[Federal Register Volume 83, Number 75 (Wednesday, April 18, 2018)]
[Rules and Regulations]
[Pages 17226-17278]
[FR Doc No: 2018-07741]

Vol. 83

Wednesday,

No. 75

April 18, 2018

Part II

Environmental Protection Agency

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

40 CFR Part 50

Review of the Primary National Ambient Air Quality Standards for Oxides
of Nitrogen; Final Rule

Federal Register / Vol. 83 , No. 75 / Wednesday, April 18, 2018 /
Rules and Regulations

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

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 50

[EPA-HQ-OAR-2013-0146; FRL-9976-78-OAR]
RIN 2060-AR57

Review of the Primary National Ambient Air Quality Standards for
Oxides of Nitrogen

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final action.

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

SUMMARY: Based on the Environmental Protection Agency's (EPA's) review
of the air quality criteria addressing human health effects of oxides
of nitrogen and the primary national ambient air quality standards
(NAAQS) for oxides of nitrogen, as measured by nitrogen dioxide
(NO2), the EPA is retaining the current standards, without
revision.

DATES: This final action is effective on May 18, 2018.

ADDRESSES: The EPA has established a docket for this action under
Docket ID No. EPA-HQ-OAR-2013-0146. Incorporated into this docket is a
separate docket established for the Integrated Science Assessment for
this review (Docket ID No. EPA-HQ-ORD-2013-0232). All documents in
these dockets are listed on the www.regulations.gov website. Although
listed in the index, some information is not publicly available, e.g.,
CBI or other information whose disclosure is restricted by statute.
Certain other material, such as copyrighted material, is not placed on
the internet and will be publicly available only in hard copy form. It
may be viewed, with prior arrangement, at the EPA Docket Center.
Publicly available docket materials are available either electronically
in www.regulations.gov or in hard copy at the Air and Radiation Docket
Information Center, EPA/DC, WJC West Building, Room 3334, 1301
Constitution Ave. NW, Washington, DC. The Public Reading Room is open
from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal
holidays. The telephone number for the Public Reading Room is (202)
566-1744 and the telephone number for the Air and Radiation Docket
Information Center is<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Ms. Breanna Alman, Health and
Environmental Impacts Division, Office of Air Quality Planning and
Standards, U.S. Environmental Protection Agency, Mail Code C504-06,
Research Triangle Park, NC 27711; telephone:<PHONE_NUMBER>; fax: (919)
541-0237; email: [email protected].

Availability of Information Related to This Action

    A number of the documents that are relevant to this decision are
available through the EPA's website at https://www.epa.gov/naaqs/nitrogen-dioxide-no2-primary-air-quality-standards. These documents
include the Integrated Review Plan for the Primary National Ambient Air
Quality Standards for Nitrogen Dioxide (U.S. EPA, 2011a), available at
https://www3.epa.gov/ttn/naaqs/standards/nox/data/201406finalirpprimaryno2.pdf, the Integrated Science Assessment for
Oxides of Nitrogen--Health Criteria (U.S. EPA, 2016a), available at
https://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=310879, and the
Policy Assessment for the Review of the Primary National Ambient Air
Quality Standards for Oxides of Nitrogen (U.S. EPA, 2017a), available
at https://www.epa.gov/naaqs/policy-assessment-review-primary-national-ambient-air-quality-standards-oxides-nitrogen. These and other related
documents are also available for inspection and copying in the EPA
docket identified above.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary

I. Background
    A. Legislative Requirements
    B. Related NO2 Control Programs
    C. Review of the Air Quality Criteria and Standards for Oxides
of Nitrogen
    D. Summary of Proposed Decisions
    E. Organization and Approach to Final Decisions
II. Rationale for Decision on the Primary Standards
    A. Introduction
    1. Characterization of NO2 Air Quality
    2. Overview of the Health Effects Evidence
    3. Overview of Risk and Exposure Assessment Information
    B. Conclusions on the Primary Standards
    1. Basis for the Proposed Decision
    2. The CASAC Advice in This Review
    3. Comments on the Proposed Decision
    4. Administrator's Conclusions
    C. Decision on the Primary Standards
III. Statutory and Executive Order Reviews
    A. Executive Order 12866: Regulatory Planning and Review and
Executive Order 13563: Improving Regulation and Regulatory Review
    B. Executive Order 13771: Reducing Regulation and Controlling
Regulatory Costs
    C. Paperwork Reduction Act (PRA)
    D. Regulatory Flexibility Act (RFA)
    E. Unfunded Mandates Reform Act (UMRA)
    F. Executive Order 13132: Federalism
    G. Executive Order 13175: Consultation and Coordination With
Indian Tribal Governments
    H. Executive Order 13045: Protection of Children From
Environmental Health and Safety Risks
    I. Executive Order 13211: Actions Concerning Regulations That
Significantly Affect Energy Supply, Distribution or Use
    J. National Technology Transfer and Advancement Act (NTTAA)
    K. Executive Order 12898: Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations
    L. Determination Under Section 307(d)
    M. Congressional Review Act (CRA)
References

Executive Summary

    This document describes the completion of the EPA's current review
of the primary NAAQS for oxides of nitrogen, of which nitrogen dioxide
(NO2) is the component of greatest concern for health and is
the indicator for the primary NAAQS. This review of the standards and
the air quality criteria (the scientific information upon which the
standards are based) is required by the Clean Air Act (CAA) on a
periodic basis. In conducting this review, the EPA has carefully
evaluated the currently available scientific literature on the health
effects of NO2, focusing particularly on the information
newly available since the conclusion of the last review. This section
briefly summarizes background information about this action and the
Administrator's decision to retain the current primary NO2
standards. A full discussion of these topics is provided later in this
document.

Summary of Background Information

    There are currently two primary standards for oxides of nitrogen: A
1-hour standard established in 2010 at a level of 100 parts per billion
(ppb) based on the 98th percentile of the annual distribution of daily
maximum 1-hour NO2 concentrations, averaged over 3 years,
and an annual standard, originally set in 1971, at a level of 53 ppb
based on annual average NO2 concentrations.
    Sections 108 and 109 of the CAA govern the establishment, review,
and revision, as appropriate, of the NAAQS to protect public health and
welfare. The CAA requires the EPA to periodically review the air
quality criteria--the science upon which the standards are based--and
the standards themselves. This review of the primary (health-based)
NO2 NAAQS is being conducted pursuant to these statutory
requirements. The schedule for

completing this review is established by a federal court order, which
requires signature of a notice setting forth the EPA's final decision
by April 6, 2018.
    The last review of the primary NO2 NAAQS was completed
in 2010. In that review, the EPA supplemented the existing primary
annual NO2 standard by establishing a new short-term
standard with a level of 100 ppb, based on the 3-year average of the
98th percentile of the annual distribution of daily maximum 1-hour
concentrations (75 FR 6474, February 9, 2010). Revisions to the NAAQS
were accompanied by revisions to the data handling procedures and the
ambient air monitoring and reporting requirements, including the
establishment of requirements for states to locate monitors near
heavily trafficked roadways in large urban areas and in other locations
where maximum NO2 concentrations can occur.
    Consistent with the review completed in 2010, this review is
focused on the health effects associated with gaseous oxides of
nitrogen and on the protection afforded by the primary NO2
standards. The gaseous oxides of nitrogen include NO2 and
nitric oxide (NO), as well as their gaseous reaction products. Total
oxides of nitrogen include these gaseous species as well as particulate
species (e.g., nitrates). The EPA is separately considering the health
and non-ecological welfare effects of particulate species in the review
of the NAAQS for particulate matter (PM) (U.S. EPA, 2016b). In
addition, the EPA is separately reviewing the welfare effects
associated with NOX and SOX and the ecological
welfare effects associated with PM. (U.S. EPA, 2017b).

Summary of Decision

    In this action, the EPA is retaining the current primary
NO2 standards, without revision. This decision has been
informed by a careful consideration of the full body of scientific
evidence and information available in this review, giving particular
weight to the assessment of the evidence in the 2016 NOX
Integrated Science Assessment (ISA); analyses and considerations in the
Policy Assessment (PA); the advice and recommendations of the Clean Air
Scientific Advisory Committee (CASAC); and public comments.
    Based on these considerations, the Administrator reaches the
conclusion that the current body of scientific evidence and the results
of quantitative analyses supports his judgment that the current 1-hour
and annual primary NO2 standards, together, are requisite to
protect public health with an adequate margin of safety, and do not
call into question any of the elements of those standards. These
conclusions are consistent with the CASAC recommendations. In its
advice to the Administrator, the CASAC ``recommend[ed] retaining, and
not changing the existing suite of standards'' (Diez Roux and Sheppard,
2017). The CASAC further stated 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, in
this review, the EPA is retaining the current 1-hour and annual
NO2 primary standards, without revision.
    As in the last review, the strongest evidence continues to come
from studies examining respiratory effects following short-term
NO2 exposures.\1\ In particular, the 2016 NOX ISA
concludes 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). The strongest support
for this conclusion comes from controlled human exposure studies
examining the potential for NO2-induced increases in airway
responsiveness (AR) (which is a hallmark of asthma) in individuals with
asthma. Additional supporting evidence comes from epidemiologic studies
reporting associations between short-term NO2 exposures and
an array of respiratory outcomes related to asthma exacerbation (e.g.,
asthma-related hospital admissions and emergency department (ED) visits
in children and adults).
---------------------------------------------------------------------------

    \1\ The 2016 NOX ISA defines short-term exposures as
those with durations of minutes up to 1 month, with most studies
examining effects related to exposures in the range of 1 hour to 1
week (U.S. EPA, 2016a, p. 1-15).
---------------------------------------------------------------------------

    In addition to the effects of short-term exposures, the 2016
NOX ISA concludes that there is ``likely to be a causal
relationship'' between long-term NO2 exposures and
respiratory effects, based on the evidence for asthma development in
children. The strongest evidence supporting this conclusion comes from
recent epidemiologic studies demonstrating associations between long-
term NO2 exposures and asthma incidence. Additional support
comes from experimental studies supporting the biological plausibility
of a potential mode of action by which NO2 exposures could
cause asthma development.
    While the evidence supports the occurrence of adverse
NO2-related respiratory effects at ambient NO2
concentrations likely to have been above those allowed by the current
primary NO2 NAAQS, that evidence, together with analyses of
the potential for NO2 exposures, does not call into question
the adequacy of the public health protection provided by the current
standards. In particular, compared to the last review when the 1-hour
standard was set, evidence from controlled human exposure studies has
not altered our understanding of the NO2 exposure
concentrations that cause increased AR. Analyses based on information
from these studies indicate that the current standards provide
protection against the potential for NO2 exposures that
could increase AR in people with asthma. In addition, while
epidemiologic studies report relatively precise associations with
serious NO2-related health outcomes (i.e., ED visits,
hospital admissions, asthma incidence) in locations likely to have
violated the current 1-hour and/or annual standards during portions of
study periods, studies do not indicate such associations in locations
with NO2 concentrations that would have clearly met those
standards.
    After considering the current body of scientific evidence, the
results of quantitative analyses, the CASAC advice, and public
comments, the Administrator concludes that the current 1-hour and
annual NO2 primary standards, together, are requisite to
protect public health with an adequate margin of safety. Therefore, in
this review, the EPA is retaining the current 1-hour and annual
NO2 primary standards, without revision.

