^
Integrated Review Plan for the
Primary National Ambient Air Quality
Standards for Nitrogen Dioxide
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EPA-452/R-14-003
June 2014
Integrated Review Plan for the
Primary National Ambient Air Quality
Standards for Nitrogen Dioxide
U. S. Environmental Protection Agency
National Center for Environmental Assessment
Office of Research and Development
and
Office of Air Quality Planning and Standards
Health and Environmental Impacts Division
Research Triangle Park, North Carolina
June 2014
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DISCLAIMER
This integrated review plan serves as a public information document and as a management tool
for the U.S. Environmental Protection Agency's National Center for Environmental Assessment
and Office of Air Quality Planning and Standards in conducting the review of the national
ambient air quality standards for nitrogen dioxide. The approach described in this plan may be
modified to reflect information developed during this review, and in consideration of advice and
comments received from the Clean Air Scientific Advisory Committee and the public during the
course of the review. Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
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TABLE OF CONTENTS
Table of Contents i
List of Figures ii
List of Tables ii
LIST OF ACRONYMS/ABBREVIATIONS iii
1 INTRODUCTION 1-1
1.1 LEGISLATIVE REQUIREMENTS 1-1
1.2 OVERVIEW OF THE NAAQS REVIEW PROCESS 1-3
1.3 REVIEW OF AIR QUALITY CRITERIA FOR OXIDES OF NITROGEN AND
STANDARDS FOR NITROGEN DIOXIDE 1-7
1.4 SCOPE OF THE CURRENT REVIEW 1-11
2 STATUS AND SCHEDULE 2-1
3 KEY POLICY-RELEVANT ISSUES 3-1
3.1 CONSIDERATIONS AND CONCLUSIONS IN LAST REVIEW 3-1
3.1.1 Need for Revision 3-2
3.1.2 Elements of Revised Standard 3-6
3.1.2.1 Indicator 3-6
3.1.2.2 Averaging Times 3-6
3.1.2.3 Levels 3-8
3.1.2.4 Forms 3-10
3.1.3 Areas of Uncertainty 3-11
3.2 GENERAL APPROACH FOR THE CURRENT REVIEW 3-11
4 SCIENCE ASSESSMENT 4-1
4.1 SCOPE OF THE ISA 4-1
4.2 ORGANIZATION OF THE ISA 4-2
4.3 ASSESSMENT APPROACH 4-3
4.3.1 Introduction 4-3
4.3.2 Literature Search and Selection of Relevant Studies 4-5
4.3.3 Evaluation of Individual Study Quality 4-6
4.3.4 Integration of Evidence and Determination of Causality 4-10
4.3.5 Quality Management 4-11
4.4 SPECIFIC ISSUES TO BE ADDRESSED IN THE ISA 4-11
4.5 SCIENTIFIC AND PUBLIC REVIEW OF THE ISA 4-24
5 QUANTITATIVE RISK AND EXPOSURE ASSESSMENT 5-1
5.1 OVERVIEW OF RISK AND EXPOSURE ASSESSMENT FROM PRIOR REVIEW
5-2
5.1.1 Ambient Air Quality Characterization 5-2
5.1.1.1 Key Observations 5-5
5.1.1.2 Key Uncertainties 5-7
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5.1.2 Human Exposure Assessment 5-7
5.1.2.1 Key Observations 5-8
5.1.2.2 Key Uncertainties 5-9
5.1.3 Epidemiological-based Human Health Risk Assessment 5-10
5.1.3.1 Key Observations 5-11
5.1.3.2 Key Uncertainties 5-11
5.2 CONSIDERATION OF QUANTITATIVE ASSESSMENTS FOR THIS REVIEW
5-12
5.2.1 Air Quality Characterization 5-12
5.2.2 Human Exposure Assessment 5-16
5.2.3 Controlled Exposure-based Human Health Risk Assessment 5-19
5.2.4 Epidemiological-based Human Health Risk Assessment 5-19
5.3 SCIENTIFIC AND PUBLIC REVIEW 5-20
6 AMBIENT AIR MONITORING 6-1
6.1 CONSIDERATION OF SAMPLING AND ANALYSIS METHODS 6-1
6.2 CONSIDERATION OF AIR MONITORING NETWORK REQUIREMENTS 6-2
7 POLICY ASSESSMENT AND RULEMAKING 7-1
7.1 POLICY ASSESSMENT 7-1
7.2 RULEMAKING 7-2
8 REFERENCES 8-1
APPENDICES
Appendix A: Draft Outline for Integrated Science Assessment for Oxides of Nitrogen - Health
Criteria A-1
LIST OF FIGURES
Figure 1-1. Overview of theNAAQS Review Process 1-4
Figure 3-1. Overview of General Approach for Review of Primary NO2 Standards 3-13
Figure 4-1. General Process for Development of Integrated Science Assessments 4-4
Figure 6-1. NO2 Monitoring Network: Active Monitors as of September 2013 6-5
LIST OF TABLES
Table 1-1. Primary national ambient air quality standards for oxides of nitrogen since 1971.... 1-8
Table 2-1. Anticipated schedule for the current review 2-3
Table 5-1. Information (data, methods, models, etc.) identified as potentially important
and/or newly available to inform the air quality characterization for the current
review 5-13
Table 5-2. Information (data, methods, models, etc.) identified as potentially important
and/or newly available to inform the exposure assessment for the current
review 5-17
Table 5-3. Information (data, methods, models, etc.) identified as potentially important
and/or newly available to inform the epidemiological-based risk assessment
for the current review 5-20
ii
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LIST OF ACRONYMS/ABBREVIATIONS
AADT
AERMOD
ANPR
APEX
AQI
AQS
CAA
CAPS
CASAC
CBS A
CFR
CO
C-R
EPA
E-R
FEM
FEVi
FR
FRM
HA
HERO
HONO
HNO3
IRP
ISA
|ig/m3
m
ME
MSA
NAAQS
NCEA
NCore
NO
NO2
NO3-
NOx
NOY
NOz
O3
OAQPS
OAR
Annual Average Daily Traffic
EPA's Air Dispersion Model
Advanced notice of proposed rulemaking
EPA's Air Pollutants Exposure model
Air Quality Index
EPA's Air Quality System
Clean Air Act
Cavity attenuated phase shift
Clean Air Scientific Advisory Committee
Core Based Statistical Area
Code of Federal Regulations
Carbon monoxide
Concentration-response
Environmental Protection Agency
Exposure-response
Federal Equivalent Method
Forced expiratory volume in one second, volume of air exhaled in first
second of exhalation
Federal Register
Federal Reference Method
Hospital admissions
Health and Environmental Research Online
Nitrous acid
Nitric acid
Integrated Review Plan
Integrated Science Assessment
micrograms per cubic meter
Meters
Microenvironmental
Metropolitan Statistical Area
National Ambient Air Quality Standards
National Center for Environmental Assessment
National Core Monitoring Network
Nitric oxide
Nitrogen dioxide
Nitrate
NO+NO2
Total oxides of nitrogen (NOx + NOz)
Reactive oxides of nitrogen (e.g., HNOs, HONO, PAN, particulate
nitrates)
Ozone
Office of Air Quality Planning and Standards
Office of Air and Radiation
in
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OMB Office of Management and Budget
ORD Office of Research and Development
PA Policy Assessment
PAN Peroxyacetyl nitrate
PM Particulate matter
PM2.5 In general terms, particulate matter with an aerodynamic diameter less
than or equal to a nominal 2.5 microns (|im); a measurement of fine
particles
ppb Parts per billion
ppm Parts per million
QA Quality assurance
QMP Quality Management Plan
RE A Risk and Exposure Assessment
RIA Regulatory Impact Analysis
RTF Research Triangle Park
SES Socioeconomic status
SO2 Sulfur dioxide
TBD To be determined
IV
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1 INTRODUCTION
The U.S. Environmental Protection Agency (EPA) is conducting a review of the primary
(health-based) national ambient air quality standards (NAAQS) for nitrogen dioxide (NCh). This
Integrated Review Plan (IRP) presents the planned approach for the review. This review will
provide an integrative assessment of relevant scientific information for oxides of nitrogen and
will focus on the basic elements that define the NAAQS: the indicator,1 averaging time,2 form,3
and level.4 The EPA Administrator will consider these elements collectively in evaluating the
protection to public health afforded by the primary NCh standards.
This document is organized into eight chapters. Chapter 1 summarizes the legislative
requirements for the review of the NAAQS (section 1.1), summarizes the review process (section
1.2), provides an overview of past reviews of the primary NCh NAAQS (section 1.3), and
outlines the scope of the current review (section 1.4). Chapter 2 presents the status and schedule
for the current review. Chapter 3 provides background on the key issues and uncertainties that
informed the final decisions in the last review and presents a set of policy-relevant questions that
will serve to focus this review on the critical scientific and policy issues. Chapters 4 through 7
discuss the planned scope and organization of key assessment documents, the planned
approaches for preparing the documents, plans for scientific and public review of the documents,
and specific ambient air quality monitoring considerations. Complete reference citations are
provided in Chapter 8.
1.1 LEGISLATIVE REQUIREMENTS
Two sections of the Clean Air Act (CAA) govern the establishment, review, and revision
of the NAAQS. Section 108 (42 U.S.C. 7408) directs the Administrator to identify and list
certain air pollutants and then to issue air quality criteria for those pollutants. The Administrator
is to list those air pollutants that in her "judgment, cause or contribute to air pollution which may
reasonably be anticipated to endanger public health or welfare;" "the presence of which in the
ambient air results from numerous or diverse mobile or stationary sources;" and "for which . . .
1 The "indicator" of a standard defines the chemical species or mixture that is measured in determining
whether an area attains the standard. Nitrogen dioxide (NCh) is the indicator for the oxides of nitrogen.
2 The "averaging time" defines the time period over which ambient measurements are averaged (e.g.,
1-hour, 8-hour, 24-hour, annual).
3 The "form" of a standard defines the air quality statistic that is compared to the level of the standard in
determining whether an area attains the standard. For example, the form of the current 1-hour NCh standard is the
three-year average of the 98th percentile of the annual distribution of 1-hour daily maximum NCh concentrations.
4 The "level" defines the allowable concentration of the criteria pollutant in the ambient air.
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[the Administrator] plans to issue air quality criteria..." Air quality criteria are intended to
"accurately reflect the latest scientific knowledge useful in indicating the kind and extent of all
identifiable effects on public health or welfare which may be expected from the presence of [a]
pollutant in the ambient air . . ." 42 U.S.C. 7408(b). Section 109 (42 U.S.C. 7409) directs the
Administrator to propose and promulgate "primary" and "secondary" NAAQS for pollutants for
which air quality criteria are issued.5 Section 109(b)(l) defines a primary standard as one "the
attainment and maintenance of which in the judgment of the Administrator, based on such
criteria and allowing an adequate margin of safety, are requisite to protect the public health."6 A
secondary standard, as defined in section 109(b)(2), must "specify a level of air quality the
attainment and maintenance of which, in the judgment of the Administrator, based on such
criteria, is requisite to protect the public welfare from any known or anticipated adverse effects
associated with the presence of [the] pollutant in the ambient air."7
The requirement that primary standards provide an adequate margin of safety was
intended to address uncertainties associated with inconclusive scientific and technical
information available at the time of standard setting. It was also intended to provide a reasonable
degree of protection against hazards that research has not yet identified.8 Both kinds of
uncertainties are components of the risk associated with pollution at levels below those at which
human health effects can be said to occur with reasonable scientific certainty. Thus, in selecting
primary standards that provide an adequate margin of safety, the Administrator is seeking not
only to prevent pollution levels that have been demonstrated to be harmful but also to prevent
lower pollutant levels that may pose an unacceptable risk of harm, even if the risk is not
precisely identified as to nature or degree. The CAA does not require the Administrator to
establish a primary NAAQS at a zero-risk level or at background concentration levels, but rather
5 As discussed in section 1.4 below, this document describes the review of the primary NCh standards. The
secondary NO2 standard will be separately reviewed in conjunction with review of the secondary sulfur dioxide
(SO2) standard.
6The 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).
7 Welfare effects as defined in section 302(h) (42 U.S.C. 7602(h)) include, but are not limited to, "effects
on soils, water, crops, vegetation, man-made materials, animals, wildlife, weather, visibility and climate, damage to
and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal
comfort and well-being."
8 See Lead Industries Association v. EPA, 647 F.2d 1130, 1154 (D.C. Cir 1980); American Petroleum
Institute v. Costle, 665 F.2d 1176, 1186 (D.C. Cir. 1981); American Farm Bureau Federation v. EPA, 559 F. 3d 512,
533 (D.C. Cir. 2009); wA Association of Battery Recyclers v. EPA, 604 F. 3d 613, 617-18 (D.C. Cir. 2010).
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at a level that reduces risk sufficiently so as to protect public health with an adequate margin of
safety.9
In addressing the requirement for an adequate margin of safety, the EPA considers such
factors as the nature and severity of the health effects involved, the size of the sensitive group(s),
and the kind and degree of uncertainties. The selection of any particular approach to providing an
adequate margin of safety is a policy choice left specifically to the Administrator's judgment.10
In setting standards that are "requisite" to protect public health and welfare, as provided
in section 109(b), the EPA's task is to establish standards that are neither more nor less stringent
than necessary for these purposes. In so doing, the EPA may not consider the costs of
implementing the standards.11 Likewise, "[attainability and technological feasibility are not
relevant considerations in the promulgation of national ambient air quality standards."12
Section 109(d)(l) requires that "not later than December 31, 1980, and at 5-year intervals
thereafter, the Administrator shall complete a thorough review of the criteria published under
section 108 and the national ambient air quality standards . . . and shall make such revisions in
such criteria and standards and promulgate such new standards as may be appropriate ..."
Section 109(d)(2) requires that an independent scientific review committee "shall complete a
review of the criteria . . . and the national primary and secondary ambient air quality standards. . .
and shall recommend to the Administrator any new . . . standards and revisions of existing
criteria and standards as may be appropriate . . . ." Since the early 1980s, this independent review
function has been performed by the Clean Air Scientific Advisory Committee (CASAC).13
1.2 OVERVIEW OF THE NAAQS REVIEW PROCESS
The current process for reviewing the NAAQS includes four major phases: (1) planning,
(2) science assessment, (3) risk/exposure assessment, and (4) policy assessment and rulemaking.
Figure 1-1 provides an overview of this process, and each phase is described in more detail
9 See Lead Industries v. EPA, 647 F.2d at 1156 n.5l,_Mississippi v. EPA, 723 F. 3d 246, 255, 262-63 (D.C.
Cir. 2013).
10 See Lead Industries Association v. EPA, 647 F.2d at 1161-62; Mississippi v. EPA, 723 F. 3d at 265.
11 See generally, Whitman v. American Trucking Associations, 531 U.S. 457, 465-472, 475-76 (2001).
12 See American Petroleum Institute v. Costle, 665 F. 2d at 1185.
13 Lists of CAS AC members and of members of the CAS AC Oxides of Nitrogen Primary NAAQS Review
Panel are available at:
http://vosemite.epa.gov/sab/sabproduct.nsfAVebCASAC/CommitteesandMembership7OpenDocument.
