [179,000].........              14
                                                70          5.5-11  1,414,000 [145,000].........              13
                                                65         1.3-8.8  1,023,000 [102,000].........              11
                                                60         2.1-6.4  741,000 [73,000]............             7.3
>=15%.............................              75         1.7-2.9  391,000 [40,000]............             3.8
                                                70         0.9-2.4  276,000 [28,000]............             3.1
                                                65         0.1-1.8  168,000 [17,000]............             2.3
                                                60         0.2-1.0  101,000 [10,000]............             1.4
>=20%.............................              75         0.5-1.1  128,000 [13,000]............             1.5
                                                70         0.3-0.8  81,000 [8,000]..............             1.1
                                                65           0-0.5  43,000 [4,000]..............             0.8
                                                60           0-0.2  21,000 [2,000]..............             0.4
----------------------------------------------------------------------------------------------------------------

ii. Key Uncertainties
---------------------------------------------------------------------------

    \78\ Estimates in each urban case study area were averaged for
the years evaluated in the HREA (2006 to 2010). Ranges reflect the
ranges across urban study areas.
    \79\ Numbers of children estimated to experience decrements in
each study urban case study area were averaged over 2006 to 2010.
These averages were then summed across urban study areas. Numbers
are rounded to nearest thousand unless otherwise indicated.
    \80\ As discussed in section 4.3.3 of the HREA, the model-based
air quality adjustment approach used to estimate risks associated
with the current and alternative standards was unable to estimate
the distribution of ambient O3 concentrations in New York
City upon just meeting an alternative standard with a level of 60
ppb. Therefore, for the 60 ppb standard level the numbers of
children and asthmatic children reflect all of the urban study areas
except New York.
---------------------------------------------------------------------------

    As for exposures of concern discussed above, the PA also considers
important uncertainties in estimates of lung function risk. In addition
to the uncertainties noted for exposure estimates, the HREA identifies
several key uncertainties associated with estimates of O3-
induced lung function decrements. An uncertainty with particular
potential to impact consideration of risk estimates stems from the lack
of exposure-response information in children. In the near absence of
controlled human exposure data for children, risk estimates are based
on the assumption that children exhibit the same lung function response
following O3 exposures as healthy 18 year olds (i.e., the
youngest age for which controlled human exposure data is available)
(U.S. EPA, 2014a, section 6.5.3). This assumption is justified in part
by the findings of McDonnell et al. (1985), who reported that children
(8-11 years old) experienced FEV1 responses similar to those
observed in adults (18-35 years old). In addition, as discussed in the
ISA (U.S. EPA, 2013a, section 6.2.1), summer camp studies of school-
aged children reported O3-induced lung function decrements
similar in magnitude to those observed in controlled human exposure
studies using adults. In extending the risk model to children, the HREA
fixes the age term in the model at its highest value, the value for age
18. This approach could result in either over- or underestimates of
O3-induced lung function decrements in children, depending
on how children compare to the adults used in controlled human exposure
studies (U.S. EPA, 2014a, section 6.5.3).
    A related source of uncertainty is that the risk assessment
estimates O3-induced decrements in asthmatics using the
exposure-response relationship developed from data collected from
healthy individuals. Although the evidence has been mixed (U.S. EPA,
2013a, section <IP_ADDRESS>), several studies have reported larger
O3-induced lung function decrements in asthmatics than in
non-asthmatics (Kreit et al., 1989; Horstman et al., 1995; Jorres et
al., 1996; Alexis et al., 2000). On this issue, CASAC noted 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). To the extent
asthmatics experience larger O3-induced lung function
decrements than the healthy adults used to develop exposure-response
relationships, the HREA could underestimate the impacts of
O3 exposures on lung function in asthmatics, including
asthmatic children. The implications of this uncertainty for risk
estimates remain unknown at this time (U.S. EPA, 2014a,

section 6.5.4), and could depend on a variety of factors that have not
been well-evaluated, including the severity of asthma and the
prevalence of medication use. However, the available evidence shows
responses to O3 increase with severity of asthma (Horstman
et al., 1995) and corticosteroid usage does not prevent O3
effects on lung function decrements or respiratory symptoms in people
with asthma (Vagaggini et al., 2001, 2007).
b. Mortality and Morbidity Risk Assessments
    As discussed above (II.B.2), epidemiologic studies provide evidence
for the most serious O3-associated public health outcomes
(e.g., mortality, hospital admissions, emergency department visits).
Section II.C.3.b.i below provides an overview of the approach used in
the HREA to assessing mortality and morbidity risks based on
information from epidemiologic studies, discusses the approach in the
PA to considering epidemiology-based risk estimates, and presents a
summary of key results. Section II.C.3.b.ii summarizes key
uncertainties in epidemiology-base risk estimates.
i. Overview and Summary of Key Results
    Risk estimates based on epidemiologic studies can provide
perspective on the most serious O3-associated public health
outcomes (e.g., mortality, hospital admissions, emergency department
visits) in populations that often include at-risk groups. The HREA
estimates O3-associated risks in 12 urban study areas \81\
using concentration-response relationships drawn from epidemiologic
studies. These concentration-response relationships are based on
``area-wide'' average O3 concentrations.\82\ The HREA
estimates risks for the years 2007 and 2009 in order to provide
estimates of risk for a year with generally higher O3
concentrations (2007) and a year with generally lower O3
concentrations (2009) (U.S. EPA, 2014a, section 7.1.1).
---------------------------------------------------------------------------

