such correlations (U.S. EPA, 2016a, Table 6-1). This uncertainty is
important to consider when interpreting the epidemiologic evidence
regarding the extent to which NO2 is independently related
to asthma development.
    The 2016 NOX ISA also evaluated copollutant confounding
in long-term exposure studies beyond asthma incidence to examine
whether studies of other respiratory effects could provide information
on the potential for confounding by traffic-related copollutants.
Several studies examined correlations between NO2 and
traffic-related copollutants and found them to be relatively high in
many cases, ranging from 0.54-0.95 for PM2.5, 0.54-0.93 for
BC/EC, 0.2-0.95 for PM10, and 0.64-0.86 for OC (U.S. EPA,
2016a, Tables 6-1 and 6-3). While these correlations are often based on
model estimates, some are based on monitored pollutant concentrations
(i.e., McConnell et al. (2003) reported correlations of 0.54 with
PM2.5 and EC) (U.S. EPA, 2016a, Table 6-3). Additionally,
three studies (McConnell et al., 2003; MacIntyre et al., 2014; Gehring
et al., 2013) \60\ evaluated copollutant models with NO2 and
PM2.5, and some findings suggest that associations for
NO2 with bronchitic symptoms, lung function, and respiratory
infection are not robust because effect estimates decreased in
magnitude and became imprecise when a copollutant was added in the
model. Overall, examination of evidence from studies of other
respiratory effects indicates moderate to high correlations between
long-term NO2 concentrations and traffic-related
copollutants, with very limited evaluation of the potential for
confounding. Thus, when considering the collective evidence, it is
difficult to disentangle the independent effect of NO2 from
other traffic-related pollutants or mixtures in epidemiologic studies
(U.S. EPA, 2016a, Sections 3.4.4 and <IP_ADDRESS>).
---------------------------------------------------------------------------

    \60\ In single-pollutant models for various health endpoints,
the studies reported the following effect estimates (95% CI):
McConnell et al., 2003 (Bronchitic symptoms) 1.97 (1.22, 3.18);
MacIntyre et al., 2014 (Pneumonia) 1.30 (1.02, 1.65), (Otitis Media)
1.09 (1.02, 1.16), (Croup) 0.96 (0.83, 1.12); Gehring et al., 2013
(forced expiratory volume in 1 second) -0.98 (-1.70, -0.26), (FVC) -
2.14 (-4.20, -0.04), (peak expiratory flowF) -1.04 (-1.94, -0.13).
---------------------------------------------------------------------------

    While this uncertainty continues to apply to the epidemiologic
evidence for asthma incidence in children, the 2016 NOX ISA
explains that the uncertainty is partly reduced by the coherence of
findings from experimental studies and epidemiologic studies.
Experimental studies demonstrate effects on key events in the mode of
action proposed for the development of asthma and provide biological
plausibility for the epidemiologic evidence. For example, one study
demonstrated that airway hyperresponsiveness was induced in guinea pigs
after long-term exposure to NO2 (1,000-4,000 ppb; Kobayashi
and Miura, 1995). Other experimental studies examining oxidative stress
report mixed results, but some evidence from short-term studies
supports a relationship between NO2 exposure and increased
pulmonary inflammation in healthy humans. The 2016 NOX ISA
also points to supporting evidence from studies demonstrating that
short-term exposure repeated over several days (260-1,000 ppb) and
long-term NO2 exposure (2,000-4,000 ppb) can induce T helper
(Th)2 skewing/allergic sensitization in healthy humans and animal
models by showing increased Th2 cytokines, airway eosinophils, and
immunoglobulin E (IgE)-mediated responses (U.S. EPA, 2016a, Sections
4.3.5 and <IP_ADDRESS>). Epidemiologic studies also provide some supporting
evidence for these key events in the mode of action. Some evidence from
epidemiologic studies demonstrates associations between short-term
ambient NO2 concentrations and increases in pulmonary
inflammation in healthy children and adults, giving a possible
mechanistic understanding of this effect (U.S. EPA, 2016a, Section
<IP_ADDRESS>). Overall, evidence from experimental and epidemiologic studies
provides support for a role of NO2 in asthma development by
describing a potential role for repeated exposures to lead to recurrent
inflammation and allergic responses.
    To summarize, the 2016 NOX ISA notes that there is new
evidence available that strengthens conclusions from the last review
regarding respiratory health effects attributable to long-term ambient
NO2-exposure. The

majority of new evidence is from epidemiologic studies of asthma
incidence in children with improved exposure assessment (i.e., measured
or modeled at or near children's homes or schools), which builds upon
previous evidence for associations of long-term NO2 and
asthma incidence and also partly reduces uncertainties related to
measurement error. Explicit integration of evidence for individual
outcome categories (e.g., asthma incidence, respiratory infection)
provides improved characterization of biological plausibility,
including some new evidence from studies of short-term exposure
supporting an effect on asthma development. Although this partly
reduces the uncertainty regarding independent effects of
NO2, the potential for confounding remains a concern when
interpreting these epidemiologic studies as a result of the high
correlation with other traffic-related copollutants and the general
lack of copollutant models including these pollutants. In particular,
it remains unclear the degree to which NO2 itself may be
causing the development of asthma versus serving as a surrogate for the
broader traffic-pollutant mix.
Cardiovascular Effects and Diabetes
    In the previous review, the 2008 NOX ISA stated that the
evidence for cardiovascular effects attributable to long-term ambient
NO2 exposure was ``inadequate to infer the presence or
absence of a causal relationship.'' The epidemiologic and experimental
evidence was limited, with uncertainties related to traffic-related
copollutant confounding (U.S. EPA, 2008a). For the current review, the
body of epidemiologic evidence available is substantially larger than
that in the last review and includes evidence for diabetes. The
conclusion on causality is stronger in the current review with regard
to the relationship between long-term exposure to NO2 and
cardiovascular effects and diabetes, as the 2016 NOX ISA
judged the evidence to be ``suggestive, but not sufficient to infer'' a
causal relationship (U.S. EPA, 2016a, Section 6.3). More information on
these health effects may be found in section II.C.2.a.ii of the
proposal (87 FR 34792, July 26, 2017).
Reproductive and Developmental Effects
    In the previous review, a limited number of epidemiologic and
toxicological studies had assessed the relationship between long-term
NO2 exposure and reproductive and developmental effects. The
2008 NOX ISA concluded that there was not consistent
evidence for an association between NO2 and birth outcomes
and that evidence was ``inadequate to infer the presence or absence of
a causal relationship'' with reproductive and developmental effects
overall (U.S. EPA, 2008a). In the 2016 NOX ISA for the
current review, a number of recent studies added to the evidence base,
and reproductive effects were considered as three separate categories:
birth outcomes; fertility, reproduction, and pregnancy; and postnatal
development (U.S. EPA, 2016a, Section 6.4). Overall, the 2016
NOX ISA found the evidence to be ``suggestive of, but not
sufficient to infer, a causal relationship'' between long-term exposure
to NO2 and birth outcomes and ``inadequate to infer the
presence or absence of a causal relationship'' between long-term
exposure to NO2 and fertility, reproduction and pregnancy as
well as postnatal development. More information on these health effects
may be found in section II.C.2.a.iii of the proposal (87 FR 34792, July
26, 2017).
Total Mortality
    In the 2008 NOX ISA, a limited number of epidemiologic
studies assessed the relationship between long-term exposure to
NO2 and mortality in adults. The 2008 NOX ISA
concluded that the scarce amount of evidence was ``inadequate to infer
the presence or absence of a causal relationship'' (U.S. EPA, 2008a).
The 2016 NOX ISA for the current review concludes that
evidence is ``suggestive of, but not sufficient to infer, a causal
relationship'' between long-term exposure to NO2 and
mortality among adults (U.S. EPA, 2016a, Section 6.5.3). More
information on these health effects may be found in section II.C.2.a.iv
of the proposal (87 FR 34792, July 26, 2017).
Cancer
    The evidence evaluated in the 2008 NOX ISA was judged
``inadequate to infer the presence or absence of a causal
relationship'' (U.S. EPA, 2008a) based on a few epidemiologic studies
indicating associations between long-term NO2 exposure and
lung cancer incidence but lack of toxicological evidence demonstrating
that NO2 induces tumors. In the current review, the
conclusion drawn from the integration of evidence is ``suggestive of,
but not sufficient to infer, a causal relationship'' (U.S. EPA, 2016a,
Section 6.6.9). More information on cancer outcomes may be found in
section II.C.2.a.v of the proposal (87 FR 34792, July 26, 2017).
ii. Long-Term NO2 Concentrations in Health Studies
    In evaluating what the available health evidence indicates with
regard to the degree of public health protection provided by the
current standards, the EPA considers the long-term NO2
concentrations that have been associated with various effects. The PA
explicitly considers these NO2 concentrations within the
context of evaluating the public health protection provided by the
current standards (U.S. EPA, 2017a, Section 3.2). This section
summarizes those considerations from the PA.
    In evaluating the long-term NO2 concentrations
associated with health effects within the context of considering the
adequacy of the current standards, the PA focuses on the evidence for
asthma incidence (i.e., the type of effect for which there is the
strongest evidence supporting a ``likely to be causal'' relationship,
as discussed above). The PA specifically considers: (1) The extent to
which epidemiologic studies indicate associations between long-term
NO2 exposures and asthma development for distributions of
ambient NO2 concentrations that would likely have met the
existing standards; and (2) the extent to which effects related to
asthma development have been reported following the range of
NO2 exposure concentrations examined in experimental
studies. These considerations are discussed below for epidemiologic
studies and experimental studies.
Ambient NO2 Concentrations in Locations of Epidemiologic
Studies
    As discussed above for short-term exposures (Section II.A.2.a),
when considering epidemiologic studies of long term NO2
exposures within the context of evaluating the adequacy of the current
NO2 standards, the PA emphasizes studies conducted in the
U.S. and Canada. The PA considers the extent to which these studies
report positive and relatively precise associations with long-term
NO2 exposures and the extent to which important
uncertainties could impact the emphasis placed on particular studies.
For the studies with potential to inform conclusions on adequacy, the
PA also evaluates available air quality information in study locations,
focusing on estimated DVs over the study periods.
    The epidemiologic studies available in the current review that
evaluate associations between long-term NO2 exposures and
asthma incidence are summarized in Table 6-1 of the 2016

NOX ISA (U.S. EPA, 2016a, p. 6-7). In evaluating the
adequacy of the current NO2 standards, the PA places the
greatest emphasis on the three U.S. and Canadian studies identified in
the 2016 NOX ISA as providing key supporting evidence for
the causal determination.\61\ However, the PA also considers what the
additional three U.S. and Canadian studies not identified as key
studies in the 2016 NOX ISA can indicate about the adequacy
of the current standards, while noting the increased uncertainty in
these studies related to exposure measurement and copollutant
confounding (Table 6-5 of the 2016 NOX ISA).
---------------------------------------------------------------------------

    \61\ There are six longitudinal epidemiologic studies conducted
in the U.S. or Canada that vary in terms of the populations examined
and methods used. Of the six studies, the 2016 NOX ISA
identifies three as key studies supporting the causal determination
(Carlsten et al., 2011; Clougherty et al., 2007; Jerrett et al.,
2008).
---------------------------------------------------------------------------

    While it is appropriate to consider what these studies can tell us
with regard to the adequacy of the existing primary NO2
standards (see below), the emphasis that is placed on these
considerations reflects important uncertainties related to the
potential for confounding by traffic-related copollutants and for
exposure measurement error.
    While keeping in mind these uncertainties, the PA next considers
the ambient NO2 concentrations present at monitoring sites
in locations and time periods of U.S. and Canadian epidemiologic
studies. Specifically, the PA considers the following question: To what
extent do U.S. and Canadian epidemiologic studies report associations
with long-term NO2 in locations likely to have met the
current primary NO2 standards?
    As discussed above for short-term exposures (Section II.A.2.a),
addressing this question can provide important insights into the extent
to which NO2-health effect associations are present for
distributions of ambient NO2 concentrations that would be
allowed by the current primary standards. The presence of such
associations would support the potential for the current standards to
allow the NO2-associated asthma development indicated by
epidemiologic studies. To the degree studies have not reported
associations in locations meeting the current primary NO2
standards, there is greater uncertainty regarding the potential for the
development of asthma to result from the NO2 exposures
associated with air quality meeting those standards.
    To evaluate this issue, the PA compares NO2 estimated
DVs in study areas to the levels of the current primary NO2
standards. In addition to comparing annual DVs to the level of the
annual standard, support for consideration of 1-hour DVs comes from the
2016 NOX ISA's integrated mode of action information
describing the biological plausibility for development of asthma
(section II.B.1, below). In particular, studies demonstrate the
potential for repeated short-term NO2 exposures to induce
pulmonary inflammation and development of allergic responses. The 2016
NOX ISA states that ``findings for short-term NO2
exposure support an effect on asthma development by describing a
potential role for repeated exposures to lead to recurrent inflammation
and allergic responses,'' which are ``identified as key early events in
the proposed mode of action for asthma development'' (U.S. EPA, 2016a,
p. 6-66 and p. 6-64). More specifically, the 2016 NOX ISA
states the following (U.S. EPA, 2016a, p. 4-64):

    The initiating events in the development of respiratory effects
due to long-term NO2 exposure are recurrent and/or
chronic respiratory tract inflammation and oxidative stress. These
are the driving factors for potential downstream key events,
allergic sensitization, airway inflammation, and airway remodeling,
that may lead to the endpoint [airway hyperresponsiveness]. The
resulting outcome may be new asthma onset, which presents as an
asthma exacerbation that leads to physician-diagnosed asthma.