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Workshop on
science-policy
issues
Peer-reviewed
scientific studies
Integrated Review Plan (IRP): timeline and key
policy-relevant issues and scientific questions
EPA
proposed
decisions on
standards
Integrated Science Assessment (ISA): evaluation and
synthesis of most policy-relevant studies
I
Risk/Exposure Assessment (REA):
quantitative assessment, as warranted,
focused on key results, observations, and
uncertainties
Policy Assessment (PA): staff analysis of
policy options based on integration and
interpretation of information in the ISA and
REA
Agency decision
making and draft
proposal notice
Clean Air Scientific
Advisory Committee
(CASAC) review
Public comment
Public hearings
and comments
on proposal
Agency decision
making and draft
final notice
PA final
decisions on
standards
Figure 1-1. Overview of the NAAQS review process.
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below.14 The planning phase of the NAAQS review process begins with a science policy
workshop, which is intended to identify issues and questions to frame the review. Drawing from
the workshop discussions, a draft IRP is prepared jointly by the EPA's National Center for
Environmental Assessment (NCEA), within the Office of Research and Development (ORD),
and the EPA's Office of Air Quality Planning and Standards (OAQPS), within the Office of Air
and Radiation (OAR).15 The draft IRP is made available for CAS AC review and for public
comment. The final IRP is prepared in consideration of CASAC and public comments. This
document presents the current plan and specifies the schedule for the entire review, the process
for conducting the review, and the key policy-relevant science issues that will guide the review.
The second phase of the review, science assessment, involves the preparation of an
Integrated Science Assessment (ISA) and, if appropriate, supplementary materials. The ISA,
prepared by NCEA, provides a concise review, synthesis, and evaluation of the most policy-
relevant science, including key science judgments that are important to the design and scope of
exposure and risk assessments, as well as other aspects of the NAAQS review. The ISA (and any
supplementary materials that may be developed) provides a comprehensive assessment of the
current scientific literature pertaining to known and anticipated effects on public health and
welfare associated with the presence of the pollutant in the ambient air, emphasizing information
that has become available since the last air quality criteria review in order to reflect the current
state of knowledge. As such, the ISA forms the scientific foundation for each NAAQS review
and is intended to provide information useful in forming judgments about air quality indicator(s),
form(s), averaging time(s) and level(s) for the NAAQS. The current review process generally
includes production of a first and second draft ISA, both of which undergo CASAC and public
review prior to completion of the final ISA. Chapter 4 below provides a more detailed
description of the planned scope, organization, and assessment approach for the ISA and any
supporting materials that may be developed.
14The EPA maintains a website on which key documents developed for NAAQS reviews are made
available (http://www.epa.gov/ttn/naaqs/). The EPA's NAAQS review process has evolved overtime (Jackson,
2009). Information on the current process is available at: http://www.epa.gov/ttn/naaqs/review.html. As discussed in
section 1.3 below, this process was generally followed in the primary NCh NAAQS review completed in 2010 with
the exception that there was not a separate Policy Assessment document issued. Rather, the Risk and Exposure
Assessment (U.S. EPA, 2008b) included a policy assessment chapter (i.e., Chapter 10).
15In this review of the primary NAAQS for NC>2, a draft plan for development of the ISA was prepared by
NCEA prior to development of this draft IRP. The draft plan for development of the ISA was made available for
public comment and was the subject of a consultation with CASAC (78 FR 26026; 78 FR 27234). Comments
received during that consultation have been considered in preparation of chapter 4 in this draft IRP. Further
comments received on this draft IRP will be considered in developing a final IRP and a second draft ISA.
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In the third phase, the risk/exposure assessment phase, OAQPS staff considers
information and conclusions presented in the ISA, with regard to support provided for the
development of quantitative assessments of the risks and/or exposures for health and/or welfare
effects. As an initial step, staff prepares a planning document (REA Planning Document) that
considers the extent to which newly available scientific evidence and tools/methodologies
warrant the conduct of quantitative risk and exposure assessments. As discussed in Chapter 5
below, the REA Planning Document focuses on the degree to which important uncertainties in
the last review may be addressed by new information available in this review. Specifically, the
document considers the extent to which newly available data, methods, and tools might be
expected to appreciably affect the assessment results or address important gaps in our
understanding of the exposures and risks associated with NCh. To the extent warranted, this
document outlines a general plan, including scope and methods, for conducting assessments. The
REA Planning Document is generally prepared in conjunction with the first draft ISA16 and is
presented for consultation with CASAC and for public comment. When an assessment is
performed, one or more drafts of each risk and exposure assessment document (REA) undergoes
CASAC and public review. The REA provides concise presentations of methods, key results,
observations, and related uncertainties. Chapter 5 below discusses consideration of potential
quantitative human health-related assessments for this review.
The review process ends with the policy assessment and rulemaking phase. The Policy
Assessment (PA) is prepared prior to issuance of proposed and final rules. The PA provides a
transparent presentation of OAQPS staff analyses and conclusions regarding the adequacy of the
current standards and, if revision is considered, what revisions may be appropriate. The PA
integrates and interprets the information from the ISA and REA to frame policy options for
consideration by the Administrator. Such an evaluation of policy implications is intended to help
"bridge the gap" between the Agency's scientific assessments, presented in the ISA and
REA(s), and the judgments required of the EPA Administrator in determining whether it is
appropriate to retain or revise the NAAQS. In so doing, the PA is also intended to facilitate
CASAC's advice to the Agency and recommendations to the Administrator on the adequacy of
the existing standards and, as pertinent, on revisions that may be appropriate to consider, as
provided for in the CAA. In evaluating the adequacy of the current standards and, as appropriate,
a range of potential alternative standards, the PA considers the available scientific evidence and,
as available, quantitative risk and exposure analyses together with related limitations and
uncertainties. The PA focuses on the information that is most pertinent to evaluating the basic
16The current review of the primary NO2 standards is an exception to this general schedule. As indicated in
Table 2-1 below, the draft REA Planning Document will be made available for public comment and consultation
with CASAC at approximately the same time as the CASAC review of the second draft ISA.
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elements of national ambient air quality standards: indicator, averaging time, form, and level.
One or more drafts of a PA are released for CAS AC review and public comment prior to
completion of the final PA.
Following issuance of the final PA and consideration of conclusions presented therein,
the Agency develops and publishes a notice of proposed rulemaking that communicates the
Administrator's proposed decisions regarding the standards review. A draft notice undergoes
interagency review involving other federal agencies prior to publication.17 Materials upon which
the proposed decision is based, including the documents described above, are made available to
the public in the regulatory docket for the review.18 A public comment period, during which
public hearings are generally held, follows publication of the notice of proposed rulemaking.
Taking into account comments received on the proposed rule,19 the Agency develops a final rule
which undergoes interagency review prior to publication to complete the rulemaking process.
Chapter 7 below discusses the development of the PA and the rulemaking steps for this review.
1.3 REVIEW OF AIR QUALITY CRITERIA FOR OXIDES OF
NITROGEN AND STANDARDS FOR NITROGEN DIOXIDE
In 1971, the EPA added nitrogen oxides to the list of criteria pollutants under section
108(a)(l) of the CAA and issued the initial air quality criteria (36 FR 1515, January 30, 1971;
U.S. EPA, 1971). Based on these air quality criteria, the EPA promulgated NAAQS for nitrogen
oxides using NCh as the indicator (36 FR 8186, April 30, 1971). Both primary and secondary
standards were set at 100 micrograms per cubic meter (|ig/m3) (equal to 0.053 parts per million
(ppm)), annual average. Since then, the Agency has completed multiple reviews of the air quality
criteria and primary standards, as summarized in Table 1-1.
17 Where implementation of the proposed decision would have an annual effect on the economy of $100
million or more (e.g., by necessitating the implementation of emissions controls), the EPA develops and releases a
draft regulatory impact analysis (RIA) concurrent with the notice of proposed rulemaking. This activity is conducted
under Executive Order 12866. The RIA is conducted completely independent of the rulemaking process and, by
statute, is not considered in decisions regarding the review of the NAAQS.
18 All documents in the docket are listed in the www.regulations.gov index. Publically available docket
materials are available either electronically at www.regulations.gov or in hard copy at the Air and Radiation Docket
and Information Center. The docket ID number for this review is EPA-HQ-OAR-2013-0146.
19When issuing the final rulemaking, the Agency responds to all significant comments on the proposed rule.
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Table 1-1. Primary national ambient air quality standards for oxides of nitrogen since
1971.
Final
Rule/Decision
Indicator
Averaging
Time
Level
Form
1971
36 FR 8186
Apr 30, 1971
NO2
1 year
53 ppb
20
Annual arithmetic average
1985
50 FR 25532
Jun 19, 1985
Primary annual NCh standard retained, without revision.
1996
61 FR 52852
Oct8, 1996
Primary annual NCh standard retained, without revision.
2010
75 FR 6474
Feb 9, 2010
NO2
1 hour
100 ppb
3-year average of the 98th
percentile of the annual
distribution of daily
maximum 1-hour
concentrations
Primary annual NCh standard retained, without revision.
The EPA retained the primary and secondary NCh standards, without revision, in reviews
completed in 1985 and 1996 (50 FR 25532, June 19, 1985; 61 FR 52852, October 8, 1996). In
the latter of the two decisions, the EPA concluded that "the existing annual primary standard
appears to be both adequate and necessary to protect human health against both long- and short-
term NCh exposures" and that "retaining the existing annual standard is consistent with the
scientific data assessed in the Criteria Document (U.S. EPA, 1993) and the Staff Paper (U.S.
20 The initial standard level of the annual NC>2 standard was 100 ug/m3 which is equal to 0.053 ppm or 53
parts per billion (ppb). The units for the standard level were officially changed to ppb in the final rule issued in 2010
(75 FR 6531, February 9, 2010).
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EPA, 1995) and with the advice and recommendations of CASAC" (61 FR 52854, October 8,
1996).21
The last review of the air quality criteria for oxides of nitrogen (health criteria) and the
primary NCh standard was initiated in December 2005 (70 FR 73236, December 9, 2005).22'23
The Agency's plans for conducting the review were presented in the Integrated Review Plan for
the Primary National Ambient Air Quality Standard for Nitrogen Dioxide (2007 IRP, U.S. EPA,
2007a), which included consideration of comments received during a CASAC consultation as
well as public comment on a draft IRP. The scientific assessment for the review was described in
the 2008 Integrated Science Assessment for Oxides of Nitrogen - Health Criteria (2008 ISA,
U.S. EPA, 2008a), multiple drafts of which received review by CASAC and the public. The EPA
also conducted quantitative human risk and exposure assessments, after consultation with
CASAC and after receiving public comment on an analysis plan (U.S. EPA, 2007b). These
technical analyses were presented in the Risk and Exposure Assessment to Support the Review of
the NO 2 Primary National Ambient Air Quality Standard (2008 REA, U.S. EPA, 2008b),
multiple drafts of which received CASAC and public review.
Over the course of the last review, the EPA made several changes to the NAAQS review
process. An important change was the discontinuation of the Staff Paper, which traditionally
contained staff evaluations to bridge the gap between the Agency's science assessments and the
judgments required of the EPA Administrator in determining whether it was appropriate to retain
or revise the NAAQS.24 In the course of reviewing the second draft REA, however, 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, p.4). In addition, within the period
21 In presenting the rationale for the final decision, the EPA noted that "a 0.053 ppm annual standard would
keep annual NO2 concentrations considerably below the long-term levels for which serious chronic effects have
been observed in animals" and that "[r]etaining the existing standard would also provide protection against short-
term peak NO2 concentrations at the levels associated with mild changes in pulmonary function and airway
responsiveness observed in controlled human [exposure] studies" (61 FR 52854, October 8, 1996; 60 FR 52874,
52880, October 11, 1995).
22Documents related to the current review as well as reviews completed in 2010 and 1996 are available at:
http://www.epa.gOv/ttn/naaqs/standards/nox/s nox index.html.
23The EPA conducted a separate review of the secondary NO2 NAAQS jointly with a review of the
secondary SO2 NAAQS. The Agency retained those secondary standards, without revision, to address the direct
effects on vegetation of exposure to gaseous oxides of nitrogen and sulfur (77 FR 20218, April 3, 2012).
24 Initial changes to the NAAQS review process included a policy assessment document reflecting Agency
(rather than staff) views published as an advanced notice of public rulemaking (ANPR). Under this process, the
ANPR would have been reviewed by CASAC (Peacock, 2006).
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of CASAC's review of the second draft REA, the EPA's Deputy Administrator indicated in a
letter to the CASAC chair, addressing earlier CASAC comments on the NAAQS review process,
that the risk and exposure assessment would 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). Accordingly, the final 2008 REA included a
policy assessment chapter that considered the scientific evidence in the 2008 ISA and the
exposure and risk results presented in other chapters of the 2008 REA as they related to the
adequacy of the then current primary annual NCh standard and potential alternative standards for
consideration (U.S EPA, 2008b, chapter 10).25 CASAC discussed the final version of the 2008
REA, with an emphasis on the policy assessment chapter, during a public teleconference on
December 5, 2008 (73 FR 66895, November 12, 2008). Following that teleconference, CASAC
offered comments and advice on the primary NCh standard in a letter to the Administrator
(Samet, 2008b).
As discussed in more detail in section 3.1 below, after considering an integrative synthesis
of the body of evidence on human health effects associated with the presence of NCh in the air
and the exposure and risk information, the Administrator determined that the existing primary
NCh NAAQS, based on an annual arithmetic average, was not sufficient to protect the public
health from the array of effects that could occur following short-term exposures to ambient NCh.
In so doing, the Administrator particularly noted the potential for adverse health effects to occur
following exposures to elevated NCh concentrations that can occur around major roads (75 FR
6482). In a notice published in the Federal Register on July 15, 2009, the EPA proposed to
supplement the existing primary annual NCh standard by establishing a new short-term standard
(74 FR 34404). In a notice published in the Federal Register on February 9, 2010, the EPA
finalized a new short-term NCh standard with a level of 100 ppb, based on the 3-year average of
the 98th percentile of the annual distribution of daily maximum 1-hour concentrations. The EPA
also retained the existing primary annual NCh standard with a level of 53 ppb, annual average (75
FR 6474). The Agency's final decision included consideration of CASAC (Samet, 2009) and
25 Subsequent to the completion of the 2008 REA, EPA Administrator Jackson called for additional key
changes to the NAAQS review process including reinstating a policy assessment document that contains staff
analysis of the scientific bases for alternative policy options for consideration by senior Agency management prior
to rulemaking (Jackson, 2009). As discussed in Chapter 7 of this document, a Policy Assessment will be developed
for this review.
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public comments on the proposed rule. The EPA's final rule was upheld against challenges in a
decision issued by the U.S. Court of Appeals for the District of Columbia Circuit on July 17,
2012.26
Revisions to the NAAQS were accompanied by revisions to the data handling procedures,
the ambient air monitoring and reporting requirements, and the Air Quality Index (AQI).27 As
described in section 6.2 below, one aspect of the new monitoring network requirements included
requirements for states to locate monitors near heavily trafficked roadways in large urban areas
and in other locations where maximum NCh concentrations can occur. Subsequent to the 2010
rulemaking, the EPA revised the deadlines by which the near-road monitors are to be operational
in order to implement a phased deployment approach (78 FR 16184, March 14, 2013). As
discussed in section 6.2 below, the near-road Mh monitors will become operational between
January 1, 2014 and January 1, 2017.
1.4 SCOPE OF THE CURRENT REVIEW
Consistent with the review completed in 2010, this review will focus on health effects
associated with gaseous oxides of nitrogen and the protection afforded by the primary NCh
standards.28 The gaseous oxides of nitrogen include NCh and nitric oxide (NO) as well as their
gaseous reaction products. Total oxides of nitrogen include these gaseous species as well as
particulate species (e.g., nitrates). Collectively, we refer to the total set of species as NOv (U.S.