    \81\ The 12 urban areas evaluated are Atlanta, Baltimore,
Boston, Cleveland, Denver, Detroit, Houston, Los Angeles, New York,
Philadelphia, Sacramento, and St. Louis.
    \82\ In the epidemiologic studies that provide the health basis
for HREA risk assessments, concentration-response relationships are
based on daytime O3 concentrations, averaged across
multiple monitors within study areas. These daily averages are used
as surrogates for the spatial and temporal patterns of exposures in
study populations. Consistent with this approach, the HREA
epidemiologic-based risk estimates also utilize daytime
O3 concentrations, averaged across monitors, as
surrogates for population exposures. In this notice, we refer to
these averaged concentrations as ``area-wide'' O3
concentrations. Area-wide concentrations are discussed in more
detail in section 3.1.4 of the PA (U.S. EPA, 2014c).
---------------------------------------------------------------------------

    As in the last review of the O3 NAAQS (U.S. EPA, 2007,
pp. 2-48 to 2-54), the PA recognizes that ambient O3
concentrations, and therefore O3-associated health risks,
result from precursor emissions from various types of sources. Based on
the air quality modeling discussed in chapter 2 of the PA (U.S. EPA,
2014c), approximately 30 to 60% of average daytime O3 during
the warm season (i.e., daily maximum 8-hour concentrations averaged
from April to October) is attributable to precursor emissions from U.S.
anthropogenic sources (U.S. EPA, 2014c, section 2.4.4). The remainder
is attributable to precursor emissions from international anthropogenic
sources and natural sources. Because the HREA characterizes health
risks from all O3, regardless of source, risk estimates
reflect emissions from U.S. anthropogenic, international anthropogenic,
and natural sources.
    Compared to the weight given to HREA estimates of exposures of
concern and lung function risks, and the weight given to the evidence
(U.S. EPA, 2014c, section 4.4.1), the PA places relatively less weight
on epidemiologic-based risk estimates. In doing so, the PA notes that
the overall conclusions from the HREA likewise reflect less confidence
in estimates of epidemiologic-based risks than in estimates of
exposures and lung function risks. The determination to attach less
weight to the epidemiologic-based estimates reflects the uncertainties
associated with mortality and morbidity risk estimates, including the
heterogeneity in effect estimates between epidemiologic study areas,
the potential for epidemiologic-based exposure measurement error, and
uncertainty in the interpretation of the shape of concentration-
response functions at lower O3 concentrations (discussed
below). The PA also notes the HREA conclusion that lower confidence
should be placed in the results of the assessment of respiratory
mortality risks associated with long-term O3 exposures,
primarily because that analysis is based on only one study (even though
that study is well-designed) and because of the uncertainty in that
study about the existence and level of a potential threshold in the
concentration-response function (U.S. EPA, 2014a, section 9.6).
    In considering the epidemiology-based risk estimates, the PA
focuses on mortality risks associated with short-term O3
concentrations. In doing so, in addition to noting uncertainty in
estimates of respiratory mortality associated with long-term
O3, the PA notes that the patterns of estimated respiratory
morbidity risks across urban study areas, over years, and for different
standards are similar to the patterns of total mortality risk.
    The PA considers estimates of total risk (i.e., based on the full
distributions of ambient O3 concentrations) and estimates of
risk associated with O3 concentrations in the upper portions
of ambient distributions. A focus on estimates of total risks would
place greater weight on the possibility that concentration-response
relationships are linear over the entire distribution of ambient
O3 concentrations, and thus on the potential for morbidity
and mortality to be affected by changes in relatively low O3
concentrations. A focus on risks associated with O3
concentrations in the upper portions of the ambient distribution would
place greater weight on the uncertainty associated with the shapes of
concentration-response curves for O3 concentrations in the
lower portions of the distribution. Given that both types of risk
estimates could reasonably inform a decision on standard level,
depending on the weight placed on uncertainties in the occurrence and
the estimation of O3-attributable effects at relatively low
O3 concentrations, the PA considers both types of estimates.
Key results for O3-associated mortality risk are summarized
in Table 3 below. Table 3 presents estimates of the number of
O3-associated deaths in urban study areas, for air quality
adjusted to just meet the current and alternative standards.

     Table 3--Estimates of O3-Associated Deaths Attributable to the Full Distribution of 8-Hour Area-Wide O3
                      Concentrations and to Concentrations at or Above 20, 40, or 60 ppb O3
                               [Deaths summed across urban case study areas] \83\
----------------------------------------------------------------------------------------------------------------
                       Number of O3-associated deaths summed across urban case study areas
-----------------------------------------------------------------------------------------------------------------
                 Standard level                      Total O3         20+ ppb         40+ ppb         60+ ppb
----------------------------------------------------------------------------------------------------------------
                                                      2007
----------------------------------------------------------------------------------------------------------------
75 ppb..........................................           7,500           7,500           5,400             500
70 ppb..........................................           7,200           7,200           4,900             240
65 ppb..........................................           6,500           6,500           2,800              90
60 ppb \84\.....................................           6,400           6,400           2,300              10
----------------------------------------------------------------------------------------------------------------
                                                      2009
----------------------------------------------------------------------------------------------------------------
75 ppb..........................................           7,000           7,000           4,700             270
70 ppb..........................................           6,900           6,900           4,300              80
65 ppb..........................................           6,400           6,400           2,600              40
60 ppb..........................................           6,300           6,300           2,100              10
----------------------------------------------------------------------------------------------------------------

ii. Key  Uncertainties
---------------------------------------------------------------------------