I. Background

A. Legislative Requirements

    Two sections of the Clean Air Act (CAA or the Act) govern the
establishment and revision of the NAAQS. Section 108 (42 U.S.C. 7408)
directs the Administrator to identify and list certain air pollutants
and then to issue air quality criteria for those pollutants. The
Administrator is to list those air pollutants that in his ``judgment,
cause or contribute to air pollution which may reasonably be
anticipated to endanger public health or welfare;'' ``the presence of
which in the ambient air results from numerous or diverse mobile or
stationary sources;'' and ``for which . . . [the Administrator] plans
to issue air quality criteria . . . .'' Air quality criteria are
intended to ``accurately reflect the latest scientific knowledge useful
in indicating the kind and extent of all identifiable effects on public
health or welfare which may be expected from the presence of [a]
pollutant in the ambient air . . . .'' 42 U.S.C. 7408(b). Section 109
(42 U.S.C. 7409) directs the Administrator to propose and promulgate
``primary'' and

``secondary'' NAAQS for pollutants for which air quality criteria are
issued. Section 109(b)(1) defines a primary standard as one ``the
attainment and maintenance of which in the judgment of the
Administrator, based on such criteria and allowing an adequate margin
of safety, [is] requisite to protect the public health.'' \2\ A
secondary standard, as defined in section 109(b)(2), must ``specify a
level of air quality the attainment and maintenance of which, in the
judgment of the Administrator, based on such criteria, is requisite to
protect the public welfare from any known or anticipated adverse
effects associated with the presence of [the] pollutant in the ambient
air.'' \3\
---------------------------------------------------------------------------

    \2\ The legislative history of section 109 indicates that a
primary standard is to be set at ``the maximum permissible ambient
air level . . . which will protect the health of any [sensitive]
group of the population,'' and that for this purpose ``reference
should be made to a representative sample of persons comprising the
sensitive group rather than to a single person in such a group.''
See S. Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970).
    \3\ As specified in section 302(h) (42 U.S.C. 7602(h)) effects
on welfare include, but are not limited to, ``effects on soils,
water, crops, vegetation, man-made materials, animals, wildlife,
weather, visibility and climate, damage to and deterioration of
property, and hazards to transportation, as well as effects on
economic values and on personal comfort and well-being.''
---------------------------------------------------------------------------

    The requirement that primary standards provide an adequate margin
of safety was intended to address uncertainties associated with
inconclusive scientific and technical information available at the time
of standard setting. It was also intended to provide a reasonable
degree of protection against hazards that research has not yet
identified. See Lead Industries Association v. EPA, 647 F.2d 1130, 1154
(D.C. Cir. 1980); American Petroleum Institute v. Costle, 665 F.2d
1176, 1186 (D.C. Cir. 1981); American Farm Bureau Federation v. EPA,
559 F.3d 512, 533 (D.C. Cir. 2009); Association of Battery Recyclers v.
EPA, 604 F.3d 613, 617-18 (D.C. Cir. 2010). Both kinds of uncertainties
are components of the risk associated with pollution at levels below
those at which human health effects can be said to occur with
reasonable scientific certainty. Thus, in selecting primary standards
that provide an adequate margin of safety, the Administrator is seeking
not only to prevent pollution levels that have been demonstrated to be
harmful but also to prevent lower pollutant levels that may pose an
unacceptable risk of harm, even if the risk is not precisely identified
as to nature or degree. The CAA does not require the Administrator to
establish a primary NAAQS at a zero-risk level, see Lead Industries
Association, 647 F.2d at 1156 n.51, but rather at a level that reduces
risk sufficiently so as to protect public health with an adequate
margin of safety.
    In addressing the requirement for an adequate margin of safety, the
EPA considers such factors as the nature and severity of the health
effects involved, the size of sensitive population(s) at risk,\4\ and
the kind and degree of the uncertainties that must be addressed. The
selection of any particular approach to providing an adequate margin of
safety is a policy choice left specifically to the Administrator's
judgment. See Lead Industries Association v. EPA, 647 F.2d at 1161-62.
---------------------------------------------------------------------------

    \4\ As used here and similarly throughout this document, the
term population (or group) refers to persons having a quality or
characteristic in common, such as a specific pre-existing illness or
a specific age or lifestage.
---------------------------------------------------------------------------

    In setting primary and secondary standards that are ``requisite''
to protect public health and welfare, respectively, as provided in
section 109(b), the EPA's task is to establish standards that are
neither more nor less stringent than necessary for these purposes. In
so doing, the EPA may not consider the costs of implementing the
standards. See generally, Whitman v. American Trucking Associations,
531 U.S. 457, 465-472, 475-76 (2001). Likewise, ``[a]ttainability and
technological feasibility are not relevant considerations in the
promulgation of national ambient air quality standards.'' American
Petroleum Institute v. Costle, 665 F.2d at 1185.
    Section 109(d)(1) requires that ``not later than December 31, 1980,
and at 5-year intervals thereafter, the Administrator shall complete a
thorough review of the criteria published under section 108 and the
national ambient air quality standards . . . and shall make such
revisions in such criteria and standards and promulgate such new
standards as may be appropriate . . . .'' Section 109(d)(2) requires
that an independent scientific review committee ``shall complete a
review of the criteria . . . and the national primary and secondary
ambient air quality standards . . . and shall recommend to the
Administrator any new . . . standards and revisions of existing
criteria and standards as may be appropriate . . . .'' Since the early
1980s, this independent review function has been performed by the Clean
Air Scientific Advisory Committee (CASAC).\5\
---------------------------------------------------------------------------

    \5\ Lists of the CASAC members and members of the NO2
Review Panel are available at: http://yosemite.epa.gov/sab/sabproduct.nsf/WebCASAC/CommitteesandMembership?OpenDocument.
---------------------------------------------------------------------------

B. Related NO2 Control Programs

    States are primarily responsible for ensuring attainment and
maintenance of ambient air quality standards once the EPA has
established them. Under section 110 of the Act, 42 U.S.C. 7410, and
related provisions, states are to submit, for the EPA's approval, state
implementation plans (SIPs) that provide for the attainment and
maintenance of such standards through control programs directed to
sources of the pollutants involved. The states, in conjunction with the
EPA, also administer the Prevention of Significant Deterioration
permitting program that covers these pollutants. See 42 U.S.C. 7470-
7479. In addition, federal programs provide for nationwide reductions
in emissions of these and other air pollutants under Title II of the
Act, 42 U.S.C. 7521-7574, which involves controls for automobile,
truck, bus, motorcycle, nonroad engine and equipment, and aircraft
emissions; the new source performance standards (NSPS) under section
111 of the Act, 42 U.S.C. 7411; and the national emission standards for
hazardous air pollutants under section 112 of the Act, 42 U.S.C. 7412.
    Currently there are no areas in the United States that are
designated as nonattainment for the NO2 NAAQS (see 77 FR
9532 (February 17, 2012)). In addition, there are currently no monitors
where there are design values (DVs) \6\ above either the 1-hour or
annual standard (U.S. EPA, 2017a, Figure 2-5), with the maximum DVs in
2015 being 30 ppb (annual) and 72 ppb (hourly) (U.S. EPA, 2017a
Section, 2.3.1).
---------------------------------------------------------------------------

    \6\ The metric used to determine whether areas meet or exceed
the NAAQS is called a design value (DV). In the case of the primary
NO2 NAAQS, there are 2 types of DVs: The annual DV and
the hourly DV. The annual DV for a particular year is the average of
all hourly values within that calendar year. The hourly DV is the
three-year average of the 98th percentiles of the annual
distributions of daily maximum 1-hour NO2 concentrations.
The requirements for calculating DVs for the primary NO2
NAAQS from valid monitoring data are further specified in Appendix S
to Part 50.
---------------------------------------------------------------------------

    While NOX \7\ is emitted from a wide variety of source
types, the top three categories of sources of NOX emissions
are highway vehicles, off-highway vehicles, and stationary fuel
combustion sources.\8\ The EPA anticipates that NOX

emissions will continue to decrease over the next 20 years. For
example, Tier 2 and Tier 3 emission standards for new light-duty
vehicles, combined with the reduction of gasoline sulfur content, will
significantly reduce motor vehicle emissions of NOX, with
Tier 3 standards phasing in from model year 2017 to model year 2025.
For heavy-duty engines, new NOX standards were phased in
between the 2007 and 2010 model years, following the introduction of
ultra-low sulfur diesel fuel. More stringent NOX standards
for non-road diesel engines, locomotives, and certain marine engines
are becoming effective throughout the next decade. In future decades,
these vehicles and engines meeting more stringent NOX
standards will become an increasingly large fraction of in-use mobile
sources, leading to large NOX emission reductions.\9\
---------------------------------------------------------------------------

    \7\ In this context, NOX refers to the sum of NO and
NO2, as is common within air pollution research and
control communities. However, in the larger context of this NAAQS
review, the terms ``oxides of nitrogen'' and ``nitrogen oxides''
generally refer more broadly to gaseous oxides of nitrogen, which
include NO2 and NO, as well as their gaseous reaction
products.
    \8\ Highway vehicles include all on-road vehicles, including
light duty as well as heavy duty vehicles, both gasoline- and
diesel-powered, and on-highway motorcycles. Off-highway engines,
vehicles and equipment include aircraft, marine vessels,
locomotives, off-highway motorcycles, recreational vehicles and
other non-road products (e.g., lawnmowers, portable generators,
chainsaws, forklifts). Fuel combustion sources includes electric
power generating units (EGUs), which derive their power generation
from all types of fuels.
    \9\ Reductions in ambient NO2 concentrations could
also result from the implementation of NAAQS for other pollutants
(e.g., ozone, PM), to the extent NOX emissions are
reduced as part of the implementation of those standards.
---------------------------------------------------------------------------

C. Review of the Air Quality Criteria and Standards for Oxides of
Nitrogen

    In 1971, the EPA added oxides of nitrogen to the list of criteria
pollutants under section 108(a)(1) of the CAA and issued the initial
air quality criteria (36 FR 1515, January 30, 1971; U.S. EPA, 1971).
Based on these air quality criteria, the EPA promulgated the
NO2 NAAQS (36 FR 8186, April 30, 1971). Both primary and
secondary standards were set at 53 ppb,\10 \annual average. Since then,
the Agency has completed multiple reviews of the air quality criteria
and primary NO2 standards. In the last review, the EPA made
revisions to the primary NO2 NAAQS in order to provide
requisite protection of public health. Specifically, the EPA
supplemented the existing primary annual NO2 standard by
establishing a new short-term standard with a level of 100 ppb, based
on the 3-year average of the 98th percentile of the annual distribution
of daily maximum 1-hour concentrations (75 FR 6474, February 9, 2010).
In addition, revisions to the NAAQS were accompanied by revisions to
the data handling procedures and the ambient air monitoring and
reporting requirements, including requirements for states to locate
monitors near heavily trafficked roadways in large urban areas and in
other locations where maximum NO2 concentrations can occur.
---------------------------------------------------------------------------

    \10\ In 1971, primary and secondary NO2 NAAQS were
set at levels of 100 micrograms per cubic meter ([mu]g/m\3\), which
equals 0.053 parts per million (ppm) or 53 ppb.
---------------------------------------------------------------------------

    Industry groups filed petitions for judicial review of the 2010
rule in the U.S. Court of Appeals for the District of Columbia Circuit.
API v. EPA, 684 F.3d 1342 (D.C. Cir. 2012). The court upheld the 2010
rule, denying the petitions' challenges to the adoption of the 1-hour
NO2 NAAQS and dismissing, for lack of jurisdiction, the
challenges to statements regarding permitting in the preamble of the
2010 rule. Id. at 1354.
    Subsequent to the 2010 rulemaking, the Agency revised the deadlines
by which the near-road monitors were to be operational in order to
implement a phased deployment approach (78 FR 16184, March 14, 2013),
with a majority of the network becoming operational by 2015. In 2016,
after analyzing available monitoring data, the Agency revised the size
requirements of the near-road network, reducing the network to only
operate in Core Based Statistical Areas (CBSAs) with populations of 1
million or more (81 FR 96381, December 30, 2016).
    In February 2012, the EPA announced the initiation of the current
periodic review of the air quality criteria for oxides of nitrogen and
of the primary NO2 NAAQS and issued a call for information
in the Federal Register (77 FR 7149, February 10, 2012). A wide range
of external experts as well as the EPA staff representing a variety of
areas of expertise (e.g., epidemiology, human and animal toxicology,
statistics, risk/exposure analysis, atmospheric science, and biology)
participated in a workshop held by the EPA on February 29 to March 1,
2012, in Research Triangle Park, NC. The workshop provided an
opportunity for a public discussion of the key policy-relevant issues
around which the Agency would structure this primary NO2
NAAQS review and the most meaningful new science that would be
available to inform the EPA's understanding of these issues.
    Based in part on the workshop discussions, the EPA developed a
draft plan for the NOX ISA and subsequently a draft
Integrated Review Plan (IRP) outlining the schedule, process, and key
policy-relevant questions that would guide the evaluation of the
health-related air quality criteria for NO2 and the review
of the primary NO2 NAAQS. The draft plan for the
NOX ISA was released in May 2013 (78 FR 26026) and was the
subject of a consultation with the CASAC on June 5, 2013 (78 FR 27234).
Comments from the CASAC and the public were considered in the
preparation of the first draft ISA and the draft IRP. In addition,
preliminary draft materials for the NOX ISA were reviewed by
subject matter experts at a public workshop hosted by the EPA's
National Center for Environmental Assessment (NCEA) in May 2013 (78 FR
27374). The first draft ISA was released in November 2013 (78 FR
70040). During this time, the draft IRP was also in preparation and was
released in February 2014 (79 FR 7184). Both the draft IRP and first
draft ISA were reviewed by the CASAC at a public meeting held in March
2014 (79 FR 8701), and the first draft ISA was further discussed at an
additional teleconference held in May 2014 (79 FR 17538). The CASAC
finalized its recommendations on the first draft ISA and the draft IRP
in letters dated June 10, 2014 (Frey, 2014a; Frey, 2014b), and the
final IRP was released in June 2014 (79 FR 36801).
    The EPA released the second draft ISA in January 2015 (80 FR 5110)
and the Risk and Exposure Assessment (REA) Planning document in May
2015 (80 FR 27304). These documents were reviewed by the CASAC at a
public meeting held in June 2015 (80 FR 22993). A follow-up
teleconference with the CASAC was held in August 2015 (80 FR 43085) to
finalize recommendations on the second draft ISA. The final ISA was
released in January 2016 (81 FR 4910). The CASAC recommendations on the
second draft ISA and the draft REA planning document were provided to
the EPA in letters dated September 9, 2015 (Diez Roux and Frey, 2015a;
Diez Roux and Frey, 2015b), and the final ISA was released in January
2016 (81 FR 4910).
    After considering the CASAC advice and public comments, the EPA
prepared a draft Policy Assessment (PA), which was released on
September 23, 2016 (81 FR 65353). The draft PA was reviewed by the
CASAC on November 9-10, 2016 (81 FR 68414), and a follow-up
teleconference was held on January 24, 2017 (81 FR 95137). The CASAC
recommendations, based on its review of the draft PA, were provided in
a letter to the EPA Administrator dated March 7, 2017 (Diez Roux and
Sheppard, 2017). The EPA staff took into account these recommendations,
as well as public comments provided on the draft PA, when developing
the final PA, which was released in April 2017.\11\
---------------------------------------------------------------------------

    \11\ This document may be found at: https://www.epa.gov/naaqs/policy-assessment-review-primary-national-ambient-air-quality-standards-oxides-nitrogen.