EPA, 2013b, section 2.2, Figure 2-1). Health effects associated with the particulate species are
addressed in the review of the NAAQS for particulate matter (PM) (78 FR 30866, January 15,
26 See API v. EPA, 684 F.3d 1342 (D.C. Cir. 2012).
27 The current federal regulatory measurement methods for NCh are specified in 40 CFR part 50, Appendix
F and 40 CFR part 53. Consideration of ambient air measurements with regard to judging attainment of the
standards is specified in 40 CFR part 50, Appendix S. The NCh monitoring network requirements are specified in 40
CFR part 58, Appendix D, section 4.3. The EPA revised the AQI for NCh to be consistent with the revised primary
NO2 NAAQS as specified in 40 CFR part 58 Appendix G. Guidance on the approach for implementation of the new
standard was described in the Federal Register notices for the proposed and final rules (74 FR 34404; 75 FR 6474).
28Section 108(c) of the CAA specifies that the air quality criteria relating to NO2 include consideration of
nitric and nitrous acids, nitrites, nitrates, nitrosamines, and other derivatives of oxides of nitrogen, including
multiple gaseous and particulate species.
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2013; U.S. EPA, 2009).29 The EPA is separately reviewing the welfare effects associated with
oxides of nitrogen and the protection provided by the secondary NCh standard in conjunction
with a review of the secondary SCh standard (78 FR 53452, August 29, 2013).30
When referring to the group of gaseous oxidized nitrogen compounds as a whole, the ISA
and other assessment documents developed in this review will use the term "oxides of nitrogen."
In the last review, the EPA used "NOx" as the abbreviation for oxides of nitrogen. Based on the
definition commonly used in the scientific literature, in this review, the abbreviation NOx will
refer specifically to the sum of NCh and NO concentrations (U.S. EPA, 2013b, section 2.2).
29 Additional information on the PM NAAQS is available at:
http://www.epa.gov/ttn/naaqs/standards/pm/s_pm_index.html.
30 Additional information on the ongoing and previous review of the secondary NO2 and SO2 NAAQS is
available at: http://www.epa.gov/ttn/naaqs/standards/no2so2sec/index.html.
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2 STATUS AND SCHEDULE
In February 2012, the EPA announced the initiation of the current periodic review of the
air quality criteria for oxides of nitrogen and the primary NCh NAAQS and issued a call for
information in the Federal Register (77 FR 7149, February 10, 2012). Also, as an initial step in
the NAAQS review process described in section 1.2 above, the EPA invited a wide range of
scientific experts (from EPA and outside organizations) to participate in a workshop to discuss
the policy-relevant science to inform the development of this draft IRP. Id These experts
represented a variety of scientific disciplines, including epidemiology, human and animal
toxicology, statistics, risk/exposure analysis, and atmospheric science. This public workshop was
held February 29 to March 1, 2012, in Research Triangle Park, NC, and provided an opportunity
for the participants to broadly discuss the key policy-relevant issues around which the EPA
would structure this review of the primary NCh NAAQS and the most meaningful new science
that would be available to inform our understanding of these issues.31
Based in part on the workshop discussions, the EPA developed the Draft Plan for
Development of the Integrated Science Assessment (ISA) for Nitrogen Oxides - Health Criteria
(U.S. EPA, 2013a)32 and the draft IRP outlining the schedule, the process, and the policy-
relevant science issues identified as key to guiding the evaluation of the air quality criteria for
oxides of nitrogen and the review of the primary NCh NAAQS (U.S. EPA, 2014). The draft IRP
was made available for review by the CASAC Oxides of Nitrogen Primary NAAQS Review
Panel and for public comment (79 FR 7184, February 6, 2014). The CASAC discussed its review
of the draft IRP at a public meeting on March 12, 2014 (79 FR 8701, February 13, 2014). Advice
received from the CASAC on the draft IRP (Frey et al., 2014), as well as public comment on that
draft document, were considered in developing this final IRP.
Table 2-1 outlines the schedule under which the Agency is currently conducting this
review. The scope of the review and the key documents to be prepared during the review are
discussed throughout the rest of this document. Based on the projected schedule presented in
Table 2-1, the ISA will include consideration of new scientific studies published between
January 2008 and August 2014. The EPA will also consider near-road NCh measurement data
31 Workshop materials are available in the rulemaking docket accessible through
http://www.regulations.gov. Docket ID numberEPA-HQ-OAR-2013-0146.
32 The EPA released a draft plan outlining the plans for developing the ISA for CASAC consultation and
public review (78 FR 26026, May 3, 2013). The EPA held a consultation with CASAC on this draft plan during a
public teleconference on June 5, 2013 (78 FR 27234, May 9, 2013). CASAC (Frey, 2013) and public comments on
the draft plan were considered in developing Chapter 4 of the draft IRP (US EPA, 2014).
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through August 2014 and additional data to the extent practicable as it becomes available
through routine monitoring networks as discussed in section 6.2 below.
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Table 2-1. Anticipated schedule for the current review.
Stage of Review
Major Milestone
Target Date
Integrated Review
Plan (IRP)
Literature Search
Federal Register Call for Information
Workshop on science/policy issues
Draft plan for developing ISA
CASAC consultation on draft ISA plan
Draft IRP
CASAC review of draft IRP
Final IRP
Ongoing
February 10, 2012
February 29 - March 1, 2012
May 2013
June 5, 2013
February 2014
March 12-13, 2014
June 2014
Integrated Science
Assessment (ISA)
First draft ISA
CASAC public meeting for review of first draft ISA
Second draft ISA
CASAC/public review of second draft ISA
Final ISA
November 2013
March 12-13, 2014
October 2014
December 2014
April 2015
Risk/Exposure
Assessment (REA)
REA Planning Document
CASAC consultation/public review of REA Planning
Document
If warranted,
First draft REA
CASAC/public review of first draft REA
Second draft REA
CASAC/public review of second draft REA
Final REA
November 2014
December 2014
TBD
Policy Assessment
(PA)/Rulemaking
First draft PA
CASAC/public review of first draft PA
Second draft PA33
CASAC/public review of second draft PA
Final PA
Notice of proposed rulemaking
Notice of final rulemaking
March 2015
April 2015
December 2015
January 2016
June 2016
November 2016
August 2017
33 The anticipated schedule presented in Table 2-1 includes preparation of two draft PAs for CASAC and
public review. However, in NAAQS reviews where a new REA is not developed and where staff preliminarily
conclude in a first draft PA that it is appropriate to consider retaining the current standards, without revision, the
EPA may decide that there is no new substantive information that we would intend to add that would provide a basis
for preparing a second draft PA. In NAAQS reviews in which the newly available information calls into question the
adequacy of the current standard(s), a second draft PA is typically prepared to include staff consideration of
potential alternative standards. If the Agency determines that a second draft PA is not warranted, CASAC and public
comments on the first draft PA will be considered in preparing the final PA and the schedule adjusted accordingly.
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3 KEY POLICY-RELEVANT ISSUES
In each NAAQS review, an initial step is to address the following overarching question:
• Does the currently available scientific evidence and exposure/risk-based
information support or call into question the adequacy of the protection
afforded by the current standard(s)?
As appropriate, reviews also address a second overarching question:
• What alternative standards, if any, are supported by the currently available
scientific evidence and exposure/risk-based information and are appropriate
for consideration?
To inform our evaluation of these overarching questions in the current review, we have identified
key policy-relevant issues to be considered. These key issues reflect aspects of the health effects
evidence, air quality information, and exposure/risk information that, in our judgment, are likely
to be particularly important to inform the Administrator's decisions. They build upon the key
issues that were important in previous reviews.
Section 3.1 below describes the key considerations and conclusions from the last review
with regard to the adequacy of the primary NCh standards (section 3.1.1) and with regard to the
elements for a revised suite of standards judged in that review to provide requisite public health
protection (section 3.1.2). Section 3.2 summarizes our general approach for reviewing the
primary NCh standards in the current review and outlines the key policy-relevant issues. These
issues are presented as a series of questions that will frame our approach to considering the
extent to which the available evidence and information support retaining or revising the current
primary standards for NCh.
3.1 CONSIDERATIONS AND CONCLUSIONS IN LAST REVIEW
The last review of the primary NCh NAAQS was completed in 2010 (75 FR 6474,
February 9, 2010). In consideration of health effects evidence and air quality and exposure/risk
information available in that review, the EPA established a new short-term standard to provide
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increased public health protection, including for asthmatics and other at-risk populations,34
against an array of adverse respiratory health effects that had been linked to short-term NCh
exposures (75 FR 6498 to 6502; U.S. EPA, 2008a, sections 3.1.7 and 5.3.2.1; Table 5.3-1).
Specifically, the EPA established a short-term standard defined by the 3-year average of the 98th
percentile of the yearly distribution of daily maximum 1-hour NCh concentrations, with a level
of 100 ppb. In addition to setting the new 1-hour standard, the EPA retained the annual standard
with a level of 53 ppb (75 FR 6502). Together, the two standards were concluded to provide
protection for at-risk populations and lifestages against adverse respiratory health effects
associated with short-term exposures to NCh and effects potentially associated with long-term
exposures. As discussed further in section 6.2 below, in conjunction with the revised primary
NCh NAAQS, the EPA also established a two-tiered monitoring network composed of (1) near-
road monitors which would be placed in locations of expected maximum 1-hour NCh
concentrations near heavily trafficked roads in urban areas and (2) monitors located to
characterize areas with the highest expected NCh concentrations at the neighborhood and larger
spatial scales (also referred to as "area-wide" monitors) (75 FR 6505 to 6506, February 9, 2010).
Key policy-relevant aspects of the Administrator's decisions with regard to the need to
revise the primary NCh NAAQS, and with regard to the elements of the revised standard, are
described below in sections 3.1.1 and 3.1.2, respectively. Areas of uncertainty identified in the
last review are noted in section 3.1.3.
3.1.1 Need for Revision
The 2010 decision to revise the existing primary NCh standard was based on the extensive
body of evidence published through early 2008 and assessed in the 2008 ISA (U.S. EPA, 2008a),
including the assessment of the policy-relevant aspects of that evidence;35 the quantitative
exposure and risk analyses presented in the REA (U.S. EPA, 2008b); the advice and
recommendations of CAS AC (Samet, 2008b); and public comments (U.S. EPA, 2010). The
scientific evidence included controlled human exposure studies providing evidence of airway
34 As used here and similarly throughout this document, the term population refers to persons having a
quality or characteristic in common, such as a specific pre-existing illness or a specific age or lifestage, with
lifestage referring to a distinguishable time frame in an individual's life characterized by unique and relatively stable
behavioral and/or physiological characteristics that are associated with development and growth. Identifying at-risk
populations includes consideration of intrinsic (e.g., genetic or developmental aspects) or acquired (e.g., disease or
smoking status) factors that increase the risk of health effects occurring with exposure to oxides of nitrogen as well
as extrinsic, nonbiological factors such as those related to socioeconomic status, reduced access to health care, or
exposure.
35 As noted in section 1.3 above, due to changes in the NAAQS process, the last review of the NO2
NAAQS did not include a separate Policy Assessment. Rather, the REA for that review included a policy assessment
chapter.
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hyperresponsiveness in asthmatics following short-term exposures to NCh concentrations as low
as 100 ppb and epidemiological studies reporting associations between short-term NCh and
respiratory effects in locations that would have met the annual standard. The quantitative
analyses presented in the 2008 REA included exposure and risk estimates for air-quality adjusted
to just meet the annual standard. Based on the evidence and exposure/risk information, and based
on CASAC's advice that "the current NAAQS does not protect the public's health and that it
should be revised" (Samet, 2008b, p. 2), the Administrator concluded that the existing primary
annual NCh standard alone was not sufficient to protect public health from the array of
respiratory effects that had been reported following short-term exposures to oxides of nitrogen
(75 FR 6488 to 6490, February 9, 2010).
As an initial consideration in reaching this decision, the Administrator noted that the
evidence relating short-term (minutes to hours) NCh exposures to respiratory morbidity was
judged in the ISA to be "sufficient to infer a likely causal relationship" (75 FR 6489; U.S. EPA,
2008a, sections 3.1.7 and 5.3.2.1).36 This evidence included a large body of epidemiological
studies reporting associations between short-term NCh concentrations measured at central-site
monitors and respiratory-related symptoms, emergency department visits, and hospital
admissions. Overall, the 2008 ISA characterized the epidemiological evidence as consistent, in
that associations were reported in studies conducted in numerous locations with a variety of
methodological approaches, and coherent, in that the studies reported associations with
respiratory health outcomes that were logically linked together. In addition, a number of these
associations were statistically significant, particularly the more precise effect estimates (U.S.
EPA, 2008a, section 5.3.2.1). In studies that evaluated concentration-response (C-R)
relationships, they appeared linear within the observed range of data with "little evidence of any
effect threshold" (U.S. EPA, 2008a, sections 4.2 and 5.3.2.9). In considering the epidemiological
evidence, the Administrator acknowledged that the interpretation of the studies was complicated
by the fact that on-road vehicle exhaust emissions are a nearly ubiquitous source of combustion
pollutant mixtures that include NCh but additionally noted that ISA analyses of co-pollutants
generally found that NCh associations remained robust in multi-pollutant models (75 FR 6489).
The evidence also included controlled human exposure studies that evaluated airway
hyperresponsiveness in asthmatics following short-term (30-minute to 2-hour) exposures to NCh
concentrations at or above 100 ppb, as well as supporting evidence from animal toxicological
36In contrast, the evidence relating long-term (weeks to years) NO2 exposures to adverse health effects was
judged to be either "suggestive but not sufficient to infer a causal relationship" (respiratory morbidity) or
"inadequate to infer the presence or absence of a causal relationship" (mortality, cancer, cardiovascular effects,
reproductive/developmental effects) (75 FR 6478).
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studies (U.S. EPA, 2008a, sections 3.1.3 and 5.4). The EPA drew two broad conclusions
regarding airway responsiveness in asthmatics following NCh exposures. First, Mh exposure
may enhance the sensitivity to allergen-induced decrements in lung function and increase the
allergen-induced airway inflammatory response following 30-minute exposures of asthmatic
adults toNCh concentrations as low as 260 ppb. (U.S. EPA, 2008a, section 5.3.2.1, Figure 3.1-2).
Second, exposure to NCh resulted in small but significant increases in nonspecific airway
hyperresponsiveness in healthy and asthmatic adults. In asthmatics, the ISA concluded that such
increases were observed following 1-hour exposures to 100 ppb NCh (U.S. EPA, 2008a, sections
3.1.3.2; 5.3.2.1). The EPA further concluded that the majority of asthmatics may experience
NCh-related airway hyperresponsiveness following short-term NCh exposures between 100 and
300 ppb (U.S. EPA, 2008a, Table 3.1-3; U.S. EPA, 2008b, p. 283). Enhanced airway
responsiveness could have important clinical implications for asthmatics since transient increases
in airway responsiveness following Mh exposure have the potential to increase symptoms and
worsen asthma control (74 FR 34415, July 15, 2009; U.S. EPA, 2008a, sections 5.3.2.1 and 5.4).
