[Federal Register: July 15, 2009 (Volume 74, Number 134)]
[Proposed Rules]
[Page 34403-34466]
[DOCID:fr15jy09-40]

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Part II

Environmental Protection Agency

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40 CFR Parts 50 and 58

Primary National Ambient Air Quality Standard for Nitrogen Dioxide;
Proposed Rule

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Parts 50 and 58

[EPA-HQ-OAR-2006-0922; FRL-8926-3]
RIN 2060-AO19

Primary National Ambient Air Quality Standard for Nitrogen
Dioxide

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: Based on its review of the air quality criteria for oxides of
nitrogen and the primary national ambient air quality standard (NAAQS)
for oxides of nitrogen as measured by nitrogen dioxide
(NO2), EPA proposes to make revisions to the primary
NO2 NAAQS in order to provide requisite protection of public
health. Specifically, EPA proposes to supplement the current annual
standard by establishing a new short-term NO2 standard based
on the 3-year average of the 99th percentile (or 4th highest) of 1-hour
daily maximum concentrations. EPA proposes to set the level of this new
standard within the range of 80 to 100 ppb and solicits comment on
standard levels as low as 65 ppb and as high as 150 ppb. EPA also
proposes to establish requirements for an NO2 monitoring
network that will include monitors within 50 meters of major roadways.
In addition, EPA is soliciting comment on an alternative approach to
setting the standard and revising the monitoring network. Consistent
with the terms of a consent decree, the Administrator will sign a
notice of final rulemaking by January 22, 2010.

DATES: Comments must be received on or before September 14, 2009. Under
the Paperwork Reduction Act, comments on the information collection
provisions must be received by OMB on or before August 14, 2009.
    Public Hearings: EPA intends to hold public hearings on this
proposed rule in August 2009 in Los Angeles, California and Arlington,
VA. These will be announced in a separate Federal Register notice that
provides details, including specific times and addresses, for these
hearings.

ADDRESSES: Submit your comments, identified by Docket ID No. EPA-HQ-
OAR-2006-0922 by one of the following methods:
     http://www.regulations.gov: Follow the on-line
instructions for submitting comments.
     E-mail<EMAIL_ADDRESS>     Fax:<PHONE_NUMBER>
     Mail: Docket No. EPA-HQ-OAR-2006-0922, Environmental
Protection Agency, Mail code 6102T, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460. Please include a total of two copies.
     Hand Delivery: Docket No. EPA-HQ-OAR-2006-0922,
Environmental Protection Agency, EPA West, Room 3334, 1301 Constitution
Ave., NW., Washington, DC. Such deliveries are only accepted during the
Docket's normal hours of operation, and special arrangements should be
made for deliveries of boxed information.
    Instructions: Direct your comments to Docket ID No. EPA-HQ-OAR-
2006-0922. EPA's policy is that all comments received will be included
in the public docket without change and may be made available online at
http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through http://
www.regulations.gov or e-mail. The http://www.regulations.gov Web site
is an ``anonymous access'' system, which means EPA will not know your
identity or contact information unless you provide it in the body of
your comment. If you send an e-mail comment directly to EPA without
going through http://www.regulations.gov your e-mail address will be
automatically captured and included as part of the comment that is
placed in the public docket and made available on the Internet. If you
submit an electronic comment, EPA recommends that you include your name
and other contact information in the body of your comment and with any
disk or CD-ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA
may not be able to consider your comment. Electronic files should avoid
the use of special characters, any form of encryption, and be free of
any defects or viruses. For additional information about EPA's public
docket visit the EPA Docket Center homepage at http://www.epa.gov/
epahome/dockets.htm.
    Docket: All documents in the docket are listed in the http://
www.regulations.gov index. 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, will be publicly available only in hard copy.
Publicly available docket materials are available either electronically
in http://www.regulations.gov or in hard copy at the Air and Radiation
Docket and Information Center, EPA/DC, EPA West, 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 and
Information Center is<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Dr. Scott Jenkins, 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; e-mail<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

General Information

What Should I Consider as I Prepare My Comments for EPA?

    1. Submitting CBI. Do not submit this information to EPA through
http://www.regulations.gov or e-mail. Clearly mark the part or all of
the information that you claim to be CBI. For CBI information in a disk
or CD ROM that you mail to EPA, mark the outside of the disk or CD ROM
as CBI and then identify electronically within the disk or CD ROM the
specific information that is claimed as CBI. In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information
claimed as CBI must be submitted for inclusion in the public docket.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2.
    2. Tips for Preparing Your Comments. When submitting comments,
remember to:
     Identify the rulemaking by docket number and other
identifying information (subject heading, Federal Register date and
page number).
     Follow directions--the agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
     Explain why you agree or disagree, suggest alternatives,
and substitute language for your requested changes.
     Describe any assumptions and provide any technical
information and/or data that you used.
     Provide specific examples to illustrate your concerns, and
suggest alternatives.

     Explain your views as clearly as possible, avoiding the
use of profanity or personal threats.
     Make sure to submit your comments by the comment period
deadline identified.

Availability of Related Information

    A number of the documents that are relevant to this rulemaking are
available through EPA's Office of Air Quality Planning and Standards
(OAQPS) Technology Transfer Network (TTN) Web site at http://
www.epa.gov/ttn/naaqs/standards/nox/s_nox_index.html. These documents
include the Integrated Review Plan and the Health Assessment Plan,
available at http://www.epa.gov/ttn/naaqs/standards/nox/s_nox_cr_
pd.html, the Integrated Science Assessment (ISA), available at http://
cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=194645, and the Risk and
Exposure Assessment (REA), available at http://www.epa.gov/ttn/naaqs/
standards/nox/s_nox_cr_rea.html. These and other related documents
are also available for inspection and copying in the EPA docket
identified above.

Table of Contents

    The following topics are discussed in this preamble:

I. Background
    A. Legislative Requirements
    B. Related NO2 Control Programs
    C. Review of the Air Quality Criteria and Standards for Oxides
of Nitrogen
II. Rationale for Proposed Decisions on the Primary Standard
    A. Characterization of NO2 Air Quality
    1. Current Patterns of NO2 Air Quality
    2. NO2 Air Quality and Gradients Around Roadways
    B. Health Effects Information
    1. Adverse Respiratory Effects and Short-Term Exposure to
NO2
    a. Emergency Department Visits and Hospital Admissions
    b. Respiratory Symptoms
    c. Impaired Host Defense
    d. Airway Response
    e. Airway Inflammation
    f. Lung Function
    g. Conclusions From the ISA
    2. Other Effects With Short-Term Exposure to NO2
    a. Mortality
    b. Cardiovascular Effects
    3. Health Effects With Long-Term Exposure to NO2
    a. Respiratory Morbidity
    b. Mortality
    c. Carcinogenic, Cardiovascular, and Reproductive/Developmental
Effects
    4. NO2-Related Impacts on Public Health
    a. Pre-Existing Disease
    b. Age
    c. Genetics
    d. Gender
    e. Proximity to Roadways
    f. Socioeconomic Status
    g. Size of the At-Risk Population
    C. Human Exposure and Health Risk Characterization
    1. Evidence Base for the Risk Characterization
    2. Overview of Approaches
    3. Key Limitations and Uncertainties
    D. Considerations in Review of the Standard
    1. Background on the Current Standard
    2. Approach for Reviewing the Need to Retain or Revise the
Current Standard
    E. Adequacy of the Current Standard
    1. Evidence-Based Considerations
    2. Exposure- and Risk-Based Considerations
    3. Summary of Considerations From the REA
    4. CASAC Views
    5. Administrator's Conclusions Regarding Adequacy of the Current
Standard
    F. Conclusions on the Elements of a New Short-Term Standard and
an Annual Standard
    1. Indicator
    2. Averaging Time
    a. Short-Term Averaging Time
    b. Long-Term Averaging Time
    c. CASAC Views
    d. Administrator's Conclusions on Averaging Time
    3. Form
    4. Level
    a. Evidence-Based Considerations
    b. Exposure- and Risk-Based Considerations
    c. Summary of Consideration From the REA
    d. CASAC Views
    e. Administrator's Conclusions on Level for a 1-Hour Standard
    f. Alternative Approach to Setting the 1-Hour Standard Level
    g. Level of the Annual Standard
    G. Summary of Proposed Decisions on the Primary Standard
III. Proposed Amendments to Ambient Monitoring and Reporting
Requirements
    A. Monitoring Methods
    B. Network Design
    1. Background
    2. Proposed Changes
    a. Monitoring in Areas of Expected Maximum Concentrations Near
Major Roads
    b. Area-Wide Monitoring at Neighborhood and Larger Spatial
Scales
    3. Solicitation for Comment on an Alternative Network Design
    C. Data Reporting
IV. Proposed Appendix S--Interpretation of the Primary NAAQS for
Oxides of Nitrogen and Proposed Revisions to the Exceptional Events
Rule
    A. Background
    B. Interpretation of the Primary NAAQS for Oxides of Nitrogen
    1. Annual Primary Standard
    2. 1-Hour Primary Standard Based on the Annual 4th Highest Daily
Value Form
    3. 1-Hour Primary Standard Based on the Annual 99th Percentile
Value Form
    C. Exceptional Events Information Submission Schedule
V. Clean Air Act Implementation Requirements
    A. Designations
    B. Classifications
    C. Attainment Dates
    1. Attaining the NAAQS
    2. Consequences of Failing to Attain by the Statutory Attainment
Date
    D. Section 110(a)(2) NAAQS Infrastructure Requirements
    E. Attainment Planning Requirements
    1. Nonattainment Area SIPs
    2. New Source Review and Prevention of Significant Deterioration
Requirements
    3. General Conformity
    4. Transportation Conformity
VI. Communication of Public Health Information
VII. Statutory and Executive Order Reviews
References

I. Background

A. Legislative Requirements

    Two sections of the Clean Air Act (Act or CAA) govern the
establishment and revision of the NAAQS. Section 108 of the Act directs
the Administrator to identify and list air pollutants that meet certain
criteria, including that the air pollutant ``in his judgment, cause[s]
or contribute[s] to air pollution which may reasonably be anticipated
to endanger public health and welfare'' and ``the presence of which in
the ambient air results from numerous or diverse mobile or stationary
sources.'' 42 U.S.C. 21 7408(a)(1)(A) & (B). For those air pollutants
listed, section 108 requires the Administrator to issue air quality
criteria that ``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 ambient air * * *'' 42 U.S.C. 7408(2).
    Section 109(a) of the Act directs the Administrator to promulgate
``primary'' and ``secondary'' NAAQS for pollutants for which air
quality criteria have been issued. 42 U.S.C. 7409(1). Section 109(b)(1)
defines a primary standard as one ``the attainment and maintenance of
which in the judgment of the Administrator, based on [the air quality]
criteria and allowing an adequate margin of safety, are requisite to
protect the public health.'' \1\ 42 U.S.C. 7409(b)(1). A secondary
standard, in turn, must ``specify a level of air quality the attainment
and maintenance of which, in the judgment of the Administrator, based
on [the air quality] criteria, is requisite to protect the public

welfare from any known or anticipated adverse effects associated with
the presence of such pollutant in the ambient air.'' \2\ 42 U.S.C.
7409(b)(2).
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    \1 \ 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.'' S.
Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970).
    \2 \ EPA is currently conducting a separate review of the
secondary NO2 NAAQS jointly with a review of the
secondary SO2 NAAQS.
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    The requirement that primary standards include an adequate margin
of safety is intended to address uncertainties associated with
inconclusive scientific and technical information available at the time
of standard setting. It is also intended to provide a reasonable degree
of protection against hazards that research has not yet identified.
Lead Industries Association v. EPA, 647 F.2d 1130, 1154 (D.C. Cir
1980), cert. denied, 449 U.S. 1042 (1980); American Petroleum Institute
v. Costle, 665 F.2d 1176, 1186 (D.C. Cir. 1981), cert. denied, 455 U.S.
1034 (1982). 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 include 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.
    In addressing the requirement for a margin of safety, EPA considers
such factors as the nature and severity of the health effects involved,
the size of the at-risk population(s), 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. Lead Industries
Association v. EPA, supra, 647 F.2d at 1161-62.
    In setting standards that are ``requisite'' to protect public
health and welfare, as provided in section 109(b), EPA's task is to
establish standards that are neither more nor less stringent than
necessary for these purposes. In so doing, EPA may not consider the
costs of implementing the standards. Whitman v. American Trucking
Associations, 531 U.S. 457, 471, 475-76 (2001).
    Section 109(d)(1) of the Act requires the Administrator to
periodically undertake a thorough review of the air quality criteria
published under section 108 and the NAAQS and to revise the criteria
and standards as may be appropriate. 42 U.S.C. 7409(d)(1). The Act also
requires the Administrator to appoint an independent scientific review
committee composed of seven members, including at least one member of
the National Academy of Sciences, one physician, and one person
representing State air pollution control agencies, to review the air
quality criteria and NAAQS and to ``recommend to the Administrator any
new standards and revisions of existing criteria and standards as may
be appropriate under section 108 and subsection (b) of this section.''
42 U.S.C. 7409(d)(2). This independent review function is performed by
the Clean Air Scientific Advisory Committee (CASAC) of EPA's Science
Advisory Board.