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

    On July 14, 2017, the proposed decision to retain the
NO2 NAAQS was signed, and it was published in the Federal
Register on July 26 (82 FR 34792). The 60-day comment period ended on
September 25, 2017, and comments were received from various government,
industry, and environmental groups, as well as members of the general
public.
    In addition, in July 2016, a lawsuit was filed against the EPA that
included a claim that EPA had failed to complete its review of the
primary NO2 NAAQS within five years, as required by the CAA.
Center for Biological Diversity et al. v. McCarthy, (No. 4:16-cv-03796-
VC, N.D. Cal., July 7, 2016). Consistent with CAA section 113(g), a
notice of a proposed consent decree to resolve this litigation was
published in the Federal Register on January 17, 2017 (82 FR 4866). The
EPA received two public comments on the proposed consent decree,
neither of which disclosed facts or considerations indicating that the
Department of Justice or the EPA should withhold consent.\12\ The
parties to the litigation filed a joint motion asking the court to
enter the consent decree, and the court entered the consent decree as a
consent judgment on April 28, 2017. The consent judgment established
July 14, 2017 as the deadline for signature of a notice setting forth
the proposed decision in this review and April 6, 2018 as the deadline
for signature of a notice setting forth the final decision.
---------------------------------------------------------------------------

    \12\ One comment was received from the American Petroleum
Institute (API) and one was received from an anonymous commenter.
These comments are available in the docket for the proposed consent
decree (EPA-HQ-OGC-2016-0719).
---------------------------------------------------------------------------

    Consistent with the review completed in 2010, this review is
focused on health effects associated with gaseous oxides of nitrogen
\13\ and the protection afforded by the primary NO2
standards. The gaseous oxides of nitrogen include NO2 and
NO, as well as their gaseous reaction products. Total oxides of
nitrogen include these gaseous species as well as particulate species
(e.g., nitrates). Health effects and non-ecological welfare effects
associated with the particulate species are addressed in the review of
the NAAQS for PM (U.S. EPA, 2016b).\14\ The EPA is separately reviewing
the welfare effects associated with NOX and SOX
and the ecological welfare effects associated with PM. (U.S. EPA,
2017a).\15\
---------------------------------------------------------------------------

    \13\ These gaseous oxides of nitrogen can also be referred to as
``nitrogen oxides'' and include a broad category of gaseous oxides
of nitrogen (i.e., oxidized nitrogen compounds), including
NO2, NO, and their various reaction products.
    \14\ Additional information on the PM NAAQS is available at:
https://www.epa.gov/naaqs/particulate-matter-pm-air-quality-standards.
    \15\ Additional information on the ongoing and previous review
of the secondary NO2 and SO2 NAAQS is
available at: https://www.epa.gov/naaqs/nitrogen-dioxide-no2-and-sulfur-dioxide-so2-secondary-air-quality-standards.
---------------------------------------------------------------------------

D. Summary of Proposed Decisions

    For reasons discussed in the proposal and summarized in section
II.B.1 below, the Administrator proposed to retain the current primary
standards for NO2, without revision.

E. Organization and Approach to Final Decisions

    This action presents the Administrator's final decision in the
current review of the primary NO2 standards. The final
decision addressing the primary NO2 standards is based on a
thorough review in the 2016 NOX ISA of scientific
information on known and potential human health effects associated with
exposure to NO2 associated with levels typically found in
the ambient air. This final decision also takes into account the
following: (1) Staff assessments in the PA of the most policy-relevant
information in the ISA, as well as quantitative exposure and risk
information; (2) the CASAC advice and recommendations, as reflected in
its letters to the Administrator and its discussions of drafts of the
ISA and PA at public meetings; (3) public comments received during the
development of these documents, both in connection with the CASAC
meetings and separately; and (4) public comments received on the
proposal. The primary NO2 standards are addressed in section
II below. Section III addresses statutory and executive order reviews.

II. Rationale for Decision on the Primary Standards

    This section presents the rationale for the Administrator's
decision to retain the existing primary NO2 standards. This
rationale is based on a thorough review in the 2016 NOX ISA
of the latest scientific information, generally published through
August 2014, on human health effects associated with NO2 and
pertaining to the presence of NO2 in the ambient air. This
decision also takes into account: (1) The PA's staff assessments of the
most policy-relevant information in the ISA and staff analyses of air
quality, human exposure and health risks, upon which staff conclusions
regarding appropriate considerations in this review are based; (2) the
CASAC advice and recommendations, as reflected in discussions of drafts
of the ISA and PA at public meetings, in separate written comments, and
in the CASAC letters to the Administrator; (3) public comments received
during the development of these documents, either in connection with
the CASAC meetings or separately; and (4) public comments received on
the proposal. Section II.A provides background on the general approach
for review of the primary NO2 standards and brief summaries
of key aspects of the currently available air quality information, as
well as health effects and exposure/risk information. Section II.B
presents the Administrator's conclusions on the adequacy of the current
primary NO2 standards, drawing on consideration of this
information, advice from the CASAC, and comments from the public.
Section II.C summarizes the Administrator's decision on the primary
NO2 standards.

A. Introduction

    The Administrator's approach to reviewing the current primary
NO2 standards is based, most fundamentally, on using the
EPA's assessment of the current scientific evidence and associated
quantitative analyses to inform his judgment regarding primary
NO2 standards that protect public health with an adequate
margin of safety. In drawing conclusions with regard to the primary
standards, the final decision on the adequacy of the current standards
is largely a public health policy judgment to be made by the
Administrator. The Administrator's final decision draws upon scientific
information and analyses about health effects, population exposure and
risks, as well as judgments about how to consider the range and
magnitude of uncertainties that are inherent in the scientific evidence
and analyses.
    The approach to informing these judgments is based on the
recognition that the available health effects evidence generally
reflects a continuum, consisting of levels at which scientists
generally agree that health effects are likely to occur, through lower
levels at which the likelihood and magnitude of the response become
increasingly uncertain. This approach is consistent with the
requirements of the NAAQS provisions of the Act and with how the EPA
and the courts have historically interpreted the Act. These provisions
require the Administrator to establish primary standards that, in the
judgment of the Administrator, are requisite to protect public health
with an adequate margin of safety. In so doing, the Administrator seeks
to establish standards that are neither more nor less stringent than
necessary for this purpose. The Act does not require that primary
standards be set at a zero-risk

level, but rather at a level that avoids unacceptable risks to public
health including the health of sensitive groups. The four basic
elements of the NAAQS (indicator, averaging time, level, and form) are
considered collectively in evaluating the health protection afforded by
the current standards.
    To evaluate whether it is appropriate to consider retaining the
current primary NO2 standards, or whether consideration of
revision is appropriate, the EPA has adopted an approach in this review
that builds upon the general approach used in the last review and
reflects the broader body of evidence and information now available.
The Administrator's decisions in the prior review were based on an
integration of information on health effects associated with exposure
to NO2 with information on the public health significance of
key health effects, as well as on policy judgments as to when the
standard is requisite to protect public health with an adequate margin
of safety and advice from the CASAC and public comments. These
considerations were informed by air quality and related analyses and
quantitative exposure and risk information. Similarly, in this review,
as described in the PA, the proposal, and elsewhere in this document,
we draw on the current evidence and quantitative assessments of
exposure pertaining to the public health risk of NO2 in
ambient air. In considering the scientific and technical information
here, as in the PA, we consider both the information available at the
time of the last review and information newly available since the last
review, including most particularly that which has been critically
analyzed and characterized in the current ISA. In considering the
entire body of evidence presented in the current ISA, as in the PA and
as in the last review, we focus particularly on those health endpoints
for which the ISA finds associations with NO2 to be causal
or likely causal. The evidence-based discussions presented below draw
upon evidence from both controlled human exposure studies and
epidemiologic studies. Sections II.A.1 through II.A.3 below provide an
overview of the current NO2 air quality, health effects, and
quantitative exposure and risk information with a focus on the specific
policy-relevant questions identified for these categories of
information in the PA (U.S. EPA, 2017a, Chapter 3).
1. Characterization of NO2 Air Quality
    This section presents information on NO2 atmospheric
chemistry and ambient concentrations, with a focus on information that
is most relevant for the review of the primary NO2
standards. This section is drawn from the more detailed discussion of
NO2 air quality in the PA (U.S. EPA, 2017a, Chapter 2) and
the 2016 NOX ISA (U.S. EPA, 2016a, Chapter 2).\16\ It
presents a summary of NO2 atmospheric chemistry (section
II.A.1.a), trends in ambient NO2 concentrations (section
II.A.1.b), ambient NO2 concentrations measured at monitors
near roads (section II.A.1.c), the relationships between hourly and
annual ambient NO2 concentrations (section II.A.1.d), and
background concentrations of NO2 (section II.A.1.e).
---------------------------------------------------------------------------

    \16\ The focus is on NO2 in this document, as this is
the indicator for the current standards and is most relevant to the
evaluation of health evidence. Characterization of air quality for
the broader category of oxides of nitrogen is provided in the 2016
NOX ISA (U.S. EPA, 2016a, Chapter 2).
---------------------------------------------------------------------------

a. Atmospheric Chemistry
    Ambient concentrations of NO2 are influenced by both
direct NO2 emissions and by emissions of NO, with the
subsequent conversion of NO to NO2 primarily though reaction
with ozone (O3). The initial reaction between NO and
O3 to form NO2 occurs fairly quickly during the
daytime, with reaction times on the order of minutes. However,
NO2 can also be photolyzed to regenerate NO, creating new
O3 in the process (U.S. EPA, 2016a, Section 2.2). A large
number of oxidized nitrogen species in the atmosphere are formed from
the oxidation of NO and NO2. These include nitrate radicals
(NO3), nitrous acid (HONO), nitric acid (HNO3),
dinitrogen pentoxide (N2O5), nitryl chloride
(ClNO2), peroxynitric acid (HNO4), peroxyacetyl
nitrate and its homologues (PANs), other organic nitrates, such as
alkyl nitrates (including isoprene nitrates), and pNO3. The
sum of these reactive oxidation products and NO plus NO2
comprise the oxides of nitrogen.17 18
---------------------------------------------------------------------------

    \17\ This follows usages in Clean Air Act section 108(c): ``Such
criteria [for oxides of nitrogen] shall include a discussion of
nitric and nitrous acids, nitrites, nitrates, nitrosamines, and
other carcinogenic and potentially carcinogenic derivatives of
oxides of nitrogen.'' By contrast, within air pollution research and
control communities, the terms ``nitrogen oxides'' and
NOX are often restricted to refer only to the sum of NO
and NO2.
    \18\ See Figure 2-1 of the NO2 PA for additional
information (U.S. EPA, 2017a).
---------------------------------------------------------------------------

    Due to the close relationship between NO and NO2, and
their ready interconversion, these species are often grouped together
and referred to as NOX. The majority of NOX
emissions are in the form of NO. For example, 90% or more of tail-pipe
NOX emissions are in the form of NO, with only about 2% to
10% emitted as NO2 (Itano et al., 2014; Kota et al., 2013;
Jimenez et al., 2000; Richmond-Bryant et al., 2016). NOX
emissions require time and sufficient O3 concentrations for
the conversion of NO to NO2. Higher temperatures and
concentrations of reactants result in shorter conversion times (e.g.,
less than one minute under some conditions), while dispersion and
depletion of reactants result in longer conversion times. The time
required to transport emissions away from a roadway can vary from less
than one minute (e.g., under open conditions) to about one hour (e.g.,
for certain urban street canyons) (D[uuml]ring et al., 2011; Richmond-
Bryant and Reff, 2012). These factors can affect the locations where
the highest NO2 concentrations occur. In particular, while
ambient NO2 concentrations are often elevated near important
sources of NOX emissions, such as major roadways, the
highest measured ambient concentrations in a given urban area may not
always occur immediately adjacent to those sources.\19\
---------------------------------------------------------------------------