An update to a meta-analysis of data for nonspecific airway responsiveness that had been
considered in the previous review provided support to the conclusions on exposure
concentrations eliciting effects (Folinsbee, 1992; U.S. EPA, 1993, 60 FR 52818, October 11,
1995; U.S. EPA, 2008a, section 3.1.3.2, Tables 3.1-2 and 3.1-3).37
The exposure- and risk-based information summarized in section 5.1 below also informed
the Administrator's decisions regarding adequacy of the then-existing primary annual NCh
standard. Estimates were developed for (1) an "as-is" scenario which estimated the health risks
associated with short-term exposure to NCh at actual recent air-quality concentrations, which
were lower than what was permitted by the then-current annual NCh standard; (2) a "just meets"
scenario which estimated the health risks associated with air quality adjusted upward to simulate
just meeting the then-current annual standard; and (3) other scenarios for potential alternative
standards.
The Administrator took note of the REA conclusion that risks estimated for air quality
adjusted upward to simulate just meeting the current standard could reasonably be concluded to
be important from a public health perspective, while additionally recognizing the uncertainties
37The updates made to the analysis were to remove the results of one allergen study and to add the results
from a non-specific responsiveness study, and to discuss results for an additional exposure concentration (i.e., 100
ppb) (U.S. EPA, 2008a, section 3.1.3.2).
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associated with adjusting air quality in such analyses (75 FR 6489).38 For air quality adjusted to
just meet the existing annual standard, the REA findings given particular attention by the
Administrator included the following: "a large percentage (8 to 9%) of respiratory-related
emergency department visits in Atlanta could be associated with short-term NCh exposures; most
asthmatics in Atlanta could be exposed on multiple days per year to Mh concentrations at or
above 300 ppb, and most locations evaluated could experience on-/near-road NCh concentrations
above 100 ppb on more than half of the days in a given year" (75 FR 6489; U.S. EPA, 2008b,
section 10.3.2). The 2008 REA additionally found that, under the "as is" scenario (i.e., recent air
quality concentrations), individuals spending time on or near roads could expect to experience
short-term NCh exposures above health effect benchmark levels of concern39 multiple times per
year.
In reaching the conclusion on adequacy of the then-existing standard, the Administrator
also considered advice received from CASAC. In its advice, CASAC agreed that the primary
concern in the review was to protect against health effects that have been associated with short-
term NCh exposures. CASAC also agreed that the annual standard alone was not sufficient to
protect public health against the types of exposures that could lead to these health effects. As
noted in its letter to the EPA Administrator, "CASAC concurs with EPA's judgment that the
current NAAQS does not protect the public's health and that it should be revised" (Samet,
2008b, p. 2).
Based on the considerations summarized above, the Administrator concluded that the
then-existing NCh primary NAAQS was not requisite to protect public health with an adequate
margin of safety and that the standard should be revised in order to provide increased public
health protection against respiratory effects associated with short-term exposures, particularly for
at-risk populations and lifestages such as asthmatics, children, and older adults (75 FR 6490).
Upon consideration of approaches to revising the standard, the Administrator concluded that it
was appropriate to set a new short-term standard, as described below.
38 As described further in section 5.1 below, the 2008 REA considered air quality data from the existing
network of ambient monitors as well as data from controlled human exposure studies and epidemiological studies to
model exposure to NCh and to estimate health risks associated with short-term exposures. Additionally, recognizing
that large segments of the public live, work, go to school, or travel on or near roads, the 2008 REA also estimated
exposures that would occur in those particular locations.
39 Health effect benchmark levels evaluated in the 2008 REA ranged from 100 to 300 ppb based on
increased airway hyperresponsiveness in asthmatics (from controlled human exposure studies) (U.S. EPA, 2008b,
section 6.2).
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3.1.2 Elements of Revised Standard
In considering appropriate revisions in the last review, each of the four basic elements of
the NAAQS (indicator, averaging time, level, and form) was evaluated. The rationale for
decisions on those elements is summarized below.
3.1.2.1 Indicator
In previous reviews, the EPA focused on NCh as the most appropriate indicator for oxides
of nitrogen because the available scientific information regarding health effects was largely
indexed by NCh. In the review completed in 2010, controlled human exposure studies and animal
toxicological studies provided specific evidence for health effects following exposures to NCh.
In addition, epidemiological studies typically reported effects associated with NCh
concentrations though the degree to which monitored NCh reflected actual NCh concentrations,
as opposed to NCh plus other gaseous oxides of nitrogen, was recognized as an uncertainty (75
FR 6490, February, 9, 2010; U.S. EPA 2008b, section 2.2.3).
Based on the information available in the last review, and consistent with the views of
CASAC (Samet, 2008b, p.2; Samet, 2009, p.2), the Agency concluded it was appropriate to
continue to use NCh as the indicator for a standard that was intended to address effects associated
with exposure to NCh, alone or in combination with other gaseous oxides of nitrogen. In so
doing, the EPA recognized that measures leading to reductions in population exposures to NCh
will also reduce exposures to other oxides of nitrogen (75 FR 6490).
3.1.2.2 Averaging times
In considering the most appropriate averaging time(s) for the NCh primary NAAQS, the
Administrator noted the available scientific evidence as assessed in the ISA, the air quality
analyses presented in the REA, the conclusions of the policy assessment chapter of the REA,
CASAC recommendations, and public comments received (75 FR 6490). Her key considerations
are summarized below.
When considering averaging time, the Administrator first noted that the evidence relating
short-term (minutes to hours) NCh exposures to respiratory morbidity was judged in the ISA to
be "sufficient to infer a likely causal relationship" (U.S. EPA, 2008a, section 5.3.2.1) while the
evidence relating long-term (weeks to years) NCh exposures to adverse health effects was judged
to be either "suggestive but not sufficient to infer a causal relationship" (respiratory morbidity)
or "inadequate to infer the presence or absence of a causal relationship" (mortality, cancer,
cardiovascular effects, reproductive/developmental effects) (U.S. EPA, 2008a, sections 5.3.2.4-
5.3.2.6). The Administrator concluded that these judgments most directly supported an averaging
time that focused protection on effects associated with short-term exposures to NCh.
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As had been done in previous reviews of the NCh NAAQS, the Administrator next noted
that it was instructive to evaluate the potential for a standard based on annual average NCh
concentrations, as was the existing standard at the time of the 2010 review, to provide protection
against short-term NCh exposures. To this end, the Administrator considered REA analyses that
indicated a relatively large degree of variability in ratios of short-term (i.e., 1-hour and 24-hour)
NCh concentrations to annual average concentrations, suggesting that a standard based on annual
average NCh concentrations would not likely be an effective or efficient approach to focus
protection on short-term NCh exposures. For example, these analyses indicated that in some
areas the existing annual standard could allow 1-hour daily maximum NCh concentrations of
about 400 ppb, while in other areas the annual standard could limit 1-hour daily maximum NCh
concentrations to about 150 ppb. Thus, for purposes of protecting against the range of 1-hour
NCh exposures, the Administrator agreed with the REA conclusion that a standard based on
annual average concentrations would likely require more control than necessary in some areas
and less control than necessary in others, depending on the standard level selected (75 FR 6491).
In next considering the level of support available for specific short-term averaging times,
the Administrator noted that the policy assessment chapter of the REA considered evidence from
both experimental and epidemiological studies. Controlled human exposure studies and animal
toxicological studies provided evidence that NCh exposures from less than 1 hour up to 3 hours
can result in respiratory effects such as increased airway responsiveness and inflammation (U.S.
EPA, 2008a, section 5.3.2.7). She specifically noted the ISA conclusion that exposures of
asthmatic adults to 100 ppb NCh for 1-hour can result in small but significant increases in
nonspecific airway responsiveness (U.S. EPA, 2008a, section 5.3.2.1). In addition, the
epidemiological evidence provided support for short-term averaging times ranging from
approximately 1 hour up to 24 hours (U.S. EPA, 2008a, section 5.3.2.7). Based on this, the
Administrator concluded that a primary concern with regard to averaging time is the degree of
protection provided against effects associated with 1-hour NCh concentrations. Based on REA
analyses of ratios between 1-hour and 24-hour NCh concentrations (U.S. EPA, 2008b, section
10.4.2), she further concluded that a standard based on 1-hour daily maximum NCh
concentrations could also be effective at protecting against effects associated with 24-hour NCh
exposures.
Based on the above, the Administrator judged that it was appropriate to set a new NCh
standard with a 1-hour averaging time. She concluded that such a standard can effectively limit
short-term (i.e., 1- to 24-hours) exposures that have been linked to adverse respiratory effects.
She also retained the existing annual standard to continue to provide protection for effects
potentially associated with long-term exposures to oxides of nitrogen (75 FR 6502). These
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decisions were consistent with CASAC advice to establish a primary short-term standard for
oxides of nitrogen based on using 1-hour maximum NCh concentrations and to retain the current
annual standard40 (Samet, 2008b, p. 2; Samet, 2009, p. 2).
3.1.2.3 Levels
With consideration of the available health effects evidence, exposure and risk analyses,
and air quality information, the Administrator set the level of the new 1-hour NCh standard at
100 ppb. This standard was focused on limiting the maximum 1-hour NCh concentrations in
ambient air, including in locations near major roadways where the highest ambient NCh
concentrations can occur in urban areas (75 FR 6474).41 In establishing this new standard, the
Administrator emphasized the importance of protecting against exposures to peak concentrations
of NCh, such as those that can occur around major roadways. Available evidence and
information suggested that roadways account for the majority of exposures to peak NCh
concentrations and, therefore, are important contributors to NCh-associated public health risks.
In setting the level of the new 1-hour standard at 100 ppb, the Administrator noted that
there is no bright line clearly directing the choice of level. Rather, the choice of what is
appropriate is a public health policy judgment entrusted to the Administrator. This judgment
must include consideration of the strengths and limitations of the evidence and the appropriate
inferences to be drawn from the evidence and the exposure and risk assessments.
The Administrator judged that the existing evidence from controlled human exposure
studies supported the conclusion that the NCh-induced increase in airway responsiveness at or
above 100 ppb presented a risk of adverse effects for some asthmatics, especially those with
more serious (i.e., more than mild) asthma. The Administrator noted that the risks associated
with increased airway responsiveness cannot be fully characterized based on available controlled
human exposure studies, and thus she was not able to determine whether the increased airway
responsiveness experienced by asthmatics in these studies was an adverse health effect.
However, the Administrator concluded that asthmatics, particularly those suffering from more
severe asthma, warrant protection from the risk of adverse effects associated with the NCh-
induced increase in airway responsiveness. Therefore, the Administrator concluded that the
40 CASAC advised that "the findings of the REA do not provide assurance that a short-term standard based
on the one-hour maximum will necessarily protect the populations from long-term exposures at levels potentially
leading to adverse health effects" therefore, it recommended retaining the existing annual standard (Samet, 2008b, p.
2).
41In conjunction with this new standard, the Administrator established a 2-tiered monitoring network that
included monitors sited to measure the maximum NO2 concentrations near major roadways, as well as monitors
sited to measure maximum area-wide NCh concentrations (see section 6.2 below).
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controlled human exposure evidence supported setting a standard level no higher than 100 ppb to
reflect a cautious approach to the uncertainty regarding the adversity of the effect. However,
those uncertainties led her to also conclude that this evidence did not support setting a standard
level lower than 100 ppb.
The Administrator also considered the more serious health effects reported in NCh
epidemiological studies. She noted that a new standard focused on protecting against maximum
1-hour NCh concentrations in ambient air anywhere in an area, with a level of 100 ppb and an
appropriate form (as discussed below), would be expected to limit area-wide42 NCh
concentrations to below those in locations where epidemiological studies had reported
associations with respiratory-related hospital admissions or emergency department visits. The
Administrator also concluded that such a 1-hour standard would be consistent with the REA
conclusions based on the NCh exposure and risk information.
Given the above considerations and the comments received on the proposal, the
Administrator judged it appropriate to set a 1-hour standard focused on limiting the maximum
allowable NCh concentrations that can occur anywhere in an area, with a level of 100 ppb.
Specifically, she concluded that such a standard, with an appropriate form as discussed below,
would provide a significant increase in public health protection compared to that provided by the
annual standard alone and would be expected to protect against the respiratory effects that have
been linked with NCh exposures in both controlled human exposure and epidemiological studies.
This includes limiting exposures at and above 100 ppb for the vast majority of people, including
those in at-risk groups, and maintaining area-wide NCh concentrations well below those in
locations where key U.S. epidemiological studies had reported that ambient NCh was associated
with clearly adverse respiratory health effects, as indicated by increased hospital admissions and
emergency department visits. The Administrator also noted that a standard level of 100 ppb was
consistent with the consensus recommendation of CASAC.
In setting the standard level at 100 ppb rather than at a lower level, the Administrator also
acknowledged the uncertainties associated with the scientific evidence. She noted that a 1-hour
standard with a level lower than 100 ppb would only result in significant further public health
protection if, in fact, there is a continuum of serious, adverse health risks caused by exposure to
NCh concentrations below 100 ppb and/or associated with area-wide NCh concentrations well
below those in locations where key U.S. epidemiological studies had reported associations with
respiratory-related emergency department visits and hospital admissions. Based on the available
42As discussed above, area-wide concentrations refer to those measured by monitors that have been sited to
characterize ambient concentrations at the neighborhood and larger spatial scales (see also section 6.2 below).
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evidence, the Administrator did not believe that such assumptions were warranted. Taking into
account the uncertainties that remained in interpreting the evidence from available controlled
human exposure and epidemiologic studies, the Administrator noted that the likelihood of
obtaining benefits to public health with a standard set below 100 ppb decreased, while the
likelihood of requiring reductions in ambient concentrations that go beyond those that are needed
to protect public health increased.
3.1.2.4 Forms
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. The Agency recognizes that for
short-term standards, concentration-based forms which reflect consideration of a statistical
characterization of an entire distribution of air quality data with a focus on a single statistical metric,
such as the 98th or 99th percentile, can better reflect pollutant-associated health risks than forms based
on expected exceedances. This is the case because concentration-based forms give proportionally
greater weight to days when pollutant concentrations are well above the level of the standard than to
days when the concentrations are just above the level of the standard. 43 In addition, when averaged
over three years, these concentration-based forms are judged to provide an appropriate balance
between limiting peak pollutant concentrations and providing a stable regulatory target, facilitating
the development of stable implementation programs (75 FR 6492).
In the last review, the EPA considered two specific concentration-based forms (i.e., the 98th
and 99th percentile concentrations), averaged over 3 years, for the new 1-hour NCh standard. The
focus on the upper percentiles of the distribution was based, in part, on evidence of health effects
associated with short-term NCh exposures from experimental studies which provided information on
specific exposure concentrations that were linked to respiratory effects. The Agency proposed to
adopt either a 99th percentile or a 4th highest form, averaged over 3 years, and also solicited comment
on both 98th percentile and 7th or 8th highest forms, averaged over 3 years (74 FR 34430, July 15,
2008). Given the potential for instability in the higher percentile concentrations and the absence of
data from the proposed two-tier monitoring network (e.g., around major roadways), CASAC, in a
letter to the Administrator following issuance of the Agency's proposed rule, recommended a form
based on the 3-year average of the 98th percentile of the distribution of 1-hour daily maximum NCh
concentrations (Samet, 2009, p. 2).
In reaching her final decision in the last review, the Administrator recognized that the public
health protection provided by the new 1-hour NCh standard was based in large part on (1) the
approach used to set the standard and (2) the level of the standard in conjunction with the form of the
43 Compared to an exceedance-based form, a concentration-based form reflects the magnitude of the
exceedance of a standard level not just the fact that such an exceedance occurred.
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standard (75 FR 6493). Given that the EPA set a new primary 1-hour NCh standard that focused on
limiting the maximum allowable NCh concentration in ambient air, the Agency agreed with CASAC
that an appropriate consideration with regard to form was the extent to which specific statistics could
be unstable at locations where maximum NCh concentrations are expected (e.g., including near major
roads).