B. Related NO2 Control Programs

    States are primarily responsible for ensuring attainment and
maintenance of ambient air quality standards once EPA has established
them. Under section 110 of the Act, 42 U.S.C. 7410, and related
provisions, States are to submit, for EPA 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
EPA, also administer the prevention of significant deterioration
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 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 of the NO2 NAAQS. If the
NO2 NAAQS is revised as a result of this review, however,
some areas could be classified as non-attainment. Certain States would
then be required to develop SIPs that identify and implement specific
air pollution control measures to reduce ambient NO2
concentrations to attain and maintain the revised NO2 NAAQS,
most likely by requiring air pollution controls on sources that emit
oxides of nitrogen (NOX \3\).
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    \3\ In this document, the terms ``oxides of nitrogen'' and
``nitrogen oxides'' (NOX) refer to all forms of oxidized
nitrogen (N) compounds, including NO, NO2, and all other
oxidized N-containing compounds formed from NO and NO2.
This follows usage in the 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 the air pollution research
and control communities, the terms ``oxides of nitrogen'' and
``nitrogen oxides'' are restricted to refer only to the sum of NO
and NO2, and this sum is commonly abbreviated as
NOX. The category label used by this community for the
sum of all forms of oxidized nitrogen compounds including those
listed in Section 108(c) is NOY.
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    While NOX is emitted from a wide variety of source
types, the top three categories of sources of NOX emissions
are on-road mobile sources, electricity generating units, and non-road
mobile sources. EPA anticipates that NOX emissions will
decrease substantially over about the next 20 years as a result of the
ongoing implementation of mobile source emissions standards. In
particular, Tier 2 NOX emission standards for light-duty
vehicle emissions began phasing into the fleet beginning with model
year 2004, in combination with low-sulfur gasoline fuel standards. For
heavy-duty engines, new NOX standards are phasing in between
the 2007 and 2010 model years, following the introduction of ultra-low
sulfur diesel fuel. Lower NOX standards for nonroad diesel
engines, locomotives, and certain marine engines are becoming effective
throughout the next decade. In future decades, these lower-
NOX vehicles and engines will become an increasingly large
fraction of in-use mobile sources, effecting large NOX
emission reductions.

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

    On April 30, 1971, EPA promulgated identical primary and secondary
NAAQS for NO2 under section 109 of the Act. The standards
were set at 0.053 parts per million (ppm) (53 ppb), annual average (36
FR 8186). EPA completed reviews of the air quality criteria and
NO2 standards in 1985 and 1996 with decisions to retain the
standard (50 FR 25532, June 19, 1985; 61 FR 52852, October 8, 1996).
    EPA initiated the current review of the air quality criteria for
oxides of nitrogen and the NO2 primary NAAQS on December 9,
2005 (70 FR 73236) with a general call for information. EPA's draft
Integrated Review Plan for the Primary National Ambient Air Quality
Standard for Nitrogen Dioxide (EPA, 2007a) was made available in
February 2007 for public comment and was discussed by the CASAC via a
publicly accessible teleconference on May 11, 2007. As noted in that
plan, NOX includes multiple gaseous (e.g., NO2,
NO) and particulate (e.g., nitrate) species. Because the health effects

associated with particulate species of NOX have been
considered within the context of the health effects of ambient
particles in the Agency's review of the NAAQS for particulate matter
(PM), the current review of the primary NO2 NAAQS is focused
on the gaseous species of NOX and does not consider health
effects directly associated with particulate species.
    The first draft of the Integrated Science Assessment for Oxides of
Nitrogen-Health Criteria (ISA) and the Nitrogen Dioxide Health
Assessment Plan: Scope and Methods for Exposure and Risk Assessment
(EPA, 2007b) were reviewed by CASAC at a public meeting held on October
24-25, 2007. Based on comments received from CASAC and the public, EPA
developed the second draft of the ISA and the first draft of the Risk
and Exposure Assessment to Support the Review of the NO2
Primary National Ambient Air Quality Standard (Risk and Exposure
Assessment (REA)). These documents were reviewed by CASAC at a public
meeting held on May 1-2, 2008. Based on comments received from CASAC
and the public at this meeting, EPA released the final ISA in July of
2008 (EPA, 2008a). In addition, comments received were considered in
developing the second draft of the REA, which was released for public
review and comment in two parts. The first part of this document,
containing chapters 1-7, 9 and appendices A and C as well as part of
appendix B, was released in August, 2008. The second part of this
document, containing chapter 8 (describing the Atlanta exposure
assessment) and a completed appendix B, was released in October of
2008. This document was the subject of CASAC reviews at public meetings
on September 9 and 10, 2008 (for the first part) and on October 22,
2008 (for the second part). In preparing the final REA (EPA, 2008b),
EPA considered comments received from the CASAC and the public at those
meetings.
    In the course of reviewing the second draft REA, CASAC expressed
the view that the document would be incomplete without the addition of
a policy assessment chapter presenting an integration of evidence-based
considerations and risk and exposure assessment results. CASAC stated
that such a chapter would be ``critical for considering options for the
NAAQS for NO2'' (Samet, 2008a). In addition, within the
period of CASAC's review of the second draft REA, EPA's Deputy
Administrator indicated in a letter to the chair of CASAC, addressing
earlier CASAC comments on the NAAQS review process (Henderson, 2008),
that the risk and exposure assessment will include ``a broader
discussion of the science and how uncertainties may effect decisions on
the standard'' and ``all analyses and approaches for considering the
level of the standard under review, including risk assessment and
weight of evidence methodologies'' (Peacock, 2008, p.3; September 8,
2008).
    Accordingly, the final REA included a new policy assessment
chapter. This policy assessment chapter considered the scientific
evidence in the ISA and the exposure and risk characterization results
presented in other chapters of the REA as they relate to the adequacy
of the current NO2 primary NAAQS and potential alternative
primary NO2 standards. In considering the current and
potential alternative standards, the final REA document focused on the
information that is most pertinent to evaluating the basic elements of
national ambient air quality standards: indicator, averaging time, form
\4\, and level. These elements, which together serve to define each
standard, must be considered collectively in evaluating the health
protection afforded. CASAC discussed the final version of the REA, with
an emphasis on the policy assessment chapter, during a public
teleconference held on December 5, 2008. Following that teleconference,
CASAC offered comments and advice on the NO2 primary NAAQS
in a letter to the Administrator (Samet, 2008b).
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    \4\ The ``form'' of a standard defines the air quality statistic
that is to be compared to the level of the standard in determining
whether an area attains the standard.
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    The schedule for completion of this review is governed by a
judicial order resolving a lawsuit filed in September 2005, concerning
the timing of the current review. The order that now governs this
review, entered by the court in August 2007 and amended in December
2008, provides that the Administrator will sign, for publication,
notices of proposed and final rulemaking concerning the review of the
primary NO2 NAAQS no later than June 26, 2009 and January
22, 2010, respectively.
    This action presents the Administrator's proposed decisions on the
current primary NO2 standard. Throughout this preamble a
number of conclusions, findings, and determinations proposed by the
Administrator are noted. While they identify the reasoning that
supports this proposal, they are not intended to be final or conclusive
in nature. The EPA invites general, specific, and/or technical comments
on all issues involved with this proposal, including all such proposed
judgments, conclusions, findings, and determinations. Further, EPA
invites specific comments from CASAC on the proposed approach of
establishing a new 1-hour NO2 standard in conjunction with a
revised monitoring network that includes a substantial number of
monitors placed near major roads. In addition to requesting comment on
the overall approach, EPA invites specific comment on the level, or
range of levels, appropriate for such a standard, as well as on the
rationale that would support that level or range of levels.

II. Rationale for Proposed Decisions on the Primary Standard

    This section presents the rationale for the Administrator's
proposed decision to revise the existing NO2 primary
standard by supplementing the current annual standard with a 1-hour
standard and to specify the standards to the nearest parts per billion
(ppb). As discussed more fully below, this rationale takes into
account: (1) Judgments and conclusions presented in the ISA and the
REA; (2) CASAC advice and recommendations, as reflected in discussions
of drafts of the ISA and REA at public meetings, in separate written
comments, and in CASAC's letter to the Administrator (Samet, 2008b);
and (3) public comments received at CASAC meetings during the
development of the ISA and the REA.
    In developing this rationale, EPA has drawn upon an integrative
synthesis of the entire body of evidence on human health effects
associated with the presence of NO2 in the air. As discussed
below, this body of evidence addresses a broad range of health
endpoints associated with exposure to NO2. In considering
this entire body of evidence, EPA focuses in particular on those health
endpoints for which the ISA finds associations with NO2 to
be causal or likely causal (see section II.B below). This rationale
also draws upon the results of quantitative exposure and risk
assessments.
    As discussed below, a substantial amount of new research has been
conducted since the last review of the NO2 NAAQS, with
important new information coming from epidemiologic studies in
particular. The newly available research studies evaluated in the ISA
have undergone intensive scrutiny through multiple layers of peer
review and opportunities for public review and comment. While important
uncertainties remain in the qualitative and quantitative
characterizations of health effects attributable to exposure to ambient
NO2, the review of this

information has been extensive and deliberate.
    The remainder of this section discusses the rationale for the
Administrator's proposed decisions on the primary standard. Section
II.A presents a discussion of NO2 air quality, including
discussion of the NO2 concentration gradients that can exist
around roadways, and the current NO2 monitoring network.
Section II.B includes an overview of the scientific evidence related to
health effects associated with NO2 exposure. This overview
includes discussion of the health endpoints and at-risk populations
considered in the ISA. Section II.C discusses the approaches taken by
EPA to assess exposures and health risks associated with
NO2, including a discussion of key uncertainties associated
with the analyses. Section II.D presents the approach that is being
used in the current review of the NO2 NAAQS with regard to
consideration of the scientific evidence and exposure-/risk-based
results related to the adequacy of the current standard and potential
alternative standards. Sections II.E and II.F discuss the scientific
evidence and the exposure-/risk-based results specifically as they
relate to the current and potential alternative standards, including
discussion of the Administrator's proposed decisions on the standard.
Section II.G summarizes the Administrator's proposed decisions with
regard to the NO2 primary NAAQS.

A. Characterization of NO2 Air Quality

1. Current patterns of NO2 Air Quality
    The size of the State and local NO2 monitoring network
has remained relatively stable since the early 1980s, and currently has
approximately 400 monitors reporting data to EPA's Air Quality System
(AQS) database. \5\ At present, there are no minimum monitoring
requirements for NO2 in 40 CFR part 58 Appendix D, other
than a requirement for EPA Regional Administrator approval before
removing any existing monitors, and that any ongoing NO2
monitoring must have at least one monitor sited to measure the maximum
concentration of NO2 in that area (though, as discussed
below monitors in the current network do not measure peak
concentrations associated with on-road mobile sources that can occur
near major roadways because the network was not designed for this
purpose). EPA removed the specific minimum monitoring requirements for
NO2 of two monitoring sites per area with a population of
1,000,000 or more in the 2006 monitoring rule revisions (71 FR 61236),
based on the fact that there were no NO2 nonattainment areas
at that time, coupled with trends evidence showing an increasing gap
between national average NO2 concentrations and the current
annual standard. Additionally, the minimum requirements were removed to
provide State, local, and Tribal air monitoring agencies flexibility in
meeting higher priority monitoring needs for pollutants such as ozone
and PM2.5, or implementing the new multi-pollutant sites
(NCore network) required by the 2006 rule revisions, by allowing them
to discontinue lower priority monitoring. There are requirements in 40
CFR part 58 Appendix D for NO2 monitoring as part of the
Photochemical Assessment Monitoring Stations (PAMS) network. However,
of the approximately 400 NO2 monitors currently in
operation, only about 10 percent may be due to the PAMS requirements.
---------------------------------------------------------------------------

    \5\ It should be noted that the ISA Section 2.4.1 references a
different number of active monitors in the NO2 network.
The discrepancy between the ISA numbers and the number presented
here is due to differing metrics used in pulling data from AQS. The
ISA only references SLAMS, NAMS, and PAMS sites with defined
monitoring objectives, while the Watkins and Thompson, 2008 value
represents all NO2 sites reporting data at any point
during the year. These differences in numbers of active monitors per
year also explain why the Watkins and Thompson 2008 document
characterized the NO2 network size as relatively stable
since the early 1980s.
---------------------------------------------------------------------------