    Thus, when considering the protection provided by the current
standards against NO2-associated asthma development, the PA
considers the combined protection afforded by the 1-hour and annual
standards.\62\
---------------------------------------------------------------------------

    \62\ It is also the case that broad changes in NO2
concentrations will affect both hourly and annual metrics. This is
discussed in more detail in Section II.A.1 above, and in the CASAC
letter to the Administrator on the draft PA (Diez Roux and Sheppard,
2017). Thus, as in the recent review of the O3 NAAQS (80
FR 65292, October 26, 2015), it is appropriate here to consider the
extent to which a short-term standard could provide protection
against longer-term pollutant exposures.
---------------------------------------------------------------------------

    To inform consideration of whether a study area's air quality could
have met the current primary NO2 standards during study
periods, the PA presents DV estimates based on the NO2
concentrations measured at existing monitors during the years over
which the epidemiologic studies of long-term NO2 exposures
were conducted.\63\ \64\
---------------------------------------------------------------------------

    \63\ As discussed above for short-term exposures, the DVs
estimates reported here are meant to approximate the values that are
used when determining whether an area meets the primary
NO2 NAAQS (U.S. EPA, 2017a, Appendix A).
    \64\ The DV estimates for the epidemiologic studies of asthma
incidence conducted in the U.S. and Canada are presented in Figure
3-2 of the NO2 PA (U.S. EPA, 2017a).
---------------------------------------------------------------------------

    In interpreting these comparisons of DV estimates with the
NO2 standards, the PA also considers uncertainty in the
extent to which identified DV estimates represent the higher
NO2 concentrations likely to have been present near major
roads during study periods (section II.A.1, above). In particular, as
discussed above for short-term exposures, study area DV estimates are
based on NO2 concentrations from the generally area-wide
NO2 monitors that were present during study periods.
Calculated DV estimates could have been higher if the near-road
monitors that are now required in major U.S. urban areas had been in
place. On this issue, the PA notes that the published scientific
literature supports the occurrence of higher NO2
concentrations near roadways and that recent air quality information
from the new near-road NO2 monitoring network generally
indicates higher NO2 concentrations at near-road monitoring
sites than at non near-road monitors in the same CBSA (section II.A.c,
above). In addition, mobile source NOX emissions were
substantially higher during the majority of study periods (1986-2006)
than they are today (section II.A.b, above), and NO2
concentration gradients around roadways were generally more pronounced
during study periods than indicated by recent air quality information.
Thus, even in cases where DV estimates during study periods are at or
somewhat below the levels of current primary standards, it is not clear
that study areas would have met the standards if the currently required
near-road monitors had been in place.\65\
---------------------------------------------------------------------------

    \65\ As noted above for studies of short-term NO2
exposures (II.A.2.a), epidemiologic studies that evaluate potential
NO2 health effect associations during time periods when
near-road monitors are operational could reduce this uncertainty in
future reviews.
---------------------------------------------------------------------------

    In considering the epidemiologic studies looking at long-term
NO2 exposure and asthma development (U.S. EPA, 2017a, Figure
3-2), the PA first notes the information from the key studies as
identified in the 2016 NOX ISA (Jerrett et al., 2008;
Carlsten et al., 2011, Clougherty et al., 2007). Jerrett et al. (2008)
reported positive and relatively precise associations with asthma
incidence, based on analyses across several communities in Southern
California. Of the 11 study communities evaluated by Jerrett et al.
(2008), most (i.e., seven) had maximum annual estimated DVs that were
near (i.e., 46 ppb for the four communities represented by the
Riverside estimated DVs) or above (i.e., 60 ppb for the three
communities represented by the Los

Angeles estimated DVs) 53 ppb.\66\ These seven communities also had 1-
hour estimated DVs (maximum and mean) that were well above 100 ppb. The
other key studies (i.e., Carlsten et al., 2011; Clougherty et al.,
2007), conducted in single cities, reported positive but statistically
imprecise associations. The annual estimated DVs in locations of these
studies during study years were below 53 ppb, but maximum 1-hour
estimated DVs were near (Clougherty et al., 2007) \67\ or above
(Carlsten et al., 2011) 100 ppb.
---------------------------------------------------------------------------

    \66\ For the studies by Jerrett et al. (2008) and McConnell et
al. (2010), the majority of communities were located within the Los
Angeles and Riverside CBSAs. Because of this, DV estimates for the
Los Angeles and Riverside CBSAs were used to represent multiple
study communities.
    \67\ As noted above, even in cases where DV estimates during
study periods are at or somewhat below the levels of current
standards, it is not clear that study areas would have met the
standards if the currently required near-road monitors had been in
place during the study period.
---------------------------------------------------------------------------

    The PA also considers the information from the other U.S. and
Canadian studies available that, due to additional uncertainties, were
not identified as key studies in the 2016 NOX ISA (Clark et
al., 2010; McConnell et al., 2010; Nishimura et al., 2013). The
multicity study by Nishimura et al. (2013) reports a positive and
relatively precise association with asthma incidence, based on five
U.S. cities and Puerto Rico (see ``combined'' estimate in Figure 3-2 of
the NO2 PA). Annual estimated DVs in all study cities were
below 53 ppb, while maximum 1-hour estimated DVs were above 100 ppb in
four of the five study cities (mean 1-hour estimated DVs were also near
or above 100 ppb in most study cities). Nishimura et al. (2013) also
reported mixed results in city-specific effects estimates. McConnell et
al. (2010) also conducted a multi-community study in Southern
California and reported a positive and relatively precise association
between asthma incidence and long-term NO2 exposures based
on central-site measurements. This study encompasses some of the same
communities as Jerrett et al. (2008), and while the annual DV estimates
for these study years are more mixed, the 1-hour DV estimates
representing 10 of 13 communities are near or above 100 ppb. Finally,
Clark et al. (2010) reported a relatively precise and statistically
significant association in a study conducted over a two-year period in
British Columbia, with annual and hourly DV estimates of 32 ppb and 67
ppb, respectively. However, this result was based on central-site
NO2 measurements that have well-recognized limitations in
reflecting variability in ambient NO2 concentrations in a
community and variability in NO2 exposure among subjects.
PA Conclusions on Ambient NO2 Concentrations in Locations of
Epidemiologic Studies
    Based on the information discussed above, while epidemiologic
studies provide support for NO2-associated asthma
development at ambient NO2 concentrations likely to have
been above those allowed by the current standards, these studies do not
report such associations at ambient NO2 concentrations that
would have clearly met both of the current standards. Thus, in
evaluating the adequacy of the public health protection provided by the
current 1-hour and annual NO2 standards, the PA concludes
that epidemiologic studies do not provide a clear basis for concluding
that ambient NO2 concentrations allowed by the current
standards are independently (i.e., independent of co-occurring roadway
pollutants) associated with the development of asthma (U.S. EPA, 2017a,
section 3.3.2). This conclusion stems from consideration of the
available evidence from U.S. and Canadian studies for NO2-
associated asthma incidence, the ambient NO2 concentrations
present in study locations during study periods, and the uncertainties
and limitations inherent in the evidence and in the analysis of study
area DV estimates.
    With regard to uncertainties in the evidence, the PA particularly
notes the potential for confounding by co-occurring pollutants, as
described above, given the following: (1) The relatively high
correlations observed between long-term concentrations of
NO2 and long-term concentrations of other roadway-associated
pollutants; and (2) the general lack of information from copollutant
models on the potential for NO2 associations that are
independent of another traffic-related pollutant or mix of pollutants.
This uncertainty is an important consideration in evaluating the
potential support for adverse effects occurring below the levels of the
current primary NO2 standards.
    Furthermore, the analysis of study area estimated DVs does not
provide support for the occurrence of NO2-associated asthma
incidence in locations with ambient NO2 concentrations
clearly meeting the current NAAQS. In particular, for most of the study
locations evaluated in the lone key U.S. multi-community study (Jerrett
et al., 2008), 1-hour estimated DVs were above 100 ppb, and annual DVs
were near or above 53 ppb. In addition, the two key single-city studies
evaluated reported positive, but relatively imprecise, associations in
locations with 1-hour estimated DVs near (Clougherty et al., 2007 in
Boston) or above (Carlsten et al., 2011 in Vancouver) 100 ppb. Had
currently required near-road monitors been in operation during study
periods, estimated DVs in U.S. study locations would likely have been
higher. Other U.S. and Canadian studies evaluated were subject to
greater uncertainties in the characterization of NO2
exposures. Given this information and consideration of these
uncertainties, the degree to which these epidemiologic studies can
inform whether adverse NO2-associated effects (i.e., asthma
development) are occurring below the levels of the current primary
NO2 standards is limited.
iii. NO2 Concentrations in Experimental Studies of Long-Term
Exposure
    In addition to the evidence from epidemiologic studies, the PA also
considers evidence from experimental studies in animals and humans.\68\
Experimental studies examining asthma-related effects attributable to
long-term NO2 exposures are largely limited to animals
exposed to NO2 concentrations well above those found in the
ambient air (i.e., >=1,000 ppb). As discussed above, the 2016
NOX ISA indicates that evidence from these animal studies
supports the causal determination by characterizing ``a potential mode
of action linking NO2 exposure with asthma development''
(U.S. EPA, 2016a, p. 1-20). In particular, there is limited evidence
for increased airway responsiveness in guinea pigs with exposures to
1,000-4,000 ppb for 6-12 weeks. There is inconsistent evidence for
pulmonary inflammation across all studies, though effects were reported
following NO2 exposures of 500-2,000 ppb for 12 weeks.
Despite providing support for the ``likely to be a causal''
relationship, these experimental studies, by themselves, do not provide
insight into the occurrence of adverse health effects following
exposures below the levels of the existing primary NO2
standards.\69\
---------------------------------------------------------------------------

    \68\ While there are not controlled human exposure studies for
long-term exposures, the 2016 NOX ISA and the PA consider
the extent to which evidence from short-term studies can provide
support for effects observed in long-term exposure studies (U.S. EPA
2016a, chapter 6; U.S. EPA, 2017a, section 3).
    \69\ In addition, the 2016 NOX ISA draws from
experimental evidence for short-term exposures to support the
biological plausibility of asthma development. Consideration of the
NO2 exposure concentrations evaluated in these studies is
discussed in Section II.A.2 above.

---------------------------------------------------------------------------

Overall Conclusions for Long Term Exposures
    Taking all of the evidence and information together, including
important uncertainties, the PA revisits the extent to which the
evidence supports the occurrence of NO2-attributable asthma
development in children at NO2 concentrations below the
existing standards. Based on the considerations discussed above, the PA
concludes that the available evidence does not provide support for
asthma development attributable to long-term exposures to
NO2 concentrations that would clearly meet the existing
annual and 1-hour primary NO2 standards. This conclusion
recognizes the NO2 air quality relationships, which indicate
that meeting the 1-hour NO2 standard would be expected to
limit annual NO2 concentrations to well below the level of
the current annual standard (Section II.A.2.d, above). This conclusion
also recognizes the uncertainties in interpreting the epidemiologic
evidence within the context of evaluating the existing standards due to
the lack of near-road monitors during study periods and due to the
potential for confounding by co-occurring pollutants. Thus, the PA
concludes that epidemiologic studies of long-term NO2
exposures and asthma development do not provide a clear basis for
concluding that ambient NO2 concentrations allowed by the
current primary NO2 standards are independently (i.e.,
independent of co-occurring roadway pollutants) associated with the
development of asthma. In addition, while experimental studies provide
support for NO2-attributable effects that are plausibly
related to asthma development, the relatively high NO2
exposure concentrations used in these studies do not provide insight
into whether such effects would occur at NO2 exposure
concentrations that would be allowed by the current standards.
c. Potential Public Health Implications
    Evaluation of the public health protection provided against ambient
NO2 exposures requires consideration of populations and
lifestages that may be at greater risk of experiencing NO2-
attributable health effects. In the last review, the 2008
NOX ISA noted that a considerable fraction of the U.S.
population lives, works, or attends school near major roadways, where
ambient NO2 concentrations are often elevated (U.S. EPA,
2008a, Section 4.3). Of this population, the 2008 NOX ISA
concluded that ``those with physiological susceptibility will have even
greater risks of health effects related to NO2'' (U.S. EPA,
2008a, p. 4-12). With regard to susceptibility, the 2008 NOX
ISA concluded that ``[p]ersons with preexisting respiratory disease,
children, and older adults may be more susceptible to the effects of
NO2 exposure'' (U.S. EPA, 2008a, p. 4-12).
    In the current review, the 2016 NOX ISA again notes that
because of the large populations attending school, living, working, and
commuting on or near roads, where ambient NO2 concentrations
can be higher than in many other locations (U.S. EPA, 2016a, Section
7.5.6),\70\ there is widespread potential for elevated ambient
NO2 exposures. For example, Rowangould (2013) found that
over 19% of the U.S. population lives within 100 m of roads with an
annual average daily traffic (AADT) of 25,000 vehicles, and 1.3% lives
near roads with AADT greater than 200,000. The proportion is much
larger in certain parts of the country, mostly coinciding with urban
areas. Among California residents, 40% live within 100 m of roads with
AADT of 25,000 (Rowangould, 2013). In addition, 7% of U.S. schools
serving a total of 3,152,000 school children are located within 100 m
of a major roadway, and 15% of U.S. schools serving a total of
6,357,000 school children are located within 250 m of a major roadway
(Kingsley et al., 2014). Thus, as in the last review, the available
information indicates that large proportions of the U.S. population
potentially have elevated NO2 exposures as a result of
living, working, attending school, or commuting on or near roadways.
---------------------------------------------------------------------------