    \83\ Table 3 is based on the information in Figures 7-2 and 7-3
in the HREA (U.S. EPA, 2014a). Estimates of the numbers of
O3-associated deaths are based on concentration-response
relationships for total mortality associated with short-term
O3 from the study by Smith et al. (2009). Estimates of
the numbers O3-associated deaths are rounded to the
nearest hundred, unless otherwise indicated.
    \84\ As discussed in section 4.3.3 of the HREA, the model-based
air quality adjustment approach used to estimate risks associated
with the current and alternative standards was unable to estimate
the distribution of ambient O3 concentrations in New York
City upon just meeting an alternative standard with a level of 60
ppb. Therefore, the total number of deaths indicated for the 60 ppb
standard level reflect the 60 ppb estimates for all urban study
areas except New York City. For New York City, the estimated number
of O3-associated deaths for the 60 ppb standard level was
assumed to be equal to the number for the 65 ppb level.
---------------------------------------------------------------------------

    Compared to estimates of O3 exposures of concern and
estimates of O3-induced lung function decrements (discussed
above), the HREA conclusions reflect lower confidence in epidemiologic-
based risk estimates (U.S. EPA, 2014a, section 9.6). In particular, the
HREA highlights the heterogeneity in effect estimates between
locations, the potential for exposure measurement errors, and
uncertainty in the interpretation of the shape of concentration-
response functions at lower O3 concentrations (U.S. EPA,
2014a, section 9.6). The HREA also concludes that lower confidence
should be placed in the results of the assessment of respiratory
mortality risks associated with long-term O3, primarily
because that analysis is based on only one study, though that study is
well-designed, and because of the uncertainty in that study about the
existence and identification of a potential threshold in the
concentration-response function (U.S. EPA, 2014a, section 9.6).\85\
\86\ This section further discusses some of the key uncertainties in
epidemiologic-based risk estimates, as summarized in the PA (U.S. EPA,
2014c, section <IP_ADDRESS>), with a focus on uncertainties that can have
particularly important implications for the Administrator's
consideration of epidemiology-based risk estimates.
---------------------------------------------------------------------------

    \85\ The CASAC also concluded that ``[i]n light of the potential
nonlinearity of the C-R function for long-term exposure reflecting a
threshold of the mortality response, the estimated number of
premature deaths avoidable for long-term exposure reductions for
several levels need to be viewed with caution'' (Frey, 2014a, p. 3).
    \86\ There is also uncertainty about the extent to which
mortality estimates based on the long-term metric used in the study
by Jerrett et al. (2009) (i.e., seasonal average of 1-hour daily
maximum concentrations) reflects associations with long-term average
O3 versus repeated occurrences of elevated short-term
concentrations.
---------------------------------------------------------------------------

    The PA notes that reducing NOX emissions generally
reduces O3-associated mortality and morbidity risk estimates
in locations and time periods with relatively high ambient
O3 concentrations and increases risk estimates in locations
and time periods with relatively low concentrations (II.C.1, above).
When evaluating uncertainties in epidemiologic risk estimates, it is
important to consider (1) The extent to which the O3
response to reductions in NOX emissions appropriately
represents the trends observed in ambient O3 following
actual reductions in NOX emissions; (2) the extent to which
estimated changes in risks in urban study areas are representative of
the changes that would be experienced broadly across the U.S.
population; and (3) the extent to which the O3 response to
reductions in precursor emissions could differ with emissions reduction
strategies that are different from those used in HREA to generate risk
estimates.
    To evaluate the first issue, the HREA conducted a national analysis
evaluating trends in monitored ambient O3 concentrations
during a time period when the U.S. experienced large-scale reductions
in NOX emissions (i.e., 2001 to 2010). Analyses of trends in
monitored O3 indicate that over such a time period, the
upper end of the distribution of monitored O3 concentrations
(i.e., indicated by the 95th percentile) generally decreased in urban
and non-urban locations across the U.S. (U.S. EPA, 2014a, Figure 8-29).
During this same time period, median O3 concentrations
decreased in suburban and rural locations, and in some urban locations.
However, median concentrations increased in some large urban centers
(U.S. EPA, 2014a, Figure 8-28). As discussed in the REA, and above
(II.C.1), these increases in median concentrations likely reflect the
increases in relatively low O3 concentrations that can occur
near important sources of NOX upon reductions in
NOX emissions (U.S. EPA, 2014a, section <IP_ADDRESS>). These
patterns of monitored O3 during a period when the U.S.
experienced large reductions in NOX emissions are
qualitatively consistent with the modeled responses of O3 to
reductions in NOX emissions.
    To evaluate the second issue, the HREA conducted national air
quality modeling analyses. These analyses estimated the proportion of
the U.S. population living in locations where seasonal averages of
daily O3 concentrations are estimated to decrease in
response to reductions in NOX emissions, and the proportion
living in locations where such seasonal averages are estimated to
increase. Given the close relationship between changes in