    An analysis of the approximately 400 monitors comprising the
current NO2 monitoring network (Watkins and Thompson, 2008)
indicates that the current NO2 network has largely remained
unchanged in terms of size and target monitor objective categories
since it was introduced in the May 10, 1979 monitoring rule (44 FR
27571). The review of the current network found that the assessment of
concentrations for general population exposure and maximum
concentrations at neighborhood and larger scales were the top
objectives. A review of the distribution of listed spatial scales of
representation shows that only approximately 3 monitors are described
as microscale, representing an area on the order of several meters to
100 meters, and approximately 23 monitors are described as middle
scale, which represents an area on the order of 100 to 500 meters. This
low percentage of smaller spatially representative scale sites within
the network of approximately 400 monitoring sites indicates that the
majority of monitors have, in fact, been sited to assess area-wide
exposures on the neighborhood, urban, and regional scales, as would be
expected for a network sited to support the current annual
NO2 standard and PAMS objectives. The current network does
not include monitors placed near major roadways and, therefore,
monitors in the current network do not necessarily measure the maximum
concentrations that can occur on a localized scale near these roadways
(as discussed in the next section). It should be noted that the network
not only accommodates NAAQS related monitoring, but also serves other
monitoring objectives such as support for photochemistry analysis,
ozone modeling and forecasting, and particulate matter precursor
tracking.
2. NO2 Air Quality and Gradients Around Roadways
    On-road and non-road mobile sources account for approximately 60%
of NOX emissions (ISA, table 2.2-1) and traffic-related
exposures can dominate personal exposures to NO2 (ISA
section 2.5.4). While driving, personal exposure concentrations in the
cabin of a vehicle could be substantially higher than ambient
concentrations measured nearby (ISA, section 2.5.4). For example, mean
in-vehicle NO2 concentrations have been reported to be 2 to
3 times higher than non-traffic ambient concentrations (ISA, sections
2.5.4 and 4.3.6). In addition, estimates presented in the REA suggest
that on/near roadway NO2 concentrations could be
approximately 40% (REA, compare Tables 7-11 and 7-13) or 80% (REA,
section 7.3.2) higher on average than concentrations away from roadways
and that roadway-associated environments could be responsible for the
large majority of 1-hour peak NO2 exposures (REA, Figures 8-
17 and 8-18). Because monitors in the current network are not sited to
measure peak roadway-associated NO2 concentrations,
individuals who spend time on and/or near major roadways could
experience NO2 concentrations that are considerably higher
than indicated by monitors in the current area-wide NO2
monitoring network.
    Research suggests that the concentrations of on-road mobile source
pollutants such as NOX, carbon monoxide (CO), directly
emitted air toxics, and certain size distributions of particulate
matter (PM), such as ultrafine PM, typically display peak
concentrations on or immediately adjacent to roads (ISA, section 2.5).
This situation typically produces a gradient in pollutant
concentrations, with concentrations decreasing with increasing distance
from the road, and concentrations generally decreasing back to near
area-wide ambient levels, or typical upwind urban background

levels, within several hundred meters downwind. While this general
concept is applicable to almost all roads, the actual characteristics
of the gradient and the distance that the mobile source pollutant
signature from an individual road can be differentiated from background
or upwind concentrations are heavily dependent on factors including
traffic volumes, local topography, roadside features, meteorology, and
photochemical reactivity conditions (Baldauf, et al., 2009; Beckerman
et al., 2008; Clements et al., 2008; Hagler et al., 2009; Janssen et
al., 2001; Rodes and Holland, 1980; Roorda-Knape et al., 1998; Singer
et al., 2004; Zhou and Levy, 2007).
    Because NO2 in the ambient air is due largely to the
atmospheric oxidation of NO emitted from combustion sources (ISA,
section 2.2.1), elevated NO2 concentrations can extend
farther away from roadways than the primary pollutants also emitted by
on-road mobile sources. More specifically, review of the technical
literature suggests that NO2 concentrations may return to
area-wide or typical urban background concentrations within distances
up to 500 meters of roads, though the actual distance will vary with
topography, roadside features, meteorology, and photochemical
reactivity conditions (Baldauf et al., 2009; Beckerman et al., 2008;
Clements et al., 2008; Gilbert et al. 2003; Rodes and Holland, 1980;
Singer et al., 2004; Zhou and Levy, 2007). Efforts to quantify the
extent and slope of the concentration gradient that may exist from peak
near-road concentrations to the typical urban background concentrations
must consider the variability that exists across locations and for a
given location over time. As a result, we have identified a range of
concentration gradients in the technical literature which indicate
that, on average, peak NO2 concentrations on or immediately
adjacent to roads may typically be between 30 and 100 percent greater
than concentrations monitored in the same area but farther away from
the road (ISA, Section 2.5.4; Beckerman et al., 2008; Gilbert et al.,
2003; Rodes and Holland, 1980; Roorda-Knape et al., 1998; Singer et
al., 2004). This range of concentration gradients has implications for
revising the NO2 primary standard and for the NO2
monitoring network (see sections II.F.4 and III).

B. Health Effects Information

    In the last review of the NO2 NAAQS, the 1993
NOX Air Quality Criteria Document (1993 AQCD) (EPA, 1993)
concluded that there were two key health effects of greatest concern at
ambient or near-ambient concentrations of NO2 (ISA, section
5.3.1). The first was increased airway responsiveness in asthmatic
individuals after short-term exposures. The second was increased
respiratory illness among children associated with longer-term
exposures to NO2. Evidence also was found for increased risk
of emphysema, but this appeared to be of major concern only with
exposures to NO2 at levels much higher than then current
ambient levels (ISA, section 5.3.1). Controlled human exposure and
animal toxicological studies provided qualitative evidence for airway
hyperresponsiveness and lung function changes while epidemiologic
studies provided evidence for increased respiratory symptoms with
increased indoor NO2 exposures. Animal toxicological
findings of lung host defense system changes with NO2
exposure provided a biologically-plausible basis for the epidemiologic
results. Subpopulations considered potentially more susceptible to the
effects of NO2 exposure included persons with preexisting
respiratory disease, children, and the elderly. The epidemiologic
evidence for respiratory health effects was limited, and no studies had
considered endpoints such as hospital admissions, emergency department
visits, or mortality (ISA, section 5.3.1).
    As discussed below, evidence published since the last review
generally has confirmed and extended the conclusions articulated in the
1993 AQCD (ISA, section 5.3.2). The epidemiologic evidence has grown
substantially with the addition of field and panel studies,
intervention studies, time-series studies of endpoints such as hospital
admissions, and a substantial number of studies evaluating mortality
risk associated with short-term NO2 exposures. While not as
marked as the growth in the epidemiologic literature, a number of
recent toxicological and controlled human exposure studies also provide
insights into relationships between NO2 exposure and health
effects. The body of evidence that has become available since the last
review focuses the current review on NO2-related respiratory
effects at lower ambient and exposure concentrations.
    The ISA, along with its associated annexes, provides a
comprehensive review and assessment of the scientific evidence related
to the health effects associated with NO2 exposures. For
these health effects, the ISA characterized judgments about causality
with a hierarchy that contains five levels (ISA, section 1.3):
sufficient to infer a causal relationship, sufficient to infer a likely
causal relationship (i.e., more likely than not), suggestive but not
sufficient to infer a causal relationship, inadequate to infer the
presence or absence of a causal relationship, and suggestive of no
causal relationship. Judgments about causality were informed by a
series of aspects that are based on those set forth by Sir Austin
Bradford Hill in 1965 (ISA, Table 1.3-1). These aspects include
strength of the observed association, availability of experimental
evidence, consistency of the observed association, biological
plausibility, coherence of the evidence, temporal relationship of the
observed association, and the presence of an exposure-response
relationship. A summary of each of the five levels of the hierarchy is
provided in Table 1.3-2 of the ISA.
    Judgments made in the ISA about the extent to which relationships
between various health endpoints and exposure to NO2 are
likely causal have been informed by several factors. As discussed in
the ISA in section 1.3, these factors include the nature of the
evidence (i.e., controlled human exposure, epidemiological, and/or
toxicological studies) and the weight of evidence. The weight of
evidence takes into account such considerations as biological
plausibility, coherence of the evidence, strength of associations, and
consistency of the evidence. Controlled human exposure studies provide
directly applicable information for determining causality because these
studies are not limited by differences in dosimetry and species
sensitivity, which would need to be addressed in extrapolating animal
toxicology data to human health effects, and because they provide data
relating health effects specifically to NO2 exposures, in
the absence of the co-occurring pollutants present in ambient air.
Epidemiologic studies provide evidence of associations between
NO2 concentrations and more serious health endpoints (e.g.,
hospital admissions and emergency department visits) that cannot be
assessed in controlled human exposure studies. For these studies the
degree of uncertainty introduced by confounding variables (e.g., other
pollutants) affects the level of confidence that the health effects
being investigated are attributable to NO2 exposures alone
and/or in combination with co-occurring pollutants.
    In using a weight of evidence approach to inform judgments about
the degree of confidence that various health effects are likely to be
caused by exposure to NO2, confidence increases with the
number of studies consistently reporting a particular health endpoint,

with increasing support for the biological plausibility of the health
effects, and with the strength and coherence of the evidence.
Conclusions regarding biological plausibility, consistency, and
coherence of evidence of NO2-related health effects are
drawn from the integration of epidemiologic studies with controlled
human exposure studies and with mechanistic information from animal
toxicological studies. As discussed below, the weight of evidence is
strongest for respiratory morbidity endpoints (e.g., respiratory
symptoms, hospital admissions, and emergency department visits)
associated with short-term (e.g., 1 to 24 hours) NO2
exposures.
    For epidemiologic studies, strength of association refers to the
magnitude of the association and its statistical strength, which
includes assessment of both effect estimate size and precision. In
general, when associations yield large relative risk estimates, it is
less likely that the association could be completely accounted for by a
potential confounder or some other bias. Consistency refers to the
persistent finding of an association between exposure and outcome in
multiple studies of adequate power in different persons, places,
circumstances and times. Based on the information presented in the ISA
and summarized below in sections II.B.1-II.B.3, this section discusses
judgments concerning the extent to which relationships between various
health endpoints and ambient NO2 exposures have been judged
in the ISA to be likely causal.
    As noted above, this section is devoted to discussion of health
effects associated with NO2 exposure, as assessed in the
ISA. Section II.B.1 below discusses respiratory morbidity associated
with short-term exposure to NO2. The specific endpoints
considered in this section are respiratory-related emergency department
visits and hospital admissions, respiratory symptoms, lung host defense
and immunity, airway responsiveness, airway inflammation, and lung
function. Section II.B.2 discusses mortality and cardiovascular effects
associated with short-term exposures. Section II.B.3 discusses effects
that have been associated with long-term NO2 exposures
including respiratory morbidity, mortality, cancer, cardiovascular
effects, and reproductive/developmental effects. Section II.B.4
discusses the potential NO2-related impacts on public
health.
1. Adverse Respiratory Effects and Short-Term Exposure to
NO2
    The ISA concluded that, taken together, recent studies provide
scientific evidence that is sufficient to infer a likely causal
relationship between short-term NO2 exposure and adverse
effects on the respiratory system (ISA, section <IP_ADDRESS>). This
determination was based on consideration of the broad array of relevant
scientific evidence, as well as the uncertainties associated with that
evidence. Specifically, this determination is supported by the large
body of recent epidemiologic evidence as well as findings from human
and animal experimental studies.
    In considering the uncertainties associated with the epidemiologic
evidence, the ISA (section 5.4) noted that it is difficult to determine
``the extent to which NO2 is independently associated with
respiratory effects or if NO2 is a marker for the effects of
another traffic-related pollutant or mix of pollutants.'' On-road
vehicle exhaust emissions are a nearly ubiquitous source of combustion
pollutant mixtures that include NOX and can be an important
contributor to NO2 levels in near-road locations. Although
this complicates efforts to quantify specific NO2-related
health effects, a number of epidemiologic studies have evaluated
associations with NO2 in models that also include co-
occurring pollutants such as PM, O3, CO, and/or
SO2. The evidence summarized in the ISA indicates that
NO2 associations generally remain robust in these multi-
pollutant models and supports a direct effect of short-term
NO2 exposure on respiratory morbidity (see ISA Figures 3.1-
7, 3.1-10, 3.1-11 and Figures 1 through 3 below). The plausibility and
coherence of these effects are also supported by epidemiologic studies
of indoor NO2 as well as experimental (i.e., toxicologic and
controlled human exposure) studies that have evaluated host defense and
immune system changes, airway inflammation, and airway responsiveness
(see subsequent sections of this proposal and the ISA, section
<IP_ADDRESS>). The ISA (section 5.4) concluded that the robustness of
epidemiologic findings to adjustment for co-pollutants, coupled with
data from animal and human experimental studies, support a
determination that the relationship between NO2 and
respiratory morbidity is likely causal, while still recognizing the
relationship between NO2 and other traffic related
pollutants.
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    The epidemiologic and experimental studies encompass a number of
endpoints, including emergency department visits and hospitalizations,
respiratory symptoms, airway hyperresponsiveness, airway inflammation,
and lung function. Effect estimates from epidemiologic studies
conducted in the United States and Canada generally indicate a 2-20%
\6\ increase in risks for emergency department visits and hospital
admissions and higher risks for respiratory symptoms (ISA, section
5.4). The findings relevant to these endpoints, which provide the
rationale to support the judgment of a likely causal relationship, are
described in more detail below.
---------------------------------------------------------------------------