Given the limited available information on the variability in peak NCh concentrations near
important sources of NCh such as near major roadways, and given the recommendation from CASAC
of the potential for instability in the 99th percentile concentrations, the Administrator judged it
appropriate to set the form based on the 3-year average of the 98th percentile of the annual
distribution of daily maximum 1-hour NCh concentrations. Id. In addition, consistent with CASAC
advice (Samet, 2008b, p. 2; Samet, 2009, p.2), the EPA retained the form of the annual standard (75
FR 6502).
3.1.3 Areas of Uncertainty
While the available scientific information informing the last review was stronger and
more consistent than in previous reviews and provided a strong basis for decision making in that
review, the Agency recognized that areas of uncertainty remained. These were generally related
to the following: (1) understanding the role of NCh in the complex ambient mixture which
includes a range of co-occurring pollutants (e.g., PM2.5, ozone (Ch), CO, SCh, other traffic-
related pollutants); (2) understanding the extent to which monitored ambient NCh concentrations
used in epidemiological studies reflect exposures in study populations and the range of ambient
concentrations over which we continue to have confidence in the health effects observed in the
epidemiological studies; (3) understanding the extent to which the magnitude and potential
adversity of NCh-induced respiratory effects reported in controlled human exposures studies can
be characterized; (4) understanding the NCh concentration gradients around important sources,
such as major roads, and relating those gradients to broader ambient monitoring concentrations;
and (5) improving the characterization of NCh exposures and risk including alternative
approaches for estimated risks associated with air quality simulated to just meet current or
alternative standards.
3.2 GENERAL APPROACH FOR THE CURRENT REVIEW
The approach for this review builds on the substantial body of work done during the
course of the last review, taking into account the more recent scientific information and air
quality data now available to inform our understanding of the key policy-relevant issues. The
approach described below is most fundamentally based on using the EPA's assessment of the
current scientific evidence and associated quantitative analyses to inform the Administrator's
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judgments regarding primary standards for oxides of nitrogen that are requisite to protect public
health with an adequate margin of safety. This approach will involve translating scientific and
technical information into the basis for addressing a series of key policy-relevant questions using
both evidence- and exposure/risk-based considerations.44
Figure 3-1 summarizes the general approach, including consideration of the policy-
relevant questions which will frame the current review. The ISA, REA (if warranted), and PA
developed in this new review will provide the basis for addressing the key policy-relevant
questions and will inform the Administrator's judgment as to the adequacy of the current primary
NCh standards and decisions as to whether to retain or revise these standards. This approach
recognizes that the available health effects evidence generally reflects a continuum, consisting of
ambient concentrations at which scientists generally agree that health effects are likely to occur,
through lower concentrations at which the likelihood and magnitude of the response become
increasingly uncertain. Furthermore, this approach is consistent with the requirements of the
NAAQS provisions of the CAA and with how the EPA and the courts have historically
interpreted the CAA. As discussed in section 1.1 above, these provisions require the
Administrator to establish primary standards that, in the Administrator's judgment, are requisite
to protect public health with an adequate margin of safety. In so doing, the Administrator seeks
to establish standards that are neither more nor less stringent than necessary for this purpose. The
CAA does not require that primary standards be set at a zero-risk level, but rather at a level that
avoids unacceptable risks to public health. The four basic elements of the NAAQS (i.e.,
indicator, averaging time, form, and level) will be considered collectively in evaluating the
health protection afforded by the current or any alternative standards considered.
We note that the final decision on the adequacy of the current standards and, if
appropriate, potential alternative standards, is largely a public health policy judgment to be made
by the Administrator. The Administrator's final decision must draw upon scientific information
and analyses about health effects, population exposure and risks, as well as judgments about how
to consider the range and magnitude of uncertainties that are inherent in the scientific evidence
and analyses. As in the previous review, as well as other recent NAAQS reviews, the EPA will
consider the implications of placing more or less weight or emphasis on different aspects of the
scientific evidence and exposure/risk-based information to inform the public health policy
judgments that the Administrator will make in reaching final decisions on whether to retain or
revise the current standards in this review.
44 Evidence-based considerations include those related to the health effects evidence assessed and
characterized in the ISA. Exposure/risk-based considerations draw from the results of the quantitative analyses.
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Adequacy of Current Suite of NO2 Standards?
I
Evidence-based Considerations
5*- Does currently available evidence and
related uncertainties strengthen or call into
question prior conclusions?
5* Evidence of health effects not
previously identified?
VEvidence of effects at lower
concentrations than previously observed or
in areas that would have likely met current
standards?
>Expanded understanding of at-risk
lifestagcs and populations?
VDoes newly available information call into
question any of the baste elements of the
standards?
Risk/Exnosure-based Considerations
> Nature, magnitude, and uncertainties of
estimated exposures and risks remaining
upon just meeting the current suite of
standards?
> Roles of annual and 1-hour standards?
> Importance of remaining risks from public
health perspective?
>• Uncertainties in the exposure and risk
estimates?
Does information
call into question
adequacy of current
suite of NO,
standards?
Consider
retaining
current suite
of NO,
standards
Consideration of Potential Alternative Suites of Standards
Elements of Potential Alternative Standards
'> Indicator
> Averaging times
>Forms
>Levels
Potential alternative standards for consideration
Figure 3-1. Overview of General Approach for Review of Primary NOi Standards
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The initial overarching question in reviewing the adequacy of the current suite of primary
NCh NAAQS is whether the available body of scientific evidence, assessed in the ISA and used
as a basis for developing or interpreting any risk/exposure analyses, supports or calls into
question the scientific conclusions reached in the last review regarding health effects related to
exposures to oxides of nitrogen. The evaluation of the available scientific evidence and
risk/exposure information with regard to adequacy of the current standards will focus on key
policy-relevant issues by addressing a series of questions including the following:
• To what extent has new information altered the scientific support for the occurrence of
health effects as a result of short- and/or long-term exposure to oxides of nitrogen in the
ambient air?
o What evidence is available from recent studies focused on specific chemical
components within the broader group of oxides of nitrogen (e.g., NCh, NO, NOx) to
inform our understanding of the nature of exposures that are linked to various health
outcomes?
o To what extent is key scientific evidence becoming available to improve our
understanding of the health effects associated with various time periods of exposures,
including peak (e.g., 1-hour) and long-term exposures (e.g., more than on month to
years)?
- At what pollutant concentrations do these health effects occur?
- To what extent is new information available to improve our understanding of the
range of ambient concentrations over which we continue to have confidence in the
health effects observed in the epidemiological studies?
- Is there evidence of effects at exposure concentrations lower than previously
observed or in areas that would likely have met the current primary NCh
standards?
- To what extent are health effects associated with exposures to oxides of nitrogen,
including NCh, as opposed to one or more co-occurring pollutants (e.g., PM2.5,
CO, ozone, SO2, other traffic-related pollutants)?
- What are the important biological mechanisms and related modes of action for
these health effects and are they consistent with biological mechanisms and
modes of action characterized for oxides of nitrogen?
- To what extent is new information available to improve the characterization of the
magnitude and/or potential adversity of NO2-induced respiratory effects reported
in controlled human exposure studies?
o Has new information altered our understanding of human lifestages and populations
that are particularly at increased risk for experiencing health effects associated with
exposure to oxides of nitrogen?
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- What new information is available to inform our understanding of potential health
effects in at-risk populations and lifestages living, working, playing or going to
school near NO2 sources (e.g., near roads)?
- To what extent is new information available regarding co-occurring risk factors
that may be related to increased risk for experiencing health effects associated
with exposure to oxides of nitrogen (e.g., children with asthma)?
- Is there new or emerging evidence of health effects beyond respiratory effects in
asthmatics or effects in high exposure populations (e.g., people living, working, or
going to school in near-road environments) that suggest potential additional at-
risk lifestages and populations should be given increased focus in this review?
- Is there new information to shed light on the nature of the exposure-response
relationship in different at-risk lifestages and/or populations?
• To what extent is new information available to improve our understanding of the NCh
concentration gradients around important sources, such as major roads and combustion
sources, and to relate those gradients to broader ambient monitoring concentrations?
• To what extent does risk or exposure information suggest that exposures of concern are
likely to occur with recent ambient NCh concentrations or with concentrations that just
meet the current primary NCh standards?
o Are the estimated risks/exposures considered in this review of sufficient magnitude
such that the health effects might reasonably be judged to be important from a public
health perspective?
o What new information is available to improve our understanding of exposure
measurement error and the role of exposure in epidemiological inference, particularly
for interpreting long-term exposure studies?
o What are the important uncertainties associated with any risk/exposure estimates?
• To what extent have important uncertainties identified in the last review been reduced
and/or have new uncertainties emerged?
• To what extent does newly available information reinforce or call into question any of the
basic elements of the current primary NCh standards?
If the evidence suggests that revision of the current standards might be appropriate, the
EPA will address a second overarching question related to what alternative standards are
appropriate for consideration. Specifically, we will evaluate how the scientific information and
assessments inform decisions regarding the basic elements of the primary NCh NAAQS:
indicator, averaging time, level, and form. These elements will be considered collectively in
evaluating the health protection afforded by the current or any alternative standards considered.
With regard to consideration of alternative standards, specific policy-relevant questions that will
be addressed include the following:
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• To what extent does any new information provide support for consideration of a different
indicator for oxides of nitrogen in addition to or in place of NCh?
• To what extent does the health effects evidence evaluated in the ISA, air quality analyses,
and, if available, new REA provide support for considering any different averaging
times!
• To what extent do air quality analyses and other information provide support for
consideration of alternative standard forms'?
• What range of alternative standard levels should be considered based on the scientific
evidence evaluated in the ISA, air quality analyses and, if available, new REA45?
• What are the important uncertainties and limitations in the available evidence and
assessments and how might those uncertainties and limitations be taken into
consideration in identifying alternative standard indicators, averaging times, forms
and/or levels'?
45 As outlined in Table 2-1 and discussed in Chapter 5 below, the REA Planning Document will consider
the extent to which newly available scientific evidence and tools/methodologies warrant the conduct of new
quantitative risk and exposure assessments. To the extent completely new assessments are not developed for this
review, assessments from the last review may be interpreted in light of the newly available information in
addressing the key policy questions for the review.
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4 SCIENCE ASSESSMENT
The ISA comprises the science assessment phase of the NAAQS review process. As
outlined in section 1.4 above, the purpose of the current review is to inform the review of the
primary NCh standards only.46 Hence, the ISA will focus on updating the air quality criteria
associated with health effects evidence only.47
4.1 SCOPE OF THE ISA
The ISA provides an updated critical evaluation and synthesis of the current scientific
literature pertaining to known and anticipated public health effects of gaseous oxides of nitrogen
in the ambient air, including the nature of any remaining or newly identified uncertainties and
limitations associated with the health evidence. The ISA will primarily focus on scientific
evaluations that can inform the key policy questions described in section 3.2 above. Although
emphasis will be placed on the discussion of the health effects information, other scientific
information will also be presented and evaluated in order to provide a better understanding of the
following issues: (1) the sources of oxides of nitrogen to ambient air; (2) measurement of and
recent ambient concentrations of oxides of nitrogen including NCh, including subsequent fate
and transport in the environment; (3) important considerations related to characterizing potential
population exposures to oxides of nitrogen; and (4) the validity of inferences that can be drawn
about health effects related to exposure of oxides of nitrogen based on the methods used to assess
population exposures and the influence of other factors (e.g., other pollutants in the ambient
mixture) shown to be correlated with both oxides of nitrogen and health effects. The process for
evaluating and synthesizing scientific literature and addressing key policy questions is detailed in
the Preamble to the ISA.
The ISA is not intended to provide a detailed literature review but rather, will draw from
the existing body of evidence to synthesize the current state of knowledge on the most relevant
issues pertinent to the review of the primary NCh NAAQS. The ISA serves to revise the
46 As outlined in section 1.4 above, evidence related to potential welfare (e.g., ecosystem) effects of oxides
of nitrogen will be considered separately in the science assessment conducted as part of the review of the secondary
NAAQS for NO2 and SO2.
47In this review of the primary NAAQS for NCh, as summarized in Chapter 2 above, a draft plan for
development of the ISA was prepared by NCEA prior to development of the draft IRP. The draft plan for
development of the ISA was made available for public comment and was the subject of a consultation with CASAC
(78 FR 26026; 78 FR 27234). Comments received during that consultation were considered in preparation of chapter
4 in the draft IRP and the first draft ISA (U.S. EPA, 2013b). Further comments received on the draft IRP were
considered in preparing this final IRP and will be considered in developing the second draft ISA.
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scientific assessment available at the time of the last review. Thus, the ISA will build on the
conclusions of the last review of the air quality criteria for oxides of nitrogen as presented in the
2008 ISA and focus on peer-reviewed literature published since that document48 as well as on
any new interpretations of previously available literature. Key findings, conclusions, and
uncertainties from the 2008 ISA will be briefly summarized at the beginning of the ISA and of
individual sections. Important older studies may be discussed in detail to reinforce key concepts
and conclusions and/or if they are open to reinterpretation in light of newer data. Older studies
also may be the primary focus in some subject areas or scientific disciplines (e.g., epidemiology,
controlled human exposure, animal toxicology, atmospheric science, exposure science) where
research efforts have subsided, and these older studies remain the definitive works available in
the literature. Emphasis will be placed on studies that examine health effects relevant to humans
and concentrations of oxides of nitrogen that represent the range of human exposures across
ambient microenvironments (up to 5,000 ppb NCh, which is one to two orders of magnitude
above peak ambient concentrations as measured on roads). Other studies, generally at higher
exposure concentrations, may be included if they contain unique data, such as previously
unreported effects, evidence of the potential biological mechanism(s) for an observed effect, or
information on concentration-response relationships.
4.2 ORGANIZATION OF THE ISA
The broad organization of the ISA for the health criteria of oxides of nitrogen will be
consistent with that used in the recent assessments for other criteria pollutants (e.g., ISA for
Ozone and Related Photochemical Oxidants, U.S. EPA, 2013c). The ISA will begin with a
discussion of major legal and historical aspects of prior NAAQS reviews as well as procedures
for the assessment of scientific information. An integrative synthesis chapter will summarize the
key information for each topic area, the causal determinations for relationships between exposure
to oxides of nitrogen and health effects, information describing the extent to which health effects
can be attributable specifically to oxides of nitrogen, and other uncertainties related to the
interpretation of scientific information. The integrative synthesis chapter also will discuss policy-
relevant issues such as the exposure averaging times and lags associated with health effects, the
concentration-response relationships including whether or not the evidence supports
identification of a discernible threshold below which effects are not likely to occur, and the
public health significance of effects associated with exposure to oxides of nitrogen. Subsequent
chapters are organized by subject area (see draft outline of the ISA in Appendix A) and contain
the detailed evaluation of results from recent studies integrated with previous findings (see
48 For the current ISA, searches were conducted for studies published beginning in January 2008.
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section 4.4 below for specific issues to be addressed). Sections for each major health effect
category (e.g., respiratory effects) conclude with a causal determination about the relationship
with relevant exposures to oxides of nitrogen. The ISA will conclude with a chapter that
examines exposure and health outcome data to draw conclusions about potential at-risk lifestages
and populations (as defined in section 3.1 above).
The ISA may be supplemented with other materials if additional documentation is
required to support information contained within the ISA. These supplementary materials may
include more detailed and comprehensive coverage of relevant publications and may accompany
the ISA or be available in electronic form as output from the Health and Environmental Research
Online (HERO) database developed by EPA.49 Supplementary information that is available in
the HERO database will be presented as electronic links in the ISA.