seasonal averages of daily O3 concentrations and changes in
seasonal mortality and morbidity risk estimates, this analysis informs
consideration of the extent to which the risk results in urban study
areas represent the U.S. population as a whole. This representativeness
analysis indicates that the majority of the U.S. population lives in
locations where reducing NOX emissions would be expected to
result in decreases in warm season averages of daily maximum 8-hour
ambient O3 concentrations. Because the HREA urban study
areas tend to underrepresent the populations living in such areas
(e.g., suburban, smaller urban, and rural areas), risk estimates for
the urban study areas are likely to understate the average reductions
in O3-associated mortality and morbidity risks that would be
experienced across the U.S. population as a whole upon reducing
NOX emissions (U.S. EPA, 2014a, section <IP_ADDRESS>).
    To evaluate the third issue, the HREA assessed the O3
air quality response to reducing both NOX and VOC emissions
(i.e., in addition to assessing reductions in NOX emissions
alone) for a subset of seven urban study areas. As discussed in the PA
(U.S. EPA, 2014c, section 3.2.1), in most of the urban study areas the
inclusion of VOC emissions reductions did not alter the NOX
emissions reductions required to meet the current or alternative
standards.\87\ However, the addition of VOC reductions generally
resulted in larger decreases in mid-range O3 concentrations
(25th to 75th percentiles) (U.S. EPA, 2014a, Appendix 4D, section
4.7).\88\ In addition, in all seven of the urban study areas evaluated,
the increases in low O3 concentrations were smaller for the
NOX/VOC scenarios than the NOX alone scenarios
(U.S. EPA, 2014a, Appendix 4D, section 4.7). This was most apparent for
Denver, Houston, Los Angeles, New York, and Philadelphia. Given the
impacts on total risk estimates of increases in low O3
concentrations, these results suggest that in some locations optimized
emissions reduction strategies could result in larger reductions in
O3-associated mortality and morbidity than indicated by HREA
estimates.
---------------------------------------------------------------------------

    \87\ The exceptions are Chicago and Denver, for which the HREA
risk estimates are based on reductions in both NOX and
VOC (U.S. EPA, 2014a, section <IP_ADDRESS>). Emissions of NOX
and VOC were reduced by equal percentages, a scenario not likely to
reflect the optimal combination for reducing risks.
    \88\ This was the case for all of the urban study areas
evaluated, with the exception of New York (U.S. EPA, 2014a, Appendix
4-D, section 4.7).
---------------------------------------------------------------------------

    Section 7.4 of the HREA also highlights some additional
uncertainties associated with epidemiologic-based risk estimates (U.S.
EPA, 2014a). This section of the HREA identifies and discusses sources
of uncertainty and presents a qualitative evaluation of key parameters
that can introduce uncertainty into risk estimates (U.S. EPA, 2014a,
Table 7-4). For several of these parameters, the HREA also presents
quantitative sensitivity analyses (U.S. EPA, 2014a, sections 7.4.2 and
7.5.3). Of the uncertainties discussed in Chapter 7 of the HREA, those
related to the application of concentration-response functions from
epidemiologic studies can have particularly important implications for
consideration of epidemiology-based risk estimates, as discussed below.
    An important uncertainty is the shape of concentration-response
functions at low ambient O3 concentrations (U.S. EPA, 2014a,
Table 7-4).\89\ Consistent with the ISA conclusion that there is no
discernible population threshold in O3-associated health
effects, the HREA estimates epidemiology-based mortality and morbidity
risks for entire distributions of ambient O3 concentrations,
based on the assumption that concentration-response relationships
remain linear over those distributions. In addition, in recognition of
the ISA conclusion that certainty in the shape of O3
concentration-response functions decreases at low ambient
concentrations, the HREA also estimates total mortality associated with
various ambient O3 concentrations. The PA considers both
types of risk estimates, recognizing greater public health concern for
adverse O3-attributable effects at higher ambient
O3 concentrations (which drive higher exposure
concentrations, section 3.2.2 of the PA (U.S. EPA, 2014c)), as compared
to lower concentrations.
---------------------------------------------------------------------------

    \89\ A related uncertainty is the existence, or not, of a
threshold. The HREA addresses this issue for long-term O3
by evaluating risks in models that include potential thresholds
(II.D.2.c).
---------------------------------------------------------------------------

    A related uncertainty is that associated with the public health
importance of the increases in relatively low O3
concentrations following air quality adjustment. This uncertainty
relates to the assumption that the concentration response function for
O3 is linear, such that that total risk estimates are
equally influenced by decreasing high concentrations and increasing low
concentrations, when the increases and decreases are of equal
magnitude. Even on days with increases in relatively low area-wide
average concentrations, resulting in increases in estimated risks, some
portions of the urban study areas could experience decreases in high
O3 concentrations. To the extent adverse O3-
attributable effects are more strongly supported for higher ambient
concentrations (which are consistently reduced upon air quality
adjustment), the impacts on risk estimates of increasing low
O3 concentrations reflect an important source of
uncertainty.
    The HREA also notes important uncertainties associated with using a
concentration-response relationship developed for a particular
population in a particular location to estimate health risks in
different populations and locations (U.S. EPA, 2014a, Table 7-4). As
discussed above, concentration-response relationships derived from
epidemiologic studies reflect the spatial and temporal patterns of
population exposures during the study. The HREA applies concentration-
response relationships from epidemiologic studies to adjusted air
quality in study areas that are different from, and often larger in
spatial extent than, the areas used to generate the relationships. This
approach ensures the inclusion of the actual nonattainment monitors
that often determine the magnitude of emissions reductions for the air
quality adjustments throughout the urban study areas. This approach
also allows the HREA to estimate patterns of health risks more broadly
across a larger area, including a broader range of air quality
concentrations and a larger population. The HREA notes that it is not
possible to quantify the impacts of this uncertainty on risk estimates
in most urban case study locations, though the HREA notes that
mortality effect estimates for different portions of the New York City
core based statistical area (CBSA) vary by a factor of almost 10 (U.S.
EPA, 2014a, section 7.5.3).
    An additional, related uncertainty is that associated with applying
concentration-response functions from epidemiologic studies to adjusted
air quality. Concentration-response functions from the O3
epidemiologic studies used in the HREA are based on associations
between day to day variation in ``area-wide'' O3
concentrations (i.e., averaged across multiple monitors) and variation
in health effects. Epidemiologic studies use these area-wide
O3 concentrations, which reflect the particular spatial and
temporal patterns of ambient O3 present in study locations,
as surrogates for the pattern of O3 exposures experienced by
study populations. To the extent adjusting O3 concentrations
to just meet the current standard results in important alterations in
the spatial and/