    \6\ Effect estimates in the ISA were standardized to a 30 ppb
increase in NO2 concentrations and to a 20 ppb increase
for studies that evaluated 24-hour average concentrations.
---------------------------------------------------------------------------

a. Emergency Department Visits and Hospital Admissions
    Epidemiologic evidence exists for positive associations of short-
term ambient NO2 concentrations below the current NAAQS with
increased numbers of emergency department visits and hospital
admissions for respiratory causes, especially asthma (ISA, section
<IP_ADDRESS>). Total respiratory causes for emergency department visits and
hospitalizations typically include asthma, bronchitis and emphysema
(collectively referred to as COPD), pneumonia, upper and lower
respiratory infections, and other minor categories. Temporal
associations between respiratory emergency department visits or
hospital admissions and ambient levels of NO2 have been the
subject of over 50 peer-reviewed research publications since the review
of the NO2 NAAQS that was completed in 1996. These studies
have examined morbidity in different age groups and have often utilized
multi-pollutant models to evaluate potential confounding effects of co-
pollutants. Associations are particularly consistent among children (<
14 years) and older adults (> 65 years) when all respiratory outcomes
are analyzed together (ISA, Figures 3.1-8 and 3.1-9) and among children
and subjects of all ages for asthma admissions (ISA, Figures 3.1-12 and
3.1-13). When examined with co-pollutant models, associations of
NO2 with respiratory emergency department visits and
hospital admissions were generally robust and independent of the
effects of co-pollutants (i.e., magnitude of effect estimates remained
relatively unchanged) (ISA, Figures 3.1-10 and 3.1-11). The
plausibility and coherence of these effects are supported by
experimental (i.e., toxicologic and controlled human exposure) studies
that evaluate host defense and immune system changes, airway
inflammation, and airway responsiveness (see subsequent sections of
this document and ISA, section <IP_ADDRESS>).
    Of the respiratory emergency department visit and hospital
admission studies reviewed in the ISA, 6 key studies were conducted in
the United States (ISA, Table 5.4-1). Of these 6 studies, 4 evaluated
associations with NO2 using multi-pollutant models (Peel et
al., 2005 and updated in Tolbert et al., 2007 in Atlanta; New York
Department of Health (NYDOH), 2006 and Ito et al., 2007 in New York
City), while 2 studies evaluated only single pollutant models (Linn et
al., 2000 in Los Angeles; Jaffe et al., 2003 in Cleveland/Cincinnati,
OH). In the study by Peel and colleagues, investigators evaluated
respiratory emergency department visits among all ages in Atlanta, GA
during the period from 1993 to 2000. Using single pollutant models, a
2.4% (95% CI: 0.9%, 4.1%) increase in respiratory emergency department
visits was associated with a 30-ppb increase in 1-hour maximum
NO2 concentrations. For asthma visits, a 4.1% (95% CI: 0.8%,
7.6%) increase was estimated in individuals 2 to 18 years of age.
Tolbert and colleagues reanalyzed these data with 4 additional years of
information and found essentially similar results in single pollutant
models (2.0% increase, 95% CI: 0.5%, 3.3%). This same study found that
the associations were positive, but not statistically significant, in
multi-pollutant models that included PM10 or O3
(Figure 2 in published manuscript). In the study conducted by the
NYDOH, investigators evaluated asthma

emergency department visits in Bronx and Manhattan, New York over the
period of January 1999 to November 2000. In Bronx, a 6% (95% CI: 1%,
10%) increase in visits was estimated per 20 ppb increase in 24-hour
average concentrations of NO2 and a 7% (95% CI: 2%, 12%)
increase in visits was estimated per 30 ppb increase in daily 1-hour
maximum concentrations. These effects were not statistically
significant in 2-pollutant models that included PM2.5 or
SO2 (Tables 4a and 9 in manuscript). In Manhattan, the
authors found non-significant decreases (3% for 24-hour and a 2% for
daily 1-hour maximum) in asthma-related emergency department visits
associated with increasing NO2. In the study by Ito and
colleagues (2007), investigators evaluated respiratory emergency
department visits for asthma in New York City during the years 1999 to
2002. A 12% (95% CI: 7%, 15%) increase in risk was estimated per 20 ppb
increase in 24-hour ambient NO2. Risk estimates were robust
and remained statistically significant in multi-pollutant models that
included PM2.5, O3, CO, and SO2
(figure 8 in manuscript). With regard to the studies that evaluated
only single pollutant models, Linn et al. (2000) detected a
statistically significant increase in respiratory hospital admissions
and Jaffe et al. (2003) detected a positive, but not statistically
significant, increase in respiratory emergency department visits
associated with 24-hour NO2 concentrations.
b. Respiratory Symptoms
    Evidence for associations between NO2 and respiratory
symptoms is derived primarily from the epidemiologic literature,
although the experimental evidence for airway inflammation and immune
system effects (described in the ISA, section 3.1) does provide support
for the plausibility and coherence for the epidemiologic results (ISA,
section <IP_ADDRESS>). Consistent evidence has been observed for an
association of respiratory effects with indoor and personal
NO2 exposures in children (ISA, sections <IP_ADDRESS> and
<IP_ADDRESS>) and with ambient levels of NO2, as measured by
area-wide monitors (ISA, sections <IP_ADDRESS> and <IP_ADDRESS>, see Figure 3.1-
6). In the results of multi-pollutant models, NO2
associations in multicity studies are generally robust to adjustment
for co-pollutants including O3, CO, and PM10
(ISA, sections <IP_ADDRESS>, <IP_ADDRESS> and Figure 3.1-7). Specific studies of
respiratory symptoms are discussed in more detail below.
    Epidemiologic studies using community ambient monitors have found
associations between ambient NO2 concentrations and
respiratory symptoms (ISA, sections <IP_ADDRESS> and <IP_ADDRESS>, Figure 3.1-6)
in cities where the entire range of 24-hour average NO2
concentrations were well below the level of the current NAAQS (0.053
ppm annual average). Several studies have been published since the last
review including single-city studies (e.g., Ostro et al., 2001; Delfino
et al., 2002) and multicity studies in urban areas covering the
continental United States and southern Ontario (Schwartz et al., 1994;
Mortimer et al., 2002; Schildcrout et al., 2006).
    Schwartz et al. (1994) studied 1,844 schoolchildren, followed for 1
year, as part of the Six Cities Study that included the cities of
Watertown, MA, St. Louis, MO, Kingston-Harriman, TN, Steubenville, OH,
Topeka, KS, and Portage, WI. Respiratory symptoms were recorded daily.
The authors reported a significant association between 4-day mean
NO2 levels and incidence of cough among all children in
single-pollutant models, with an odds ratio (OR) of 1.61 (95% CI: 1.08,
2.43) standardized to a 20-ppb increase in NO2. The
incidence of cough increased up to approximately mean NO2
levels (13 ppb) (p = 0.01), after which no further increase was
observed. The significant association between cough and 4-day mean
NO2 level remained unchanged in models that included
O3 but lost statistical significance in two-pollutant models
that included PM10 (OR = 1.37 [95% CI: 0.88, 2.13]) or
SO2 (OR = 1.42 [95% CI: 0.90, 2.28]).
    Mortimer et al. (2002) studied the risk of asthma symptoms among
864 asthmatic children in New York City, NY, Washington, DC, Cleveland,
OH, Detroit, MI, St Louis, MO, and Chicago, IL. Subjects were followed
daily for four 2-week periods over the course of nine months with
morning and evening asthma symptoms and peak flow recorded. The
greatest effect was observed for morning symptoms using a 6-day moving
average, with a reported OR of 1.48 (95% CI: 1.02, 2.16) per 20 ppb
increase in NO2. Although the magnitudes of effect estimates
were generally robust in multi-pollutant models that included
O3 (OR for 20-ppb increase in NO2 = 1.40 [95% CI:
0.93, 2.09]), O3 and SO2 (OR for NO2 =
1.31 [95% CI: 0.87, 2.09]), or O3, SO2, and
PM10 (OR for NO2 = 1.45 [95% CI: 0.63, 3.34]),
they were not statistically significant.
    Schildcrout et al. (2006) investigated the association between
ambient NO2 and respiratory symptoms and rescue inhaler use
as part of the Childhood Asthma Management Program (CAMP) study. The
study reported on 990 asthmatic children living within 50 miles of an
NO2 monitor in Boston, MA, Baltimore, MD, Toronto, ON, St.
Louis, MO, Denver, CO, Albuquerque, NM, or San Diego, CA. Symptoms and
use of rescue medication were recorded daily, resulting in each subject
having an average of approximately two months of data. The authors
reported the strongest association between NO2 and increased
risk of cough for a 2-day lag, with an OR of 1.09 (95% CI: 1.03, 1.15)
for each 20-ppb increase in NO2 occurring 2 days before
measurement. Multi-pollutant models that included CO, PM10,
or SO2 produced similar results (ISA, Figure 3.1-5, panel
A). Additionally, increased NO2 exposure was associated with
increased use of rescue medication, with the strongest association for
a 2-day lag. In the single-pollutant model, the relative risk (RR) for
increased inhaler usage was 1.05 (95% CI: 1.01, 1.09).
    Evidence supporting increased respiratory symptoms following
NO2 exposures is found in studies focused on indoor sources
of NO2 (ISA, section <IP_ADDRESS>). These studies are not
confounded by the same mix of co-pollutants present in the ambient air
or by the contribution of NO2 to the formation of secondary
particles or O3 (ISA, section <IP_ADDRESS>). Specifically, in a
randomized intervention study in Australia (Pilotto et al., 2004),
asthmatic students attending schools that switched out unvented gas
heaters, a major source of indoor NO2, experienced a
decrease in both levels of NO2 and in respiratory symptoms
(e.g., difficulty breathing, chest tightness, and asthma attacks)
compared to students in schools that did not switch out unvented gas
heaters (ISA, section <IP_ADDRESS>). An earlier indoor study by Pilotto and
colleagues (1997) also found that students in classrooms with higher
levels of NO2 due primarily to indoor sources had higher
rates of respiratory symptoms (e.g., sore throat, cold) and absenteeism
than students in classrooms with lower levels of NO2. This
study detected a significant concentration-response relationship,
strengthening the argument that NO2 is causally related to
respiratory morbidity. A number of other indoor studies conducted in
homes with gas appliances have also detected significant associations
between indoor NO2 and respiratory symptoms (ISA, section
<IP_ADDRESS>).
c. Impaired Host Defense
    Impaired host-defense systems and increased risk of susceptibility
to both viral and bacterial infections after NO2 exposures
have been observed in