    \70\ The 2016 NOX ISA specifically notes that a zone
of elevated NO2 concentrations typically extends 200 to
500 m from roads with heavy traffic (U.S. EPA, 2016a, Section
2.5.3).
---------------------------------------------------------------------------

    The impacts of exposures to elevated NO2 concentrations,
such as those that can occur around roadways, are of particular concern
for populations at increased risk of experiencing adverse effects. In
the current review, the PA's consideration of potential at-risk
populations (U.S. EPA, 2017a, Section 3.4) draws from the 2016
NOX ISA's assessment of the evidence (U.S. EPA, 2016a,
Chapter 7). The 2016 NOX ISA uses a systematic approach to
evaluate factors that may increase risks in a particular population or
during a particular lifestage, noting that increased risk could be due
to ``intrinsic or extrinsic factors, differences in internal dose, or
differences in exposure'' (U.S. EPA, 2016a, p. 7-1).
    The 2016 NOX ISA evaluates the evidence for a number of
potential at-risk factors, including pre-existing diseases like asthma
(U.S. EPA, 2016a, Section 7.3), genetic factors (U.S. EPA, 2016a,
Section 7.4), sociodemographic factors (U.S. EPA, 2016a, Section 7.5),
and behavioral and other factors (U.S. EPA, 2016a, Section 7.6). The
2016 NOX ISA then uses a systematic approach for classifying
the evidence for each potential at-risk factor (U.S. EPA, 2015a,
Preamble, Section 6.a, Table III). The categories considered are
``adequate evidence,'' ``suggestive evidence,'' ``inadequate
evidence,'' and ``evidence of no effect'' (U.S. EPA, 2016a, Table 7-1).
Consistent with other recent NAAQS reviews (e.g., the recently
completed review for ozone, 80 FR 65292, October 26, 2015), the PA
focuses the consideration of potential at-risk populations on those
factors for which the 2016 NOX ISA determines there is
``adequate'' evidence (U.S. EPA, 2016a, Table 7-27). For
NO2, the at-risk populations identified include people with
asthma, children and older adults (U.S. EPA, 2016a, Table 7-27), and
this information is based primarily on evidence for asthma exacerbation
or asthma development as evidence for an independent relationship of
NO2 exposure with other health effects is more uncertain.
    The PA's consideration of the evidence supporting conclusions
regarding the populations at increased risk of NO2-related
effects specifically focuses on the following question: To what extent
does the currently available scientific evidence expand the
understanding of populations and/or lifestages that may be at greater
risk for NO2-related health effects? (U.S. EPA, 2017a, p. 3-
40).
    In addressing this question, the PA considers the evidence in the
2016 NOX ISA for effects in people with asthma, children,
and older adults (U.S. EPA, 2016a, Chapter 7, Table 7-27),
respectively, as described below.
People With Asthma
    Approximately 8.0% of adults and 9.3% of children (age <18 years)
in the U.S. currently have asthma (Blackwell et al., 2014; Bloom et
al., 2013), and it is the leading chronic illness affecting children
(U.S. EPA, 2016a, Section 7.3.1). Individuals with pre-existing
diseases like asthma may be at greater risk for some air pollution-
related health effects if they are in a compromised biological state.
    As in the last review, controlled human exposure studies
demonstrating NO2-induced increases in AR provide key
evidence that people with asthma are more sensitive than people without
asthma to the effects of short-term NO2 exposures. In
particular, a meta-analysis conducted by Folinsbee et al. (1992)

demonstrated that NO2 exposures from 100 to 300 ppb
increased AR in the majority of adults with asthma, while AR in adults
without asthma was increased only for NO2 exposure
concentrations greater than 1,000 ppb (U.S. EPA, 2016a, Section 7.3.1).
The Brown (2015) meta-analysis showed that following resting exposures
to NO2 concentrations in the range of 100 to 530 ppb, about
a quarter of individuals with asthma experience clinically relevant
increases in AR to non-specific bronchial challenge. Results of
epidemiologic studies are less clear regarding potential differences
between populations with and without asthma (U.S. EPA, 2016a, Section
7.3.1). Additionally, studies of activity patterns do not clearly
indicate differences in time spent outdoors to suggest differences in
NO2 exposure. However, the Folinsbee et al. (1992) meta-
analysis of information from controlled human exposure studies, which
supported the 2016 NOX ISA's determination of a causal
relationship between short-term exposures and respiratory effects,
clearly demonstrates that adults with asthma are at increased risk for
NO2-related respiratory health effects compared to healthy
adults. Thus, consistent with observations made in the 2008
NOX ISA (U.S. EPA, 2008a), in the current review the 2016
NOX ISA determines that the ``evidence is adequate to
conclude that people with asthma are at increased risk for
NO2-related health effects'' (U.S. EPA, 2016a, p. 7-7).
Children
    According to the 2010 census, 24% of the U.S. population is less
than 18 years of age, with 6.5% less than 6 years of age (Howden and
Meyer, 2011). The National Human Activity Pattern Survey shows that
children spend more time than adults outdoors (Klepeis et al., 1996),
and a longitudinal study in California showed a larger proportion of
children reported spending time engaged in moderate or vigorous outdoor
physical activity (Wu et al., 2011b). In addition, children have a
higher propensity than adults for oronasal breathing (U.S. EPA, 2016a,
Section <IP_ADDRESS>) and the human respiratory system is not fully
developed until 18-20 years of age (U.S. EPA, 2016a, Section 7.5.1).
Higher activity along with higher ventilation rates relative to lung
volume and higher propensity for oronasal breathing could potentially
result in greater NO2 penetration to the lower respiratory
tracts of children; however, this effect has not been examined for
NO2 (U.S. EPA, section <IP_ADDRESS>). All of these factors could
contribute to children being at higher risk than adults for effects
attributable to ambient NO2 exposures (U.S. EPA, 2016a,
Section <IP_ADDRESS>).
    Epidemiologic evidence across diverse locations (U.S., Canada,
Europe, Asia, Australia) consistently demonstrates NO2-
associated health effects with both short- and long-term exposures in
children. In particular, short-term increases in ambient NO2
concentrations are consistently associated with larger increases in
asthma-related hospital admissions, ED visits, or outpatient visits in
children than in adults (U.S. EPA, 2016a, Section <IP_ADDRESS>, Table 7-13).
These results seem to indicate NO2-associated impacts that
are 1.8 to 3.4-fold larger in children (Son et al., 2013; Ko et al.,
2007; Atkinson et al., 1999; Anderson et al., 1998). In addition,
asthma development in children has been reported to be associated with
long-term NO2 exposures, based on exposure periods spanning
infancy to adolescence (U.S. EPA, 2016a, Section <IP_ADDRESS>). Given the
consistent epidemiologic evidence for associations between ambient
NO2 and asthma-related outcomes, including the larger
associations with short-term exposures observed in children, the 2016
NOX ISA concludes the evidence ``is adequate to conclude
that children are at increased risk for NO2-related health
effects'' (U.S. EPA, 2016a, p. 7-32).
Older Adults
    According to the 2012 National Population Projections issued by the
U.S. Census Bureau, 13% of the U.S. population was age 65 years or
older in 2010, and by 2030, this fraction is estimated to grow to 20%
(Ortman et al., 2014). Recent epidemiologic findings expand on evidence
available in the 2008 NOX ISA that older adults may be at
increased risk for NO2-related health effects. (U.S. EPA,
2016a, Table 7-15). While it is not clear that older adults experience
greater NO2 exposures or doses, epidemiologic evidence
generally indicates greater risk of NO2-related health
effects in older adults compared with younger adults. For example,
comparisons of older and younger adults with respect to NO2-
related asthma exacerbation generally show larger (one to threefold)
effects in adults ages 65 years or older than among individuals ages
15-64 years or 15-65 years (Ko et al., 2007; Villeneuve et al., 2007;
Migliaretti et al., 2005; Anderson et al., 1998). Results for all
respiratory hospital admissions combined also tend to show larger
associations with NO2 among older adults ages 65 years or
older (Arbex et al., 2009; Wong et al., 2009; Hinwood et al., 2006;
Atkinson et al., 1999). The 2016 NOX ISA determined that,
overall, the consistent epidemiologic evidence for asthma-related
hospital admissions and ED visits ``is adequate to conclude that older
adults are at increased risk for NO2-related health
effects'' (U.S. EPA, 2016a, p. 7-37).
PA Conclusions on At-Risk Populations
    As described in the PA, and consistent with the last review, the
2016 NOX ISA determined that the available evidence is
adequate to conclude that people with asthma, children, and older
adults are at increased risk for NO2-related health effects.
The large proportions of the U.S. population that encompass each of
these groups and lifestages (i.e., 8% adults and 9.3% children with
asthma, 24% all children, 13% all older adults) underscores the
potential for important public health impacts attributable to
NO2 exposures. These impacts are of particular concern for
members of these populations and lifestages who live, work, attend
school, or otherwise spend a large amount of time in locations of
elevated ambient NO2, including near heavily trafficked
roadways.
3. Overview of Risk and Exposure Assessment Information
    Beyond the consideration of the scientific evidence, discussed
above in Section II.A.2, the EPA also considers the extent to which new
or updated quantitative analyses of NO2 air quality,
exposures, or health risks could inform conclusions on the adequacy of
the public health protection provided by the current primary
NO2 standards. Conducting such quantitative analyses, if
appropriate, could inform judgments about the public health impacts of
NO2-related health effects and could help to place the
evidence for specific effects into a broader public health context. To
this end, in the REA Planning document (U.S. EPA, 2015b) and in the PA
(U.S. EPA, 2017a), the staff evaluated the extent to which the
available evidence and information provide support for conducting new
or updated analyses of NO2 exposures and/or health risks,
beyond the analyses conducted in the 2008 REA (U.S. EPA, 2008b). In
doing so, staff carefully considered the assessments developed as part
of the last review of the primary NO2 NAAQS (U.S. EPA,
2008b) and the newly available scientific and technical information,
particularly considering the degree to which updated analyses in the
current review are likely to substantially add to the understanding of
NO2 exposures and/or health risks. In

developing the final PA, staff also considered the CASAC advice and
public input received on the REA Planning document (U.S. EPA, 2017a,
Chapter 4) and on the draft PA (Diez Roux and Sheppard, 2017). Based on
these considerations, the PA included updated analyses examining the
occurrence of NO2 air quality concentrations (i.e., as
surrogates for potential NO2 exposures) that may be of
public health concern (see below and Appendix B of U.S. EPA, 2017a).
These analyses, summarized below and discussed in more detail in
Chapter 4 of the PA (U.S. EPA, 2017a), have been informed by advice
from the CASAC and input from the public on the REA Planning document
(Diez Roux and Frey, 2015b) and on the draft PA (Diez Roux and
Sheppard, 2017). Updated risk estimates based on information from
epidemiology studies on respiratory health effects associated with
short and long-term exposure to NO2 were not conducted in
the current review given that these analyses would be subject to the
same uncertainties identified in the 2008 REA (U.S. EPA, 2017a, Section
4-1). The CASAC agreed with this conclusion on short-term
NO2 exposures in its review of the REA Planning document,
and for long-term exposures they agreed but encouraged the EPA to
consider the feasibility of such an assessment for long-term exposures
(Diez Roux and Frey, 2015b, p. 5). In its review of the draft PA the
CASAC agreed with the EPA's conclusions on the feasibility of an
epidemiologic risk assessment based on evidence of long-term
NO2 exposures (Diez Roux and Sheppard, 2016, p. 2).\71\
---------------------------------------------------------------------------

    \71\ After considering the factors discussed above, we conclude
that a quantitative risk assessment based on epidemiologic studies
of long-term NO2 exposures is not warranted in this
review because of a lack of U.S. epidemiologic studies identified by
the 2016 NOX ISA as being key studies, lack of baseline
incidence rates for the health effects of interest, uncertainty
regarding the shape of the concentration-response function, and a
lack of studies that have controlled for potential confounders,
making it difficult to determine the true magnitude of effect (U.S.
EPA, 2017a, sections <IP_ADDRESS> and <IP_ADDRESS>).
---------------------------------------------------------------------------

a. Overview of Approach to Estimating Potential NO2
Exposures
    To provide insight into the potential occurrence of NO2
air quality concentrations that may be of public health concern, the PA
included new analyses comparing NO2 air quality to health-
based benchmarks in 23 study areas (U.S. EPA, 2017a, Table 4-1). The
selection of study areas focused on CBSAs with near-road monitors in
operation,\72\ CBSAs with the highest NO2 design values, and
CBSAs with a relatively large number of NO2 monitors overall
(i.e., providing improved spatial characterization).\73\
---------------------------------------------------------------------------