or temporal patterns of ambient O3, there is uncertainty in
the appropriateness of applying concentration-response functions from
epidemiologic studies (which necessarily reflect a different air
quality distribution than the modelled distribution) to estimate health
risks associated with adjusted O3 air quality. In
particular, this uncertainty could be important to the extent that (1)
factors associated with space modify the effects of O3 on
health or (2) spatial mobility is a key driver of individual-level
exposures. Although the impact of this uncertainty on risk estimates
cannot be quantified (U.S. EPA, 2014a, Table 7-4), it has the potential
to become more important as model adjustment results in larger changes
in spatial and temporal patterns of ambient O3
concentrations across urban study areas.
    The use of a national concentration-response function to estimate
respiratory mortality associated with long-term O3 is a
source of uncertainty. Risk estimates generated in sensitivity analyses
using region-specific effect estimates differ substantially from the
core estimates based on a single national-level effect estimate (U.S.
EPA, 2014a; Table 7-14). Furthermore, the risk estimates generated
using the regional effect estimates display considerable variability
across urban study areas (U.S. EPA, 2014a; Table 7-14), reflecting the
substantial variability in the underlying effect estimates (see Jerrett
et al., 2009, Table 4). While the results of the HREA sensitivity
analyses evaluating this uncertainty point to the potential for
regional heterogeneity in the long-term risk estimates, the relatively
large confidence intervals associated with regional effect estimates
resulted in the HREA conclusion that staff does not have confidence in
the regionally based risk estimates themselves.
    Finally, the HREA does not quantify any reductions in risk that
could be associated with reductions in the ambient concentrations of
pollutants other than O3, resulting from control of
NOX. For example, as discussed in chapter 2 of the PA (U.S.
EPA, 2014c), NOX emissions contribute to ambient
NO2, and NOX and VOCs can contribute to secondary
formation of PM2.5 constituents, including ammonium sulfate
(NH4SO4), ammonium nitrate
(NH4NO3), and organic carbon (OC). Therefore, at
some times and in some locations, control strategies that would reduce
NOX emissions (i.e., to meet an O3 standard)
could reduce ambient concentrations of NO2 and
PM2.5, resulting in health benefits beyond those directly
associated with reducing ambient O3 concentrations. In
issuing its advice, CASAC likewise noted the potential reductions in
criteria pollutants other than ozone as a result of NOx reductions, and
the resulting potential public health benefits (Frey, 2014a, pp. 10 and
11).