4.3 ASSESSMENT APPROACH
4.3.1 Introduction
The NCEA-RTP is responsible for preparing the ISA. In each NAAQS review,
development of the science assessment begins with a "Call for Information" published in the
Federal Register. This notice announces EPA's initiation of activities in the preparation of the
ISA for the specific NAAQS review and invites the public to assist through the submission of
research studies in the identified subject areas. This and subsequent key components of the
process currently followed for the development of an ISA (i.e., the development process) are
presented in Figure 4-1 and are described in greater detail in the Preamble to the ISA. Section 1.2
above briefly describes how the ISA fits into the larger NAAQS review process.
Important aspects of the development of the ISA are described in the sections below, including
the approach for searching the literature and identifying relevant publications and informing
specific policy-relevant questions that are intended to guide the assessment. These
responsibilities are undertaken by expert authors of the ISA chapters which include EPA staff
with extensive knowledge in their respective fields and extramural scientists solicited by the
EPA for their expertise in specific fields. The process for scientific and public review of drafts of
the ISA is described in section 4.5 below.
49
For more information on the HERO database, see http://hero.epa.gov/.
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Literature Search and
Study Selection
Evaluation of Individual Study Quality
After study selection, the quality of individual studies is evajuated by EPA or outside experts in the fields of
atmospheric science, exposure assessment, dosimetry, animal toxicology, controlled human exposure studies,
epidemiology, ecology and other welfare effects, considering the design, methods, conduct, and documentation of
each study. Strengths and limitations of individual studies that may affect the interpretation of the study are
considered.
Develop Initial Sections
Review and summarize new study results and
findings and conclusions from previous
assessments by category of outcome/effect and
by discipline, e.g., lexicological studies of lung
function.
Peer Input Consultation
Review of initial draft materials by scientists
from both outside and within EPA in public
meeting or public teleconference.
Evaluation, Synthesis and Integration of Evidence
Integrate evidence from scientific disciplines-for example, lexicological, controlled human exposure and
epidemiological study findings for particular health outcome. Evaluate evidence for related groups of endpoints or
outcomes to draw conclusions regarding health or welfare effect categories, integrating health or welfare effects
evidence with information on mode of action and exposure assessment.
Development of Scientific Conclusions and Causal Determinations
Characterize weight of evidence and develop judgments regarding causality for health or welfare effect categories.
Develop conclusions regarding concentration- or dose-response relationships, potentially at-risk populations,
lifestages, or ecosystems.
Draft Integrated Science Assessment
Evaluation and integration of newly published studies
after each draft
Clean Air Scientific Advisory Committee
Independent review of draft documents for scientific
quality and sound implementation of causal
framework; anticipated review of two drafts of ISA in
public meetings.
Public Comments
Comments on draft ISA solicited by EPA
Final Integrated Science Assessment
Source: Modified from Figure II of the Preamble to the ISA (U.S. EPA, 2013b).
Figure 4-1. General process for development of Integrated Science Assessments.
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4.3.2 Literature Search and Selection of Relevant Studies
The NCEA-RTP uses a structured approach to identify relevant studies for consideration
and inclusion in the ISA. A Federal Register notice is published to announce the initiation of a
review and request information, including relevant literature, from the public. In addition, the
NCEA-RTP identifies publications by conducting a recursive multi-tiered literature search
process that includes extensive manual and computer-aided citation mining of computer
databases (e.g., PubMed, Web of Science) on specific topics in a variety of disciplines. The
search strategies are designed a priori and iteratively modified to optimize identification of
pertinent published papers. A broad search string is developed with keywords such as oxides of
nitrogen, NOx, NCh, NO, nitric acid, peroxyacetyl nitrate, and total reactive nitrogen, and the
specific syntax is tailored for each database. Papers are identified for inclusion in several
additional ways: specialized searches on specific topics; relational searches that identify recent
publications that have cited references from previous assessments; identification of relevant
literature by expert scientists; recommendations from the public and CASAC during the call for
information and external review process; and review of citations in previous assessments. These
search methods are used to identify recent research published or accepted for publication since
the 2008 ISA for Oxides of Nitrogen, i.e., starting in January 2008 through approximately two
months before the release of the second external review draft of the ISA (target of October 2014,
see Table 21). Studies published after that date may also be included in the ISA if they provide
new information that impacts one or more key scientific issues. Studies published after the ISA
cut-off date also may be considered in subsequent phases of the NAAQS review, after assessing
whether they provide new information that impacts key scientific issues.
Once identified through the multipronged search strategy, ISA authors (EPA staff and
extramural scientists) review studies for relevance. Inclusion criteria consist of epidemiological,
lexicological, and controlled human exposure studies or reports that examine health effects in
relation to exposure to gaseous oxides of nitrogen and studies or reports on sources, emissions,
atmospheric chemistry, human exposure, dosimetry, or modes of action of gaseous oxides of
nitrogen. To be included in the ISA, these studies and reports also have undergone scientific peer
review and have been published or accepted for publication. Some publications retrieved from
the literature search are excluded as not being relevant (e.g., do not meet aforementioned criteria)
based on screening of the title or citation (e.g., not about air pollution, conference abstract) and
are not documented further. For other publications, decisions about relevance require reading
beyond the title. These publications are labeled as "considered" for inclusion in the ISA and are
documented in the HERO database. On the HERO project page for the ISA for Oxides of
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Nitrogen, documentation of references consists of bibliographic information and a label as to
whether the reference is considered and/or cited.
From the group of "considered" references, studies and reports are selected for inclusion
in the ISA based on review of the abstract and full text. The selection process is based on the
extent to which the study is potentially policy-relevant and informative. Potentially policy-
relevant and informative studies include those that provide a basis for or describe the relationship
between oxides of nitrogen and effects, in particular, those studies that reduce uncertainty on
critical issues. Also pertinent are studies that offer innovation in method or design or present
novel information on effects or issues previously not identified. Uncertainty can be addressed,
for example, by analyses of potential confounding or effect modification by copollutants or other
factors, analyses of concentration-response or dose-response relationships, or analyses related to
time between exposure and response. In keeping with the purpose to accurately reflect the latest
scientific knowledge, a majority of the discussion in the ISA will describe studies published
since the 2008 ISA. However, evidence from previous studies will be included to integrate with
results from recent studies, and in some cases, characterize the key policy-relevant information
in a particular subject area or scientific discipline. Analyses conducted by the EPA using
publicly available data, for example, air quality and emissions data, also are considered for
inclusion in the ISA. Individual study quality is not used as a criterion for study inclusion, and
informative studies are not limited to specific study designs, model systems, or outcomes. The
combination of approaches described above is intended to produce the comprehensive collection
of pertinent studies needed to address the key scientific issues that form the basis of the ISA.
References are cited in the ISA by a hyperlink to the HERO database and also are compiled into
reference lists.
4.3.3 Evaluation of Individual Study Quality
After selecting studies for inclusion, individual study (from previous assessments or
recently published) quality is evaluated by considering the design, methods, conduct, and
documentation of each study but not considering whether the study results are positive, negative,
or null. Further, the ISA forms independent conclusions about the strength of inference from
study results weighing the authors' conclusions and independently evaluating study quality as
detailed below and in the Preamble. This uniform approach aims to consider the strengths,
limitations, and possible roles of chance, confounding, and other biases that may affect the
interpretation of the results from individual studies. In assessing the scientific quality of studies,
the following broad parameters are considered:
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• How clearly were the study design, study groups, methods, data, and results presented to
allow for study evaluation?
• To what extent are the air quality data, exposure, or dose metrics of adequate quality to
serve as credible exposure indicators?
• Were the study populations, subjects, or animal models adequately selected, and are they
sufficiently well-defined to allow for meaningful comparisons between study or exposure
groups?
• Are the statistical analyses appropriate, properly performed, and properly interpreted? Do
the analytical methods provide adequate sensitivity and precision to support study
conclusions?
• Are likely covariates (i.e., potential confounding factors, modifying factors) adequately
controlled for or taken into account in the study design or statistical analyses?
• Are the health endpoint measurements meaningful, valid, and reliable?
Additional considerations specific to particular scientific disciplines are discussed below.
Atmospheric Science and Exposure Assessment
Atmospheric science and exposure assessment studies focus on measurement, chemistry,
fate, and transport of ambient air pollution as well as exposure to ambient air pollution using
quality-assured field, experimental, and/or modeling techniques. The most informative
measurement-based studies will include detailed descriptive statistics for high-quality
measurements made at varying spatial and temporal scales. These studies will also include a
clear and comprehensive description of measurement techniques and quality control procedures
used. Quality control metrics (e.g., method detection limits) and quantitative relationships
between and within pollutant measurements (e.g., regression model coefficients, intercepts, and
fit statistics) should be provided when appropriate. Measurements including contrasting
conditions for various time periods (e.g., weekday/weekend, season), populations, geographic
regions, land use types (e.g., urban/rural), and proximity to various source sectors are particularly
useful. The most informative modeling-based studies will incorporate appropriate chemistry,
transport, dispersion, and/or exposure modeling techniques with a clear and comprehensive
description of model science, evaluation procedures, and metrics.
Exposure measurement error, which refers to the uncertainty associated with the exposure
metrics used to represent exposure of an individual or population, can be an important
contributor to uncertainty in air pollution epidemiological study results. Exposure measurement
error can influence epidemiological associations observed between ambient pollutant
concentrations and health outcomes by biasing effect estimates toward or away from the null
and/or widening confidence intervals around those estimates (Zeger et al., 2000). Factors that
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could influence error in exposure estimates include, but are not limited to, spatial patterns in
ambient concentrations, non-ambient sources of exposure, topography of the natural and built
environment, meteorology, air quality measurement instrument errors, model uncertainties, time-
activity patterns, and the infiltration of outdoor pollutants into indoor environments. Additional
information present in high-quality exposure studies includes location and activity information
from diaries, questionnaires, global positioning system data, or other means, as well as
information on commuting patterns.
Epidemiology
In evaluating the quality of epidemiological studies and strength of inference from their
results, the EPA additionally considers whether a given study: (1) presents quantitative
information on associations of health effects with short- or long-term exposures that represent
ambient concentrations of oxides of nitrogen across various microenvironments; (2) examines
health effects of multiple species of oxides of nitrogen; (3) assesses oxides of nitrogen as a
component of a complex mixture of air pollutants (of primary interest are other pollutants
emitted by motor vehicles, including carbon monoxide, PM and various inorganic and organic
components) by considering concentrations of copollutants, correlations of oxides of nitrogen
with these copollutants, potential copollutant interactions (e.g., synergistic effects of oxides of
nitrogen with other pollutants), potential copollutant confounding (e.g., bias of associations
observed between oxides of nitrogen and health endpoints by the effects of copollutants), and
other methods to assess the independent effect of oxides of nitrogen; (4) examines other potential
confounding factors or effect modifiers (e.g., socioeconomic status [SES]); and/or (5) examines
exposure estimates that capture the spatial pattern of oxides of nitrogen in the study area. Also
informative are studies that evaluate potential at-risk lifestages or populations; health endpoints
not previously researched extensively; and important methodological issues (e.g., lag or time
period between exposure and effects, model specifications, thresholds, mortality displacement)
related to the health effects of exposure to oxides of nitrogen. Among epidemiological studies
characterized as high quality by these parameters, emphasis will be given to multicity studies
that employ standard methodological analyses for evaluating effects of oxides of nitrogen across
cities, provide overall estimates for effects by pooling information across cities, and examine
consistency of results across cities. To address specific issues relevant to standard setting in the
U.S., such as regional heterogeneity in effects, emphasis will be placed on studies that involve
exposures and population characteristics that are relevant to current U.S. populations (e.g.,
studies conducted in the U.S. or Canada).
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Controlled Human Exposure and Animal Toxicology
Controlled human exposure and animal toxicological studies experimentally evaluate the
health effects of administered exposures in human volunteers and animal models under highly
controlled laboratory conditions. Controlled human exposure studies are also referred to as
human clinical studies. These experiments allow investigators to expose subjects or animal
models to known concentrations of oxides of nitrogen under carefully regulated environmental
conditions and/or activity levels. In addition to the general quality considerations discussed
previously, controlled human exposure and animal toxicological studies will be evaluated with
respect to details reported on the design, experimental procedures, and analytical methodology of
each study with focus on: (1) characterization of the exposure concentration or inhaled dose,
dosing regimen (e.g., duration), and exposure route; (2) characterization of the pollutant(s) (i.e.,
oxides of nitrogen species); (3) sample size and statistical power to detect differences; and (4)
control of other variables that could influence the occurrence of effects. The evaluation of study
design generally includes consideration of factors that minimize bias in results such as
randomization, blinding and allocation concealment of study subjects, investigators, and research
staff, and unexplained loss of animals or withdrawal/exclusion of subjects. Additionally, studies
must include appropriate control groups and exposures to allow for accurate interpretation of
results relative to the pollutant exposure. Emphasis is placed on studies that address
concentration-dependent responses or time-course of responses. Also, with the recognition that
controlled human exposure studies typically are conducted in young adults and healthy
individuals, emphasis will be placed on studies that investigate potentially at-risk lifestages or
populations (e.g., with pre-existing disease). In addition, consideration will be given to studies
that investigate exposure to oxides of nitrogen separately and then simultaneously or sequentially
with other pollutants such as particulate matter, sulfur dioxide, and ozone.
Controlled human exposure or animal toxicological studies involving exposures that
approximate expected human exposures in terms of concentration, duration, and route of
exposure are of particular interest. The ISA will define relevant NCh or NO exposures as those
up to 5,000 ppb, which is one to two orders of magnitude above peak ambient concentrations as
measured on roads. Studies using higher concentration exposures or doses will be considered to
the extent that they provide information relevant to understanding mode of action or
mechanisms, interspecies variation, or at-risk human lifestages and populations. In vitro studies
may be included if they provide mechanistic insight for effects examined in vivo or in
epidemiological studies. In vitro studies of NCh are particularly informative if conducted in
anatomically relevant cells such as lung epithelium or other airway cells.
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4.3.4 Integration of Evidence and Determination of Causality
As described in the Preamble to the ISA, the EPA uses a consistent and transparent basis
for the integration of scientific evidence and evaluation of the causal nature of air
pollution-related health effects in the ISA. For the evaluation of human health effects, the main
lines of evidence are controlled human exposure, epidemiological, and toxicological studies, and
evidence is integrated from previous and recent studies. Other information including mechanistic
evidence, toxicokinetics, and exposure assessment may be highlighted if it is relevant to the
evaluation of health effects and if it is of sufficient importance to affect the overall evaluation.
The relative importance of different sources of evidence to the conclusions varies by pollutant or
assessment, as does the availability of different sources of evidence for causality determination.
In judgments of causality, scientists will also evaluate uncertainty in the scientific evidence,
considering issues such as generalizing results from a small number of controlled human
exposure subjects to the larger population; quantitative extrapolations of observed pollutant-
induced pathophysiological alterations from laboratory animals to humans; confounding by co-
exposure to other ambient pollutants, meteorological factors, or other factors; the potential for
effects to be due to exposure to air pollution mixtures; and the influence of exposure
measurement error on epidemiological study findings. Judgments of causality also are informed
by the extent to which uncertainty in one line of evidence (e.g., potential confounding in
epidemiological results) is addressed by another line of evidence (e.g., coherence with
experimental findings, mode of action information). Thus, evidence integration is not a
unidirectional process but occurs iteratively within and across scientific disciplines and related
outcomes.