    \72\ As discussed above, near-road monitors are required within
50 m of major roads in large urban areas that met certain criteria
for population size or traffic volume. 40 CFR part 58, appendix E,
Sec. 6.4(a). Most near-road monitors are sited within about 30 m of
the road, and in some cases they are sited almost at the roadside
(i.e., as close as 2 m from the road; http://www3.epa.gov/ttn/amtic/nearroad.html) (U.S. EPA, 2017a, Section 2.2.2).
    \73\ Based on these criteria, a total of 23 CBSAs from across
the U.S. were selected as study areas (U.S. EPA, 2017a, Appendix B,
Figure B2-1). Further evaluation indicates that these 23 study areas
are among the most populated CBSAs in the U.S.; they have among the
highest total NOX emissions and mobile source
NOX emissions in the U.S.; and they include a wide range
of stationary source NOX emissions (U.S. EPA, 2017a,
Appendix B, Figures B2-2 to B2-8).
---------------------------------------------------------------------------

    Air quality-benchmark comparisons were conducted in study areas
with unadjusted air quality and with air quality adjusted upward to
just meet the existing 1-hour standard.\74\ Upward adjustment was
required because all locations in the U.S. meet the current
NO2 NAAQS.
---------------------------------------------------------------------------

    \74\ In all study areas, ambient NO2 concentrations
required smaller upward adjustments to just meet the 1-hour standard
than to just meet the annual standard. Therefore, when adjusting air
quality to just meet the current primary NO2 NAAQS, the
PA applied the adjustment needed to just meet the 1-hour standard.
For additional information on the air quality adjustment approach
see Appendix B, Section B2.4.1 in the PA (U.S. EPA, 2017a).
---------------------------------------------------------------------------

    In identifying the range of NO2 health-based benchmarks
to evaluate, and the weight to place on specific benchmarks within this
range, the PA considered both the group mean responses reported in
individual studies of AR and the results of a meta-analysis that
combined individual-level data from multiple studies (Brown, 2015; U.S.
EPA, 2016a, Section <IP_ADDRESS>). When taken together, the results of
controlled human exposure studies and of the meta-analysis by Brown
(2015) support consideration of NO2 benchmarks from 100 to
300 ppb, based largely on studies of non-specific AR in study
participants exposed to NO2 at rest.\75\ \76\ Given
uncertainties in the evidence, including the lack of an apparent dose-
response relationship and uncertainty in the potential adversity of
reported increases in AR, the risks of these exposures cannot be fully
characterized based on existing studies and caution is appropriate when
interpreting the potential public health implications of 1-hour
NO2 concentrations at or around these benchmarks. This is
particularly the case for the 100 ppb benchmark, given the less
consistent results across individual studies at this exposure
concentration (see Section II.A.2 above and U.S. EPA, 2017a, Section
4.2.1).
---------------------------------------------------------------------------

    \75\ Benchmarks from the upper end of this range are supported
by the results of individual studies, the majority of which
consistently reported statistically significant increases in AR
following NO2 exposures at or above 250 ppb, and by the
results of the meta-analysis by Brown (2015). Benchmarks from the
lower end of this range are supported by the results of the meta-
analysis, even though individual studies generally do not report
statistically significant NO2-induced increases in AR
following exposures below 200 ppb.
    \76\ While benchmarks between 100 to 200 ppb were considered,
analyses were only conducted on concentrations between 100 to 200
ppb as even in the worst-case years (i.e., the years with the
largest number of days at or above benchmarks), no study areas had
any days with 1-hour NO2 concentrations at or above 200
ppb.
---------------------------------------------------------------------------

b. Results of Updated Analyses
    In considering the results of these updated analyses, the EPA
focuses on the number of days per year that 1-hour NO2
concentrations at or above the respective benchmarks could occur at
each monitoring site in each study area.
    Based on the results of these analyses (U.S. EPA, 2017a, Tables 4-1
and 4-2), the EPA makes the following key observations for study areas
when air quality was unadjusted (``as-is'') and when air quality was
adjusted to just meet the current 1-hour NO2 standard (U.S.
EPA, 2017a, Section <IP_ADDRESS>). For unadjusted air quality:
     One-hour ambient NO2 concentrations in study
areas, including those near major roadways, were always below 200 ppb,
and were virtually always below 150 ppb.
    [cir] Even in the worst-case years (i.e., the years with the
largest number of days at or above benchmarks), no study areas had any
days with 1-hour NO2 concentrations at or above 200 ppb, and
only one area had any days (i.e., one day) with 1-hour concentrations
at or above 150 ppb.
     One-hour ambient NO2 concentrations in study
areas, including those near major roadways, only rarely reached or
exceeded 100 ppb. On average in all study areas, 1-hour NO2
concentrations at or above 100 ppb occurred on less than one day per
year.
    [cir] Even in the worst-case years, most study areas had either
zero or one day with 1-hour NO2 concentrations at or above
100 ppb (7 days in the single worst-case location and worst-case year).

For air quality adjusted to just meet the current primary 1-hour
NO2 standard:
     The current standard is estimated to allow no days in
study areas with 1-hour ambient NO2 concentrations at or
above 200 ppb. This is true for both area-wide and near-road monitoring
sites, even in the worst-case years.
     The current standard is estimated to allow almost no days
with 1-hour ambient NO2 concentrations at or above 150 ppb,
based on both area-wide and

near-road monitoring sites (i.e., zero to one day per year, on
average).
    [cir] In the worst-case years in most study areas, the current
standard is estimated to allow either zero or one day with 1-hour
ambient NO2 concentrations at or above 150 ppb. In the
single worst-case year and location, the current standard is estimated
to allow eight such days.
     At area-wide monitoring sites in most of the study areas,
the current standard is estimated to allow from one to seven days per
year, on average, with 1-hour ambient NO2 concentrations at
or above 100 ppb. At near-road monitoring sites in most of the study
areas, the current standard is estimated to allow from about one to 10
days per year with such 1-hour concentrations.
    [cir] In the worst-case years in most of the study areas, the
current standard is estimated to allow from about 5 to 20 days with 1-
hour NO2 concentrations at or above 100 ppb (30 days in the
single worst-case location and year).
c. Uncertainties
    There are a variety of limitations and uncertainties in these
comparisons of NO2 air quality with health-based benchmarks.
In particular, there are uncertainties in the evidence underlying the
benchmarks themselves, uncertainties in the upward adjustment of
NO2 air quality concentrations, and uncertainty in the
degree to which monitored NO2 concentrations reflect the
highest potential NO2 concentrations. Each of these is
discussed below.
i. Health-Based Benchmarks
    The primary goal of this analysis is to inform conclusions
regarding the potential for the existing primary NO2
standards to allow exposures to ambient NO2 concentrations
that may be of concern for public health. As discussed in detail above
(Sections II.A.2), the meta-analysis by Brown (2015) indicates the
potential for increased AR in some people with asthma following
NO2 exposures from 100 to 530 ppb, while individual studies
show more consistent results above 250 ppb. While it is possible that
certain individuals could be more severely affected by NO2
exposures than indicated by existing studies, which have generally
evaluated adults with mild asthma,\77\ there remains uncertainty in the
degree to which the effects identified in individual studies within the
Brown (2015) meta-analysis would be of public health concern,
specifically at lower concentrations (e.g., 100 ppb). In particular,
the uncertainties regarding the potential for adverse effects following
NO2 exposures at lower concentrations when looking across
individual studies complicate the interpretation of comparisons between
ambient NO2 concentrations and health-based benchmarks. When
considered in the context of the less consistent results observed
across individual studies following exposures to 100 ppb
NO2, in comparison to the more consistent results at higher
exposure concentrations,\78\ these uncertainties have the potential to
be of particular importance for interpreting the public health
implications of ambient NO2 concentrations at or around the
100 ppb benchmark.\79\
---------------------------------------------------------------------------

    \77\ Brown (2015, p. 3) notes, however, that one study included
in the meta-analysis (Avol et al., 1989) evaluated children aged 8
to 16 years and that disease status varied across studies, ranging
from ``inactive asthma up to severe asthma in a few studies.''
    \78\ As discussed previously, while the meta-analysis indicates
that a statistically significant majority of study volunteers
experienced increased non-specific AR following exposures to 100 ppb
NO2, results were only marginally significant when
specific AR was also included in the analysis. In addition,
individual studies do not consistently indicate increases in AR
following exposures to 100 ppb NO2.
    \79\ Sensitivity analyses included in Appendix B of the PA (U.S.
EPA, 2017a, Section 3.2, table B3-1) also evaluated 1-hour
NO2 benchmarks below 100 ppb (i.e., 85, 90, 95 ppb),
though the available health evidence does not provide a clear a
basis for determining what exposures to such NO2
concentrations might mean for public health.
---------------------------------------------------------------------------

    With regard to the magnitude and clinical relevance of the
NO2-induced increase in AR in particular, the meta-analysis
by Brown (2015) attempts to address this uncertainty and inconsistency
across individual studies. Specifically, as discussed above (Section
II.A.2), the meta-analysis evaluates the available individual-level
data on the magnitude of the change in AR following resting
NO2 exposures. Brown (2015) reports that the magnitude of
the increases in AR observed following resting NO2 exposures
from 100 to 530 ppb was large enough to be of potential clinical
relevance in about a quarter of the 72 study volunteers with available
data. This is based on the fraction of exposed individuals who
experienced a halving of the PD of challenge agent following
NO2 exposures. This magnitude of change has been recognized
by the ATS and the ERS as a ``potential indicator, although not a
validated estimate, of clinically relevant changes in [AR]'' (Reddel et
al., 2009) (U.S. EPA, 2016a, p. 5-12). Although there is uncertainty in
using this approach to characterize whether a particular response in an
individual is ``adverse,'' it can provide insight into the potential
for adversity, particularly when applied to a population of exposed
individuals. While this analysis by Brown (2015) indicates the
potential for some people with asthma to experience effects of clinical
relevance following resting NO2 exposures from 100 to 530
ppb, it is based on a subset of volunteers for which non-specific AR
was reported following exposures to NO2 and air at rest, and
the interpretation of these results for any specific exposure
concentration within the range of 100 to 530 ppb is uncertain (see
section II.A.2, above).
ii. Approach to Adjusting Ambient NO2 Concentrations
    These analyses use historical air quality relationships as the
basis for adjusting ambient NO2 concentrations to just meet
the current 1-hour standard (U.S. EPA, 2017a, Appendix B). The approach
to adjusting ambient NO2 concentrations was supported by the
CASAC, who found the approach both suitable and appropriate (Diez Roux
and Frey, 2015b, p.1). This approach is meant to illustrate a
hypothetical scenario and does not represent expectations regarding
future air quality trends. There are, however, some uncertainties in
this approach. If ambient NO2 concentrations were to
increase in some locations to the point of just meeting the current
standards, it is not clear that the spatial and temporal relationships
reflected in the historical data would persist. In particular, as
discussed in Section 2.1.2 of the PA (U.S. EPA, 2017a), ongoing
implementation of existing regulations is expected to result in
continued reductions in ambient NO2 concentrations over much
of the U.S. (i.e., reductions beyond the ``unadjusted'' air quality
used in these analyses). Thus, if ambient NO2 concentrations
were to increase to the point of just meeting the existing 1-hour
NO2 standard in some areas, the resulting air quality
patterns may not be similar to those estimated in the PA's air quality
adjustments.
    There is also uncertainty in the upward adjustment of
NO2 air quality because three years of data are not yet
available from most near-road monitors. In most study areas, estimated
DVs were not calculated at near-road monitors and, therefore, near-road
monitors were generally not used as the basis for identifying
adjustment factors for just meeting the existing standard.\80\ In
locations where near-road monitors

measure the highest NO2 DVs, reliance on those near-road
monitors to identify air quality adjustment factors would likely result
in smaller adjustments being applied to monitors in the study area.
Thus, monitors in such study areas would be adjusted upward by smaller
increments, potentially reducing the number of days on which the
current standard is estimated to allow 1-hour NO2
concentrations at or above benchmarks. Given that near-road monitors in
most areas measure higher 1-hour NO2 concentrations than the
area-wide monitors in the same CBSA (U.S. EPA, 2017a, Figures 2-7 to 2-
10), this uncertainty has the potential to impact results in many of
the study areas. While the magnitude of the impact is unknown at
present, the inclusion of additional years of near-road monitoring
information in the determination of air quality adjustments could
result in fewer estimated 1-hour NO2 concentrations at or
above benchmarks in some study areas.
---------------------------------------------------------------------------