D. Conclusions on the Adequacy of the Current Primary Standard

    The initial issue to be addressed in the current review of the
primary O3 standard is whether, in view of the advances in
scientific knowledge and additional information, the existing standard
should be revised. In evaluating whether it is appropriate to retain or
revise the current standard, the Administrator's considerations build
upon those in the 2008 review, including consideration of the broader
body of scientific evidence and exposure and health risk information
now available, as summarized above (II.A to II.C).
    In developing conclusions on the adequacy of the current primary
O3 standard, the Administrator takes into account both
evidence-based and quantitative exposure- and risk-based
considerations. Evidence-based considerations include the assessment of
evidence from controlled human exposure, animal toxicological, and
epidemiologic studies for a variety of health endpoints. The
Administrator focuses on health endpoints for which the evidence is
strong enough to support a ``causal'' or a ``likely to be causal''
relationship, based on the ISA's integrative synthesis of the entire
body of evidence. The Administrator's consideration of quantitative
exposure and risk information draws from the results of the exposure
and risk assessments presented in the HREA.
    The Administrator's consideration of the evidence and exposure/risk
information is informed by the considerations and conclusions presented
in the PA (U.S. EPA, 2014c). The purpose of the PA is to help ``bridge
the gap'' between the scientific and technical information assessed in
the ISA and HREA, and the policy decisions that are required of the
Administrator (U.S. EPA, 2014c, Chapter 1). The PA's evidence-based and
exposure-/risk-based considerations and conclusions are summarized
below in sections II.D.1 to II.D.3. CASAC advice to the Administrator
and public commenter views are summarized in section II.D.4. Section
II.D.5 presents the Administrator's proposed conclusions concerning the
adequacy of the public health protection provided by the current
standard, and her proposed decision to revise that standard.
1. Summary of Evidence-Based Considerations in the PA
    In considering the available scientific evidence, the PA evaluates
the O3 concentrations in health effects studies (U.S. EPA,
2014c, section 3.1.4). Specifically, the PA characterizes the extent to
which effects have been reported for the O3 exposure
concentrations evaluated in controlled human exposure studies and over
the distributions of ambient O3 concentrations in locations
where epidemiologic studies have been conducted. These considerations,
as they relate to the adequacy of the current standard, are presented
in detail in section 3.1.4 of the PA (U.S. EPA, 2014c) and are
summarized briefly below for controlled human exposure and
epidemiologic panel studies (II.D.1.a), epidemiologic studies of short-
term O3 exposures (II.D.1.b), and epidemiologic studies of
long-term O3 exposures (II.D.1.c). Section II.D.1.d
summarizes the PA conclusions based on consideration of the scientific
evidence.
a. Concentrations in Controlled Human Exposure and Panel Studies
    The evidence from controlled human exposure studies and panel
studies is assessed in section 6.2 of the ISA (U.S. EPA, 2013a) and is
summarized in section 3.1.2 of the PA (U.S. EPA, 2014c). As discussed
above (II.B), controlled human exposure studies have generally been
conducted with young, healthy adults, and have evaluated exposure
durations less than 8 hours. Panel studies have evaluated a wider range
of study populations, including children, and have generally evaluated
associations with O3 concentrations averaged over several
hours (U.S. EPA, 2013a, section <IP_ADDRESS>).\90\
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    \90\ The PA focuses on panel studies that used on-site
monitoring, and that are highlighted in the ISA for the extent to
which monitored ambient O3 concentrations reflect
exposure concentrations in their study populations (U.S. EPA, 2013a,
section <IP_ADDRESS>).
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    As summarized above (II.B), a large number of controlled human
exposure studies have reported lung function decrements, respiratory
symptoms, airway inflammation, AHR, and/or impaired lung host defense
in young, healthy adults engaged in moderate, intermittent exertion,
following 6.6-hour O3 exposures. These studies have
consistently reported such effects following exposures to O3
concentrations of 80 ppb or greater. In addition to lung function
decrements, available studies have also evaluated respiratory symptoms
or airway

inflammation following exposures to O3 concentrations below
75 ppb. Table 3-1 in the PA highlights the group mean results of
individual controlled human exposure studies that have evaluated
exposures of healthy adults to O3 concentrations below 75
ppb (U.S. EPA, 2014c). The studies included in Table 3-1 of the PA
indicate a combination of lung function decrements and respiratory
symptoms following 6.6 hour exposures to O3 concentrations
as low as 72 ppb, and lung function decrements and airway inflammation
following 6.6 hour exposures to O3 concentrations as low as
60 ppb (based on group means).
    The PA also notes consistent results in some panel studies of
O3-associated lung function decrements. In particular, the
PA notes that epidemiologic panel studies in children and adults
consistently indicate O3-associated lung function decrements
when on-site monitored concentrations were below 75 ppb, although the
evidence becomes less consistent at lower O3 concentrations
(U.S. EPA, 2014c, section <IP_ADDRESS>).\91\
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    \91\ As indicated in the PA (U.S. EPA, 2014c, Table 3-2), key
O3 panel studies evaluated averaging periods ranging from
10 minutes to 12 hours.
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    Thus, controlled human exposure studies and panel studies have
reported respiratory effects in adults and children following exposures
to O3 concentrations below 75 ppb (albeit over shorter
averaging periods than the 8 hour averaging time of the current
O3 standard). The PA notes that such impairments in
respiratory function have the potential to be adverse, based on ATS
guidelines for adversity and based on advice from CASAC (Frey, 2014c,
pp. 5 and 6) (U.S. EPA, 2014c, section 3.1.3). In addition, the PA
notes that if they become serious enough, these respiratory effects
could lead to the types of clearly adverse effects commonly reported in
O3 epidemiologic studies (e.g., respiratory emergency
department visits, hospital admissions). Therefore, the PA concludes
that the respiratory effects experienced following exposures to
O3 concentrations lower than 75 ppb could be adverse in some
individuals, particularly if experienced by members of at-risk
populations (e.g., people with asthma, children).\92\
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    \92\ These effects were reported in healthy individuals.
Consistent with CASAC advice (Samet, 2011; Frey, 2014a, p. 14; Frey,
2014c, p. 7), it is a reasonable inference that the effects would be
greater in magnitude and potential severity for at-risk groups. See
National Environmental Development Ass'n Clean Air Project v. EPA,
686 F. 3d 803, 811 (D.C. Cir. (2012) (making this point).
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b. Concentrations in Epidemiologic Studies--Short-Term
    The PA also considers distributions of ambient O3
concentrations in locations where epidemiologic studies have evaluated
O3-associated hospital admissions, emergency department
visits, and/or mortality (U.S. EPA, 2014c, section <IP_ADDRESS>). When
considering epidemiologic studies within the context of the current
standard, the PA emphasizes those studies conducted in the U.S. and
Canada. Such studies reflect air quality and exposure patterns that are
likely more typical of the U.S. population than the air quality and
exposure patterns reflected in studies conducted outside the U.S. and
Canada (U.S. EPA, 2014c, section <IP_ADDRESS>).\93\ The PA also emphasizes
studies reporting associations with effects judged in the ISA to be
robust to confounding by other factors, including co-occurring air
pollutants. In addition to these factors, the PA considers the
statistical precision of study results, the extent to which studies
report associations in at-risk populations, and the extent to which the
biological plausibility of associations at various ambient
O3 concentrations is supported by controlled human exposure
and/or animal toxicological studies. These considerations help inform
the range of ambient O3 concentrations over which the
evidence indicates the most confidence in O3-associated
health effects, and the range of concentrations over which confidence
in such associations is appreciably lower.
---------------------------------------------------------------------------