    \19\ Ambient NO2 concentrations around stationary
sources of NOX emissions are similarly impacted by the
availability of O3 and by meteorological conditions,
although surface-level NO2 concentrations can be less
impacted in cases where stationary source NOX emissions
are emitted from locations elevated substantially above ground
level.
---------------------------------------------------------------------------

b. National Trends in NOX Emissions and Ambient
NO2 Concentrations
    Ambient concentrations of NO2 in the U.S. are due
largely to NOX emissions from anthropogenic sources.
Background NO2 is estimated to make up only a small fraction
of current ambient concentrations (U.S. EPA, 2016a, Section 2.5.6; U.S.
EPA, 2017a, Section 2.3.4).\20\ Nationwide estimates indicate that
there has been a 61% reduction in total NOX emissions from
1980 to 2016 (U.S. EPA, 2017a, Section 2.1.2, Figure 2-2). These
reductions have been driven primarily by decreases in emissions from
mobile sources and fuel combustion (U.S. EPA, 2017a, Section 2.1.2,
Figure 2-3).
---------------------------------------------------------------------------

    \20\ Background concentrations of a pollutant can be defined in
various ways, depending on context and circumstances. Background
concentrations of NO2 are discussed in the 2016
NOX ISA (U.S. EPA, 2016a, Section 2.5.6) and the PA (U.S.
EPA, 2017a, Section 2.3.4).
---------------------------------------------------------------------------

    Long-term trends in NO2 DVs across the U.S. show that
ambient concentrations of NO2 have been declining, on
average, since 1980 (U.S. EPA, 2017a, Figure 2-4). Data have been
collected for at least some part of the period since 1980 at 2099 sites
in the U.S., with individual sites having a wide range in duration and
continuity of operations across multiple decades. Overall, the majority
of sampling sites have observed statistically significant downward
trends in ambient NO2

concentrations (U.S. EPA, 2017a, Figure 2-5).\21\ The annual and hourly
DVs trended upward in less than 4% of the sites.\22\ Even considering
the fact that there are a handful of sites where upward trends in
NO2 concentrations have occurred, the maximum DVs in 2015
across the whole monitoring network were well below the NAAQS, with the
highest values being 30 ppb (annual) and 72 ppb (hourly) (U.S. EPA,
2017a, Section 2.3.1).
---------------------------------------------------------------------------

    \21\ Based on an analysis of data from sampling sites with
sufficient data to produce at least five valid DVs.
    \22\ It is not clear what specific sources may be responsible
for the upward trends in ambient NO2 concentrations at
these sites. (See U.S. EPA, 2017a, Section 2.1.2).
---------------------------------------------------------------------------

c. Near-Road NO2 Air Quality
    The largest single source of NOX emissions is on-road
vehicles, and emissions are primarily in the form of NO, with
NO2 formation requiring both time and sufficient
O3 concentrations. Depending on local meteorological
conditions and O3 concentrations, ambient NO2
concentrations can be higher near roadways than at sites in the same
area but farther removed from the road (and from other sources of
NOX emissions).
    When considering the historical relationships between
NO2 concentrations at monitors near roadways and monitors
farther away from roads, NO2 DVs are generally highest at
sampling sites nearest to the road (less than 50 meters) and decrease
as distance from the road increases (U.S. EPA, 2017a, Section 2.3.2,
Figure 2-6). This relationship is more pronounced for annual DVs than
for hourly DVs. The general pattern of decreasing DVs with increasing
distance from the road has persisted over time, though the absolute
difference (in terms of ppb) between NO2 concentrations
close to roads and those farther from roads has generally decreased
over time (U.S. EPA, 2017a, Section 2.3.2, Figure 2-6).
    In addition, data from the recently deployed network \23\ of
dedicated near-road NO2 monitors indicate that daily maximum
1-hour NO2 concentrations are generally higher at near-road
monitors than at non-near-road monitors in the same CBSA (U.S. EPA,
2017a, Figures 2-7 to 2-10). The 98th percentiles of 1-hour daily
maximum concentrations (the statistic most relevant to the 1-hour
standard) were highest at near-road monitors (i.e., higher than all
non-near-road monitors in the same CBSA) in 58% to 77% of the CBSAs
evaluated, depending on the year (U.S. EPA, 2017a, Section 2.3.2,
Figures 2-7 to 2-10).\24\
---------------------------------------------------------------------------

    \23\ Prior to the 2010 rulemaking, monitors were ``not sited to
measure peak roadway-associated NO2 concentrations . . .
.'' (75 FR 6479).
    \24\ The upper end of this range (i.e., 77%) reflects more
recent years during which most near-road monitors were in operation.
The lower end of this range (i.e., 58%) reflects the smaller number
of near-road monitors in operation during the early years of the
deployment of the near-road network.
---------------------------------------------------------------------------

d. Relationships between Hourly and Annual NO2
Concentrations
    Control programs have resulted in substantial reductions in
NOX emissions since the 1980s. These reductions in
NOX emissions have decreased both short-term peak
NO2 concentrations and annual average concentrations (U.S.
EPA, 2017a, Section 2.3.1). Since the 1980s, the median annual
NO2 DV has decreased by about 65% and the median 1-hour DV
has decreased by about 50% (U.S. EPA, 2017a, Section 2.3.3, Figure 2-
10). These DVs were measured predominantly by NO2 monitors
located at area-wide monitoring sites; data from the new near-road
monitoring network were not included the analysis of the relationship
between hourly and annual NO2 concentrations due to the
limited amount of data available.\25\ At various times in the past, a
number of these area-wide sites would have violated the 1-hour standard
without violating the annual standard. However, no sites would have
violated the annual standard without also violating the 1-hour standard
(U.S. EPA, 2017a, p. 2-21). Furthermore, examination of historical data
indicates that 1-hour DVs at or below 100 ppb generally correspond to
annual DVs below 35 ppb, with many monitors recording annual
concentrations around 30 ppb. (U.S. EPA, 2017a, p. 2-21, Figure 2-11).
Based on this, an area meeting the 1-hour standard with its level of
100 ppb would be expected to maintain annual average NO2
concentrations well below the 53 ppb level of the annual standard (U.S.
EPA, 2017a, Figure 2-11). It will be important to re-evaluate the
relationship between 1-hour and annual standards as more data become
available from recently deployed near-road monitors.
---------------------------------------------------------------------------

    \25\ Area-wide sites are intended to characterize ambient
NO2 concentrations at the neighborhood and larger spatial
scales.
---------------------------------------------------------------------------

2. Overview of the Health Effects Evidence
    This section summarizes the available scientific evidence on the
health effects of NO2 exposures. These summaries are based
primarily on the assessment of the evidence in the 2016 NOX
ISA (U.S. EPA, 2016a) and on the PA's consideration of that evidence in
evaluating the public health protection provided by the current primary
NO2 standards (U.S. EPA, 2017a).
    In the current review of the primary NO2 NAAQS, the 2016
NOX ISA uses frameworks to characterize the strength of the
available scientific evidence for health effects attributable to
NO2 exposures and to classify the evidence for factors that
may increase risk in some populations \26\ or lifestages (U.S. EPA,
2016a, Preamble, Section 6). These frameworks provide the basis for
robust, consistent, and transparent evaluation of the scientific
evidence, including uncertainties in the evidence, and for drawing
conclusions on air pollution-related health effects and at-risk
populations. With regard to characterization of the health effects
evidence, the 2016 NOX ISA uses a five-level hierarchy to
classify the overall weight of evidence into one of the following
categories: Causal relationship; likely to be a causal relationship;
suggestive of, but not sufficient to infer, a causal relationship;
inadequate to infer a causal relationship; and not likely to be a
causal relationship (U.S. EPA, 2016a, Preamble, Table II).\27\ As
discussed further below, in evaluating the public health protection
provided by the current standards, the EPA's focus is on health effects
determined to have a ``causal'' or a ``likely to be causal''
relationship with NO2 exposures. In the ISA, a ``causal''
relationship is supported when, ``the consistency and coherence of
evidence integrated across scientific disciplines and related health
outcomes are sufficient to rule out chance, confounding, and other
biases with reasonable confidence'' (U.S. EPA, 2016a, p. 1-5). A
``likely to be causal'' relationship is supported when ``there are
studies where results are not explained by chance, confounding, or
other biases, but uncertainties remain in the evidence overall. For
example, the influence of other pollutants is difficult to address, or
evidence among scientific disciplines may be limited or inconsistent''
(U.S. EPA, 2016a, p. 1-5). Many of the health effects evaluated in the
ISA, have complex etiologies. For instance, diseases such as asthma are
typically initiated by multiple agents. For example, outcomes depend on
a

variety of factors such as age, genetic background, nutritional status,
immune competence, and social factors (U.S. EPA, 2017a, Preamble,
Section 5.b). Thus, exposure to NO2 is likely one of several
contributors to the health effects evaluated in the ISA.
---------------------------------------------------------------------------

    \26\ The term ``population'' refers to people having a quality
or characteristic in common, including a specific pre-existing
illness or a specific age or lifestage.
    \27\ In this review, as in past reviews, there were causal
determination changes for different endpoint categories. For more
information on changes in causal determinations from the previous
review, see below and Table 1-1 of the 2016 NOX ISA (U.S.
EPA, 2016a).
---------------------------------------------------------------------------

    With regard to identifying specific populations or lifestages that
may be at increased risk of health effects related to NO2
exposures, the 2016 NOX ISA characterizes the evidence for a
number of ``factors'', including both intrinsic (i.e., biologic, such
as pre-existing disease or lifestage) and extrinsic (i.e., non-
biologic, such as diet or socioeconomic status) factors. The categories
considered in classifying the evidence for these potential at-risk
factors are ``adequate evidence,'' ``suggestive evidence,''
``inadequate evidence,'' and ``evidence of no effect'' (U.S. EPA,
2016a, Section 5.c, Table II). Within the PA, the focus is on the
consideration of potential at-risk populations and lifestages for which
the 2016 NOX ISA judges there is ``adequate'' evidence (U.S.
EPA, 2016a, Table 7-27).
    The sections below summarize the evidence for effects related to
short-term NO2 exposures (e.g., minutes up to 1 month) and
the evidence for effects related to long-term NO2 exposures
(e.g., months to years).\28\ The final section discusses the potential
public health implications of NO2 exposures, based on the
evidence for populations and lifestages at increased risk of
NO2-related effects. The focus of these sections is on
health effects that the 2016 NOX ISA has determined to have
a ``causal'' or ``likely to be causal'' relationship with
NO2. Health effects whose causal determinations have changed
since the last review are also briefly addressed. More information on
health effects for which causal determinations are suggestive of, but
not sufficient to infer a causal relationship or inadequate to infer a
causal relationship (i.e., health effects for which the evidence is
weaker) may be found in section II.C of the proposal (87 FR 34792, July
26, 2017).
---------------------------------------------------------------------------

    \28\ Short-term exposures are defined as those with durations of
minutes up to 1 month, with most studies examining effects related
to exposures in the range of 1 hour to 1 week (2016 NOX
ISA, p. 1-15).
---------------------------------------------------------------------------

a. Health Effects With Short-Term Exposure to NO2
    This section discusses the evidence for health effects following
short-term NO2 exposures. Section II.B.2.a.i discusses the
nature of the health effects that have been shown to occur following
short-term NO2 exposures and the strength of the evidence
supporting various effects, based on the assessment of that evidence in
the 2016 NOX ISA. Section II.B.2.a.ii discusses the
NO2 concentrations at which health effects have been
demonstrated to occur, based on the considerations and analyses
included in the PA. Section II.B.2.a.iii discusses NO2
concentrations in controlled human exposure studies, while section
II.B.2.a.iv. discusses NO2 concentrations in locations of
epidemiologic studies.
i. Nature of Effects
    Across previous reviews of the primary NO2 NAAQS (U.S.
EPA, 1993; U.S. EPA, 2008a), evidence has consistently demonstrated
respiratory effects attributable to short-term NO2
exposures. In the last review, the 2008 NOX ISA concluded
that evidence was ``sufficient to infer a likely causal relationship
between short-term NO2 exposure and adverse effects on the
respiratory system'' based on the large body of epidemiologic evidence
demonstrating positive associations with respiratory symptoms and
hospitalization or ED visits as well as supporting evidence from
controlled human exposure and animal studies (U.S. EPA, 2008a, p. 5-6).
Evidence for cardiovascular effects and mortality attributable to
short-term NO2 exposures was weaker and was judged
``inadequate to infer the presence or absence of a causal
relationship'' and ``suggestive of, but not sufficient to infer, a
causal relationship,'' respectively. The 2008 NOX ISA noted
an overarching uncertainty in determining the extent to which
NO2 is independently associated with effects or whether
NO2 is a marker for the effects of another traffic-related
pollutant or mix of pollutants (U.S. EPA, 2008a, Section <IP_ADDRESS> to
<IP_ADDRESS>).
    For the current review, there is newly available evidence for both
respiratory effects and other health effects that was critically
evaluated in the 2016 NOX ISA as part of the full body of
evidence informing the nature of the relationship between health
effects and short-term exposures to NO2 (U.S. EPA,
2016a).\29\ Chapter 5 of the 2016 NOX ISA presents a
detailed assessment of the evidence for health effects associated with
short-term NO2 exposures (U.S. EPA, 2016a). In considering
the available evidence and the causal determinations presented in the
2016 NOX ISA, consistent with the PA (U.S. EPA, 2017a), this
action focuses on respiratory effects described below. Cardiovascular
effects and mortality are also briefly addressed.
---------------------------------------------------------------------------