    \80\ However, in a few study locations near-road monitors did
contribute to the calculation of air quality adjustments, as
described in Appendix B of the PA (U.S. EPA, 2017a, Table B2-7).
---------------------------------------------------------------------------

iii. Degree to Which Monitored NO2 Concentrations Reflect
the Highest Potential NO2 Exposures
    To the extent there are unmonitored locations where ambient
NO2 concentrations exceed those measured by monitors in the
current network, the potential for NO2 exposures at or above
benchmarks could be underestimated. In the last review, this
uncertainty was determined to be particularly important for potential
exposures on and around roads. The 2008 REA estimated that the large
majority of modeled exposures to ambient NO2 concentrations
at or above benchmarks occurred on or near roads (U.S. EPA, 2008b,
Figures 8-17 and 8-18). When characterizing ambient NO2
concentrations, the 2008 REA attempted to address this uncertainty by
estimating the elevated NO2 concentrations that can occur on
or near the road. These estimates were generated by applying
literature-derived adjustment factors to NO2 concentrations
at monitoring sites located away from the road.
    In the current review, given that the 23 selected study areas have
among the highest NOX emissions in the U.S., and given the
siting characteristics of existing NO2 monitors, this
uncertainty likely has only a limited impact on the results of the air
quality-benchmark comparisons. In particular, as described above,
mobile sources tend to dominate NOX emissions within most
CBSAs, and the 23 study areas evaluated have among the highest mobile
source NOX emissions in the U.S. (U.S. EPA, 2017a, Appendix
B, Section B2.3.2). Most study areas have near-road NO2
monitors in operation, which are required within 50 m of the most
heavily trafficked roadways in large urban areas. The majority of these
near-road monitors are sited within 30 m of the road, and several are
sited within 10 m (see Atlanta, Cincinnati, Denver, Detroit, and Los
Angeles in the EPA's database of metadata for near-road monitors).\81\
Thus, as explained in the PA, even though the location of highest
NO2 concentrations around roads can vary (U.S. EPA, 2017a,
Section 2.1), the near-road NO2 monitoring network, with
monitors sited from 2 to 50 m away from heavily trafficked roads, is
likely to effectively capture the types of locations around roads where
the highest NO2 concentrations can occur.\82\
---------------------------------------------------------------------------

    \81\ This database is found at http://www3.epa.gov/ttn/amtic/nearroad.html.
    \82\ In the current review, sensitivity analyses included in
Appendix B of the PA use updated data from the scientific literature
(Richmond-Bryant et al., 2016) to estimate ``on-road''
NO2 concentrations based on monitored concentrations
around a roadway in Las Vegas (Appendix B, Section B2.4.2). However,
there remains considerable uncertainty in the relationship between
on-road and near-road NO2 concentrations, and in the
degree to which they may differ. Therefore, in evaluating the
potential for roadway-associated NO2 exposures, the PA
focuses on the concentrations at locations of near-road monitors
(U.S. EPA, 2017a, Chapter 4). However, it remains possible that some
areas (e.g., street canyons in urban environments) could have higher
ambient NO2 concentrations than indicated by near-road
monitors. Sensitivity analyses estimating the potential for on-road
NO2 exposures are described in Appendix B of the PA (U.S.
EPA, 2017a).
---------------------------------------------------------------------------

    This conclusion is consistent with the 2016 NOX ISA's
analysis of available data from near-road NO2 monitors,
which indicates that near-road monitors with target roads having the
highest traffic counts also had among the highest 98th percentiles of
1-hour daily maximum NO2 concentrations (U.S. EPA, 2016a,
Section <IP_ADDRESS>). The 2016 NOX ISA concludes that
``[o]verall, the very highest 98th percentile 1-hour maximum
concentrations were generally observed at the monitors adjacent to
roads with the highest traffic counts'' (U.S. EPA, 2016a, p. 2-66).
    It is also important to consider the degree to which air quality-
benchmark comparisons appropriately characterize the potential for
NO2 exposures near non-roadway sources of NOX
emissions. As noted in the PA, the 23 selected study areas include
CBSAs with large non-roadway sources of NOX emissions. This
includes study areas with among the highest NOX emissions
from electric power generation facilities (EGUs) and airports, the two
types of non-roadway sources that are associated with the highest
NOX emissions in the U.S (U.S. EPA, 2017a, Appendix B,
Section B2.3.2).
    While it is difficult to isolate non-road impacts from certain non-
road sources like ports and airports, looking at monitors that are
influenced by non-road emissions can help characterize the potential
for such exposures. As discussed below, several study areas have non-
near-road NO2 monitors sited to better characterize the
impacts of such sources.
    As described in the PA (U.S. EPA, 2017a, Section <IP_ADDRESS>), table 2-
12 in the 2016 NOX ISA (U.S. EPA, 2016a) summarizes
NO2 concentrations at selected monitoring sites that are
likely to be influenced by non-road sources, including ports, airports,
border crossings, petroleum refining, or oil and gas drilling. For
example, the Los Angeles, CA, CBSA includes one of the busiest ports
and one of the busiest airports in the U.S. Out of 18 monitors in the
Los Angeles CBSA, three of the five highest 98th percentile 1-hour
maximum concentrations were observed at the near-road site, the site
nearest the port, and the site adjacent to the airport (U.S. EPA,
2016a, section <IP_ADDRESS>). In the Chicago, IL, CBSA, the highest hourly
NO2 concentration measured in 2014 (105 ppb) occurred at the
Schiller Park, IL monitoring site, located adjacent to O'Hare
International Airport, and very close to a major rail yard (i.e.,
Bedford Park Rail Yard) and to a four-lane arterial road (US 12 and US
45) (U.S. EPA, 2016a, Section <IP_ADDRESS>). Thus, beyond the NO2
near-road monitors, some NO2 monitors in study areas are
also sited to capture high ambient NO2 concentrations around
important non-roadway sources of NOX emissions. In addition,
one of the highest 1-hour daily maximum NO2 concentrations
recorded in recent years (136 ppb) was observed at a Denver, CO, site
that is not part of the near-road monitoring network. This
concentration was observed at a monitor located one block from high-
rise buildings that form the edge of the high-density central business
district. This monitor is likely influenced by commercial heating and
other activities, as well as local traffic (U.S. EPA, 2016a, Section
<IP_ADDRESS>).
d. Conclusions
    As discussed above and in the REA Planning document (U.S. EPA,
2015b, Section 2.1.1), an important uncertainty identified in the 2008
REA was the characterization of 1-hour NO2 concentrations
around major roadways. In the current review, data from recently
deployed near-road NO2 monitors improves understanding of
such ambient NO2 concentrations.
    As discussed in Section I.B, recent NO2 concentrations
measured in all U.S.

locations meet the existing primary NO2 NAAQS. Based on
these recent (i.e., unadjusted) ambient measurements, analyses estimate
almost no potential for 1-hour exposures to NO2
concentrations at or above benchmarks, even at the lowest benchmark
examined (i.e., 100 ppb).
    Analyses of air quality adjusted upwards to just meet the current
1-hour standard estimate no days with 1-hour NO2
concentrations at or above the 200 ppb benchmark, and virtually none
for exposures at or above 150 ppb. This is the case for all years,
including worst-case years and in study areas with near-road monitors
sited within a few meters of heavily trafficked roads. With respect to
the lowest benchmark evaluated, analyses estimate that the current 1-
hour standard allows the potential for exposures to 1-hour
NO2 concentrations at or above 100 ppb on some days (e.g.,
in most study areas, about one to 10 days per year, on average).\83\
---------------------------------------------------------------------------

    \83\ Because the results show almost no days with 1-hour ambient
NO2 concentrations above 150 ppb, the results for the 100
ppb benchmark are due primarily to 1-hour NO2
concentrations that are closer to 100 ppb than 200 ppb.
---------------------------------------------------------------------------

    These results are consistent with expectations, given that the
current 1-hour standard, with its 98th percentile form, is anticipated
to limit, but not eliminate, exposures to 1-hour NO2
concentrations at or above 100 ppb.\84\ These results are similar to
the results presented in the REA from the last review (U.S. EPA, 2008b,
tables 7-23 through 7-25), based on NO2 concentrations at
the locations of area-wide ambient monitors (U.S. EPA, 2017a, Appendix
B, Section B5.9, Table B5-66). In contrast, compared to the on/near-
road simulations in the last review, these results indicate
substantially less potential for 1-hour exposures to NO2
concentrations at or above these benchmarks, though there is some
uncertainty as to whether these results fully characterize on and near-
road exposures, in part because most near-road monitors do not yet have
three years of data. (U.S. EPA, 2017a, Appendix B, Section B5.9, Table
B5-66).\85\
---------------------------------------------------------------------------

    \84\ The 98th percentile generally corresponds to the 7th or 8th
highest 1-hour concentration in a year.
    \85\ On-/near-road simulations in the last review estimated that
a 1-hour NO2 standard with a 98th percentile form and a
100 ppb level could allow about 20 to 70 days per year with 1-hour
NO2 concentrations at or above the 200 ppb benchmark and
about 50 to 150 days per year with 1-hour concentrations at or above
the 100 ppb benchmark (U.S. EPA, 2017a, Appendix B, Table B5-66).
---------------------------------------------------------------------------

    When these results and associated uncertainties are taken together,
the current 1-hour NO2 standard is expected to allow
virtually no potential for exposures to the NO2
concentrations that have been shown most consistently to increase AR in
people with asthma (i.e., above 200 ppb), even under worst-case
conditions across a variety of study areas with among the highest
NOX emissions in the U.S. Such NO2 concentrations
were not estimated to occur, even at monitoring sites adjacent to some
of the most heavily trafficked roadways. In addition, the current
standard is expected to limit, though not eliminate, exposures to 1-
hour concentrations at or above 100 ppb. Though the current standard is
estimated to allow 1-hour NO2 concentrations at or above 100
ppb on some days, there is uncertainty regarding the adversity of the
reported NO2-induced increases in AR following exposures to
100 ppb NO2. However, by limiting exposures to
NO2 concentrations at or above 100 ppb, the current standard
provides protection against exposures to higher NO2
concentrations, for which the evidence of potentially adverse
NO2-attributable effects is more consistent, as well as
against exposures to NO2 concentrations at 100 ppb, for
which the evidence of potentially adverse NO2-attributable
effects is less consistent, but where the meta-analysis indicates that
a marginally significant majority of study participants experienced an
increase in AR following exposures (Brown, 2015).
    Given the results of these analyses, and the uncertainties inherent
in their interpretation, the PA concludes that there is little
potential for exposures to ambient NO2 concentrations that
would be of clear public health concern in locations meeting the
current 1-hour standard. Additionally, while a lower level for the 1-
hour standard (i.e., lower than 100 ppb) would be expected to further
limit the potential for exposures to 100 ppb NO2, the public
health implications of such reductions are unclear, particularly given
that no additional protection would be expected against exposures to
NO2 concentrations at or above the higher benchmarks (i.e.,
200 ppb and above), as the REA analyses already estimate no days with
1-hour NO2 concentrations at or above the 200 ppb benchmark
in areas just meeting the current 1-hour standard. Thus, the PA
concludes that these analyses comparing ambient NO2
concentrations to health-based benchmarks do not provide support for
considering potential alternative standards that provide a different
degree of public health protection. Additionally, in its review of the
PA, the CASAC stated that it was ``satisfied with the short-term
exposure health-based benchmark analysis presented in the draft PA''
and that it ``support[ed] the decision not to conduct any new or
updated quantitative risk analyses related to long-term exposure to
NO2'' (Diez Roux and Sheppard, 2017).

B. Conclusions on the Primary Standards

    In drawing conclusions on the adequacy of the current primary
NO2 standards, in view of the advances in scientific
knowledge and additional information now available, the Administrator
considers the evidence base, information, and policy judgments that
were the foundation of the last review and reflects upon the body of
evidence and information newly available in this review. In so doing,
the Administrator has taken into account both evidence-based and
exposure- and risk-based considerations, advice from the CASAC, and
public comment. Evidence-based considerations draw upon the EPA's
assessment and integrated synthesis of the scientific evidence from
epidemiological studies and controlled human exposure studies
evaluating health effects related to exposures to NO2 as
presented in the ISA, with a focus on policy-relevant considerations as
discussed in the PA. The exposure- and risk-based considerations draw
from the results of the quantitative analyses presented in the 2008 REA
and the additional updated analyses presented in the PA (as summarized
in section II.D of the proposal and section II.A.3 above) and
consideration of these results in the PA. As described in section
II.A.2 of the proposal, consideration of the evidence and exposure/risk
information in the PA and by the Administrator is framed by
consideration of a series of key policy-relevant questions. Section
II.B.1 below summarizes the rationale for the Administrator's proposed
decision, drawing from section II.E.4 of the proposal. Advice received
from the CASAC in this review is briefly summarized in section II.B.2
below. A fuller presentation of PA considerations and conclusions, and
advice from the CASAC, which were all taken into account by the
Administrator, is provided in sections II.E.1 through II.E.3 of the
proposal. Public comments on the proposed decision are addressed in
section II.B.3 below. The Administrator's conclusions in this review
regarding the current primary standards are described in section II.B.4
below.
1. Basis for the Proposed Decision
    At the time of the proposal, the Administrator carefully considered
the

assessment of the current evidence and the conclusions reached in the
2016 NOX ISA; the currently available exposure/risk
information, including associated limitations and uncertainties;
considerations and staff conclusions and associated rationales
presented in the PA; the advice and recommendations from the CASAC; and
public comments that had been offered up to that point. In reaching his
proposed conclusion on the primary standard, the Administrator took
note of evidence-based considerations (as summarized in section
II.B.1.a below) and exposure- and risk-based considerations (as
summarized in section II.B.1.b below).
a. Evidence-Based Considerations
    In considering the evidence available in the current review with
regard to adequacy of the current 1-hour and annual NO2
standards, the first topic of consideration was the nature of the
health effects attributable to NO2 exposures, drawing upon
the integrated synthesis of the health evidence in the 2016
NOX ISA and the evaluations in the PA (Chapter 3). The
following questions guided this consideration: (1) To what extent does
the currently available scientific evidence alter or strengthen
conclusions from the last review regarding health effects attributable
to ambient NO2 exposures? (2) Are previously identified
uncertainties reduced or do important uncertainties remain? (3) Have
new uncertainties been identified? These questions were addressed in
the proposal for both short-term and long-term NO2
exposures, with a focus on health endpoints for which the 2016
NOX ISA concludes that the evidence indicates there is a
``causal'' or ``likely to be a causal'' relationship.
    With regard to short-term NO2 exposures, the proposal
noted that, as in the last review, the strongest evidence continues to
come from studies examining respiratory effects. In particular, the
2016 NOX ISA concludes that evidence indicates a ``causal''
relationship between short-term NO2 exposure and respiratory
effects, based on evidence related to asthma exacerbation. While this
conclusion reflects a strengthening of the causal determination,
compared to the last review, this strengthening is based largely on a
more specific integration of the evidence related to asthma
exacerbations rather than on the availability of new, stronger
evidence. The proposal further noted that additional evidence has
become available since the last review, as summarized below. However,
this evidence has not fundamentally altered the understanding of the
relationship between short-term NO2 exposures and
respiratory effects.
    The strongest evidence supporting this ISA causal determination
comes from controlled human exposure studies demonstrating
NO2-induced increases in AR in individuals with asthma. A
meta-analysis of data from these studies indicates the majority of
exposed individuals, generally with mild asthma, experienced increased
AR following exposures to NO2 concentrations as low as 100
ppb, while individual studies most consistently report such increases
following exposures to NO2 concentrations at or above 250
ppb. Most of the controlled human exposure studies assessed in the 2016
NOX ISA were available in the last review, particularly
studies of non-specific AR. As in the last review, there remains
uncertainty due to the lack of an apparent dose-response relationship
between NO2 exposures and AR and uncertainty in the
potential adversity of NO2-induced increases in AR.\86\
---------------------------------------------------------------------------