    \93\ Nonetheless, the PA recognizes the importance of all
studies, including international studies, in the ISA's assessment of
the weight of the evidence that informs causality determinations.
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    This section summarizes the PA conclusions regarding the extent to
which health effect associations have been reported for ambient
O3 concentrations likely to have met the current
O3 standard. Section II.D.1.b.i summarizes PA analyses and
conclusions based on analyses evaluating the extent to which
epidemiologic studies have reported health effect associations in
locations that would likely have met the current O3
standard. Section II.D.1.b.ii summarizes PA conclusions based on
analyses evaluating the O3 air quality in locations where
epidemiologic studies have characterized confidence intervals around
cut point analyses or concentration-response functions. Section
II.D.1.b.iii summarizes the important uncertainties in these analyses.
i. Associations in Locations Likely Meeting Current Standard
    The PA considers the extent to which U.S. and Canadian
epidemiologic studies have reported associations with mortality or
morbidity in locations that would likely have met the current
O3 standard during the study period (U.S. EPA, 2014c,
section 3.14.2). Addressing this issue can provide important insights
into the extent to which O3-health effect associations are
present for distributions of ambient O3 concentrations that
would be allowed by the current standard. To the extent associations
are reported in study areas that would have met the current standard,
those associations indicate that the current standard could allow the
types of clearly adverse O3-associated effects reported in
epidemiologic studies (e.g., mortality, hospital admissions, emergency
department visits).\94\ In considering these analyses, the PA also
notes that the lack of such associations in locations meeting the
current standard indicates increased uncertainty in the extent to which
O3-associated health effects would persist upon reducing
O3 precursor emissions in order to meet that standard.
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    \94\ See ATA III, 283 F.3d at 370 (EPA justified in revising
NAAQS when health effect associations are observed in epidemiologic
studies at levels allowed by the NAAQS); State of Mississippi v.
EPA, 744 F. 3d at 1345 (same).
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    The PA identifies U.S. and Canadian studies of respiratory hospital
admissions, respiratory emergency department visits, and mortality
(total, respiratory, cardiovascular) from the ISA (U.S. EPA, 2013a,
Tables 6-28, 6-42, and 6-53, and section 6.2.8; U.S. EPA, 2014c,
Appendix 3D). Analysis of study area air quality indicates that the
large majority of epidemiologic study areas evaluated would have
violated the current standard during study periods (U.S. EPA, 2014c,
Appendix 3D). However, the PA notes that a single-city study conducted
in Seattle, a location that would have met the current standard over
the entire study period, reported positive and statistically
significant associations with respiratory emergency department visits
in children and adults (Mar and Koenig, 2009). The PA also notes four
Canadian multicity studies that reported positive and statistically
significant associations with respiratory morbidity or mortality, and
for which the majority of study cities would have met the current
standard over the entire study periods (Cakmak et