    \29\ A list of causal determinations from the 2016
NOX ISA for the current review, and those from the
previous review, for respiratory effects, cardiovascular effects,
and mortality is presented in Table 3-1 of the NO2 PA
(U.S. EPA, 2017a).
---------------------------------------------------------------------------

Respiratory Effects
    The 2016 NOX ISA concludes that evidence supports a
causal relationship between respiratory effects and short-term
NO2 exposures, primarily based on evidence for asthma
exacerbation. In reaching this conclusion, the 2016 NOX ISA
notes that ``epidemiologic, controlled human exposure, and animal
toxicological evidence together can be linked in a coherent and
biologically plausible pathway to explain how NO2 exposure
can trigger an asthma exacerbation'' (U.S. EPA, 2016a, p. 1-17). In the
last review, the 2008 NOX ISA described much of the same
evidence and determined it was ``sufficient to infer a likely causal
relationship'' with respiratory effects, citing uncertainty as to
whether the epidemiologic results for NO2 could be
disentangled from effects related to other traffic-related pollutants.
In contrast to the current review, the 2008 NOX ISA
evaluated evidence for the broad category of respiratory effects and
did not explicitly evaluate the extent to which various lines of
evidence supported effects on more specific endpoints such as asthma
exacerbation (i.e., asthma attacks). In the current review, the 2016
NOX ISA states that ``the determination of a causal
relationship is not based on new evidence as much as it is on the
integrated findings for asthma attacks with due weight given to
experimental studies'' (U.S. EPA, 2016a, p. 1xxxiii).\30\
---------------------------------------------------------------------------

    \30\ Experimental studies, such as controlled human exposure
studies, provide support for effects of exposures to NO2
itself, and generally do not reflect the complex atmospheres to
which people are exposed. Thus, unlike epidemiologic studies,
experimental studies that evaluate exposures to NO2
itself are not subject to uncertainties related to the potential for
copollutant confounding.
---------------------------------------------------------------------------

    Strong evidence supporting this causal determination in the 2016
NOX ISA comes from a meta-analysis of controlled human
exposure studies that evaluate the potential for increased AR \31\
following 20-minute to 1-hour NO2 exposures (Brown,
2015).\32\ While

individual controlled human exposure studies can lack statistical power
to identify effects, the meta-analysis of individual-level data
combined from multiple studies has greater statistical power due to
increased sample size.\33\ AR has been the key respiratory outcome from
controlled human exposures in the previous and the current review of
the primary NO2 NAAQS. The 2016 NOX ISA
specifically notes that ``airway hyperresponsiveness can lead to poorer
control of symptoms and is a hallmark of asthma'' (U.S. EPA, 2016a, p.
1-18). Brown (2015) examined the relationship between AR and
NO2 exposures in subjects with asthma across the large body
of controlled human exposure studies,\34\ most of which were available
in the last review (U.S. EPA, 2017a, Tables 3-2 and 3-3). More
specifically, the meta-analysis identified the fraction of individuals
having an increase in AR following NO2 exposure, compared to
the fraction having a decrease, across studies.\35\ The meta-analysis
also stratified the data to consider the influence of factors that may
affect results including exercise versus rest and non-specific versus
specific challenge agents.\36\
---------------------------------------------------------------------------

    \31\ The 2016 NOX ISA states that AR is ``inherent
responsiveness of the airways to challenge by bronchoconstricting
agents'' (U.S. EPA, 2016a, p. 5-9). Airway hyperresponsiveness
refers to increased sensitivity of the airways to an inhaled
bronchoconstricting agent. This is often quantified as the dose of
challenge agent that results in a 20% reduction in forced expiratory
volume for 1 second (FEV1), but some studies report the
change in FEV1 for a specified dose of challenge agent.
The change in specific airways resistance (sRaw) is also used to
quantify AR.
    \32\ These studies evaluate the effect of inhaled NO2
on the inherent responsiveness of the airways to challenge by
bronchoconstricting agents.
    \33\ A meta-analysis synthesizes data from multiple studies
using statistical analyses.
    \34\ These controlled human exposure studies were conducted in
people with asthma, a group at increased risk for NO2-
related effects. The severity of asthma varied across studies,
ranging from inactive asthma up to severe asthma, with the majority
of study participants having a mild form of asthma. (Brown, 2015).
    \35\ More information on the distribution of study subjects
across NO2 concentrations can be found below (section
II.A.2.ii). Information on the fraction of individuals who
experienced an increase versus a decrease stratified by
concentration can also be found in that section.
    \36\ ``Bronchial challenge agents can be classified as
nonspecific (e.g., histamine; SO2; cold air) or specific
(i.e., an allergen). Nonspecific agents can be differentiated
between `direct' stimuli (e.g., histamine, carbachol, and
methacholine) which act on airway smooth muscle receptors and
`indirect' stimuli (e.g., exercise, cold air) which act on smooth
muscle through intermediate pathways, especially via inflammatory
mediators. Specific allergen challenges (e.g., house dust mite, cat
allergen) also act `indirectly' via inflammatory mediators to
initiate smooth muscle contraction and bronchoconstriction.'' (U.S.
EPA, 2016a, p. 5-8).
---------------------------------------------------------------------------

    The results from the meta-analysis demonstrate that the majority of
study volunteers with asthma experienced increased AR following resting
exposure to NO2 concentrations ranging from 100 to 530 ppb,
relative to filtered air. Limitations in this evidence result from the
lack of an apparent dose-response relationship, uncertainty in the
potential adversity of responses, and the general focus of available
studies on people with mild asthma, rather than more severe asthma.
These controlled human exposure studies, the meta-analysis, and
uncertainties in this body of evidence are discussed in greater detail
below.
    The 2016 NOX ISA further characterizes the clinical
relevance of these increases in AR, using an approach that is based on
guidelines from the American Thoracic Society (ATS) and the European
Respiratory Society (ERS) for the assessment of therapeutic agents
(Reddel et al., 2009). Specifically, based on individual-level
responses reported in a subset of studies, the 2016 NOX ISA
considered a halving of the provocative dose (PD) to indicate responses
that may be clinically relevant.37 38 With regard to this
approach, the 2016 NOX ISA notes that ``in a joint statement
of the [ATS] and [ERS], one doubling dose change in PD is recognized 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).
---------------------------------------------------------------------------

    \37\ PD is the dose of challenge agent required to elicit a
specified change in a measure of lung function, typically a 20%
decrease in FEV1 or a 100% increase in specific airway
resistance (sRaw).
    \38\ The 2016 NOX ISA's characterization of a
clinically relevant response is based on evidence from controlled
human exposure studies evaluating the efficacy of inhaled
corticosteroids that are used to prevent bronchoconstriction and AR
as described by Reddel et al. (2009). Generally, a change of at
least one doubling dose is considered to be an indication of
clinical relevance. Based on this, a halving of the PD is taken in
the 2016 NOX ISA to represent an increase in AR that
indicates a clinically relevant response.
---------------------------------------------------------------------------

    Studies considered for inclusion into the meta-analyses by Brown
(2015) were identified from the meta-analysis by Goodman et al. (2009),
the 2016 NOX ISA, and a literature search for controlled
human exposure studies of individuals with asthma exposed to
NO2 that were published since the 2008 NOX ISA.
In one analysis, Brown (2015) showed that NO2 exposures from
100 to 530 ppb resulted in a halving of the dose of a challenge agent
required to increase AR (i.e., a halving of the PD) in about a quarter
of study volunteers. While these results support the potential for
clinically relevant increases in AR in some individuals with asthma
following NO2 exposures within the range of 100 to 530 ppb,
uncertainty remains given that the analysis of PD is limited to a
subset of the studies in which non-specific AR was assessed in
individuals following resting exposures to NO2 and air.\39\
In addition, compared to conclusions based on the entire range of
NO2 exposure concentrations evaluated (i.e., 100 to 530
ppb), there is greater uncertainty in reaching conclusions about the
potential for clinically relevant effects at any particular
NO2 exposure concentration within this range.
---------------------------------------------------------------------------

    \39\ Section <IP_ADDRESS> of the PA (U.S. EPA, 2017a) includes
additional discussion of these uncertainties.
---------------------------------------------------------------------------

    Controlled human exposure studies discussed in the 2016
NOX ISA also evaluated a range of other respiratory effects,
including lung function decrements, respiratory symptoms, and pulmonary
inflammation. The evidence does not consistently demonstrate these
effects following exposures to NO2 concentrations at or near
those found in the ambient air in the U.S. However, a subset of studies
using NO2 exposures to 260 ppb for 15-30 min or 400 ppb for
up to 6 hours provide evidence that study volunteers with asthma and
allergy can experience increased inflammatory responses following
allergen challenge. Evidence for pulmonary inflammation was more mixed
across studies that did not use an allergen challenge following
NO2 exposures ranging from 300-1,000 ppb (U.S. EPA, 2016a,
Section <IP_ADDRESS>).
    In addition to this evidence for NO2-induced increases
in AR and allergic inflammation in controlled human exposure studies,
the 2016 NOX ISA also describes evidence from epidemiologic
studies for positive associations between short-term NO2
exposures and an array of respiratory outcomes related to asthma. Thus,
coherence and biological plausibility is demonstrated in the evidence
integrated between controlled human exposure studies and the various
asthma-related outcomes examined in epidemiologic studies. The 2016
NOX ISA indicates that epidemiologic studies consistently
demonstrate NO2-health effect associations with asthma
hospital admissions and ED visits among subjects of all ages and
children, and with asthma symptoms in children (U.S. EPA, 2016a,
Sections <IP_ADDRESS> and <IP_ADDRESS>). The robustness of the evidence is
demonstrated by associations found in studies conducted in diverse
locations in the U.S., Canada, and Asia, including several multicity
studies. The evidence for asthma exacerbation is substantiated by
several recent studies with strong exposure assessment characterized by
measuring NO2 concentrations in subjects' location(s).
Epidemiologic studies also demonstrated associations between short-term
NO2 exposures and respiratory symptoms, lung function
decrements, and pulmonary inflammation, particularly for measures of
personal total and ambient NO2 exposures and NO2
measured outside schools. This is important because there is
considerable spatial variability in NO2