    \86\ This is particularly true at low concentrations (i.e., 100
ppb).
---------------------------------------------------------------------------

    Supporting evidence for a range of NO2-associated
respiratory effects also comes from epidemiologic studies. In this
regard, the proposal placed particular focus on studies that have
examined NO2 associations with asthma-related hospital
admissions or ED visits, outcomes which are clearly adverse. While some
recent epidemiologic studies provide new evidence based on improved
exposure characterizations and copollutant modeling, these studies are
consistent with the evidence from the last review and do not
fundamentally alter the understanding of the respiratory effects
associated with ambient NO2 exposures. Due to limitations in
the available epidemiologic methods, uncertainty remains in the current
review regarding the extent to which findings for NO2 are
confounded by traffic-related copollutants (e.g., PM2.5, EC/
BC, CO), as well as regarding the potential for exposure measurement
error and the extent to which near-road NO2 concentrations
are reflected in the available air quality data.
    Thus, while some new evidence is available in this review, the
proposal noted that that new evidence did not substantially alter the
understanding of the respiratory effects that occur following short-
term NO2 exposures. This evidence is summarized in Section
II.C.1 of the proposal, as well as in Section II.A.2 above, and is
discussed in detail in the 2016 NOX ISA (U.S. EPA, 2016a,
section 5.2.2).
    With regard to long-term NO2 exposures, the 2016
NOX ISA concludes that there is ``likely to be a causal
relationship'' between long-term NO2 exposure and
respiratory effects, based largely on the evidence for asthma
development in children. New epidemiologic studies of asthma
development have increasingly utilized improved exposure assessment
methods (i.e., measured or modeled concentrations at or near children's
homes and followed for many years), which partly reduces uncertainties
from the last review related to exposure measurement error. Explicit
integration of evidence for individual outcome categories (e.g., asthma
incidence, respiratory infection) provides an improved characterization
of biological plausibility and mode of action. This improved
characterization includes the assessment of new evidence supporting a
potential role for repeated short-term NO2 exposures in the
development of asthma. Uncertainties in interpreting associations with
asthma development include high correlations between long-term average
ambient concentrations of NO2 and long-term concentrations
of other traffic-related pollutants, together with the general lack of
epidemiologic studies evaluating copollutant models that include
traffic-related pollutants. Specifically, the extent to which
NO2 may be serving primarily as a surrogate for the broader
traffic-related pollutant mix remains unclear. Thus, while the evidence
for respiratory effects related to long-term NO2 exposures
has become stronger since the last review, there remain important
uncertainties to consider in evaluating this evidence within the
context of the adequacy of the current standards. This evidence is
summarized in Section II.C.2 of the proposal, as well as in Section
II.A.2 above, and is discussed in detail in the 2016 NOX ISA
(U.S. EPA, 2016a, section 6.2.2).
    Given the evaluation of the evidence in the 2016 NOX
ISA, and the 2016 NOX ISA's causal determinations, the EPA's
further consideration of the evidence in the proposal focused on
studies of asthma exacerbation (short-term exposures) and asthma
development (long-term exposures) and on what these bodies of evidence
indicate with regard to the basic elements of the current primary
NO2 standards. In particular, the EPA considered the
following question: To what extent does the available evidence for
respiratory effects attributable to either short- or long-term
NO2 exposures support or call into question the basic
elements of the

current primary NO2 standards? In addressing this question,
the sections below summarize the proposal's consideration of the
evidence in the context of the indicator, averaging times, levels, and
forms of the current standards.
i. Indicator
    The indicator for both the current annual and 1-hour NAAQS for
oxides of nitrogen is NO2. While the presence of gaseous
species other than NO2 has long been recognized (U.S. EPA,
2016a, Chapter 2), no alternative to NO2 has been advanced
as being a more appropriate surrogate for ambient gaseous oxides of
nitrogen. Both previous and recent controlled human exposure studies
and animal toxicology studies provide specific evidence for health
effects following exposure to NO2. Similarly, the large
majority of epidemiologic studies report health effect associations
with NO2, as opposed to other gaseous oxides of nitrogen. In
addition, because emissions that lead to the formation of
NO2 generally also lead to the formation of other
NOX oxidation products, measures leading to reductions in
population exposures to NO2 can generally be expected to
lead to reductions in population exposures to other gaseous oxides of
nitrogen. Therefore, an NO2 standard can also be expected to
provide some degree of protection against potential health effects that
may be independently associated with other gaseous oxides of nitrogen
even though such effects are not discernable from currently available
studies. Given these considerations, the PA reached the conclusion that
it is appropriate in the current review to consider retaining the
NO2 indicator for standards meant to protect against
exposures to gaseous oxides of nitrogen. In its review of the draft PA,
the CASAC agreed with this conclusion (Diez Roux and Sheppard, 2017).
In light of these considerations, EPA proposed to retain the indicator
for the current standards.
ii. Averaging Time
    The current primary NO2 standards are based on 1-hour
and annual averaging times. The proposal explained that, together,
these standards can provide protection against short- and long-term
NO2 exposures.
    In establishing the 1-hour standard in the last review, the
Administrator considered evidence from both experimental and
epidemiologic studies. She noted that controlled human exposure studies
and animal toxicological studies provided evidence that NO2
exposures from less than one hour up to three hours can result in
respiratory effects such as increased AR and inflammation. These
included five controlled human exposure studies that evaluated the
potential for increased AR following 1-hour exposures to 100 ppb
NO2 in people with asthma. In addition, epidemiologic
studies had reported health effect associations with both 1-hour and
24-hour NO2 concentrations, without indicating that either
of these averaging periods was more closely linked with reported
effects. Thus, the available experimental evidence provided support for
considering an averaging time of shorter duration than 24 hours while
the epidemiologic evidence provided support for considering both 1-hour
and 24-hour averaging times. Given this evidence, the Administrator
concluded that, at a minimum, a primary concern with regard to
averaging time was the level of protection provided against 1-hour
NO2 exposures. Based on available analyses of NO2
air quality, she further concluded that a standard with a 1-hour
averaging time could also be effective at protecting against effects
associated with 24-hour NO2 exposures (75 FR 6502, February
9, 2010).
    Based on the considerations summarized above, the Administrator
judged in the last review that it was appropriate to set a new
NO2 standard with a 1-hour averaging time. She concluded
that such a standard would be expected to effectively limit short-term
(e.g., 1- to 24-hours) NO2 exposures that had been linked to
adverse respiratory effects. She also retained the existing annual
standard to continue to provide protection against effects potentially
associated with long-term exposures to oxides of nitrogen (75 FR 6502,
February 9, 2010). These decisions were consistent with the CASAC
advice in the last review to establish a short-term primary standard
for oxides of nitrogen based on using 1-hour maximum NO2
concentrations and to retain the current annual standard (Samet, 2008,
p. 2; Samet, 2009, p. 2).
    The proposal explained that, as in the last review, support for a
standard with a 1-hour averaging time comes from both the experimental
and epidemiologic evidence. Controlled human exposure studies evaluated
in the 2016 NOX ISA continue to provide evidence that
NO2 exposures from less than one hour up to three hours can
result in increased AR in individuals with asthma (U.S. EPA, 2016a,
Tables 5-1 and 5-2). These controlled human exposure studies provide
key evidence supporting the 2016 NOX ISA's determination
that ``[a] causal relationship exists between short-term NO2
exposure and respiratory effects based on evidence for asthma
exacerbation'' (U.S. EPA, 2016a, p. 1-17). In addition, the
epidemiologic literature assessed in the 2016 NOX ISA
provides support for short-term averaging times ranging from 1 hour up
to 24 hours (e.g., U.S. EPA, 2016a Figures 5-3, 5-4 and Table 5-12). As
in the last review, the 2016 NOX ISA concludes that there is
no indication of a stronger association for any particular short-term
duration of NO2 exposure (U.S. EPA, 2016a, section 1.6.1).
Thus, a 1-hour averaging time reasonably reflects the exposure
durations used in the controlled human exposure studies that provide
the strongest support for the 2016 NOX ISA's determination
of a causal relationship. In addition, a standard with a 1-hour
averaging time is expected to provide protection against the range of
short-term exposure durations that have been associated with
respiratory effects in epidemiologic studies (i.e., 1 hour to 24
hours). Thus, in the PA, staff reached the conclusion that, when taken
together, the combined evidence from experimental and epidemiologic
studies continues to support an NO2 standard with a 1-hour
averaging time to protect against health effects related to short-term
NO2 exposures. In its review of the draft PA, the CASAC
found that there continued to be scientific support for the 1-hour
averaging time (Diez Roux and Sheppard, 2017, p. 7). In light of these
considerations, EPA proposed to retain the averaging time for the
current 1-hour standard.
    With regard to protecting against long-term exposures, the proposal
explained that the evidence supports considering the overall protection
provided by the combination of the annual and 1-hour standards. The
current annual standard was originally promulgated in 1971 (36 FR 8186,
April 30, 1971), based on epidemiologic studies reporting associations
between respiratory disease and long-term exposure to NO2.
The annual standard was retained in subsequent reviews, in part to
provide a margin of safety against the serious effects reported in
animal studies using long-term exposures to high NO2
concentrations (e.g., above 8,000 ppb) (U.S. EPA, 1995, section 7).
    As described above, evidence newly available in the current review
demonstrates associations between long-term NO2 exposures
and asthma development in children, based on NO2
concentrations averaged over year of birth, year of diagnosis, or
entire lifetime. Supporting evidence indicates that repeated short-term
NO2 exposures could contribute to this asthma development.
In particular, the 2016

NOX ISA states that ``findings for short-term NO2
exposure support an effect on asthma development by describing a
potential role for repeated exposures to lead to recurrent inflammation
and allergic responses,'' which are ``identified as key early events in
the proposed mode of action for asthma development'' (U.S. EPA, 2016a,
pp. 6-64 and 6-65). Taken together, the evidence supports the potential
for recurrent short-term NO2 exposures to contribute to the
asthma development that has been reported in epidemiologic studies to
be associated with long-term exposures. For these reasons, the PA
reached the conclusion that, in establishing standards to protect
against adverse health effects related to long-term NO2
exposures, the evidence supports the consideration of both 1-hour and
annual averaging times. In its review of the draft PA, the CASAC
supported this approach of considering the protection provided against
long-term NO2 exposures by considering the combination of
the annual and 1-hour NO2 standards. With reference to the
current annual standard, the CASAC specifically noted that ``it is the
suite of the current 1-hour and annual standards, together, that
provide protection against adverse effects'' (Diez Roux and Sheppard,
2017, p. 9). In light of these considerations, EPA proposed to retain
the averaging time for the current annual standard.
iii. Level and Form
    In evaluating the extent to which evidence supports or calls into
question the levels or forms of the current NO2 standards,
the EPA considered the following question: To what extent does the
evidence indicate adverse respiratory effects attributable to short- or
long-term NO2 exposures lower than previously identified or
below the existing standards? In addressing this question, it is useful
to consider the range of NO2 exposure concentrations that
have been evaluated in experimental studies (controlled human exposure
and animal toxicology) and the ambient NO2 concentrations in
locations where epidemiologic studies have reported associations with
adverse outcomes. The proposal's consideration of these issues is
discussed below for short-term and long-term NO2 exposures.
Short-Term
    Controlled human exposure studies demonstrate the potential for
increased AR in some people with asthma following 30-minute to 1-hour
exposures to NO2 concentrations near those in the ambient
air (U.S. EPA, 2017a, Section 3.2.2).\87\ In evaluating the
NO2 exposure concentrations at which increased AR has been
observed, the proposal considered both the group mean results reported
in individual studies and the results from a recent meta-analysis
evaluating individual-level data (Brown, 2015; U.S. EPA, 2016a, Section
<IP_ADDRESS>).\88\
---------------------------------------------------------------------------