al., 2006; Dales et al., 2006; Katsouyanni et al., 2009; Stieb et al.,
2009).\95\
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    \95\ In addition, a study by Vedal et al. (2003) was included in
the 2006 AQCD (U.S. EPA, 2006a). This study reported positive and
statistically significant associations with mortality in Vancouver
during a time period when the study area would have met the current
standard (U.S. EPA, 2007). This study was not assessed in the ISA in
the current review (U.S. EPA, 2013a).
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    The PA concludes that the single-city study by Mar and Koenig
(2009) indicates the presence of associations with mortality and
morbidity for an ambient distribution of O3 that would have
met the current standard (U.S. EPA, 2014c, section <IP_ADDRESS>). The PA
notes that interpretation of the air quality concentrations in the
multicity study locations evaluated in this review is complicated by
uncertainties in the extent to which multicity effect estimates can be
attributed to ambient O3 in the majority of locations, which
would have met the current standard, versus O3 in the
smaller number of locations that would have violated the standard.
While acknowledging this uncertainty in interpreting air quality in
multicity studies, the PA notes that multicity effect estimates in the
four studies cited above are largely influenced by locations meeting
the current standard (i.e., given that most study areas would have met
this standard). Therefore, the PA concludes that Canadian multicity
studies, in addition to the single-city study in Seattle, suggest
confidence in the presence of associations with mortality and morbidity
for ambient distributions of O3 that would have met the
current standard (U.S. EPA, 2014c, section <IP_ADDRESS>).
ii. Air Quality Associated With Cut Point Analyses and Concentration-
Response Functions
    The PA also considers the extent to which additional epidemiologic
studies of mortality or morbidity, specifically those conducted in
locations that would have violated the current standard, can inform
consideration of adequacy of the current standard (U.S. EPA, 2014c,
section <IP_ADDRESS>). In doing so, the PA notes that health effect
associations reported in epidemiologic studies are influenced by the
full distributions of ambient O3 concentrations, including
concentrations below the level of the current standard. The PA focuses
on studies that have explicitly characterized O3 health
effect associations, including confidence in those associations, for
various portions of distributions of ambient O3
concentrations.
    The U.S. multicity study by Bell et al. (2006) reported health
effect associations for air quality subsets restricted to ambient
O3 concentrations below one or more predetermined cut
points. In these analyses, effect estimates were based only on the
subsets of days contributing to averaged O3 concentrations
below cut points ranging from 5 to 60 ppb (Bell et al., 2006, Figure
2).\96\ The PA notes that such ``cut point'' analyses can provide
information on the magnitude and statistical precision of effect
estimates for defined distributions of ambient concentrations, which
may in some cases include distributions that would meet the current
standard (U.S. EPA, 2014c, section <IP_ADDRESS>). The cut points below which
confidence intervals become notably wider depend in large part on data
density and, therefore, cut point analyses provide insight into the
ambient concentrations below which the available air quality
information becomes too sparse to support conclusions about the nature
of concentration-response relationships with a high degree of
confidence (U.S. EPA, 2014c, section <IP_ADDRESS>).
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    \96\ In the published study, 2-day rolling averages of 24-hour
average O3 concentrations were calculated in each study
location (based on averaging across monitors in study locations with
multiple monitors).
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    The PA considers the extent to which the cut-point analyses
reported by Bell et al. (2006) indicate health effect associations for
distributions of ambient O3 concentrations that would likely
have met the current standard. The PA particularly focuses on the
lowest cut-point for which the association between O3 and
mortality was reported to be statistically significant (i.e., 30 ppb,
based on visual inspection of Figure 2 in the published study). Based
on the O3 air quality concentrations that met the criteria
for inclusion in the 30 ppb cut point analysis, 95% of study areas had
3-year averages of annual 4th highest daily maximum 8-hour
O3 concentration at or below 75 ppb over the entire study
period (U.S. EPA, 2014c, section <IP_ADDRESS>, Table 3-6). Though there are
important uncertainties in this analysis, as discussed below, the PA
concludes that these results suggest that the large majority of air
quality distributions that provided the basis for the positive and
statistically significant association with mortality at the 30 ppb cut
point would likely have met the current O3 standard.
    The PA also analyzes air quality for studies that have reported
confidence intervals around concentration-response functions over
distributions of ambient O3 concentrations (U.S. EPA, 2014c,
section <IP_ADDRESS>). Confidence intervals around concentration-response
functions can provide insights into the range of ambient concentrations
over which the study indicates the most confidence in the reported
health effect associations (i.e., where confidence intervals are
narrowest), and into the range of ambient concentrations below which
the study indicates that uncertainty in the nature of such associations
becomes notably greater (i.e., where confidence intervals become
markedly wider). As with cut point analyses, the concentrations below
which confidence intervals become markedly wider are intrinsically
related to data density, and do not necessarily indicate the absence of
an association.
    The PA focuses on two U.S. single-city studies that have reported
confidence intervals around concentration-response functions (Silverman
and Ito, 2010; Strickland et al., 2010). Based on the published
analyses, the PA identifies the ranges of ambient O3
concentrations over which these studies indicate the highest degree of
confidence in the reported linear concentration-response functions
(U.S. EPA, 2014c, section <IP_ADDRESS>). For the lower ends of these ranges,
air quality analyses in the PA indicate that over 99% of days had
maximum 8-hour O3 concentrations (i.e., from highest
monitors in study locations) at or below 75 ppb. For comparison, the
annual 4th highest daily maximum 8-hour O3 concentration
generally corresponds to the 98th or 99th percentile of the seasonal
distribution, depending on the length of the O3 season.
    The PA concludes that these analyses of air quality data from the
study locations evaluated by Silverman and Ito (2010) and Strickland et
al. (2010) indicate a relatively high degree of confidence in reported
statistical associations with respiratory health outcomes on days when
virtually all monitored 8-hour O3 concentrations were 75 ppb
or below (U.S. EPA, 2014c, section <IP_ADDRESS>). Though these analyses do
not identify true design values, the presence of O3-
associated respiratory effects on such days provides insight into the
types of health effects that could occur in locations with maximum
ambient O3 concentrations at or below the level of the
current standard.
iii. Important Uncertainties
    In considering the above evidence within the context of developing
overall conclusions on the current and potential alternative standards,
the PA also takes into account important uncertainties in these
analyses of air quality in locations of epidemiologic study areas.
These uncertainties are summarized in this

section. The PA's consideration of the evidence, including the
associated uncertainties, in reaching conclusions on the current and
potential alternative standards is summarized in sections II.D.3
(current standard) and II.E.4.b (potential alternative standards)
below.
    The PA notes that while multicity studies generally have greater
statistical power and geographic coverage than single-city studies,
there is often greater uncertainty in conclusions about the extent to
which multicity effect estimates reflect associations with air quality
meeting the current standard (U.S. EPA, 2014c, section <IP_ADDRESS>.1). This
is particularly the case for the multicity studies evaluated in this
review with some study locations meeting the current standard and
others violating that standard. Specifically for the four Canadian
multicity studies discussed above, the PA notes that interpretation of
air quality information is complicated by uncertainties in the extent
to which multicity effect estimates can be attributed to ambient
O3 in the majority of locations, which would have met the
current standard, versus O3 in the smaller number of
locations that would have violated the standard.
    The PA also notes important uncertainties in multicity studies that
evaluate the potential for thresholds to exist, as was done in the
study by Bell et al. (2006). Specifically, the ISA highlights the
regional heterogeneity in O3 health effect associations as a