epidemiologic, controlled human exposure, and animal toxicological
studies (ISA, section 3.1.1 and <IP_ADDRESS>). A recent epidemiologic study
(Chauhan et al., 2003) provides evidence that increased personal
exposure to NO2 worsened virus-associated symptoms and
decreased lung function in children with asthma. The limited evidence
from controlled human exposure studies indicates that NO2
may increase susceptibility to lung injury by subsequent viral
challenge at exposures of as low as 600 ppb for 3 hours in healthy
adults (Frampton et al., 2002). Toxicological studies have shown that
lung host defenses, including mucociliary clearance and immune cell
function, are sensitive to NO2 exposure, with effects
observed at concentrations of less than 1000 ppb (ISA, section 3.1.7).
When taken together, epidemiologic and experimental studies linking
NO2 exposure with viral illnesses provide coherent and
consistent evidence that NO2 exposure can result in lung
host defense or immune system effects (ISA, sections 3.1.7 and
<IP_ADDRESS>). This group of outcomes also provides some plausibility for
other respiratory system effects. For example, effects on ciliary
action (clearance) or immune cell function (i.e. macrophage
phagocytosis) could be the basis for the effects observed in
epidemiologic studies, including increased respiratory illness or
respiratory symptoms (ISA, section <IP_ADDRESS>). Proposed mechanisms by
which NO2, in conjunction with viral infections, may
exacerbate airway symptoms are summarized in the ISA (Table 3.1-1).
d. Airway Response
    In acute exacerbations of asthma, bronchial smooth muscle
contraction occurs quickly to narrow the airway in response to exposure
to various stimuli including allergens or irritants.
Bronchoconstriction is the dominant physiological event leading to
clinical symptoms and interference with airflow (National Heart, Lung,
and Blood Institute, 2007). Inhaled pollutants such as NO2
may enhance the inherent responsiveness of the airway to a challenge by
allergens and nonspecific agents (ISA, section 3.1.3). In the
laboratory, airway responses can be measured by assessing changes in
pulmonary function (e.g., decline in FEV1) or changes in the
inflammatory response (e.g., using markers in bronchoalveolar lavage
(BAL) fluid or induced sputum) (ISA, section 3.1.3).
    The ISA (section <IP_ADDRESS>) drew two broad conclusions regarding
airway responsiveness in asthmatics following NO2 exposure.
First, the ISA concluded that NO2 exposure may enhance the
sensitivity to allergen-induced decrements in lung function and
increase the allergen-induced airway inflammatory response at exposures
as low as 260 ppb NO2 for 30 minutes (ISA, section <IP_ADDRESS>
and Figure 3.1-2). Second, exposure to NO2 has been found to
enhance the inherent responsiveness of the airway to subsequent
nonspecific challenges in controlled human exposure studies (section
<IP_ADDRESS>). In general, small but significant increases in nonspecific
airway responsiveness were observed in the range of 200 to 300 ppb
NO2 for 30-minute exposures and at 100 ppb NO2
for 60-minute exposures in asthmatics. These conclusions are consistent
with results from animal toxicological studies which have detected 1)
increased immune-mediated pulmonary inflammation in rats exposed to
house dust mite allergen following exposure to 5000 ppb NO2
for 3-h and 2) increased responsiveness to non-specific challenges
following sub-chronic (6-12 weeks) exposure to 1000 to 4000 ppb
NO2 (ISA, section <IP_ADDRESS>).
    Enhanced airway responsiveness could have important clinical
implications for asthmatics since transient increases in airway
responsiveness following NO2 exposure have the potential to
increase symptoms and worsen asthma control (ISA, section 5.4). In
addition, the ISA cited the controlled human exposure literature on the
NO2 airway response as being supportive of the epidemiologic
evidence on respiratory morbidity (ISA, section 5.4). Because studies
on airway responsiveness have been used to identify potential health
effect benchmark values and to inform the identification of potential
alternative standards for evaluation (see REA, sections 4.5 and 5),
more detail is provided below on the specific studies that form the
basis for the conclusions in the ISA regarding this endpoint.
    Folinsbee (1992) conducted a meta-analysis using individual level
data from 19 NO2 controlled human exposure studies measuring
airway responsiveness in asthmatics (ISA, section <IP_ADDRESS>). These
studies included NO2 exposure levels between 100 and 1000
ppb and most of them used nonspecific bronchoconstricting agents such
as methacholine, carbachol, histamine, or cold air. The largest effects
were observed for asthmatics at rest. Among asthmatics exposed at rest,
76% experienced increased airway responsiveness following exposure to
NO2 levels between 200 and 300 ppb. Results from an update
of this meta-analysis, which focused only on data for nonspecific
responsiveness, are presented in the ISA (Table 3.1-3).\7\ When exposed
at rest, 66% of asthmatics experienced an increase in airway
responsiveness following exposure to 100 ppb NO2, 67% of
asthmatics experienced an increase in airway responsiveness following
exposure to NO2 concentrations between 100 and 150 ppb
(inclusively), 75% of subjects experienced an increase in airway
responsiveness following exposure to NO2 concentrations
between 200 and 300 ppb (inclusively), and 73% of subjects experienced
an increase in airway responsiveness following exposure to
NO2 concentrations above 300 ppb. Effects of NO2
exposure on the direction of airway responsiveness were statistically
significant at all of these levels. Because this meta-analysis
evaluated only the direction of the change in airway responsiveness, it
is not possible to discern the magnitude of the change from these data.
However, the results do suggest that short-term (i.e., 30-min to 3-h)
exposures to NO2 at near-ambient levels (<300 ppb) can alter
airway responsiveness in people with mild asthma (ISA, section
<IP_ADDRESS>).
---------------------------------------------------------------------------

    \7\ The updated meta-analysis added a study that evaluated non-
specific airway responsiveness following exposure to 260 ppb NO2 and
removed a study that evaluated allergen-induced airway
responsiveness following exposure to 100 ppb NO2.
---------------------------------------------------------------------------

    Several studies published since the 1996 review evaluate the
potential for low-level exposures to NO2 to enhance the
response to specific allergen challenge in mild asthmatics (ISA,
section <IP_ADDRESS>). These studies suggest that NO2 may enhance
the sensitivity to allergen-induced decrements in lung function and
increase the allergen-induced airway inflammatory response. Strand et
al. (1997) demonstrated that single 30-minute exposures to 260 ppb
NO2 increased the late phase response to allergen challenge
4 hours after exposure, as measured by changes in lung function. In a
separate study (Strand et al., 1998), 4 daily repeated exposures to 260
ppb NO2 for 30 minutes increased both the early and late-
phase responses to allergen, as measured by changes in lung function.
Barck et al. (2002) used the same exposure and challenge protocol in
the earlier Strand study (260 ppb for 30 min, with allergen challenge 4
hours after exposure), and performed BAL 19 hours after the allergen
challenge to determine NO2 effects on the allergen-induced
inflammatory response. Compared with air followed by allergen,
NO2 followed by allergen caused an

increase in the BAL recovery of polymorphonuclear (PMN) cells and
eosinophil cationic protein (ECP) as well as a reduction in total BAL
fluid volume and cell viability. ECP is released by degranulating
eosinophils, is toxic to respiratory epithelial cells, and is thought
to play a role in the pathogenesis of airway injury in asthma.
Subsequently, Barck et al. (2005) exposed 18 mild asthmatics to air or
260 ppb NO2 for 15 minutes on day 1, followed by two 15
minute exposures separated by 1 hour on day 2, with allergen challenge
after exposures on both days 1 and 2. Sputum was induced before
exposure on day 1 and after exposures (morning of day 3). Compared to
air plus allergen, NO2 plus allergen resulted in increased
levels of ECP in both sputum and blood and increased myeloperoxidase
levels in blood.
    All exposures in these studies (Barck et al., 2002, 2005; Strand et
al., 1997, 1998) used subjects at rest. They used an adequate number of
subjects, included air control exposures, randomized exposure order,
and separated exposures by at least 2 weeks. Together, they indicate
the possibility for effects on allergen responsiveness in some
asthmatics following brief exposures to 260 ppb NO2. Other
recent studies have failed to find effects using similar, but not
identical, approaches (ISA, section <IP_ADDRESS>). The differing findings
may relate in part to differences in timing of the allergen challenge,
the use of multiple versus single-dose allergen challenge, the use of
BAL versus sputum induction, exercise versus rest during exposure, and
differences in subject susceptibility (ISA, section <IP_ADDRESS>).
e. Airway Inflammation
    Effects of NO2 on airway inflammation have been observed
in controlled human exposure and animal toxicological studies at higher
than ambient levels (400-5000 ppb). Controlled human exposure studies
provide evidence for increased airway inflammation at NO2
concentrations of <2000 ppb. The onset of inflammatory responses in
healthy subjects appears to be between 100 and 200 ppm-minutes, i.e.,
1000 ppb for 2 to 3 hours (ISA, Figure 3.1-1). Increases in biological
markers of inflammation were not observed consistently in healthy
animals at levels of less than 5000 ppb; however, increased
susceptibility (as indicated by biochemical markers of inflammation) to
NO2 concentrations of as low as 400 ppb was observed when
lung vitamin C was reduced (by diet) to levels that were <50% of
normal. The few available epidemiologic studies were suggestive of an
association between ambient NO2 concentrations and
inflammatory response in the airway in children, though the
associations were inconsistent in the adult populations examined (ISA,
section 3.1.2 and <IP_ADDRESS>). These data provide some evidence for
biological plausibility and one potential mechanism for other
respiratory effects, such as exacerbation of asthma symptoms and
increased emergency department visits for asthma (ISA, section
<IP_ADDRESS>).
f. Lung Function
    Recent epidemiologic studies that examined the association between
ambient NO2 concentrations and lung function in children and
adults have produced inconsistent results (ISA, sections <IP_ADDRESS> and
<IP_ADDRESS>). Controlled human exposure studies generally did not find
direct effects of NO2 on lung function in healthy adults at
levels as high as 4000 ppb (ISA, section <IP_ADDRESS>). For asthmatics, the
direct effects of NO2 on lung function also have been
inconsistent at exposure concentrations of less than 1000 ppb
NO2.
g. Conclusions From the ISA
    As noted previously, the ISA concluded that the findings of
epidemiologic, controlled human exposure, and animal toxicological
studies provide evidence that is sufficient to infer a likely causal
relationship for respiratory effects following short-term
NO2 exposure (ISA, sections 3.1.7 and <IP_ADDRESS>). The ISA
(section 5.4) concluded that the strongest evidence for an association
between NO2 exposure and adverse human health effects comes
from epidemiologic studies of respiratory symptoms, emergency
department visits, and hospital admissions. These studies include panel
and field studies, studies that control for the effects of co-occurring
pollutants, and studies conducted in areas where the whole distribution
of ambient 24-hour average NO2 concentrations was below the
current NAAQS level of 53 ppb (annual average). With regard to this
evidence, the ISA concluded that NO2 epidemiologic studies
provide ``little evidence of any effect threshold'' (ISA, section
<IP_ADDRESS>, p. 5-15). In studies that have evaluated concentration-
response relationships, they appear linear within the observed range of
data (ISA, section <IP_ADDRESS>).
    Overall, the epidemiologic evidence for respiratory effects has
been characterized in the ISA as consistent, in that associations are
reported in studies conducted in numerous locations with a variety of
methodological approaches. Considering this large body of epidemiologic
studies alone, the findings have also been characterized as coherent in
that the studies report associations with respiratory health outcomes
that are logically linked together. In addition, a number of these
associations are statistically significant, particularly the more
precise effect estimates (ISA, section <IP_ADDRESS>). These epidemiologic
studies are supported by evidence from toxicological and controlled
human exposure studies, particularly those that evaluated airway
hyperresponsiveness in asthmatic individuals (ISA, section 5.4). The
ISA concluded that together, the epidemiologic and experimental data
sets form a plausible, consistent, and coherent description of a
relationship between NO2 exposures and an array of adverse
respiratory health effects that range from the onset of respiratory
symptoms to hospital admissions.
2. Other Effects With Short-Term Exposure to NO2
a. Mortality
    The ISA concluded that the epidemiologic evidence is suggestive,
but not sufficient, to infer a causal relationship between short-term
exposure to NO2 and all-cause and cardiopulmonary-related
mortality (ISA, section <IP_ADDRESS>). Results from several large U.S. and
European multicity studies and a meta-analysis study indicate positive
associations between ambient NO2 concentrations and the risk
of all-cause (nonaccidental) mortality, with effect estimates ranging
from 0.5 to 3.6% excess risk in mortality per standardized increment
(20 ppb for 24-hour averaging time, 30 ppb for 1-hour averaging time)
(ISA, section 3.3.1, Figure 3.3-2, section <IP_ADDRESS>). In general, the
NO2 effect estimates were robust to adjustment for co-
pollutants. Both cardiovascular and respiratory mortality have been
associated with increased NO2 concentrations in
epidemiologic studies (ISA, Figure 3.3-3); however, similar
associations were observed for other pollutants, including PM and
SO2. The range of risk estimates for excess mortality is
generally smaller than that for other pollutants such as PM. In
addition, while NO2 exposure, alone or in conjunction with
other pollutants, may contribute to increased mortality, evaluation of
the specificity of this effect is difficult. Clinical studies showing
hematologic effects and animal toxicological studies showing
biochemical, lung host defense, permeability, and inflammation changes