    \87\ As discussed in Section II.C of the proposal and Section
II.A.2 above, experimental studies have not reported other
respiratory effects following short-term exposures to NO2
concentrations at or near those found in the ambient air.
    \88\ As noted earlier in this section, group mean responses in
individual studies, and the variability in those responses, can
provide insight into the extent to which observed changes in AR are
due to NO2 exposures, rather than to chance alone,
allowing us to evaluate the strength of the NO2 and AR
relationship across different concentrations of NO2 in
each study, and these studies have the advantage of being based on
the same exposure conditions. The meta-analysis by Brown (2015) can
also provide insight into the extent to which observed changes are
due to NO2 exposures, but has the additional benefit of
aiding in the identification of trends in individual-level responses
across studies and has the advantage of increased power to detect
effects, even in the absence of statistically significant effects in
individual studies, though each study in the meta-analysis may not
be based on the exact same exposure conditions.
---------------------------------------------------------------------------

    When individual-level data were combined in a meta-analysis, Brown
(2015) reported that statistically significant majorities of study
participants experienced increased AR following resting exposures to
NO2 concentrations from 100 to 530 ppb. In some affected
individuals, the magnitudes of these increases were large enough to
have potential clinical relevance. Following exposures to 100 ppb
NO2 specifically, the lowest exposure concentration
evaluated, a marginally statistically significant majority of study
participants experienced increased AR.\89\ As discussed in more detail
in Section II.C.1 of the proposal, and in Section II.A.2 above,
individual studies consistently report statistically significant
NO2-induced increases in AR following resting exposures to
NO2 concentrations at or above 250 ppb but have generally
not reported statistically significant increases in AR following
resting exposures to NO2 concentrations from 100 to 200 ppb.
Limitations in this evidence include the lack of an apparent dose-
response relationship between NO2 and AR and remaining
uncertainty in the adversity of the reported increases in AR. These
uncertainties become increasingly important at the lower NO2
exposure concentrations (i.e., at or near 100 ppb), as the evidence for
NO2-induced increases in AR becomes less consistent across
studies at these lower concentrations.
---------------------------------------------------------------------------

    \89\ Brown (2015) reported a p-value of 0.08 when data were
combined from studies of specific and non-specific AR. When the
analysis was restricted only to non-specific AR following exposures
to 100 ppb NO2, the percentage who experienced increased
AR was larger and statistically significant. In contrast, when the
analysis was restricted only to specific AR following exposures to
100 ppb NO2, the majority of study participants did not
experience increased AR (U.S. EPA, 2016a; Brown 2015).
---------------------------------------------------------------------------

    The epidemiologic evidence from U.S. and Canadian studies, as
considered in the PA and summarized in the proposal, provided
information about the ambient NO2 concentrations in
locations where such studies have examined associations with asthma-
related hospital admissions or ED visits (short-term) or with asthma
incidence (long-term). In particular, these studies informed
consideration of the extent to which NO2-health effect
associations are consistent, precise, statistically significant, and
present for distributions of ambient NO2 concentrations that
likely would have met the current standards. To the extent
NO2-health effect associations are reported in study areas
that would likely have met the current standards, the evidence would
support the potential for the current standards to allow the
NO2-associated effects indicated by those studies. In the
absence of studies reporting associations in locations meeting the
current NO2 standards, there would be greater uncertainty
regarding the potential for reported effects to be caused by
NO2 exposures that occur with air quality meeting those
standards. There are also important uncertainties in the epidemiologic
evidence which warrant consideration, including the potential for
copollutant confounding and exposure measurement error and the extent
to which near-road NO2 concentrations are reflected in the
available air quality data.
    With regard to epidemiologic studies of short-term NO2
exposures conducted in the U.S. or Canada, the proposal noted the
following. First, the only recent multicity study evaluated (Stieb et
al., 2009), which had maximum 1-hour DVs ranging from 67 to 242 ppb,
did not report a positive association between NO2 and ED
visits. In addition, of the single-city studies (U.S. EPA, 2017a,
Figure 3-1) that reported positive and relatively precise associations
between NO2 and asthma hospital admissions and ED visits,
most locations had NO2 concentrations likely to have
violated the current 1-hour NO2 standard over at least part
of the study period. Specifically, most of these locations had maximum
estimated DVs at or above 100 ppb and, had near-road NO2
monitors been in place during study periods, DVs would likely have been
higher. Thus, it is likely that even

the one study location with a maximum DV of 100 ppb (Atlanta) would
have violated the existing 1-hour standard during study periods.\90\
For the study locations with maximum DVs below 100 ppb, mixed results
have been reported, with associations that are generally statistically
non-significant and imprecise. As with the studies reporting more
precise associations, near-road monitors were not in place during these
study periods. If they had been, 1-hour DVs could have been above 100
ppb. In drawing conclusions based on this epidemiologic evidence, the
proposal also considered the potential for copollutant confounding as
ambient NO2 concentrations are often highly correlated with
other pollutants. This can complicate attempts to distinguish between
independent effects of NO2 and effects of the broader
pollutant mixture. While this has been addressed to some extent in
available studies, uncertainty remains for the most relevant
copollutants (i.e., those related to traffic such as PM2.5,
EC/BC, and CO). Taken together, while available U.S. and Canadian
epidemiologic studies report NO2-associated hospital
admissions and ED visits in locations likely to have violated the
current 1-hour NO2 standard, the proposal placed weight on
the PA's conclusion that these studies do not indicate the occurrence
of such NO2-associated effects in locations and time periods
with NO2 concentrations that would clearly have met the
current 1-hour NO2 standard (i.e., with its level of 100 ppb
and 98th percentile form).
---------------------------------------------------------------------------

    \90\ Based on recent air quality information for Atlanta, 98th
percentiles of daily maximum 1-hour NO2 concentrations
are higher at near-road monitors than non-near-road monitors (U.S.
EPA, 2017a, Figures 2-9 and 2-10). These differences could have been
even more pronounced during study periods, when NOX
emissions from traffic sources were higher (U.S. EPA, 2017a, Section
2.1.2).
---------------------------------------------------------------------------

    In giving further consideration specifically to the form of the 1-
hour standard, the proposal noted that the available evidence and
information in this review is consistent with that informing
consideration of form in the last review. The last review focused on
the upper percentiles of the distribution of NO2
concentrations based, in part, on evidence for health effects
associated with short-term NO2 exposures from experimental
studies which provided information on specific exposure concentrations
that were linked to respiratory effects (75 FR 6475, February 9, 2010).
In that review, the EPA specified a 98th percentile form, rather than a
99th percentile, for the new 1-hour standard. In combination with the
1-hour averaging time and 100 ppb level, a 98th percentile form was
judged to provide appropriate public health protection. In addition,
compared to the 99th percentile, a 98th percentile form was expected to
provide greater regulatory stability.\91\ In addition, the proposal
noted that a 98th percentile form is consistent with the EPA's
consideration of uncertainties in the health effects that have the
potential to occur at 100 ppb. Specifically, when combined with the 1-
hour averaging time and the level of 100 ppb, the 98th percentile form
limits, but does not eliminate, the potential for exposures to 100 ppb
NO2.\92\ In light of these considerations, EPA proposed to
retain the level and form for the current 1-hour standard.
---------------------------------------------------------------------------

    \91\ As noted in the last review, a less stable form could
result in more frequent year-to-year shifts between meeting and
violating the standard, potentially disrupting ongoing air quality
planning without achieving public health goals (75 FR 6493, February
9, 2010).
    \92\ The 98th percentile typically corresponds to about the 7th
or 8th highest daily maximum 1-hour NO2 concentration in
a year.
---------------------------------------------------------------------------

Long-Term
    With regard to health effects related to long-term NO2
exposures, the proposal first considered the basis for the current
annual standard. It was originally set to protect against
NO2-associated respiratory disease in children reported in
some epidemiologic studies (36 FR 8186, April 30, 1973). In subsequent
reviews, the EPA has retained the annual standard, judging that it
provides protection with an adequate margin of safety against the
effects that have been reported in animal studies following long-term
exposures to NO2 concentrations well above those found in
the ambient air (e.g., above 8,000 ppb for the development of lesions
similar to those found in humans with emphysema) (60 FR 52879, October
11, 1995). In the 2010 review, the EPA noted that, though some evidence
supported the need to limit long-term exposures to NO2, the
evidence for adverse health effects attributable to long-term
NO2 exposures did not support changing the level of the
annual standard (75 FR 6474, February 9, 2010).
    In the current review, the strengthened ``likely to be causal''
relationship between long-term NO2 exposures and respiratory
effects is supported by epidemiologic studies of asthma development and
related effects demonstrated in animal toxicological studies. While
these studies strengthen the evidence for effects of long-term
exposures, compared to the last review, they are subject to
uncertainties resulting from the methods used to assign NO2
exposures, the high correlations between NO2 and other
traffic-related pollutants, and the lack of information regarding the
extent to which reported effects are independently associated with
NO2 rather than the overall mixture of traffic-related
pollutants. The potential for such confounding is particularly
important to consider when interpreting epidemiologic studies of long-
term NO2 exposures given: (1) The relatively high
correlations observed between measured and modeled long-term ambient
concentrations of NO2 and long-term concentrations of other
roadway-associated pollutants; (2) the general lack of information from
copollutant models on the potential for NO2 associations
that are independent of other traffic-related pollutants or mixtures;
and (3) the general lack of supporting information from experimental
studies that evaluate long-term exposures to NO2
concentrations near those in the ambient air. Thus, it remains unclear
the degree to which the observed effects in these studies are
independently related to exposure to ambient concentrations of
NO2. The epidemiologic evidence from some U.S. and Canadian
studies is also subject to uncertainty with regard to the extent to
which the studies accurately characterized exposures of the study
populations, further limiting what these studies can tell us regarding
the adequacy of the current primary NO2 standards.
    While the proposal recognized the above uncertainties, it
considered what studies of long-term NO2 and asthma
development indicate with regard to the adequacy of the current primary
NO2 standards. As discussed above for short-term exposures,
the proposal considered the degree to which the evidence indicates
adverse respiratory effects associated with long-term NO2
exposures in locations that would have met the current NAAQS. As
summarized in Section II.C.2 of the proposal, and in Section II.A.2
above, the causal determination for long-term exposures is supported
both by studies of long-term NO2 exposures and by studies
indicating a potential role in asthma development for repeated short-
term exposures to high NO2 concentrations.\93\
---------------------------------------------------------------------------

    \93\ There remains some uncertainty as to whether the health
effects associated with long term exposure to NO2 are due
to repeated higher short term exposures, a longer, cumulative
exposure, or some mixture of both.
---------------------------------------------------------------------------

    As such, when considering the ambient NO2 concentrations
present during study periods, the proposal considered these
concentrations within

the context of both the 1-hour and annual NO2 standards.
Analyses of historical data indicate that 1-hour DVs at or below 100
ppb generally correspond to annual DVs below 35 ppb.\94\ The CASAC
noted this relationship, stating that ``attainment of the 1-hour
standard corresponds with annual design value averages of 30 ppb
NO2'' (Diez Roux and Sheppard, 2017). Thus, meeting the 1-
hour standard with its level of 100 ppb would be expected to maintain
annual average NO2 concentrations below the 53 ppb level of
the current annual standard.
---------------------------------------------------------------------------

    \94\ As noted in the PA, near-road monitors were not included in
this analysis due to the limited amount of data available (U.S. EPA,
2017a, Figure 2-11).
---------------------------------------------------------------------------