concentrations, and measurements in subjects' locations may better
represent variability in ambient NO2 exposures compared to
measurements at central site monitors (U.S. EPA, 2016a, Sections 2.5.3
and 3.4.4). Epidemiologic studies also consistently indicate ambient or
personal NO2-associated increases in exhaled nitric oxide
(eNO, a marker of airway inflammation), which is coherent with
experimental findings for allergic inflammation (U.S. EPA, 2016a,
Section <IP_ADDRESS>).
    In assessing the evidence from epidemiologic studies, the 2016
NOX ISA not only considers the consistency of effects across
studies, but also evaluates other study attributes that affect study
quality, including potential confounding and exposure assignment.
Regarding potential confounding, the 2016 NOX ISA notes that
NO2 associations with asthma-related effects persist with
adjustment for temperature; humidity; season; long-term time trends;
and PM10, SO2, or O3. Recent studies
also add findings for NO2 associations that generally
persist with adjustment for a key copollutant, including
PM2.5 and traffic-related copollutants such as elemental
carbon (EC) or black carbon (BC), ultra-fine particles (UFPs), or
carbon monoxide (CO) (U.S. EPA, 2016a, Figures 5-16 and 5-17, Table 5-
38). Confounding by organic carbon (OC), PM metal species, or volatile
organic compounds (VOCs) is rarely studied, but NO2
associations with asthma exacerbation tend to persist in the few
available copollutant models. The 2016 NOX ISA recognizes,
however, that copollutant models have inherent limitations and cannot
conclusively rule out confounding (U.S. EPA, 2015a, Preamble, Section
4.b).
    The 2016 NOX ISA also notes that results based on
personal exposures or pollutants measured at people's locations provide
support for NO2 associations that are independent of
PM2.5, EC/BC, organic carbon (OC), or UFPs. Compared to
ambient NO2 concentrations measured at central-site
monitors, personal NO2 exposure concentrations and indoor
NO2 concentrations exhibit lower correlations with many
traffic-related copollutants (e.g., r = -0.37 to 0.31). Thus, these
health effect associations with personal and indoor NO2 may
be less prone to confounding by these traffic-related copollutants
(U.S. EPA, 2016a, Section 1.4.3).
    Overall, the strongest evidence supporting the conclusion of the
causal relationship determined in the 2016 NOX ISA comes
from controlled human exposure studies demonstrating NO2-
induced increases in AR in individuals with asthma, with supporting
evidence for a range of respiratory effects from epidemiologic studies.
The conclusion of a causal relationship in the 2016 NOX ISA
is based on this evidence and its explicit integration within the
context of effects related to asthma exacerbation. 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, and thus do not themselves provide substantively new
information. However, by pooling data from a subset of studies, the
newly available meta-analysis (Brown, 2015) has partially addressed an
uncertainty from the last review by demonstrating the potential for
clinically relevant increases in AR following exposures to
NO2 concentrations in the range of 100 to 530 ppb.
    Similarly, the epidemiologic evidence that is newly available in
the current review is consistent with evidence from the last review and
does not alter the fundamental understanding of the respiratory effects
related to ambient NO2 exposures. New epidemiologic evidence
does, however, reduce some uncertainty from the last review regarding
the extent to which effects may be independently related to
NO2, as there is more evidence from studies using measures
that may better capture personal exposure, as well as a more robust
evidence base examining copollutant confounding. Some uncertainty
remains in the epidemiologic evidence regarding confounding by the most
relevant copollutants, as it can be difficult to disentangle the
independent effects of highly correlated pollutants (i.e.,
NO2 and traffic-related pollutants).
Cardiovascular Effects
    The evidence for a causal relationship between cardiovascular
health effects and short-term NO2 exposures in the 2016
NOX ISA was judged ``suggestive of, but not sufficient to
infer, a causal relationship'' (U.S. EPA, 2016a, Section 5.3.11), which
reflects a conclusion that the evidence for a causal relationship is
stronger in the last review, when the conclusion was that the evidence
was ``inadequate to infer the presence or absence of a causal
relationship.'' The 2016 determination was primarily supported by
consistent epidemiologic evidence from multiple new studies indicating
associations between NO2 concentrations and myocardial
infarction. More information on these health effects may be found in
section II.C.1.a.ii of the proposal (87 FR 34792, July 26, 2017).
Mortality
    The 2016 NOX ISA concludes that the evidence for a
causal relationship between short-term NO2 exposures and
total mortality is ``suggestive of, but not sufficient to infer, a
causal relationship'' (U.S. EPA, 2016a, Section 5.4.8), which is the
same conclusion reached in the last review (U.S. EPA, 2008a). More
information on these health effects may be found in section
II.C.1.a.iii of the proposal (87 FR 34792, July 26, 2017).
ii. Short-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, it is appropriate to consider the short-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 NO2 exposure concentrations associated
with health effects within the context of considering the adequacy of
the current standards, the PA focuses on the evidence for asthma-
related effects (i.e., the type of effect for which there is the
strongest evidence supporting a causal relationship, as discussed in
the section above). The PA specifically considers to what extent the
evidence indicates adverse asthma-related effects attributable to
short-term exposures to NO2 concentrations lower than
previously identified or below the existing standards (U.S. EPA, 2017a,
p. 3-11). In addressing this issue, the PA considers the extent to
which NO2-induced effects have been reported over the ranges
of NO2 exposure concentrations evaluated in controlled human
exposure studies and the extent to which NO2-associated
effects have been reported for distributions of ambient NO2
concentrations in epidemiologic study locations that meet existing
standards. These considerations are discussed below for controlled
human exposure studies and epidemiologic studies.
iii. NO2 Concentrations in Controlled Human Exposure Studies
    Controlled human exposure studies, most of which were available and
considered in the last review, have evaluated various respiratory
effects following short-term NO2 exposures. These include
AR, inflammation and

oxidative stress, respiratory symptoms, and lung function decrements.
Generally, when considering respiratory effects from controlled human
exposure studies in healthy adults without asthma, the evidence does
not indicate respiratory symptoms or lung function decrements following
NO2 exposures below 4,000 ppb, and limited evidence
indicates airway inflammation following exposures below 1,500 ppb (U.S.
EPA, 2016a, Section 5.2.7).\40\ There is a substantial body of evidence
demonstrating increased AR in healthy adults with exposures in the
range of 1,500-3,000 ppb.
---------------------------------------------------------------------------

    \40\ Exposure durations were from one to three hours in studies
evaluating AR and respiratory symptoms, and up to five hours in
studies evaluating lung function decrements.
---------------------------------------------------------------------------

    Evidence for respiratory effects following exposures to
NO2 concentrations at or near those found in the ambient air
is strongest for AR in individuals with asthma (U.S. EPA, 2016a,
Section 5.2.2 p. 5-7). As discussed above, increased AR has been
reported in people with asthma following exposures to NO2
concentrations as low as 100 ppb. In contrast, controlled human
exposure studies evaluated in the 2016 NOX ISA do not
provide consistent evidence for respiratory symptoms, lung function
decrements, or pulmonary inflammation in adults with asthma following
exposures to NO2 concentrations at or near those in ambient
air (i.e., <1,000 ppb; U.S. EPA, 2016a, Section 5.2.2). There is some
indication of allergic inflammation in adults with allergy and asthma
following exposures to 260-1,000 ppb. However, the generally high
exposure concentrations in these studies make it difficult to interpret
the likelihood that these effects could potentially occur following
NO2 exposures at or below the level of the current
standards.\41\
---------------------------------------------------------------------------

    \41\ Despite the difficulty in interpreting the likelihood that
these effects would occur at concentrations closer to the current
standards, as described later (section II.A.3) the current standards
are expected to protect against exposures at the exposure
concentrations used in these studies.
---------------------------------------------------------------------------

    Thus, in considering the exposure concentrations evaluated in
controlled human exposure studies, the PA focuses on the body of
evidence for NO2-induced increases in AR in adults with
asthma. In evaluating the NO2 exposure concentrations at
which increased AR is observed, the PA considers both the group mean
results reported in individual studies and the results evaluated across
studies in the meta-analysis by Brown (2015; U.S. EPA, 2016a, Section
<IP_ADDRESS>). 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, having 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, with the additional benefit of aiding in the
identification of trends in individual-level responses across studies
and the advantage of increased power to detect effects, even in the
absence of statistically significant effects in individual studies,
although each study in the meta-analysis may not be based on the exact
same exposure conditions.\42\
---------------------------------------------------------------------------

    \42\ Tables 3-2 and 3-3 in the NO2 PA (adapted from
the 2016 NOX ISA; U.S. EPA, 2016a, Tables 5-1 and 5-2)
provide details for the studies examining AR in individuals with
asthma at rest and with exercise, respectively. These tables note
various study details including the exposure concentration, duration
of exposure, type of challenge (nonspecific or specific), number of
study subjects, number of subjects having an increase or decrease in
AR following NO2 exposure, average PD: The dose of
challenge agent required to elicit a particular magnitude of change
in FEV1 or other measure of lung function) across
subjects, and the statistical significance of the change in AR
following NO2 exposures.
---------------------------------------------------------------------------

Consideration of Group Mean Results From Individual Studies
    Individual controlled human exposure studies have generally not
reported statistically significant increases in AR following resting
exposures to NO2 concentrations from 100 to 200 ppb. In
considering such studies, the PA notes that the lowest NO2
concentration to which individuals with asthma have been exposed is 100
ppb, with an exposure duration of 60 minutes in all studies at this
concentration. Of the five studies conducted at 100 ppb, a
statistically significant increase in AR following exposure to
NO2 was only observed in the study by Orehek et al. (1976)
(n = 20). Of the four studies that did not report statistically
significant increases in AR following exposures to 100 ppb
NO2, three reported weak trends towards decreased AR (n =
20, Ahmed et al., 1983b; n = 15, Hazucha et al., 1983; n = 8,
Tunnicliffe et al., 1994), and one reported a trend towards increased
AR (n = 20, Ahmed et al., 1983a). Resting exposures to 140 ppb
NO2 resulted in increases in AR that reached marginal
statistical significance (n = 20, Bylin et al., 1988). In addition, the
one study conducted at 200 ppb demonstrated a trend towards increased
AR, but this study was small and its results were not statistically
significant (n = 4, Orehek et al., 1976). Thus, as noted above,
individual controlled human exposure studies have generally not
reported statistically significant increases in AR following resting
exposures to NO2 concentrations from 100 to 200 ppb. Group
mean responses in these studies suggest a trend towards increased AR
following exposures to 140 and 200 ppb NO2, while trends in
the direction of group mean responses were inconsistent following
exposures to 100 ppb NO2.
    In considering studies in individuals with asthma conducted with
exercise and at lower concentrations, the PA notes that three studies
evaluated NO2 exposure concentrations between 150 and 200
ppb (n = 19, Roger et al., 1990; n = 31, Kleinman et al., 1983; n = 11,
Jenkins et al., 1999). Of these studies, only Kleinman et al. (1983)
reported a statistically significant increase in AR following
NO2 exposure (i.e., at 200 ppb). Roger et al. (1990) and
Jenkins et al. (1999) did not report statistically significant
increases, but showed weak trends for increases in AR following
exposures to 150 ppb and 200 ppb NO2, respectively. Thus, as
with studies of resting exposures, studies that evaluated exposures to
150 to 200 ppb NO2 with exercise report trends toward
increased AR, though results are generally not statistically
significant.
    Several studies evaluated exposures of individuals with asthma to
NO2 concentrations above 200 ppb. Of the five studies that
evaluated 30-minute resting exposures to NO2 concentrations
from 250 to 270 ppb, NO2-induced increases in AR were
statistically significant in three (n = 14, J[ouml]rres et al., 1990; n
= 18, Strand et al., 1988; n = 20, Bylin et al., 1988). Statistically
significant increases in AR are also more consistently reported across
studies that evaluated resting exposures to 400-530 ppb NO2,
with three of four studies reporting a statistically significant
increase in AR following such exposures. However, studies conducted
with exercise do not indicate consistent increases in AR following
exposures to NO2 concentrations from 300 to 600 ppb (U.S.
EPA, 2017a, Table 3-3).\43\
---------------------------------------------------------------------------

    \43\ There are eight additional studies with exercising
exposures to 300-350 ppb NO2 as presented in Table 3-3 of
the NO2 PA, with exposure durations ranging from 30-240
minutes. Results across these studies are inconsistent, with only
two of eight reporting statistically significant results. Only one
of four studies with exercising exposures of 400 or 600 ppb reported
statistically significant increases in AR.
---------------------------------------------------------------------------

Consideration of Results From the Brown (2015) Meta-Analysis
    As discussed above, the 2016 NOX ISA assessment of the
evidence for AR

in individuals with asthma also focuses on a recently published meta-
analysis (Brown, 2015) investigating individual-level data from
controlled human exposure studies. While individual controlled human
exposure studies can lack statistical power to identify effects, the
meta-analysis of individual-level data combined from multiple studies
(Brown, 2015) has greater statistical power due to increased sample
size. The meta-analysis considered individual-level responses,
specifically whether individual study subjects experienced an increase
or decrease in AR following NO2 exposure compared to
exposure to filtered air.\44\ Evidence was evaluated together across
all studies and also stratified for exposures conducted with exercise
and at rest, and for measures of specific and non-specific AR. The 2016
NOX ISA notes that these methodological differences may have
important implications with regard to results (U.S. EPA, 2016a
(discussing Brown, 2015; Goodman et al., 2009)), which informed the
2016 NOX ISA's emphasis on studies of resting exposures and
non-specific challenge agents. Overall, the Brown meta-analysis
presents the fraction of individuals having an increase in AR following
exposure to various NO2 concentrations (i.e., 100 ppb, 100
ppb to < 200 ppb, 200 ppb up to and including 300 ppb, and above 300
ppb) (U.S. EPA, 2016a, Section <IP_ADDRESS>).\45\
---------------------------------------------------------------------------

    \44\ More specifically, the Brown (2015) meta-analysis combined
information from the studies presented in Tables 3-2 and 3-3 of the
PA. It compared the number of study participants who experienced an
increase in AR following NO2 exposures to the number who
experienced a decrease in AR. Study participants who experienced no
change in AR were not included in comparisons. P-value refers to the
significance level of a two-tailed sign test.
    \45\ The number of participants in each study and the number
having an increase or decrease in AR is indicated in Tables 3-2 and
3-3 of the NO2 PA.
---------------------------------------------------------------------------

    When evaluating results from the meta-analysis, the PA first
considers results across all exposure conditions combined (i.e.,
resting, exercising, non-specific challenge, and specific challenge).
For 100 ppb NO2 exposures, Brown (2015) reported that, of
the study participants who experienced either an increase or decrease
in AR following NO2 exposures, 61% experienced an increase
(p = 0.08). For 100 to < 200 ppb NO2 exposures, 62% of study
subjects experienced an increase in AR following NO2
exposures (p = 0.014). For 200 to 300 ppb NO2 exposures, 58%
of study subjects experienced an increase in AR following
NO2 exposures (p = 0.008). For exposures above 300 ppb
NO2, 57% of study subjects experienced an increase in AR
following NO2 exposures, though this fraction was not
statistically significantly different from the fraction experiencing a
decrease.
    The PA also considers the results of Brown (2015) for various
subsets of the available studies, based on the exposure conditions
evaluated (i.e., resting, exercising) and the type of challenge agent
used (i.e., specific, non-specific). For exposures conducted at rest,
across all exposure concentrations (i.e., 100-530 ppb NO2, n
= 139; U.S. EPA, 2017a, Table 3-2), Brown (2015) reported that a
statistically significant fraction of study participants (71%, p
<0.001) experienced an increase in non-specific AR following
NO2 exposures, compared to the fraction that experienced a
decrease in AR. The meta-analysis also presented results for various
concentrations or ranges of concentrations. Following resting exposure
to 100 ppb NO2, 66% of study participants experienced
increased non-specific AR. For exposures to concentrations of 100 ppb
to < 200 ppb, 200 ppb up to and including 300 ppb, and above 300 ppb,
increased non-specific AR was reported in 67%, 78%, and 73% of study
participants, respectively.\46\ For non-specific challenge agents, the
differences between the fraction of individuals who experienced
increased AR following resting NO2 exposures and the
fraction who experienced decreased AR reached statistical significance
for all of the ranges of exposure concentrations evaluated (p < 0.001).
---------------------------------------------------------------------------