with short-term exposures to NO2 provide limited evidence of
plausible pathways by which risks of mortality may be increased, but no
coherent picture is evident at this time (ISA, section <IP_ADDRESS>).
b. Cardiovascular Effects
    The ISA concluded that the available evidence on cardiovascular
health effects following short-term exposure to NO2 is
inadequate to infer the presence or absence of a causal relationship at
this time (ISA, section <IP_ADDRESS>). Evidence from epidemiologic studies
of heart rate variability, repolarization changes, and cardiac rhythm
disorders among heart patients with ischemic cardiac disease are
inconsistent (ISA, section <IP_ADDRESS>). In most studies, associations with
PM were found to be similar or stronger than associations with
NO2. Generally positive associations between ambient
NO2 concentrations and hospital admissions or emergency
department visits for cardiovascular disease have been reported in
single-pollutant models (ISA, section <IP_ADDRESS>); however, most of these
effect estimate values were diminished in multi-pollutant models that
also contained CO and PM indices (ISA, section <IP_ADDRESS>). Mechanistic
evidence of a role for NO2 in the development of
cardiovascular diseases from studies of biomarkers of inflammation,
cell adhesion, coagulation, and thrombosis is lacking (ISA, section
<IP_ADDRESS>). Furthermore, the effects of NO2 on various
hematological parameters in animals are inconsistent and, thus, provide
little biological plausibility for effects of NO2 on the
cardiovascular system (ISA, section <IP_ADDRESS>).
3. Health Effects With Long-Term Exposure to NO2
a. Respiratory Morbidity
    The ISA concluded that overall, the epidemiologic and experimental
evidence is suggestive, but not sufficient, to infer a causal
relationship between long-term NO2 exposure and respiratory
morbidity (ISA, section <IP_ADDRESS>). The available database evaluating the
relationship between respiratory illness in children and long-term
exposures to NO2 has increased since the 1996 review of the
NO2 NAAQS. A number of epidemiologic studies have examined
the effects of long-term exposure to NO2 and reported
positive associations with decrements in lung function and partially
irreversible decrements in lung function growth (ISA, section 3.4.1,
Figures 3.4-1 and 3.4-2). Specifically, results from the California-
based Children's Health Study, which evaluated NO2 exposures
in children over an 8-year period, demonstrated deficits in lung
function growth (Gauderman et al., 2004). This effect has also been
observed in Mexico City, Mexico (Rojas-Martinez et al., 2007a,b) and in
Oslo, Norway (Oftedal et al., 2008), with decrements ranging from 1 to
17.5 ml per 20-ppb increase in annual NO2 concentration.
Similar associations have been found for PM, O3, and
proximity to traffic (<500 m), though these studies did not report the
results of co-pollutant models. The high correlation among traffic-
related pollutants makes it difficult to accurately estimate
independent effects in these long-term exposure studies (ISA, section
<IP_ADDRESS>). With regard to asthma incidence and long-term NO2,
two major cohort studies, the Children's Health Study (Gauderman et
al., 2005) and a birth cohort study in the Netherlands (Brauer et al.,
2007), observed significant associations. However, several other
studies failed to find consistent associations between long-term
NO2 exposure and asthma outcomes (ISA, section <IP_ADDRESS>).
Similarly, epidemiologic studies conducted in the United States and
Europe reported inconsistent results regarding an association between
long-term exposure to NO2 and respiratory symptoms (ISA,
sections 3.4.3 and <IP_ADDRESS>). While some positive associations were
noted, a large number of symptom outcomes were examined and the results
across specific outcomes were inconsistent (ISA, section <IP_ADDRESS>).
    Animal toxicological studies may provide biological plausibility
for the chronic effects of NO2 that have been observed in
epidemiologic studies (ISA, sections 3.4.5 and <IP_ADDRESS>). The main
biochemical targets of NO2 exposure appear to be
antioxidants, membrane polyunsaturated fatty acids, and thiol groups.
NO2 effects include changes in oxidant/antioxidant
homeostasis and chemical alterations of lipids and proteins. Lipid
peroxidation has been observed at NO2 exposures as low as 40
ppb for 9 months and at exposures of 1200 ppb for 1 week, suggesting
lower effect thresholds with longer durations of exposure. Other
studies showed decreases in formation of key arachidonic acid
metabolites in alveolar macrophages following NO2 exposures
of 500 ppb. NO2 has been shown to increase collagen
synthesis rates at concentrations as low as 500 ppb. This could
indicate increased total lung collagen, which is associated with
pulmonary fibrosis, or increased collagen turnover, which is associated
with remodeling of lung connective tissue. Morphological effects
following chronic NO2 exposures have been identified in
animal studies that link to these increases in collagen synthesis and
may provide plausibility for the deficits in lung function growth
described in epidemiologic studies of long-term exposure to
NO2 (ISA, section 3.4.5).
b. Mortality
    The ISA concluded that the epidemiologic evidence is inadequate to
infer the presence or absence of a causal relationship between long-
term exposure to NO2 and mortality (ISA, section <IP_ADDRESS>).
In the United States and European cohort studies examining the
relationship between long-term exposure to NO2 and
mortality, results have been inconsistent (ISA, section <IP_ADDRESS>).
Further, when associations were suggested, they were not specific to
NO2 but also implicated PM and other traffic indicators. The
relatively high correlations reported between NO2 and PM
indices make it difficult to interpret these observed associations at
this time (ISA, section <IP_ADDRESS>).
c. Carcinogenic, Cardiovascular, and Reproductive/Developmental Effects
    The ISA concluded that the available epidemiologic and
toxicological evidence is inadequate to infer the presence or absence
of a causal relationship for carcinogenic, cardiovascular, and
reproductive and developmental effects related to long-term
NO2 exposure (ISA, section <IP_ADDRESS>). Epidemiologic studies
conducted in Europe have shown an association between long-term
NO2 exposure and increased incidence of cancer (ISA, section
<IP_ADDRESS>). However, the animal toxicological studies have provided no
clear evidence that NO2 acts as a carcinogen (ISA, section
<IP_ADDRESS>). The very limited epidemiologic and toxicological evidence do
not suggest that long-term exposure to NO2 has
cardiovascular effects (ISA, section <IP_ADDRESS>). The epidemiologic
evidence is not consistent for associations between NO2
exposure and fetal growth retardation; however, some evidence is
accumulating for effects on preterm delivery (ISA, section <IP_ADDRESS>).
Scant animal evidence supports a weak association between
NO2 exposure and adverse birth outcomes and provides little
mechanistic information or biological plausibility for the
epidemiologic findings.
4. NO2-Related Impacts on Public Health
    Specific groups within the general population are likely at
increased risk

for suffering adverse effects from NO2 exposure. This could
occur because they are affected by lower levels of NO2 than
the general population (susceptibility), because they experience a
larger health impact than the general population to a given level of
exposure (susceptibility), and/or because they are exposed to higher
levels of NO2 than the general population (vulnerability).
The term susceptibility generally encompasses innate (e.g., genetic or
developmental) and/or acquired (e.g., age or disease) factors that make
individuals more likely to experience effects with exposure to
pollutants. The severity of health effects experienced by a susceptible
subgroup may be much greater than that experienced by the population at
large. Factors that may influence susceptibility to the effects of air
pollution include age (e.g., infants, children, elderly); gender; race/
ethnicity; genetic factors; and pre-existing disease/condition (e.g.,
obesity, diabetes, respiratory disease, asthma, chronic obstructive
pulmonary disease (COPD), cardiovascular disease, airway
hyperresponsiveness, respiratory infection, adverse birth outcome)
(ISA, sections 4.3.1, 4.3.5, and <IP_ADDRESS>). In addition, certain groups
may experience relatively high exposure to NO2, thus forming
a potentially vulnerable population (ISA, section 4.3.6). Factors that
may influence exposures and/or susceptibility to air pollution include
socioeconomic status (SES), education level, air conditioning use,
proximity to roadways, geographic location, level of physical activity,
and work environment (e.g., indoor versus outdoor) (ISA, section
4.3.5). The ISA discussed factors that can confer susceptibility and/or
vulnerability to air pollution with most of the discussion devoted to
factors for which NO2-specific evidence exists (ISA, section
4.3). These factors are discussed below.
a. Pre-Existing Disease
    A number of health conditions have been found to put individuals at
greater risk for adverse events following exposure to air pollution. In
general, these include asthma, COPD, respiratory infection, cardiac
conduction disorders, congestive heart failure (CHF), diabetes, past
myocardial infarction (MI), obesity, coronary artery disease, low birth
weight/prematurity, and hypertension (ISA, sections 4.3.1, 4.3.5, and
<IP_ADDRESS>). In addition to these conditions, epidemiologic evidence
indicates that individuals with bronchial or airway
hyperresponsiveness, as determined by methacholine provocation, may be
at increased risk for experiencing respiratory symptoms (ISA, section
4.3.1). In considering NO2 specifically, the ISA evaluated
studies on asthmatics, individuals with cardiopulmonary disease, and
diabetics (ISA, sections <IP_ADDRESS> and <IP_ADDRESS>). These groups are
discussed in more detail below.
    Epidemiologic and controlled human exposure studies, supported by
animal toxicology studies, have provided evidence for associations
between NO2 exposure and respiratory effects in asthmatics
(ISA, section <IP_ADDRESS>). The ISA found evidence from epidemiologic
studies for an association between ambient NO2 and
children's hospital admissions, emergency department visits, and calls
to doctors for asthma. Long-term NO2 exposure was associated
with aggravation of asthma effects that include symptoms, medication
use, and lung function. Time-series studies demonstrated a relationship
in children between hospital admissions or emergency department visits
for asthma and ambient NO2 levels, even after adjusting for
co-pollutants such as PM and CO (ISA, section <IP_ADDRESS>). Important
evidence was available from epidemiologic studies of indoor
NO2 exposures. Recent studies have shown associations with
asthma attacks and severity of virus-induced asthma (ISA, section
<IP_ADDRESS>). In addition, in controlled human exposure studies, airway
hyperresponsiveness in asthmatics occurred following exposure to
ambient or near-ambient NO2 concentrations (ISA, sections
<IP_ADDRESS>-<IP_ADDRESS>). Compared to asthma, less evidence is available to
support cardiovascular disease as a mediator of susceptibility to
NO2. However, recent epidemiologic studies report that
individuals with preexisting conditions (e.g., including diabetes, CHF,
prior MI) may be at increased risk for adverse cardiac health events
associated with ambient NO2 concentrations (ISA, section
<IP_ADDRESS>). The small number of controlled human exposure and animal
toxicological studies that have evaluated cardiovascular endpoints
provide only limited supporting evidence for susceptibility to
NO2 in persons with cardiovascular disease (ISA, section
<IP_ADDRESS>).
b. Age
    The ISA identified infants, children (i.e., <18 years of age), and
older adults (i.e., >65 years of age) as groups that are potentially
more susceptible than the general population to the health effects
associated with ambient NO2 concentrations (ISA, section
4.3.2). The ISA found evidence that associations of NO2 with
respiratory emergency department visits and hospitalizations were
stronger among children and older adults, though not all studies had
comparable findings on this issue (ISA, section 4.3.2). In addition,
long-term exposure studies suggest effects in children that include
impaired lung function growth, increased respiratory symptoms and
infections, and onset of asthma (ISA, section 3.4 and 4.3.2). In some
studies, associations between NO2 and hospitalizations or
emergency department visits for CVD have been observed in elderly
populations. Among studies that observed positive associations between
NO2 and mortality, a comparison indicated that, in general,
the elderly population was more susceptible than the non-elderly
population to NO2 effects (ISA, section 4.3.2).
c. Genetics
    As noted in the ISA (section 4.3.4), genetic factors related to
health outcomes and ambient pollutant exposures merit consideration.
Several criteria should be satisfied in selecting and establishing
useful links between polymorphisms in candidate genes and adverse
respiratory effects. First, the candidate gene must be significantly
involved in the pathogenesis of the adverse effect of interest. Second,
polymorphisms in the gene must produce a functional change in either
the protein product or in the level of expression of the protein.
Third, in epidemiologic studies, the issue of confounding by other
environmental exposures must be carefully considered (ISA, section
4.3.4). Investigation of genetic susceptibility to NO2
effects has focused on the glutathione S-tranferase (GST) gene. Several
GST genes have common, functionally-important alleles that affect host
defense in the lung (ISA, section 4.3.4). GST genes are inducible by
electrophilic species (e.g., reactive oxygen species) and individuals
with genotypes that result in enzymes with reduced or absent peroxidase
activity are likely to have reduced defenses against oxidative insult.
This could potentially result in increased susceptibility to inhaled
oxidants and radicals. However, data on genetic susceptibility to
NO2 are only beginning to emerge and, while it remains
plausible that there are genetic factors that can influence health
responses to NO2, the few available studies do not provide
specific support for genetic susceptibility to NO2 exposure
(ISA, section 4.3.4).
d. Gender
    As reported in the ISA, a limited number of NO2 studies
have stratified results by gender. The results of these studies were
mixed, and the ISA did not