The EPA uses a framework to provide a consistent and transparent basis for classifying
the weight of available evidence according to a five-level hierarchy: (1) causal relationship; (2)
likely to be a causal relationship; (3) suggestive but not sufficient to infer a causal relationship;
(4) inadequate to infer a causal relationship; and (5) not likely to be a causal relationship (U.S.
EPA, 2013c, Table II). In the framework, key considerations in drawing conclusions about
causality include consistency of findings for an endpoint across studies, coherence of the
evidence across disciplines and across related endpoints, and biological plausibility, including
key events within modes of action. As judged by these parameters, evidence that rules out
chance, confounding, and other biases with reasonable confidence is sufficient to infer a causal
relationship. Increasing uncertainty due to limited available information, inconsistency, and/or
limited coherence and biological plausibility leads to conclusions increasingly lower in the
hierarchy. Causal determinations are developed for major health effect categories (e.g.,
respiratory effects) or more specific groups of related outcomes and for the range of exposure
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concentrations of oxides of nitrogen defined to be relevant to ambient concentrations (e.g., up to
5,000 ppb Mh). Findings based on higher exposure concentrations may be considered if they
inform biological plausibility and potential modes of action and if biological mechanisms have
not been demonstrated to differ based on exposure concentration. Causal determinations are
based on the confidence in the body of evidence, considering study design and quality and
strengths and weaknesses in the overall collection of previous and recent studies across
disciplines. In discussing the causal determination, the EPA characterizes the evidence on which
the judgment is based, including the weight of evidence for individual endpoints within the
health effect category or group of related endpoints.
4.3.5 Quality Management
NCEA participates in the Agency-wide Quality Management System, which requires the
development of a Quality Management Plan (QMP). Implementation of the NCEA QMP ensures
that all data generated or used by NCEA scientists are "of the type and quality needed and
expected for their intended use" and that all information disseminated by NCEA adheres to a
high standard for quality including objectivity, utility, and integrity. Quality assurance (QA)
measures detailed in the QMP are being employed for the current primary NCh NAAQS review,
including the development of the ISA for the health criteria of oxides of nitrogen. NCEA QA
staff is responsible for the review and approval of quality-related documentation. NCEA
scientists are responsible for the evaluation of all inputs to the ISA, including primary (new) and
secondary (existing) data, to ensure their quality is appropriate for their intended purpose. NCEA
adheres to Data Quality Objectives, which identify the most appropriate inputs to the science
assessment and provide QA instruction for researchers citing secondary information. The
approaches utilized to search the literature and criteria applied to select and evaluate studies were
detailed in the two preceding subsections. Generally, NCEA scientists rely on scientific
information found in peer-reviewed journal articles, books, and government reports. The ISA
also can include information that is integrated or reduced from multiple sources to create new
figures, tables, or summation, which is subject to rigorous quality assurance measures to ensure
their accuracy.
4.4 SPECIFIC ISSUES TO BE ADDRESSED IN THE ISA
The ISA for oxides of nitrogen will contain information relevant to considering whether
it is appropriate to retain or revise the current primary NCh standards. Decisions on the specific
content of the ISA will be guided by policy-relevant questions that frame the entire review of the
primary NCh NAAQS as outlined in section 3.2 above. These policy-relevant questions are
related to two overarching issues. The first issue is whether new evidence reinforces or calls into
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question the evidence presented and evaluated in the last primary NCh NAAQS review, with
respect to factors such as the plausibility of health effects caused by exposure to oxides of
nitrogen and concentrations of oxides of nitrogen associated with health effects. The second
issue is whether uncertainties from the last review have been reduced and/or whether new
uncertainties have emerged, especially regarding the potential for correlated traffic-related
pollutants but not NCh independently to be responsible for health effects observed in association
with NO2. The ISA also will address a set of more specific policy-relevant questions related to
the available scientific evidence that stem from these issues. These questions were derived from
the last primary NCh NAAQS review, as well as from discussions of the scientific evidence that
occurred at the February/March 2012 kickoff workshop for the current review (77 FR 7149,
February 10, 2012); a CAS AC consultation on the draft plan for development of the ISA (U.S.
EPA, 2013a; 78 FR 27234, May 9, 2013; Frey, 2013); a public workshop that included review of
initial draft materials for the ISA (78 FR 27374, May 10, 2013), and CASAC review of the draft
IRP (Frey, 2014). The specific questions to be addressed in the ISA are listed below by topic
area. In the ISA, most of these topic areas will be discussed in separate chapters or sections.
Atmospheric Science and Ambient Concentrations
The ISA will present and evaluate data related to ambient concentrations of oxides of
nitrogen; sources leading to the presence of oxides of nitrogen in the atmosphere; and physical
and chemical processes that determine the formation, degradation, and lifetime of oxides of
nitrogen in the atmosphere. Key conclusions from the 2008 ISA were that motor vehicles and
power plants are the major U.S. sources of NOx emissions and that ambient concentrations of
NCh display heterogeneity across spatial and temporal scales, are higher near roadways, and are
correlated with ambient concentrations of several other traffic-related pollutants (U.S. EPA,
2008a, section 5.2.1). The formation and reactions of NCh are strongly influenced by volatile
organic compounds and Os. The relationships among these pollutants are critical to the
understanding of ambient NCh concentrations. In the current review, with regard to air quality
and atmospheric chemistry, specific policy-relevant questions that will be addressed include:
• What new information is available to inform our understanding of the atmospheric
chemistry of oxides of nitrogen? How does new information characterize the role of
atmospheric chemistry in determining relationships among oxides of nitrogen species?
What new information is available with respect to formation of nitroaromatics and
nitropyrenes, which have shown toxic effects and thus, may be important in assessing
health effects from multipollutant exposures? How does the near-source environment
(e.g., near major highways or large combustion sources) influence chemistry of oxides of
nitrogen?
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• What new information exists regarding characterization of sources of ambient oxides of
nitrogen in both urban and rural environments? What are the relevant spatial and
temporal scales for considering ambient emissions of oxides of nitrogen? What new
information is available regarding existing and emerging sources of energy and impacts
on emissions of oxides of nitrogen?
• To what extent have new methods been developed to improve measurements of oxides of
nitrogen, particularly those that measure NCh directly? How have these new methods
reduced interference problems in measuring oxides of nitrogen? What limitations still
remain?
• Based on recent air quality and emissions data, what is known about recent emissions and
resulting ambient concentrations of oxides of nitrogen? How have emissions and
concentrations of NOx and of NCh changed since the 2008 ISA? To what extent can new
data sources (e.g., satellites) or air quality analyses be used to improve the
characterization of ambient concentrations of oxides of nitrogen?
• What spatial and temporal patterns can be seen in ambient NCh and NOx concentrations?
In particular, what spatial and temporal patterns can be seen on a micro-scale near
sources including major roadways and combustion sources such as power plants and
biomass burning? What do ambient air quality characterizations (including examinations
of the influence of meteorological parameters) indicate about spatial patterns on
neighborhood, urban, regional, and national scales?
• Based on air quality and emissions data for oxides of nitrogen and atmospheric chemistry
models, what are likely background concentrations of oxides of nitrogen in the absence of
anthropogenic emissions?
• What new information is available to characterize the influence of meteorological
parameters on micro- to neighborhood-scale concentrations of oxides of nitrogen?
• What information is available on interactions between oxides of nitrogen and
copollutants in the atmosphere that may alter the spatial distributions of oxides of
nitrogen?
Human Exposure
The ISA will evaluate the factors that influence exposure to ambient oxides of nitrogen
and the measurement error and other uncertainties associated with extrapolation of ambient
concentrations to personal exposures to oxides of nitrogen of ambient origin, particularly in the
context of interpreting results from epidemiological studies. The evaluation will build upon the
discussion in the 2008 ISA, which concluded that relationships between ambient concentrations
and personal exposures were inconsistent and more poorly characterized for long-term than
short-term exposures. Further, measurement error associated with using ambient Mh
concentrations obtained from central site monitors as measures of short-term exposure in
epidemiological studies tended to bias the magnitude of associations between ambient NCh and
health effects toward the null (U.S. EPA, 2008a, section 5.2.2). The ISA will describe sources of
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potential exposure measurement error, the strengths and limitations of various exposure
assessment method, and implications on inferences about epidemiological relationships observed
between oxides of nitrogen and health effects. Exposure measurement error and its impact on the
strength of epidemiological inference can depend on a number of factors including study design,
the extent of spatial variability in ambient concentrations in the selected study areas, time-
activity patterns of the study population, and the exposure assessment method. For example,
exposure measurement error may differ by the exposure period of interest as most
epidemiological studies of short-term exposure (e.g., population-level time-series studies, panel
studies) rely on temporal variation in exposure while epidemiological studies of long-term
exposure (e.g., longitudinal cohort studies) rely on spatial variability of exposure. The
uncertainties related to exposure measurement error and impact on epidemiological inference
will inform judgments about the confidence in the body of epidemiological results and in turn,
causal determinations for the various health effect categories evaluated. In the current review,
with regard to exposure assessment and implications on epidemiological inference about health
effects, specific policy-relevant questions that will be addressed include:
• How have modeling techniques such as sub-grid scale modeling within chemical
transport models, air quality dispersion models, and land use regression models been
advanced in recent years? What new information is available regarding modeled
estimates of spatially-resolved (at the micro-, middle-, and neighborhood scales) ambient
NCh and NOx concentrations used for exposure assessment?
• To what extent have hybrid modeling approaches that combine ambient concentrations
with air quality models been recently developed to improve the spatial and temporal
resolution of exposure estimates within a community? What advancements have been
made regarding validation of hybrid models and their ability to estimate source
attribution for exposures to NCh or NOx?
• What are the relationships between oxides of nitrogen measured at stationary monitoring
sites and personal short-term and long-term exposure? What evidence is available
regarding these relationships in environments near roads or other sources?
• What new information exists about the relationship between NO, NO2, and NOx
concentrations and indicators of near-source pollution including distance to sources (e.g.,
major roadways) and source activity levels (e.g., traffic counts)?
• What studies are available to examine the relationship between near-road oxides of
nitrogen, on-road oxides of nitrogen, and in-vehicle exposures to oxides of nitrogen?
Given the concern over short-term exposures at or less than one hour in duration, are the
directly emitted NO2/NOx ratios sufficiently high such that on-road commuting NO2
exposure is a significant component of total NO2 exposure?
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• To what extent is information available characterizing how well the current area-wide
and near-road NCh monitoring sites represent exposures to populations living near major
roads?
• What new information exists regarding characterization of error in assessment of short-
term and long-term exposure of oxides of nitrogen and how it influences personal-
ambient exposure relationships? What implications does exposure measurement error
have on inference about epidemiological relationships observed between oxides of
nitrogen and health effects? Do the implications vary according to factors such as
exposure duration, study design, and exposure assessment method?
• What information is available regarding differences in exposure patterns for oxides of
nitrogen and personal-ambient exposure relationships among various lifestages and
specific groups within populations? What implications do these potential differences in
exposure measurement error have on inferences about relationships with health effects
observed in general population studies versus those conducted in specific lifestages and
groups within the population (e.g., people with underlying health condition)?
• What are the implications for epidemiology for assessing health effects of exposures to
oxides of nitrogen when there are instrumentation errors, such as interference in
measurements of ambient NCh concentrations from other nitrogen compounds?
• What new information exists regarding exposure to oxides of nitrogen in a multipollutant
context with other gaseous pollutants (e.g., carbon monoxide, nitrous acid), particle phase
pollutants (e.g., ultrafine particles, black carbon, organic carbon, transition metals)
generated by traffic or other combustion sources, or of a mixture of traffic-related
pollutants?
o To what extent do NCh measurements serve as surrogates of exposure to the other
pollutants listed above? How does information about pollutant co-exposures aid in
evaluation of copollutant confounding in epidemiological associations between
oxides of nitrogen and health effects?
o How do interactions among pollutants in the atmosphere influence exposure to oxides
of nitrogen? How does information about pollutant interactions aid in evaluation of
effect measure modification in epidemiological associations between oxides of
nitrogen and health effects?
• What new information exists regarding indoor exposures to oxides of nitrogen, including
those generated indoors and those that infiltrate from outdoors? What new information is
available regarding how oxides of nitrogen are generated indoors?
• What new information is available regarding the interaction of indoor oxides of nitrogen
with organic compounds emitted from home cleaning and deodorizing products to form
organic nitrates indoors that may influence human exposure to NCh?
Dosimetry and Modes of Action
The ISA will evaluate literature focusing on dosimetry and modes of action that may
underlie the health outcomes associated with exposure to NCh and/or NO. These topic areas will
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be evaluated using both human and animal data. The 2008 ISA concluded that inhaled NCh, at
ambient-relevant concentrations, reacts with constituents of the epithelial lining fluid of the
respiratory tract, including antioxidants, to form secondary reaction products (U.S. EPA, 2008a,
section 2.6). These secondary reaction products initiate a cascade of events that are thought to be
responsible for health effects observed in association with NCh exposure. Additionally, findings
of NCh-induced changes in airway responsiveness, airway inflammation, and lung host defenses
were described as key mechanistic support for NCh-related respiratory effects such as respiratory
symptoms and emergency department visits. In the current review, specific policy-relevant
questions related to dosimetry and modes of action that will be addressed include:
• What new information is available to inform our understanding of the potential biological
mechanisms underlying responses to NCh and/or NO exposures at concentrations defined
in the ISA to be environmentally relevant (up to 5,000 ppb, see section 4.3.4 above), with
a focus on response pathway(s) and exposure-dose-response relationships?
• What information is available to characterize intra- and inter-individual variability in
biological responses following exposure to NCh and/or NO?
• What are the effects of host factors such as lifestage, sex, pre-existing disease, genetic
background, and physical activity on the uptake of NO2 and/or NO and cellular and tissue
responses as well as biological mechanisms that may underlie health effects associated
with exposure to oxides of nitrogen?
• What information is available to discern the relative contributions to local NO2 and/or
NO of: (1) ambient exposures toNO2 and/or NO; (2) dietary consumption of nitrite and
nitrate which undergo transformation to NO; and (3) endogenous formation of NO2
and/or NO?
• What NO2 and/or NO reaction products, including oxides of nitrogen metabolites, can be
found in the cells, tissues, or fluids of the respiratory tract and in the systemic circulation
that may serve as markers of NO2 and/or NO exposure and effect?
• What biological processes, from the molecular to whole organ level, can be qualitatively
or quantitatively compared across species?
• To what extent can the inhalation dosimetry of NO2 and/or NO be extrapolated between
species, qualitatively or quantitatively?
• Do interactions between other inhaled pollutants and NO2 and/or NO influence the
mechanisms underlying the health effects of NO2 and/or NO? If so, how might this
information provide understanding of the potential for a copollutant to act as an effect
measure modifier of health effects related to oxides of nitrogen?