    As discussed in Section II.C.1 of the proposal, and in Section
II.A.2 above, while annual estimated DVs in study locations were often
below 53 ppb, maximum 1-hour estimated DVs in most locations were near
or above 100 ppb. Because these study-specific estimated DVs are based
on the area-wide NO2 monitors in place during study periods,
they do not reflect the NO2 concentrations near the largest
roadways, which are expected to be higher in most urban areas. Had
near-road monitors been in place during study periods estimated
NO2 DVs based on near-road concentrations likely would have
been higher in many locations, and would have been more likely to
exceed the level of the annual and/or 1-hour standard(s) (U.S. EPA,
2016a, section <IP_ADDRESS>, e.g., Tables 2-6 and 2-8, Figures 2-16 and 2-
17).
    Given the paucity of epidemiologic studies conducted in areas that
were close to or below the current standards, and considering that no
near-road monitors were in place during the study periods, the proposal
placed weight on the PA's conclusion that the epidemiologic evidence
does not provide support for NO2-attributable asthma
development in children in locations with NO2 concentrations
that would have clearly met the current annual and 1-hour
NO2 standards. The strongest epidemiologic evidence
informing the level at which effects may occur comes from U.S. and
Canadian epidemiologic studies that are subject to critical
uncertainties related to copollutant confounding and exposure
assessment. Furthermore, the proposal noted the PA's evaluation
indicating that most of the locations included in epidemiologic studies
of long-term NO2 exposure and asthma incidence would likely
have violated either one or both of the current NO2
standards, over at least parts of the study periods. In light of these
considerations, EPA proposed to retain the level and form for the
current annual standard.
b. Exposure- and Risk-Based Considerations
    Exposure- and risk-based considerations were also important to the
proposed decision and its rationale, like the consideration of the
health evidence discussed in section II.B.1.a above. As described in
greater detail in Section II.A.3 above, and in the REA Planning
document (U.S. EPA, 2015b, Section 2.1.1) and the PA (U.S. EPA, 2017a,
Chapter 4), the EPA conducted updated analyses comparing ambient
NO2 concentrations (i.e., as surrogates of potential
exposures) to health-based benchmarks, with a particular focus on study
areas where near-road monitors have been deployed. These analyses were
presented in the PA. The staff further concluded in the PA that updated
quantitative risk assessments were not supported in the current review,
based on uncertainties in the available evidence and the likelihood
that such analyses would be subject to the same uncertainties
identified in the risk estimates in the prior review (U.S. EPA, 2017a,
Chapter 4). The CASAC stated that it was ``satisfied with the short-
term exposure health-based benchmark analysis presented in the draft
PA'' and that it ``support[ed] the decision not to conduct any new or
updated quantitative risk analyses related to long-term exposure to
NO2'' (Diez Roux and Sheppard, 2017).
    When considering analyses comparing NO2 air quality with
health-based benchmarks, the proposal began by noting the PA's focus on
the following specific questions: (1) To what extent are ambient
NO2 concentrations that may be of public health concern
estimated to occur in locations meeting the current NO2
standards? (2) What are the important uncertainties associated with
those estimates?
    As discussed in section II.A.3 above, and in section II.D.1 of the
proposal, benchmarks are based on information from controlled human
exposure studies of NO2 exposures and AR. In identifying
specific NO2 benchmarks, and considering the weight to place
on each, the updated analyses in the PA consider both the group mean
results reported in individual studies and the results of a meta-
analysis that combined data from multiple studies (Brown, 2015; U.S.
EPA, 2016a, Section <IP_ADDRESS>), as described above.
    When taken together, the results of individual controlled human
exposure studies and of the meta-analysis by Brown (2015) support
consideration of NO2 benchmarks between 100 and 300 ppb,
based largely on studies of non-specific AR in people with asthma
exposed to NO2 at rest. As discussed in more detail in
section II.D of the proposal, benchmarks from the upper end of this
range are supported by the results of individual studies, the majority
of which reported statistically significant increases in AR following
NO2 exposures at or above 250 ppb, and by the results of the
meta-analysis by Brown (2015). Benchmarks from the lower end of this
range, including 100 ppb, are supported by the results of the meta-
analysis, even though individual studies do not consistently report
statistically significant NO2-induced increases in AR at
these lower concentrations. In particular, while the meta-analysis
indicates that the majority of study participants with asthma
experienced an increase in AR following exposures to 100 ppb
NO2 (Brown, 2015), individual studies have not generally
reported statistically significant increases in AR following resting
exposures to 100 ppb NO2.\95\
---------------------------------------------------------------------------

    \95\ Meta-analysis results for exposures to 100 ppb
NO2 were statistically significant when analyses were
restricted to non-specific AR, but not when analyses were restricted
to specific AR (Brown, 2015).
---------------------------------------------------------------------------

    In further considering the potential public health implications of
exposures to NO2 concentrations at or around benchmarks,
there are multiple uncertainties, as discussed in section II.C.I of the
proposal and section II.A.3 above. As discussed in more detail in those
sections, these uncertainties include the lack of an apparent a dose-
response relationship between NO2 and AR in people with
asthma, and uncertainty in the potential adversity of the reported
NO2-induced increases in AR.
    As discussed in section II.D.2 of the proposal, and in section
II.A.3 above, analyses of unadjusted air quality, which meets the
current standards in all locations, indicate almost no potential for 1-
hour exposures to NO2 concentrations at or above any of the
benchmarks examined, including 100 ppb. Analyses of air quality
adjusted upwards to just meet the current 1-hour standard \96\ indicate
virtually no potential for 1-hour exposures to NO2
concentrations at or above 200 ppb (or 300 ppb) and almost none for
exposures

at or above 150 ppb.\97\ This is the case for both estimates averaged
over multiple years and estimates in worst-case years, including at
near-road monitoring sites within a few meters of heavily trafficked
roads. With respect to the lowest benchmark evaluated, analyses
estimate that there is potential for exposures to 1-hour NO2
concentrations at or above 100 ppb on some days (e.g., about one to 10
days per year, on average, at near-road monitoring sites). As described
above, this result is consistent with expectations, given that the
current 1-hour standard, with its 98th percentile form, is expected to
limit, but not eliminate, the occurrence of 1-hour NO2
concentrations of 100 ppb.
---------------------------------------------------------------------------

    \96\ In all study areas, ambient NO2 concentrations
required smaller upward adjustments to just meet the 1-hour standard
than to just meet the annual standard. Therefore, when adjusting air
quality to just meet the current NO2 NAAQS, the
adjustment needed to just meet the 1-hour standard was applied (U.S.
EPA, 2017a, Section 4.2.1).
    \97\ Comparisons of NO2 air quality to health-based
benchmarks that estimated occurrences of NO2
concentrations exceeding the 150 and 200 ppb health-based benchmarks
are found in Figure 4-1 of the PA (U.S. EPA, 2017a).
---------------------------------------------------------------------------

    Section II.D.2 of the proposal noted that these analyses indicate
that the current 1-hour NO2 standard is expected to allow
virtually no potential for exposures to the NO2
concentrations that have been shown most consistently to increase AR in
people with asthma, even under worst-case conditions across a variety
of study areas with among the highest NOX emissions in the
U.S. Such NO2 concentrations are not estimated to occur,
even at monitoring sites adjacent to some of the most heavily
trafficked roadways. In addition, the current 1-hour standard provides
protection against NO2 exposures that have the potential to
exacerbate asthma symptoms, but for which the evidence indicates
greater uncertainty in the risk of such effects occurring (i.e., at or
near 100 ppb). Given the results of these analyses, and the
uncertainties inherent in their interpretation, the proposal placed
weight on the PA's conclusion that there is little potential for
exposures to ambient NO2 concentrations that would be of
public health concern in locations meeting the current 1-hour standard.
2. The CASAC Advice in This Review
    In the current review of the primary NO2 standards the
CASAC has provided advice and recommendations based on its review of
drafts of the 2016 NOX ISA (Frey, 2014a; Diez Roux and Frey,
2015a), of the REA Planning document (Diez Roux and Frey, 2015b), and
of the draft PA (Diez Roux and Sheppard, 2017). This section summarizes
key CASAC advice regarding the strength of the evidence for respiratory
effects, the quantitative analyses conducted and presented in the PA,
and the adequacy of the current primary NO2 standards to
protect the public health.
    Briefly, with regard to the strength of the evidence for
respiratory effects, the CASAC agreed with the 2016 NOX ISA
conclusions. In particular, the CASAC concurred ``with the finding that
short-term exposures to NO2 are causal for respiratory
effects based on evidence for asthma exacerbation'' (Diez Roux and
Sheppard, 2017, p. 7). It further noted that ``[t]he strongest evidence
is for an increase in airway responsiveness based on controlled human
exposure studies, with supporting evidence from epidemiologic studies''
(Diez Roux and Sheppard, 2017, p. 7). The CASAC also agreed with the
2016 NOX ISA conclusions on long-term exposures and
respiratory effects, specifically stating the following (Diez Roux and
Sheppard, 2017, p. 7):

    Long-term exposures to NO2 are likely to be causal
for respiratory effects, based on asthma development. The strongest
evidence is for asthma incidence in children in epidemiologic
studies, with supporting evidence from experimental animal studies.
Current scientific evidence for respiratory effects related to long-
term exposures is stronger since the last review, although
uncertainties remain related to the influence of copollutants on the
association between NO2 and asthma incidence.

    With regard to support for the updated quantitative analyses
conducted in the current review, the CASAC agreed with the conclusions
in the PA.\98\ In particular, the CASAC noted that it was ``satisfied
with the short-term exposure health-based benchmark analysis presented
in the Draft PA and agree[d] with the decision to not conduct any new
model-based or epidemiologic-based analyses'' (Diez Roux and Sheppard,
2017, p. 5). The CASAC further supported ``the decision not to conduct
any new or updated quantitative risk analyses related to long-term
exposure to NO2,'' noting ``that existing uncertainties in
the epidemiologic literature limit the ability to properly estimate and
interpret population risk associated with NO2, specifically
within a formal risk assessment framework'' (Diez Roux and Sheppard,
2017, p. 5).
---------------------------------------------------------------------------

    \98\ The PA conclusions build upon the preliminary conclusions
presented in the REA Planning document, which was also reviewed by
the CASAC (Diez Roux and Frey, 2015b).
---------------------------------------------------------------------------

    In addition, in its review of the draft PA, the CASAC agreed with
its conclusion that the available evidence, taken together, does not
support the need for increased protection against short- or long-term
NO2 exposures, beyond that provided by the existing
standards, stating that ``[t]he CASAC concurs with the EPA that the
current scientific literature does not support a revision to the
primary NAAQS for nitrogen dioxide'' (Diez Roux and Sheppard, 2017, p.
9). Further, the CASAC concurred with the draft PA's preliminary
conclusion that it is appropriate to consider retaining the current
primary NO2 standards without revision, stating that, ``the
CASAC recommends retaining, and not changing the existing suite of
standards'' (Diez Roux and Sheppard, 2017). The CASAC further provided
the following advice with respect to the individual elements of the
standards:
     Indicator and averaging time: The CASAC stated ``there is
strong evidence for the selection of NO2 as the indicator of
oxides of nitrogen'' and ``for the selection of 1-hour and annual
averaging times'' (Diez Roux and Sheppard, 2017, p. 9). With regard to
averaging time in particular, the CASAC stated that ``[c]ontrolled
human and animal studies provide scientific support for a 1-hour
averaging time as being representative of an exposure duration that can
lead to adverse effects'' (Diez Roux and Sheppard, 2017, p. 7). The
CASAC further concluded that ``[e]pidemiologic studies provide support
for the annual averaging time, representative of likely to be causal
associations between long-term exposures, or repeated short-term
exposures, and asthma development'' (Diez Roux and Sheppard, 2017, p.
7).
     Level of the 1-hour standard: The CASAC stated ``there are
notable adverse effects at levels that exceed the current standard, but
not at the level of the current standard. Thus, the CASAC advises that
the current 1-hour standard is protective of adverse effects and that
there is not a scientific basis for a standard lower than the current
1-hour standard'' (Diez Roux, and Sheppard 2017, p. 9).
     Form of the 1-hour standard: The CASAC also ``recommends
retaining the current form'' for the 1-hour standard (Diez Roux and
Sheppard, 2017). Recognizing that the form allowed for some 1-hour
concentrations that exceeded 100 ppb, the CASAC explained that ``a
scientific rationale for this form is there is uncertainty regarding
the severity of adverse effects at a level of 100 ppb NO2,
and thus some potential for maximum daily levels to exceed this
benchmark with limited frequency may nonetheless be protective of
public health'' (Diez Roux and Sheppard, 2017, p. 10). It further noted
that the choice of form reflected the Administrator's policy judgment.
(Diez Roux and Sheppard, 2017, p. 10).

     Level of the annual standard: In providing advice on the
level of the annual standard, the CASAC commented that the long-term
epidemiologic studies ``imply the possibility of adverse effects at
levels below that of the current annual standard'' (Diez Roux and
Sheppard, 2017, p. 8). However, the CASAC recognized that these studies
``are also subject to uncertainty, including possible confounding with
other traffic-related pollutants'' (Diez Roux and Sheppard, 2017, p.
8). The CASAC also commented that these epidemiologic studies may have
uncertainty related to exposure error and pointed out that estimated
DVs in study areas do not account for near-road monitoring.
Furthermore, the CASAC recognized the causal associations between long-
term exposures, or repeated short-term exposures, and asthma
development (Diez Roux and Sheppard, 2017, p. 7) and the
appropriateness of considering the protection provided by the current
suite of standards together (Diez Roux and Sheppard, 2017, p. 9).
Therefore, the CASAC advice on the annual standard takes into account
the degree of protection provided by that standard, in combination with
the current 1-hour standard. In particular, the CASAC recognized that
meeting the 1-hour NO2 standard can limit long-term
NO2 concentrations to below the level of the annual
standard, observing that ``an hourly DV of 100 ppb NO2 is
associated with DV values that average approximately 30 ppb
NO2'' and that ``there is insufficient evidence to make a
scientific judgment that adverse effects occur at annual DVs less than
30 ppb NO2'' (Diez Roux and Sheppard, 2017, p. 9). Thus, in
providing support for retaining the existing annual standard, the CASAC
specifically noted that ``the current suite of standards is more
protective of annual exposures compared to the annual standard by
itself'' and that ``it is the suite of the current 1-hour and annual
standards, together, that provide protection against adverse effects''
(Diez Roux and Sheppard, 2017, p. 9). Therefore, the CASAC ``recommends
retaining the existing suite of standards'' (Diez Roux and Sheppard,
2017, p. 9), including the current annual standard.