    \46\ For the exposure category of ``above 300 ppb'', exposures
included 400, 480, 500, and 530 ppb. No studies conducted at rest
used concentrations between 300 and 400 ppb.
---------------------------------------------------------------------------

    In contrast to the results from studies conducted at rest, the
fraction of individuals having an increase in AR following
NO2 exposures with exercise was not consistently greater
than 50%, particularly when looking at the allergen challenge group,
and none of the results were statistically significant (Brown, 2015).
Across all NO2 exposures with exercise, measures of non-
specific AR were available for 241 individuals, 54% of whom experienced
an increase in AR following NO2 exposures relative to air
controls. There were no studies in this group conducted at 100 ppb, and
for exercising exposures to 150-200 ppb, 250-300 ppb, and 350-600 ppb,
the fraction of individuals with increased non-specific AR was 59%,
55%, and 49%, respectively.
    In addition to examining results from studies of non-specific AR,
the meta-analysis also considered results from studies that evaluated
changes in specific AR (i.e., AR following an allergen challenge; n =
130, U.S. EPA, 2017a, Table 3-3) following NO2 exposures.
The results do not indicate statistically significant fractions of
individuals having an increase in specific AR following exposure to
NO2 at concentrations below 400 ppb, even when considering
resting and exercising exposures separately (Brown, 2015). Of the three
studies that evaluated specific AR at concentrations of 400 ppb, one
was conducted at rest (Tunnicliffe et al., 1994). This study reported
that all individuals experienced increased AR following 400 ppb
NO2 exposures (Brown, 2015, Table 4). In contrast, for
exposures during exercise, most study subjects did not experience
NO2-induced increases in specific AR. In contrast, for
exposures during exercise, most study subjects did not experience
NO2-induced increases in specific AR.\47\ Overall, results
across studies are less consistent for increases in specific AR
following NO2 exposures.
---------------------------------------------------------------------------

    \47\ 48% experienced increased AR and 52% experienced decreased
AR, based on individual-level data for study participants exposed to
350 ppb (Riedl et al., 2012) or 400 ppb (Jenkins et al., 1999;
Witten et al., 2005) NO2.
---------------------------------------------------------------------------

Uncertainties in Evidence for AR
    When considering the evidence for NO2-induced increases
in AR in individuals with asthma, there are important uncertainties
that should be considered. One uncertainty is that available studies of
NO2 and AR have generally evaluated adults with mild asthma,
while people with more severe asthma could experience more serious
effects and/or effects following exposures to lower NO2
concentrations.\48\ Additional uncertainties include the lack of an
apparent dose-response relationship and uncertainty in the potential
adversity of the reported effects; each of these is discussed below.
---------------------------------------------------------------------------

    \48\ Brown (2015) notes, however, that disease status varied in
the studies included in the meta-analysis, ranging from ``inactive
asthma up to severe asthma in a few studies.''
---------------------------------------------------------------------------

    Both the meta-analysis by Brown (2015) and an additional meta-
analysis and meta-regression by Goodman et al. (2009) conclude that
there is no indication of a dose-response relationship for exposures
between 100 and 600 ppb NO2 and increased AR in individuals
with asthma. A dose-response relationship generally increases
confidence that observed effects are due to pollutant exposures rather
than to chance, and can be used to inform the characterization of the
magnitude of the effects; however, the lack of an apparent dose-
response relationship does not necessarily

indicate that there is no relationship between the exposure and effect,
particularly in these analyses based largely on between-subject
comparisons (i.e., as opposed to comparisons within the same subject
exposed to multiple concentrations). As discussed in the 2016
NOX ISA, there are a number of methodological differences
across studies that could contribute to between-subject differences and
that could obscure or complicate a dose-response relationship between
NO2 and AR (U.S. EPA, 2016a, section <IP_ADDRESS>).\49\ These
include subject activity level (rest versus exercise) during
NO2 exposure, asthma medication usage, choice of airway
challenge agent, method of administering the bronchoconstricting
agents, and physiological endpoint used to assess AR. Such
methodological differences across studies likely contribute to the
variability and uncertainty in results across studies and complicate
interpretation of the overall body of evidence for NO2-
induced AR. Thus, while the lack of an apparent dose-response
relationship adds uncertainty to the interpretation of controlled human
exposure studies of AR and reduces the ability to fully characterize
the health risks associated with these exposures, it does not indicate
the lack of an NO2 effect.
---------------------------------------------------------------------------

    \49\ For instance, Brown (2015) notes that the few studies
evaluating effects at multiple NO2 concentrations and at
resting exposures may indicate some support for a dose-response
relationship, as they show increasing AR with increasing exposure
concentrations.
---------------------------------------------------------------------------

    An additional uncertainty in interpreting these studies within the
context of considering the adequacy of the protection provided by the
current primary NO2 NAAQS is the potential adversity of the
reported NO2-induced increases in AR. As discussed above,
the meta-analysis by Brown (2015) used an approach that is consistent
with guidelines from the ATS and the ERS for the assessment of
therapeutic agents (Reddel et al., 2009) to assess the potential for
clinical relevance of these responses. Specifically, based on
individual-level responses reported in a subset of studies, Brown
(2015) considered a halving of the PD to indicate responses that may be
clinically relevant. With regard to this approach, the 2016
NOX ISA notes that ``one doubling dose change in PD is
recognized 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). While 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.\50\
---------------------------------------------------------------------------

    \50\ As noted above, the degree to which populations in U.S.
urban areas have the potential for such NO2 exposures is
evaluated in Chapter 4 of the PA and described in Section II.A.3
below.
---------------------------------------------------------------------------

    Five studies provided data for each individual's PD. These five
studies provided individual-level data for a total of 72 study
participants (116 AR measurements) and eight NO2 exposure
concentrations, for resting exposures and non-specific bronchial
challenge agents. Across exposures to 100, 140, 200, 250, 270, 480,
500, and 530 ppb NO2, 24% of study participants experienced
a halving of the PD (indicating increased AR) while 8% showed a
doubling of the PD (indicating decreased AR). The relative
distributions of the PDs at different concentrations were similar, with
no dose-response relationship indicated (Brown, 2015). While these
results support the potential for clinically relevant increases in AR
in some individuals with asthma following NO2 exposures
within the range of 100 to 530 ppb, uncertainty remains given that this
analysis is limited to a subset of studies. In addition, compared to
conclusions based on the entire range of NO2 exposure
concentrations evaluated (i.e., 100 to 530 ppb), there is greater
uncertainty in reaching conclusions about the potential for clinically
relevant effects at any particular NO2 exposure
concentration within this range.
PA Conclusions on Short-Term NO2 Concentrations in
Controlled Human Exposure Studies
    As in the last review, a meta-analysis of individual-level data
supports the potential for increased AR in individuals with generally
mild asthma following 30 minute to 1 hour exposures to NO2
concentrations from 100 to 530 ppb, particularly for resting exposures
and measures of non-specific AR (n = 33 to 70 for various ranges of
NO2 exposure concentrations). In about a quarter of these
individuals, increases were large enough to be of potential clinical
relevance. Individual studies most consistently report statistically
significant NO2-induced increases in AR following exposures
to NO2 concentrations at or above 250 ppb. Individual
studies (n = 4 to 20) generally do not report statistically significant
increases in AR following exposures to NO2 concentrations at
or below 200 ppb, though the evidence suggests a trend toward increased
AR following NO2 exposures from 140 to 200 ppb. In contrast,
individual studies do not indicate a consistent trend towards increased
AR following 1-hour exposures to 100 ppb NO2. Important
limitations in this evidence include the lack of an apparent dose-
response relationship between NO2 and AR and uncertainty in
the adversity of the reported increases in AR. These limitations become
increasingly important at the lower NO2 exposure
concentrations (i.e., at or near 100 ppb), where the evidence for
NO2-induced increases in AR is not consistent across
studies. The PA placed weight on that lack of consistency, when
considered in light of the lack of an apparent dose-response
relationship between NO2 and increased AR, as well as the
uncertainty in the adversity of the reported effect.
iv. Consideration of NO2 Concentrations in Locations of
Epidemiologic Studies
    In addition to considering the exposure concentrations evaluated in
the controlled human exposure studies, the PA also considers
distributions of ambient NO2 concentrations in locations
where epidemiologic studies have examined NO2 associations
with asthma-related hospital admissions or ED visits. These outcomes
are clearly adverse and study results comprise a key line of
epidemiologic evidence in the determination of a causal relationship in
the 2016 NOX ISA (U.S. EPA, 2016a, Section 5.2.9). As in
other NAAQS reviews (U.S. EPA, 2014; U.S. EPA, 2011), when considering
epidemiologic studies within the context of evaluating the adequacy of
the current standards, the PA emphasizes those studies conducted in the
U.S. and Canada.\51\ For short-term exposures to NO2, the PA
emphasizes studies reporting associations with effects judged in the
2016 NOX ISA to be robust to confounding by other factors,
including exposure to co-occurring air pollutants. In addition, the PA
considers the statistical precision of study results and the inclusion
of at-risk populations for which the NO2-health effect
associations may be larger. These considerations help inform the range
of ambient NO2 concentrations where there is the most
confidence for NO2-associated health effects and the range
of concentrations over which confidence in such effects is appreciably

lower. In consideration of these issues, the PA specifically focuses on
the following question: To what extent have U.S. and Canadian
epidemiologic studies reported associations between asthma-related
hospital admissions or ED visits and short-term NO2
concentrations in study areas that would have met the current 1-hour
NO2 standard during the study period?
---------------------------------------------------------------------------

    \51\ Such studies are likely to reflect air quality and exposure
patterns that are generally applicable to the U.S. In addition, air
quality data corresponding to study locations and study time periods
are often readily available for studies conducted in the U.S. and
Canada. Nonetheless, the PA recognizes the importance of all
studies, including other international studies, in the 2016
NOX ISA's assessment of the weight of the evidence that
informs the causal determinations.
---------------------------------------------------------------------------

    Addressing this question can provide important insights into the
extent to which NO2-associated health effects 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 effects indicated by epidemiologic
studies. To the degree studies have not reported associations in
locations meeting the current NO2 standards, there is
greater uncertainty regarding the potential for the reported effects to
occur following the NO2 exposures associated with air
quality meeting those standards.
    The emphasis that the proposal and this final action place on
studies to inform the question above is discussed in more detail in the
proposal for this action (82 FR 34792, July 26, 2017, section II.F.4).
Briefly, in addressing the question above, the PA places the greatest
emphasis on studies reporting positive and relatively precise (i.e.,
relatively narrow 95% confidence intervals (CI)) health effect
associations. In evaluating whether such associations are likely to
reflect NO2 concentrations meeting the existing 1-hour
standard, the PA considers the 1-hour ambient NO2
concentrations measured at monitors in study locations during study
periods. The PA also considers what additional information is available
regarding the ambient NO2 concentrations that could have
been present in the study locations during the study periods (e.g.,
around major roads). When considered together, this information can
provide important insights into the extent to which NO2
health effect associations have been reported for NO2 air
quality concentrations that likely would have met the current 1-hour
NO2 standard.
    The PA evaluates U.S. and Canadian studies of respiratory-related
hospital admissions and ED visits, with a focus on studies of asthma-
related effects (studies identified from Table 5-10 in U.S. EPA,
2016a).\52\ For each NO2 monitor in the locations included
in these studies, and for the ranges of years encompassed by studies,
the PA identifies the 3-year averages of the 98th percentiles of the
annual distributions of daily maximum 1-hour NO2
concentrations.\53\ These concentrations approximate the DVs that are
used when determining whether an area meets the 1-hour primary
NO2 NAAQS.\54\ Thus, these estimated DVs can provide
perspective on whether study areas would likely have met or exceeded
the primary 1-hour NO2 NAAQS during the study periods. Based
on this approach, study locations would likely have met the current 1-
hour standard over the entire study period if all of the hourly DV
estimates were at or below 100 ppb.
---------------------------------------------------------------------------