draw conclusions regarding the potential for gender to confer
susceptibility to the effects of NO2 (ISA, section 4.3.3).
e. Proximity to Roadways
    Certain groups may experience relatively high exposure to
NO2, thus forming a potentially vulnerable population. The
ISA included discussion of populations reported to experience increased
NO2 exposures on or near roadways (ISA, section 4.3.6).
Large gradients in NOX concentrations near roadways may lead
to increased exposures for individuals residing, working, traveling, or
attending school in the vicinity of roadways. Many studies find that
indoor, personal, and outdoor NO2 levels are strongly
associated with proximity to traffic or to traffic density (ISA,
section 4.3.6).
    That adverse respiratory effects can be associated with proximity
to roadways has been demonstrated in a number of studies. For example,
Gauderman and colleagues (2007) reported reduced lung function growth
in children who lived within 500 m of a freeway compared to children
who lived at least 1500 m from a freeway. In a separate study,
Gauderman and colleagues (2005) reported that the incidence of
physician-diagnosed asthma increased with both increasing
NO2 concentrations outside the child's residence and
decreasing distance between the child's residence and a major freeway.
    In addition to those who live near major roadways, individuals who
spend time commuting on major roadways can also be exposed to
relatively higher concentrations of NO2 than the ones
reported at monitors away from the roads. Due to high air exchange
rates, NO2 concentrations inside a vehicle can rapidly
approach ambient concentrations on the roadway during commuting (ISA,
section 4.3.6). Mean in-vehicle NO2 concentrations are often
between 2 and 3 times higher than ambient levels measured at monitors
located away from the road (ISA, section 4.3.6). Due to the potential
for high peak exposures while driving, total personal exposure could be
underestimated if exposures while commuting are not considered.
Therefore, individuals with occupations that require them to be in
traffic or close to traffic (e.g., bus and taxi drivers, highway patrol
officers, toll collectors) and individuals with long commutes could be
exposed to relatively high levels of NO2 compared to the
ambient levels measured at fixed-site monitors located away from the
roadway.
f. Socioeconomic Status
    The ISA discussed evidence that SES modifies the effects of air
pollution (section 4.3.6). Many recent studies examined modification by
SES indicators on the association between mortality and PM or other
indices such as traffic density, distance to roadway, or a general air
pollution index (ISA, section 4.3.6). SES modification of
NO2 associations has been examined in fewer studies.
However, in a study conducted in Seoul, South Korea, community-level
SES indicators modified the association of air pollution with emergency
department visits for asthma. Of the five criteria air pollutants
evaluated, NO2 showed the strongest association in lower SES
districts compared to high SES districts (Kim et al., 2007). In
addition, Clougherty et al. (2007) evaluated exposure to violence (a
potential surrogate for SES) as a modifier of the effect of traffic-
related air pollutants, including NO2, on childhood asthma.
The authors reported an elevated risk of asthma with an increase in
NO2 exposure solely among children with above-median
exposure to violence in their neighborhoods (ISA, section 4.3.6).
Although these recent studies have evaluated the impact of SES on
vulnerability to NO2, they are too few in number to draw
definitive conclusions (ISA, section <IP_ADDRESS>).
g. Size of the At-Risk Population
    The population potentially affected by NO2 is large. A
considerable fraction of the population resides, works, or attends
school near major roadways, and these individuals are likely to have
increased exposure to NO2 (ISA, section 4.4). Based on data
from the 2003 American Housing Survey, approximately 36 million
individuals live within 300 feet (~90 meters) of a four-lane highway,
railroad, or airport (ISA, section 4.4).\8\ Furthermore, in California,
2.3% of schools with a total enrollment of more than 150,000 students
were located within approximately 500 feet of high-traffic roads, with
a higher proportion of non-white and economically disadvantaged
students attending those schools (ISA, section 4.4). Of this
population, asthmatics and members of other susceptible groups
discussed above will have even greater risks of experiencing health
effects related to NO2 exposure. In the United States,
approximately 10% of adults and 13% of children have been diagnosed
with asthma, and 6% of adults have been diagnosed with COPD (ISA,
section 4.4). The prevalence and severity of asthma is higher among
certain ethnic or racial groups such as Puerto Ricans, American
Indians, Alaskan Natives, and African Americans (ISA, section 4.4). A
higher prevalence of asthma among persons of lower SES and an excess
burden of asthma hospitalizations and mortality in minority and inner-
city communities have been observed (ISA, section 4.4). In addition,
based on U.S. census data from 2000, about 72.3 million (26%) of the
U.S. population are under 18 years of age, 18.3 million (7.4%) are
under 5 years of age, and 35 million (12%) are 65 years of age or
older. Therefore, large portions of the U.S. population are in age
groups that are likely at-risk for health effects associated with
exposure to ambient NO2. The size of the potentially at-risk
population suggests that exposure to ambient NO2 could have
a significant impact on public health in the United States.
---------------------------------------------------------------------------

    \8\ The most current American Housing Survey (http://
www.census.gov/hhes/www/housing/ahs/ahs.html) is from 2007 and lists
a higher fraction of housing units within the 300 foot boundary than
do prior surveys. According to Table IA-6 from that report (http://
www.census.gov/hhes/www/housing/ahs/ahs07/tab1a-6.pdf), out of
128,303,000 total housing units in the United States, 20,016,000
were reported by the surveyed occupant or landlord as being within
300 feet of a 4-or-more lane highway, railroad, or airport. That
constitutes 15.613% of the total housing units in the U.S. Assuming
equal distributions, with a current population of 306,330,199, that
means that there would be 47.8 million people meeting the 300 foot
criteria.
---------------------------------------------------------------------------

C. Human Exposure and Health Risk Characterization

    To put judgments about NO2-associated health effects
into a broader public health context, EPA has drawn upon the results of
the quantitative exposure and risk assessments. Judgments reflecting
the nature of the evidence and the overall weight of the evidence are
taken into consideration in these quantitative exposure and risk
assessments, discussed below. These assessments provide estimates of
the likelihood that asthmatic individuals would experience exposures of
potential concern and estimates of the incidence of NO2-
associated respiratory emergency department visits under varying air
quality scenarios (e.g., just meeting the current or alternative
standards), as well as characterizations of the kind and degree of
uncertainties inherent in such estimates.
    This section describes the approach taken in the REA to
characterize NO2-related exposures and health risks. Goals
of the REA included estimating short-term exposures and potential human
health risks associated with (1) recent levels of ambient
NO2; (2) NO2 levels adjusted to simulate just
meeting the current standard; and (3) NO2 levels adjusted to
simulate just meeting

potential alternative standards. This section discusses the scientific
evidence from the ISA that was used as the basis for the risk
characterization (II.C.1), the approaches used in characterizing
exposures and risks (II.C.2), and important uncertainties associated
with these analyses (II.C.3). The results of the exposure and risk
analyses, as they relate to the current and potential alternative
standards, are discussed in subsequent sections of this proposal
(sections II.E and II.F, respectively).
1. Evidence Base for the Risk Characterization
    For purposes of the quantitative characterization of NO2
health risks, the REA determined that it was appropriate to focus on
endpoints for which the ISA concluded that the available evidence is
sufficient to infer either a causal or a likely causal relationship.
This was generally consistent with judgments made in other recent NAAQS
reviews (e.g., see EPA, 2005).
    As noted above in section II.A, the only health effect category for
which the evidence was judged in the ISA to be sufficient to infer
either a causal or a likely causal relationship is respiratory
morbidity following short-term NO2 exposure. Therefore, for
purposes of characterizing health risks associated with NO2,
the REA focused on respiratory morbidity endpoints that have been
associated with short-term NO2 exposures. Other health
effects (e.g., those associated with long-term exposures) are
considered as part of the evidence-based evaluation of potential
alternative standards (see section II.F.2). In evaluating the
appropriateness of specific endpoints for use in the NO2
risk characterization, the REA considered both epidemiologic and
controlled human exposure studies.
    When evaluating epidemiologic studies as to their appropriateness
for use as the basis for a quantitative risk assessment, the REA
considered several factors. First, the REA concluded that studies
conducted in the United States are preferable to those conducted
outside the United States given the potential for effect estimates to
be impacted by factors such as the ambient pollutant mix, the placement
of monitors, activity patterns of the population, and characteristics
of the healthcare system. Second, the REA concluded that studies of
ambient NO2 are preferable to those of indoor
NO2, which focus on individuals exposed to NO2
from indoor sources. These indoor sources can result in exposure
patterns, NO2 levels, and co-pollutants that are different
from those typically associated with ambient NO2. Therefore,
although indoor studies made important contributions to the evidence
base for causality judgments in the ISA, the preferred approach for
conducting a quantitative risk assessment based on the epidemiologic
literature to inform decisions regarding an ambient NO2
standard is to consider studies of ambient NO2. Third, the
REA concluded that it was appropriate to focus on studies of emergency
department visits and hospital admissions given the clear public health
significance of these endpoints and the availability of baseline
incidence data. Finally, the REA concluded that it was appropriate to
focus on studies that evaluated NO2 health effect
associations using both single- and multi-pollutant models. Taking
these factors into consideration, the epidemiology-based risk
assessment in the REA focused on the study conducted in Atlanta,
Georgia by Tolbert et al. (2007). This assessment is described in more
detail in the REA (chapter 9).
    In identifying health endpoints from controlled human exposure
studies on which to focus the characterization of NO2 health
risks, the REA concluded that it was appropriate to focus on endpoints
that occur at or near ambient levels of NO2 and endpoints
that may be important from a public health perspective. Controlled
human exposure studies have addressed the consequences of short-term
(e.g., 30-minutes to several hours) NO2 exposures for a
number of health endpoints including airway responsiveness, host
defense and immunity, inflammation, and lung function (ISA, section
3.1). With regard to the NO2 levels at which different
effects have been documented, the ISA concluded: (1) In asthmatics
NO2 may increase the allergen-induced airway inflammatory
response at exposures as low as 260 ppb for 30 min (ISA, Figure 3.1-2),
and NO2 exposures between 200 and 300 ppb for 30 minutes or
100 ppb for 60-minutes can result in small, but significant, increases
in nonspecific airway responsiveness (ISA, section <IP_ADDRESS>); (2)
limited evidence indicates that NO2 may increase
susceptibility to injury by subsequent viral challenge following
exposures of 600-1500 ppb for 3 hours; (3) evidence exists for
increased airway inflammation at NO2 concentrations less
than 2000 ppb; and (4) the direct effects of NO2 on lung
function in asthmatics have been inconsistent at exposure
concentrations below 1000 ppb (ISA, section <IP_ADDRESS>). Therefore, of the
health effects caused by NO2 in controlled human exposure
studies, the only effect identified by the ISA to occur at or near
ambient levels is increased airway responsiveness in asthmatics.
    The REA concluded that airway responsiveness in the asthmatic
population is an appropriate focus for the risk characterization for
several reasons. First, the ISA concluded that ``persons with
preexisting pulmonary conditions are likely at greater risk from
ambient NO2 exposures than the general public, with the most
extensive evidence available for asthmatics as a potentially
susceptible group'' (ISA, section <IP_ADDRESS>). Second, when discussing the
clinical significance of NO2-related airway
hyperresponsiveness in asthmatics, the ISA concluded that ``transient
increases in airway responsiveness following NO2 exposure
have the potential to increase symptoms and worsen asthma control''
(ISA, sections 3.1.3 and 5.4). That this effect could have public
health implications is suggested by the large size of the asthmatic
population in the United States (ISA, Table 4.4-1). Third,
NO2 effects on airway responsiveness in asthmatics are part
of the body of experimental evidence that provides plausibility and
coherence for the effects observed on hospital admissions and emergency
department visits in epidemiologic studies (ISA, section <IP_ADDRESS>). As a
result of these considerations, of the endpoints from controlled human
exposure studies, the REA focused on airway responsiveness in
asthmatics for purposes of quantifying risks associated with ambient
NO2 (see below).
    Because many of the studies of airway responsiveness evaluated only
a single level of NO2 and because of methodological
differences between the studies, the data are not sufficient to derive
an exposure-response relationship in the range of interest. Therefore,
the REA concluded that the most appropriate approach to characterizing
risks based on the controlled human exposure evidence for airway
responsiveness was to compare estimated NO2 air quality and
exposure levels with potential health effect benchmark levels. In this
review, the term ``exposures of potential concern'' is defined as
personal exposures to 1-hour ambient NO2 concentrations at
and above specific benchmark levels. Benchmark levels represent
NO2 exposure concentrations reported to increase airway
responsiveness in most asthmatics, as discussed above in section
II.B.1.d. Although the analysis of exposures of potential concern was
conducted using discrete benchmark levels (i.e., 100, 150, 200, 250,
300 ppb), EPA recognizes that there is no sharp