    \52\ Strong support was also provided by epidemiologic studies
for respiratory symptoms, but the majority of studies on respiratory
symptoms were only conducted over part of a year, complicating the
evaluation of a DV based on data from 3 years of monitoring data
relative to the respective health effect estimates. For more
information on these studies and the estimated DVs in the study
locations, see Appendix A of the PA (U.S. EPA, 2017a).
    \53\ All study locations had maximum annual DVs below 53 ppb
(U.S. EPA, 2017a, Appendix A).
    \54\ As described in section I.B., a DV is a statistic that
describes the air quality status of a given area relative to the
NAAQS and that is typically used to classify nonattainment areas,
assess progress towards meeting the NAAQS, and develop control
strategies. For the 1-hour NO2 standard, the DV is
calculated at individual monitors and based on 3 consecutive years
of data collected from that site. In the case of the 1-hour
NO2 standard, the DV for a monitor is based on the 3-year
average of the 98th percentile of the annual distribution of daily
maximum 1-hour NO2 concentrations. For more information
on these studies and the calculation of the study area DVs
estimates, see Appendix A of the NO2 PA (U.S. EPA,
2017a).
---------------------------------------------------------------------------

    A key limitation in these analyses of NO2 DV estimates
is that currently required near-road NO2 monitors were not
in place during study periods. The studies evaluated were based on air
quality from 1980-2006, with most studies spanning the 1990s to early
2000s. There were no specific near-road monitoring network requirements
during these years, and most areas did not have monitors sited to
measure NO2 concentrations near the most heavily trafficked
roadways. In addition, mobile source NOX emissions were
considerably higher during the time periods of the available
epidemiologic studies than in more recent years (U.S. EPA, 2017a,
section 2.1.2), suggesting that the NO2 concentration
gradients around major roads could have been more pronounced than
indicated by data from recently deployed near-road monitors.\55\ This
information suggests that if the current near-road monitoring network
had been in operation during study periods, NO2
concentrations measured at near-road monitors would likely have been
higher than those identified in the PA (U.S. EPA, 2017a, Figure 3-1).
This uncertainty particularly limits the degree to which strong
conclusions about whether an area would have met the current 1-hour
standard during the study period can be reached based on study areas
with DV estimates that are at or just below 100 ppb.\56\
---------------------------------------------------------------------------

    \55\ Recent data indicate that, for most near-road monitors,
measured 1-hour NO2 concentrations are higher than those
measured at all of the non-near-road monitors in the same CBSA
(Section II.A.1.d).
    \56\ 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.
---------------------------------------------------------------------------

    With this key limitation in mind, the PA considers what the
available epidemiologic evidence indicates with regard to the adequacy
of the public health protection provided by the current 1-hour standard
against short-term NO2 exposures. To this end, the PA
highlights the epidemiologic studies examining associations between
asthma hospitalizations or ED visits and short-term exposures to
ambient NO2 that were conducted in the U.S. and Canada (U.S.
EPA, 2017a, Figure 3-1). These studies were identified and evaluated in
the 2016 NOX ISA and include both the few recently published
studies and the studies that were available in the previous review.
    In considering the epidemiologic information presented in the U.S.
and Canadian studies, the PA notes that multicity studies tend to have
greater power to detect associations. The one multicity study that has
become available since the last review (Stieb et al., 2009) reported a
null association with asthma ED visits, based on study locations with
maximum estimated DVs ranging from 67-242 ppb (six of seven study
cities had maximum estimated DVs at or above 85 ppb). Of the single-
city studies identified, those reporting positive and relatively
precise associations were conducted in locations with maximum, and
often mean, estimated DVs at or above 100 ppb (i.e., Linn et al., 2000;
Peel et al., 2005; Ito et al., 2007; Villeneuve et al., 2007; Burnett
et al., 1999; Strickland et al., 2010). Maximum estimated DVs from
these study locations ranged from 100 to 242 ppb (U.S. EPA, Figure 3-
1). For the other single-city studies, two reported more mixed results
in locations with maximum estimated DVs around 90 ppb (Jaffe et al.,
2003; ATSDR, 2006).\57\ Associations in these studies

were generally not statistically significant, were less precise (i.e.,
wider 95% CI), and included a negative association (Manhattan, NY). One
single-city study was conducted in a location with 1-hour estimated DVs
well below 100 ppb (Li et al., 2011), though the reported associations
were not statistically significant and were relatively imprecise. Thus,
of the U.S. and Canadian studies that can most clearly inform
consideration of the adequacy of the current NO2 primary
standards, the lone multicity study did not report a positive health
effect association, and the single-city studies reporting positive and
relatively precise associations were generally conducted in locations
with maximum 1-hour estimated DVs at or above 100 ppb (i.e., up to 242
ppb). The evidence for associations in locations with maximum estimated
DVs below 100 ppb is more mixed and reported associations are generally
less precise.
---------------------------------------------------------------------------

    \57\ The study by the U.S. Agency for Toxic Substances and
Disease Registry (ATSDR) was not published in a peer-review journal.
Rather, it was a report prepared by the New York State Department of
Health's Center for Environmental Health, the New York State
Department of Environmental Conservation and Columbia University in
the course of performing work contracted for and sponsored by the
New York State Energy Research and Development Authority and the
ATSDR.
---------------------------------------------------------------------------

    An uncertainty in this body of evidence is the potential for
copollutant confounding. Copollutant (two-pollutant) models can be used
in epidemiologic studies in an effort to disentangle the independent
pollutant effects, though there can be limitations in these models due
to differential exposure measurement error and high correlations with
traffic-related copollutants. For NO2, the copollutants that
are most relevant to consider are those from traffic sources such as
CO, EC/BC, UFP, and VOCs such as benzene, as well as PM2.5
and PM10 (U.S. EPA, 2016a, Section 3.5).\58\ Of the studies
examining asthma-related hospital admissions and ED visits in the U.S.
and Canada, three examined copollutant models (Ito et al., 2007;
Villeneuve et al., 2007; Strickland et al., 2010). Ito et al. (2007)
found that in copollutant models with PM2.5, SO2,
CO, or O3, NO2 consistently had the strongest
effect estimates that were robust to the inclusion of other pollutants.
Villeneuve et al. (2007) utilized a model including NO2 and
CO (r = 0.74) for ED visits in the warm season and reported that
associations for NO2 were robust to CO. Strickland et al.
(2010) found that the relationship between ambient NO2 and
asthma ED visits in Atlanta, GA, was robust in models including
O3, but copollutant models were not analyzed for other
pollutants, and the correlations between NO2 and other
pollutants were not reported. Taken together, these studies provide
some evidence for independent effects of NO2 for asthma-
related hospital admissions and ED visits, but some important traffic-
related copollutants (e.g., EC/BC, VOCs) have not been examined in this
body of evidence and the limitations of copollutant models in
demonstrating an independent association are noted (U.S. EPA, 2016a,
section 3.5).
---------------------------------------------------------------------------

    \58\ In this case, differential exposure measurement error
occurs when exposure measurement error varies by pollutant (e.g.,
within a model exposure to PM2.5 may be estimated with
higher accuracy than exposure to SO2).
---------------------------------------------------------------------------

    Considering this evidence together, the PA notes the following
observations. First, the only recent multicity study evaluated, which
had maximum estimated DVs ranging from 67 to 242 ppb, did not report a
positive association between NO2 and ED visits (Stieb et
al., 2009). In addition, of the single-city studies reporting positive
and relatively precise associations between NO2 and asthma
hospital admissions and ED visits, most locations likely had
NO2 concentrations above the current 1-hour NO2
standard over at least part of the study period. Although maximum
estimated DVs for the studies conducted in Atlanta were 100 ppb (Peel
et al., 2005; Strickland et al., 2010), it is likely that those DVs
would have been higher than 100 ppb if currently required near-road
monitors had been in place. For the study locations with maximum
estimated DVs below 100 ppb, mixed results are reported with
associations that are generally lack precision and are not
statistically significant, indicating that associations between
NO2 concentrations and asthma-related ED visits are more
uncertain in locations that could have met the current standards. Given
that near-road monitors were not in operation during study periods, it
is not clear that these DVs below 100 ppb indicate study areas that
would have met the current 1-hour standard.
    Thus, while epidemiologic studies provide support for
NO2-associated hospital admissions and ED visits at ambient
NO2 concentrations likely to have been above those allowed
by the current 1-hour standard, the PA reaches the conclusion that
available U.S. and Canadian epidemiologic studies do not provide
support for such NO2-associated outcomes in locations with
NO2 concentrations that would have clearly met that
standard.
b. Health Effects With Long-Term Exposure to NO2
    This section discusses the evidence for health effects associated
with long-term NO2 exposures. Section II.A.2.b.i discusses
the nature of the health effects that have been shown to be associated
with long-term NO2 exposures and the strength of the
evidence supporting various effects, based on the assessment of that
evidence in the 2016 NOX ISA. Sections II.A.2.b.ii and
II.A.2.b.iii discuss the NO2 concentrations at which health
effects have been demonstrated to occur based on the considerations and
analyses included in the PA.
i. Nature of Effects
    In the last review of the primary NO2 NAAQS, evidence
for health effects related to long-term ambient NO2 exposure
was judged ``suggestive of, but not sufficient to infer a causal
relationship'' for respiratory effects and ``inadequate to infer the
presence or absence of a causal relationship'' for several other health
effect categories. These included cardiovascular effects and
reproductive and developmental effects, as well as cancer and total
mortality. In the current review, new epidemiologic evidence, in
conjunction with explicit integration of evidence across related
outcomes, has resulted in strengthening of some of the causal
determinations. Though the evidence of health effects associated with
long-term exposure to NO2 is more robust than in previous
reviews, there are still a number of uncertainties limiting
understanding of the role of long-term NO2 exposures in
causing health effects.
    Chapter 6 of the 2016 NOX ISA presents a detailed
assessment of the evidence for health effects associated with long-term
NO2 exposures (U.S. EPA, 2016a). This evidence is summarized
briefly below for respiratory effects. Cardiovascular effects and
diabetes, reproductive and developmental effects, premature mortality,
and cancer are also briefly addressed.
Respiratory Effects
    The 2016 NOX ISA concluded that there is ``likely to be
a causal relationship'' between long-term NO2 exposure and
respiratory effects, based primarily on evidence integrated across
disciplines for a relationship with asthma development in children.\59\
Evidence for other respiratory outcomes integrated across epidemiologic
and experimental studies, including decrements in lung function and
partially irreversible decrements in lung development, respiratory
disease severity, chronic bronchitis/asthma incidence in adults,
chronic obstructive

pulmonary disease (COPD) hospital admissions, and respiratory
infections, is less consistent and has larger uncertainty as to whether
there is an independent effect of long-term NO2 exposure
(U.S. EPA, 2016a, Section 6.2.9). As noted above, NO2 is
only one of many etiologic agents that may contribute to respiratory
health effects such as the development of asthma in children.
---------------------------------------------------------------------------

    \59\ Asthma development is also referred to as ``asthma
incidence'' in this document and elsewhere. Both asthma development
and asthma incidence refer to the onset of the disease rather than
the exacerbation of existing disease.
---------------------------------------------------------------------------

    The conclusion of a ``likely to be causal relationship'' in the
current review represents a change from 2008 NOX ISA
conclusion that the evidence was ``suggestive of, but not sufficient to
infer, a causal relationship'' (U.S. EPA, 2008a, Section <IP_ADDRESS>). This
strengthening of the causal determination is due to the epidemiologic
evidence base, which has expanded since the last review, and biological
plausibility from some experimental studies (U.S. EPA, 2016a, Table 1-
1). This expanded evidence includes several recently published
longitudinal studies that indicate positive associations between asthma
incidence in children and long-term NO2 exposures, with
improved exposure assessment in some studies based on NO2
modeled estimates for children's homes or NO2 measured near
children's homes or schools. Associations were observed across various
periods of exposure, including first year of life, year prior to asthma
diagnosis, and cumulative exposure. In addition, the 2016
NOX ISA notes several other strengths of the evidence base
including the general timing of asthma diagnosis and relative
confidence that the NO2 exposure preceded asthma development
in longitudinal studies, more reliable estimates of asthma incidence
based on physician-diagnosis in children older than 5 years of age from
parental report or clinical assessment, as well as residential
NO2 concentrations estimated from land use regression models
with good NO2 prediction in some studies.
    While the causal determination has been strengthened in this
review, important uncertainties remain. For example, the 2016
NOX ISA notes that, as in the last review, a ``key
uncertainty that remains when examining the epidemiologic evidence
alone is the inability to determine whether NO2 exposure has
an independent effect from that of other pollutants in the ambient
mixture'' (U.S. EPA, 2016a, Section <IP_ADDRESS>, p. 6-21). While a few
studies have included copollutant models for respiratory effects other
than asthma development, the 2016 NOX ISA states that
``[e]pidemiologic studies of asthma development in children have not
clearly characterized potential confounding by PM2.5 or
traffic-related pollutants [e.g., CO, BC/EC, volatile organic compounds
(VOCs)]'' (U.S. EPA, 2016a, p. 6-64). The 2016 NOX ISA
further notes that ``[i]n the longitudinal studies, correlations with
PM2.5 and BC were often high (e.g., r = 0.7-0.96), and no
studies of asthma incidence evaluated models to address copollutant
confounding, making it difficult to evaluate the independent effect of
NO2'' (U.S. EPA, 2016a, p. 6-64). High correlations between
NO2 and other traffic-related pollutants were based on
modeling, and studies of asthma incidence that used monitored
NO2 concentrations as an exposure surrogate did not report