breakpoint within the continuum ranging from at and above 300 ppb down
to 100 ppb. In considering the concept of exposures of potential
concern, it is important to balance concerns about the potential for
health effects and their severity with the increasing uncertainty
associated with our understanding of the likelihood of such effects at
lower NO2 levels. Within the context of this continuum,
estimates of exposures of potential concern at discrete benchmark
levels provide some perspective on the potential public health impacts
of NO2-related health effects that have been demonstrated in
controlled human exposure studies but cannot be evaluated in
quantitative risk assessments (i.e., increased airway responsiveness).
They also help in understanding the extent to which such impacts could
change by just meeting the current and potential alternative standards.
    The NO2-related increase in airway responsiveness is
plausibly linked to the NO2-associated morbidity reported in
epidemiologic studies (e.g., increased respiratory symptoms, emergency
department visits and hospital admissions). However, estimates of the
number of asthmatics likely to experience exposures of potential
concern cannot be translated directly into quantitative estimates of
the number of people likely to experience specific health effects,
since sufficient information to draw such comparisons is not available.
Due to individual variability in responsiveness, only a subset of
asthmatics exposed at and above a specific benchmark level can be
expected to experience health effects. The amount of weight to place on
the estimates of exposures of potential concern at any of these
benchmark levels depends in part on the weight of the scientific
evidence concerning health effects associated with NO2
exposures at and above that benchmark level. It also depends on
judgments about the importance from a public health perspective of the
health effects that are known or can reasonably be inferred to occur as
a result of exposures at and above the benchmark level. Such public
health policy judgments are embodied in the NAAQS standard setting
criteria (i.e., standards that, in the judgment of the Administrator,
are requisite to protect public health with an adequate margin of
safety).
2. Overview of Approaches
    As noted above, the purpose of the assessments described in the REA
was to characterize air quality, exposures, and health risks associated
with recent ambient levels of NO2, with NO2
levels that could be associated with just meeting the current
NO2 NAAQS, and with NO2 levels that could be
associated with just meeting potential alternative standards. To
characterize health risks, we employed three approaches in the REA. In
the first approach, for each air quality scenario, NO2
concentrations at fixed-site monitors and simulated concentrations on/
near roadways were compared to potential health effect benchmark values
derived from the controlled human exposure literature. In the second
approach, modeled estimates of actual exposures in asthmatics were
compared to potential health effect benchmarks. In the third approach,
concentration-response relationships from an epidemiologic study were
used in conjunction with baseline incidence data and recent or
simulated ambient concentrations to estimate health impacts. An
overview of the approaches to characterizing health risks is provided
below and each approach has been described in more detail in the REA
(chapters 6 through 9).
    In the first approach, we compared ambient NO2
concentrations with potential health effect benchmark levels for
NO2. The ambient NO2 concentrations used in these
analyses were based on those measured at monitors in the current
NO2 monitoring network. These monitored concentrations were
compared to benchmark levels directly and were also used, in
conjunction with literature-derived characterizations of the
NO2 concentration gradient around roadways, as the basis for
estimating NO2 concentrations on/near roadways. Scenario-
driven air quality analyses were performed using ambient NO2
concentrations for the years 1995 though 2006. With this approach,
NO2 air quality serves as a surrogate for exposure. All U.S.
monitoring sites where NO2 data have been collected, and
that met completeness criteria (REA, chapter 7), were represented by
this analysis. As such, the results generated were considered a broad
characterization of national air quality and human exposures that might
be associated with these concentrations. An advantage of this approach
is its relative simplicity; however, there is uncertainty associated
with the assumption that NO2 air quality can serve as an
adequate surrogate for total exposure to ambient NO2. Actual
exposures might be influenced by factors not considered by this
approach, including small scale spatial variability in ambient
NO2 concentrations (which might not be captured by the
network of fixed-site ambient monitors) and spatial/temporal
variability in human activity patterns.
    In the second approach, we used an inhalation exposure model to
generate more realistic estimates of personal exposures in asthmatics
(REA, chapter 8 for more detail on this assessment). This analysis
estimated temporally and spatially variable ambient NO2
concentrations and simulated human contact with these pollutant
concentrations. The approach was designed to incorporate exposures that
are not necessarily captured by the existing ambient monitoring data,
including those that occur on or near roadways. AERMOD, an EPA
dispersion model, was used to estimate 1-hour ambient NO2
concentrations using emissions estimates from stationary and on-road
mobile sources.\9\ The Air Pollutants Exposure (APEX) model, an EPA
human exposure model, was then used to estimate population exposures
using the hourly census block level NO2 concentrations
estimated by AERMOD. A probabilistic approach was used to model
individual exposures considering the time people spend in different
microenvironments and the variable NO2 concentrations that
occur within these microenvironments across time, space, and
microenvironment type. Estimates of personal exposure were compared to
potential NO2 health benchmark levels. This approach to
assessing exposures was more resource intensive than using ambient
levels as a surrogate for exposure; therefore, the final REA included
the analysis of only one specific location in the U.S. (Atlanta MSA).
Although the geographic scope of this analysis was restricted, the
approach provided estimates of NO2 exposures in asthmatics
in Atlanta, particularly those exposures associated with important
emission sources of NOX, and the analysis served to
complement the broad air quality characterization.
---------------------------------------------------------------------------

    \9\ Estimated emissions from Hartsfield International Airport in
Atlanta, a non-road mobile source, were also included in this
analysis.
---------------------------------------------------------------------------

    For the characterization of risks in both the air quality analysis
and the exposure modeling analysis described above, the REA used a
range of short-term potential health effect benchmarks. As noted above,
the levels of potential benchmarks are based on NO2 exposure
levels that have been associated with increased airway responsiveness
in asthmatics in controlled human exposure studies (ISA, section
<IP_ADDRESS>). Benchmark values of 100, 150, 200, 250, and 300 ppb were
compared to both NO2 air quality levels and to estimates of
NO2 exposure in asthmatics. When

NO2 air quality was used as a surrogate for exposure, the
output of the analysis was an estimate of the number of times per year
specific locations experience 1-hour levels of NO2 that
exceed a particular benchmark. When personal exposures were simulated,
the output of the analysis was an estimate of the number of asthmatics
at risk for experiencing daily maximum 1-hour levels of NO2
of ambient origin that exceed a particular benchmark. An advantage of
using the benchmark approach to characterize health risks is that the
effects observed in controlled human exposure studies clearly result
from NO2 exposure. A disadvantage of this approach is that
the magnitude of the NO2 effect on airway responsiveness can
vary considerably from individual to individual and not all asthmatics
would be expected to respond to the same levels of NO2
exposure. Therefore, the public health impacts of NO2-
induced airway hyperresponsiveness are difficult to quantify.
    In the third approach, we estimated respiratory emergency
department visits as a function of ambient levels of NO2
measured at a fixed-site monitor representing ambient air quality for
an urban area. In this approach, concentration-response functions from
an epidemiologic study (Tolbert et al., 2007) were used, in combination
with baseline incidence data for respiratory emergency department
visits in the Atlanta area and ambient NO2 monitoring data,
to estimate the impact on emergency department visits of ambient levels
of NO2. Compared to the risk characterization based on the
air quality and exposure analyses described above, this approach to
characterizing health risks has several advantages. For example, the
public health significance of respiratory emergency department visits
is less ambiguous, in terms of its impact on individuals, than is an
increase of unknown magnitude in the airway response. In addition, the
concentration-response relationship reflects real-world levels of
NO2 and co-pollutants present in ambient air. However, as
noted previously, a disadvantage of this approach is the ambiguity and
complexity associated with quantifying the contribution of
NO2 to emergency department visits relative to the
contributions of co-occurring pollutants.
3. Key Limitations and Uncertainties
    A number of key uncertainties should be considered when
interpreting the results of these analyses. While the air quality,
exposure, and quantitative risk analyses are each associated with
unique uncertainties, they also share some uncertainties in common.
Important uncertainties shared by these analyses, as well as
uncertainties specifically associated with the air quality, exposure,
and risk analyses, are discussed below.
    In order to simulate just meeting the current annual standard and
many of the alternative 1-hour standards analyzed, an adjustment
(either upward or downward) of recent ambient NO2
concentrations was required. As noted in the REA, an upward adjustment
does not reflect a judgment that levels of NO2 are likely to
increase across the country or in any specific location under the
current standard or any of the potential alternative standards.
However, it does acknowledge that, under the current standard and some
of the alternative standards evaluated, an increase in NO2
concentrations would be permitted. The benefit of these air quality
adjustments is that they can inform consideration of the current and
alternative standards by providing estimates of health risks that could
be associated with ambient air quality levels that just meet these
standards. In adjusting air quality to simulate just meeting these
standards, the analyses in the REA assumed that the overall shape of
the distribution of NO2 concentrations in an area would not
change. While the REA concluded that this is a reasonable assumption in
the absence of evidence supporting a different distribution, and while
available analyses support this approach (Rizzo, 2008), the REA
recognized this as an important uncertainty. It may be an especially
important uncertainty for those scenarios where considerable adjustment
is required to simulate just meeting one or more of the standards (REA,
section 8.12).
    In addition, simulation of just meeting different alternative
standards was achieved by adjusting NO2 concentrations at
monitors in the current area-wide network. Therefore, resulting
estimates of the potential public health implications of different
decisions are most directly relevant to a standard focused specifically
on the area-wide NO2 concentrations that are the primary
target of the current monitoring network. However, as discussed below
(sections II.F.4.e and III), with this notice the Administrator is
proposing to establish a standard focused specifically on the peak
concentrations to which individuals can be exposed from on-road mobile
source emissions on or near major roadways and to support such a
standard with a monitoring network that includes monitors placed near
major roadways. This proposed shift in the monitoring network
introduces uncertainty in the extent to which the exposure and risk
analyses presented in the REA can directly inform decisions on the
proposed standard.
    In addition to the general uncertainties discussed above, some
uncertainties are specific to the air quality analyses. In order to
estimate ambient NO2 concentrations on or near roadways in
the air quality analyses, the REA used empirically-derived
relationships between ambient concentrations measured at fixed-site
monitors in the current NO2 monitoring network and on/near-
road concentrations. The data used to develop the relationships were
likely collected under different conditions (e.g., different
meteorological conditions which can affect important parameters in this
relationship, such as the production of NO2 from NO). The
REA noted that the extent to which these conditions are representative
of the times and places included in our analyses is unknown. Therefore,
there is uncertainty in the degree to which the relationships used to
estimate on/near-road NO2 concentrations reflect the actual
relationship in the locations and over the time periods of interest.
    Potential health benchmark levels used in the air quality analyses
were based largely on a meta-analysis (ISA, Table 3.1-3) of controlled
human exposure studies of airway hyperresponsiveness. One important
source of uncertainty with regard to this approach is that controlled
human exposure studies have typically involved volunteers with mild
asthma. Data are lacking for more severely affected asthmatics, who may
be more susceptible (ISA, section <IP_ADDRESS>). As a result, the potential
health effect benchmarks could underestimate risks in populations with
greater susceptibility. While approaches to classifying asthma severity
differ, some estimates indicate that over half of asthmatics could be
classified as moderate or severe (Fuhlbrigge et al., 2002; Stout et
al., 2006). A second important source of uncertainty with regard to
this approach is that the meta-analysis showed increased airway
responsiveness in asthmatics at the lowest NO2 level for
which data were available (i.e. 100 ppb). Controlled human exposure
studies have not evaluated the possibility of NO2 effects on
airway responsiveness in asthmatics at exposure concentrations below
100 ppb. A third important source of uncertainty associated with this
approach is that the meta-analysis provided information on the
direction of the NO2-induced airway response, but not on the
magnitude of the response.

Therefore, although the ISA did conclude that increased airway
responsiveness associated with NO2 exposure could increase
symptoms and worsen asthma control (ISA, section 5.4), the full public
health implications of benchmark exceedances are uncertain.
    The Atlanta exposure assessment was also associated with a number
of key uncertainties that should be considered when interpreting the
results with regard to decisions on the standard. Some of these
uncertainties, including those associated with benchmark levels, were
shared with the air quality analyses. Additional uncertainties
associated specifically with the Atlanta exposure assessment are
discussed briefly below.
    When compared to ambient measurement data, predicted upper
percentile NO2 concentrations may be 10-50% higher. Because
these predicted concentrations are used as inputs for the exposure
modeling, this suggests the possibility that the exposure assessment is
over-predicting upper percentile NO2 exposures. Other
approaches used to evaluate exposure results (i.e., comparison to
personal exposure monitoring results and comparison of exposure-to-
ambient concentration ratios with those identified in the ISA) have
suggested that exposure estimates are reasonable. However, the
possibility cannot be ruled out that benchmark exceedances are over-
predicted in the Atlanta exposure analysis.
    The exposure assessment was limited to Atlanta and the extent to
which these results are representative of other locations in the U.S.
is uncertain. The REA (section 8.11) concluded that the Atlanta
exposure estimates are likely representative of other moderate to large
urban areas. However, the REA also recognized that, given the greater
proximity of the population to mobile sources in large urban areas such
as Los Angeles, New York, and Chicago (see REA, Tables 8-14 and 8-15),
the estimates of benchmark exceedances in Atlanta may be smaller than
in these larger cities.
    A number of key uncertainties should also be considered when
interpreting the results of the Atlanta risk assessment with regard to
decisions on the standard. Some of these, including the appropriateness
of generalizing results from Atlanta, are shared with the Atlanta
exposure assessment. Additional uncertainties associated specifically
with the Atlanta risk assessment are discussed briefly below.
    There is uncertainty about whether the association between
NO2 and emergency department visits actually reflects a
causal relationship across the range of daily and hourly concentration
levels in the epidemiologic studies. The ISA (section 5.4, p. 5-15)
noted that when interpreting the NO2 epidemiologic results,
``It is difficult to determine * * * the extent to which NO2
is independently associated with respiratory effects or if
NO2 is a marker for the effects of another traffic-related
pollutant or mix of pollutants (see section 5.2.2 for more details on
exposure issues). A factor contributing to uncertainty in estimating
the NO2-related effect from epidemiologic studies is that
NO2 is a component of a complex air pollution mixture from
traffic related sources that include CO and various forms of PM.'' This
uncertainty should be considered when interpreting the quantitative
NO2 risk estimates based on the Atlanta epidemiologic study.
However, in discussing these uncertainties, the ISA (section 5.4, p. 5-
16) concluded that, ``Although this complicates the efforts to
disentangle specific NO2-related health effects, the
evidence summarized in this assessment indicates that NO2
associations generally remain robust in multi-pollutant models and
supports a direct effect of short-term NO2 exposure on