Health Effects
In the 2008 ISA, the health effects evidence for oxides of nitrogen was largely indexed by
studies of NO2 with the bulk of the evidence provided by short-term exposure studies evaluating
respiratory effects. The EPA will build on this assessment and evaluate the newly available
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literature related to respiratory, cardiovascular, reproductive, and developmental health effects,
mortality, and cancer associated with exposure to oxides of nitrogen. Depending on data
availability, other health effects also may be evaluated, for example, those related to the central
nervous system or gastrointestinal system. The ISA will evaluate health effects that occur
following both short- and long-term exposures as examined in epidemiological, controlled
human exposure, and animal toxicological studies. Efforts will be directed at identifying the
concentrations at which effects are observed, including those in potential at-risk lifestages and
populations, and assessing the role of oxides of nitrogen within the broader mixture of ambient
pollutants. The discussion of health effects also will be integrated with relevant information on
dosimetry and modes of action. In the current review, with regard to consideration of health
effects associated with short-and long-term exposure to oxides of nitrogen, specific policy-
relevant questions that will be addressed include the following:
Short-Term (i.e., minutes to up to one month) and Long-Term (i.e., more than one month to
years) Exposure
• What do studies across scientific disciplines (i.e., controlled human exposure, animal
toxicological, epidemiological) indicate about the relationships of exposures to oxides of
nitrogen with health effects that are examined in relation to both short-term and long-
term exposure: respiratory effects, cardiovascular effects, and premature mortality?
• How does evidence for health effects associated with oxides of nitrogen compare among
healthy individuals, those with pre-existing disease states (e.g., people with asthma or
cardiovascular disease), particular lifestages, or groups characterized by other factors that
potentially modify risk (e.g., genetic, nutritional)?
• At what ambient concentrations of oxides of nitrogen are associations with the various
health effects observed in epidemiological studies most well characterized?
• To what extent does the scientific evidence support the occurrence of health effects of
exposure to oxides of nitrogen at ambient concentrations that are lower than those
previously demonstrated? If so, what uncertainties are related to these associations and
are the health effects in question important from a public health perspective?
• What evidence is available regarding the shape of concentration-response relationships
between exposure to oxides of nitrogen and various health endpoints?
o Is there evidence to support the identification of a discernible threshold below which
health effects will not occur?
• What evidence is available regarding the nature of health effects from interactions
between oxides of nitrogen and other ambient air pollutants in comparison to health
effects following exposure to oxides of nitrogen alone?
o To what extent are the observed epidemiological health effect associations
attributable to ambient oxides of nitrogen, another ambient pollutant, or to the
pollutant mixtures that oxides of nitrogen may be representing? What information is
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available specifically from studies conducted in populations spending time or living
near roads or other sources? To what extent do findings from experimental studies
provide biological plausibility for the effects observed in epidemiological studies?
Short-Term Exposure
• How do results of recent studies or new interpretations of previous findings expand our
understanding of the relationship between short-term exposure to oxides of nitrogen and
airway hyperresponsiveness or other lung function changes, inflammation, host defense
against infection disease, respiratory symptoms, and asthma exacerbations?
• What new information is available on the effects of short-term exposure to oxides of
nitrogen on acute cardiovascular events in humans such as myocardial infarction, stroke,
increases in blood pressure, and arrhythmias?
• To what extent does short-term exposure to oxides of nitrogen contribute to premature
mortality and health effects beyond the respiratory and cardiovascular systems?
• What is the extent of coherence of findings for effects such as hospital admissions,
emergency department visits, and mortality with changes in lung function, airway
hyperresponsiveness, heart rate variability, and vasomotor function? What other
biomarkers of early effect may be used in the assessment of health effects?
• To what extent does information across epidemiological, controlled human exposure, and
animal toxicological studies on the pattern of exposure to oxides of nitrogen (e.g., peak,
repeated peak, average) provide understanding of the time course for changes in health
effects? What information is available on time-activity patterns of study subjects such as
time spent outdoors or activity levels that can aid in the understanding of nature of
exposure or dosimetry of ambient oxides of nitrogen that are associated with health
effects?
• To what extent do data across epidemiological, controlled human exposure, and animal
toxicological studies provide information on health effects related to specific oxides of
nitrogen (e.g., NCh, NO) or averaging times of exposure to oxides of nitrogen that are
relevant to the 1-hour standard? What data exist comparing associations of health effects
among various short-term metrics of exposure to oxides of nitrogen (e.g., 1-hour versus
24-hour)?
• What information is available on the health effects of on-road or near-road commuting or
occupational exposures to oxides of nitrogen on health outcomes?
Long-Term Exposure
• How do the results of recent studies expand our understanding of the relationships
between long-term exposure to oxides of nitrogen and chronic respiratory effects
manifested as a reduction in lung function, a reduction in lung development, or
morphological changes?
• To what extent does long-term exposure to oxides of nitrogen promote exacerbation and
development of asthma or other chronic lung diseases, cardiovascular diseases, and other
conditions?
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• To what extent does long-term exposure to oxides of nitrogen contribute to other health
effects or changes in molecular and cellular processes, e.g., cognitive, behavioral,
reproductive, developmental, cancer or epigenetic effects?
• What information is available on the effects of exposures to oxides of nitrogen on health
outcomes in populations living near major roads or working on or near major roads?
• What information is available regarding the effect of long-term, low-concentration
exposure to oxides of nitrogen on an individual's sensitivity to short-term but higher
concentration exposures?
• What evidence is available regarding health effects related to long-term exposure
windows other than annual or lifetime average (e.g., preconception, pregnancy average,
pregnancy trimester average)? What data are available comparing associations of health
effects among various long-term oxides of nitrogen exposure metrics (e.g., annual,
seasonal, pregnancy average)?
Causality
In the 2008 ISA, the EPA concluded that the findings of epidemiological, controlled
human exposure, and animal toxicological studies collectively provided evidence "sufficient to
infer a likely causal relationship " between short-term NCh exposures and respiratory effects
(U.S. EPA, 2008a, sections 3.1.7 and 5.3.2.1). In looking at abroader range of health effects
associated with short- or long-term exposures to oxides of nitrogen, the 2008 ISA concluded
there was evidence "suggestive but not sufficient to infer a causal relationship" between short-
term NCh exposures and premature mortality and between long-term NCh exposures and
respiratory effects (U.S. EPA, 2008a, sections 5.3.2.3 and 5.3.2.4). Furthermore, the 2008 ISA
concluded that the scientific evidence was "inadequate to infer the presence or absence of a
causal relationship" between short-term NCh exposures and cardiovascular effects as well as
between long-term NCh exposures and cardiovascular effects, reproductive and developmental
effects, premature mortality, and cancer (U.S. EPA, 2008a, sections 5.3.2.2, 5.3.2.5, and 5.3.2.6).
The causal determinations, based on the causal framework and integration of available
evidence from previous and recent studies (see sections 4.3.3 and 4.3.4 above), were presented
with a summary of the available evidence at the end of the sections for each broad health effect
category and in the integrative synthesis chapter at the beginning of the ISA. In the current
review, specific policy-relevant questions related to the causality determinations that will be
addressed include:
• Does the evidence base from recent studies contain new information to support or re-
evaluate the causal determinations made for relationships between NCh exposure and
various health effects in the 2008 ISA?
• What is the strength of inference from epidemiological studies based on the extent to
which they have:
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o Examined exposure metrics that capture the spatial and/or temporal pattern of oxides
of nitrogen in the study area
o Assessed potential confounding by other traffic-related pollutants and other factors?
• What information is available to support a rationale for forming causal determinations for
other oxides of nitrogen (e.g., NO, NOx)?
• What information is available regarding the health impacts of a decrease in ambient
concentrations of oxides of nitrogen to inform causal determinations?
Uncertainties/Limitations
The causal determinations described above for the relationships between NCh exposure
and health effects were informed by uncertainties and limitations in the evidence. The 2008 ISA
noted the possibility that pollutants other than oxides of nitrogen within the broad ambient
mixture were responsible for health effects observed in association with NCh and/or limited
information from experimental studies to provide biological plausibility (U.S. EPA, 2008a,
section 5.3). The 2008 ISA also described uncertainty related to the use of ambient NCh
concentrations to represent personal ambient NCh exposure (U.S. EPA, 2008a, section 5.2.2). In
each of the health effects sections and the integrative synthesis chapter, the ISA will evaluate
uncertainties and limitations in the scientific data. These uncertainties also will inform causal
determinations.
The ISA will evaluate potential confounding by other ambient pollutants in a hierarchical
manner. Based on their stronger correlations with ambient oxides of nitrogen and consequent
stronger potential for confounding, primary attention will be given to traffic-related pollutants
such as carbon monoxide, fine particulate matter, black/elemental carbon, and ultrafine particles.
The ISA also will evaluate potential confounding by other traffic-related pollutants such as
volatile organic compounds and other criteria pollutants such as sulfur dioxide and ozone. To
assess the independent effects of oxides of nitrogen, the ISA will examine whether
epidemiological associations with oxides of nitrogen are found in copollutant models, which is
the predominant method used in air pollution epidemiology to estimate the effect of one pollutant
for a given concentration of a copollutant. The ISA also will evaluate whether oxides of nitrogen
show interactions with copollutants or joint effects in associations with health outcomes. The
assessment of potential confounding, interactions, or joint effects will draw upon results from
health effects studies as well as available information on copollutant interactions in the
atmosphere that influence the spatial distributions and modes of action for oxides of nitrogen and
copollutants. In the absence of these aforementioned methods, the ISA will examine whether
single-pollutant epidemiological associations with health effects in a given study differ between
oxides of nitrogen and copollutants and examine the magnitude of correlation among pollutants.
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Drawing from discussion about the strengths and limitations of various exposure
assessment methods, the ISA will evaluate the strength of inference in epidemiological studies
by considering information such as the exposure duration being examined, the extent of spatial
and/or temporal variability in ambient oxides of nitrogen in the study area, the distribution of
monitoring sites in the study area, the performance of exposure models used, and time-activity
patterns of the study population. To the extent available, data from near-road monitoring
networks will be used to characterize the spatial distributions in ambient NCh concentrations and
human exposures, and in turn, the potential exposure measurement error in particular study areas
based on the particular method of exposure assessment used. The adequacy of exposure
assessment will be considered in weighing the quality of evidence, and in turn, forming causal
determinations.
Epidemiological evidence is unlikely to completely address the aforementioned
uncertainties. Any individual study is unlikely to evaluate all potentially correlated copollutants.
And, the limitations of epidemiological methods to separate effects of highly correlated
pollutants or separate the effects of more than two pollutants in the same model are well
recognized. With respect to exposure measurement error, studies with personal ambient exposure
measurements are not likely to be available. Thus, coherence with other lines of evidence are
important to inform uncertainties in the epidemiological evidence regarding copollutant
confounding and exposure measurement error. Controlled human exposure and toxicological
studies that show effects on similar outcomes at relevant NCh exposures or effects on key
cellular and molecular events in biological pathways leading to the health effect are important in
providing biological plausibility. As well, epidemiological studies of indoor NCh are informative
because relationships with copollutants may differ from those in outdoor environments.
In the current review, specific policy-relevant questions related to the evaluation of
uncertainties/limitations that will be addressed include:
• To what extent are the observed health effect associations attributable specifically to
ambient oxides of nitrogen versus only other pollutants contained in the broader air
pollution mixture? For example, the ISA will consider the possibility that ambient
concentrations of NCh serve not only as an indicator for oxides of nitrogen but as a
surrogate for exposure to other vehicle exhaust gaseous and paniculate pollutants.
o What information about the independent health effects of exposure to oxides of
nitrogen can be synthesized from the various lines of available evidence, for example,
copollutant models, associations with other traffic-related pollutants, analysis of
indoor NCh, comparisons of results from locations with varying pollutant mixtures,
studies of traffic proximity or intensity, and experimental studies?
o How does confounding by co-exposure to other ambient traffic-related pollutants
(e.g., particulate matter, carbon monoxide) or meteorological factors influence
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relationships observed between health effects and both short- and long-term
exposures to oxides of nitrogen? To what extent do other factors serve as potential
confounding factors in epidemiological studies (e.g., age, SES, other exposures such
as noise)?
• What information is available to assess the influence of exposure measurement error on
uncertainty in epidemiological study results?
o How can the influence of exposure measurement error be assessed through the
examination of various study designs, study populations, exposure assessment
methods, spatial and/or temporal variability in ambient concentrations, spatial
alignment of study population and ambient measurements, and analytical models?
o What information is available regarding the time-activity patterns of study subjects
including time spent outdoors, spatial distribution of study subjects and ambient
monitors, exposure assessment methods, potential interference in the measurement of
NCh from other oxides of nitrogen in low traffic, downwind locations?
At-risk Lifestages and Populations
The ISA will evaluate an array of factors that may characterize potential at-risk lifestages
or populations: intrinsic factors (biological factors such as age or genetic variants), acquired
factors (e.g., pre-existing disease), extrinsic factors (nonbiological factors such as diet, low SES),
and/or factors affecting dose or exposure (e.g., sex, age, outdoor activity or work, low SES,
physical activity). The 2008 ISA discussed persons with pre-existing respiratory disease (e.g.,
people with asthma), children, and older adults as populations and lifestages potentially at
greater risk of NCh-related health effects (U.S. EPA, 2008a, section 5.3.2.8). Since completion of
the 2008 ISA, the EPA has developed a framework to provide a consistent and transparent basis
for classifying the weight of evidence for factors that may characterize at-risk lifestages or
populations according to one of four levels: adequate evidence, suggestive evidence, inadequate
evidence, and evidence of no effect (U.S. EPA, 2013c, Table 8-1). In this framework, key
considerations in drawing such conclusions include consistency of findings for a factor within a
discipline and, where available, coherence of the evidence across disciplines. Several lines of
evidence inform conclusions about at-risk lifestages and populations but primarily includes
observational or experimental studies that compare exposure to oxides of nitrogen or
relationships with health effects among groups that vary by some characteristic such as pre-
existing disease or age (i.e., exposure or effect modification). Also relevant are comparisons of
results among observational or experimental studies that examine different population
characteristics or time windows of exposure and experimental studies that examine health effects
of oxides of nitrogen in a group with a particular characteristic (e.g., genetic background, pre-
existing disease).
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The various factors listed above may influence risk by increasing exposure, dose, or
biological effect at a given dose, and some factors (e.g., SES) may contribute to risk in multiple
ways. Conclusions will be drawn for the collective body of information available for a particular
at-risk lifestage or population, not separately to classify risk due to increased exposure, dose, or
biological effect. In the current review, with regard to at-risk lifestages and populations, specific
policy-relevant questions that will be addressed include:
• Based on evidence integrated across studies and disciplines that examine factors that may
increase exposure to oxides of nitrogen and/or risk of health effects related to exposure to
oxides of nitrogen, what conclusions can be drawn about the presence of at-risk lifestages
(e.g., the developing fetus, children, older adults) or populations and/or critical time
windows of exposure?
• To what extent do living, working, attending school, or exercising near major roads or
commuting on roads contribute to greater exposure to oxides of nitrogen and/or risk of
related health effects? Given the concentration gradients observed for ambient oxides of
nitrogen with distance to roads, what information is available regarding the sizes and
sociodemographic characteristics of populations living near major roads?
• Which disciplines contribute information about particular at-risk lifestages and
populations, and to what extent does limited or lack of information from specific
disciplines produce uncertainty in conclusions about at-risk lifestages and populations?
• How does recent information compare with that evaluated in the 2008 ISA regarding
people with pre-existing respiratory disease, genetic variants, or low SES as potential at-
risk populations and children or older adults as potential at-risk lifestages?
• What information is available that provides insight as to whether a potential at-risk
lifestage or population has higher exposure or dose of oxides of nitrogen, has a greater
biological response to a given exposure, and/or experiences health effects at lower
exposure concentrations?
• What is the extent of the coherence of evidence regarding potential at-risk lifestages or
populations for both short- and long-term exposures to oxides of nitrogen?
• What quantitative information is available to characterize the magnitude of greater
biological response or risk of health effects associated with exposure to oxides of
nitrogen in a particular at-risk lifestage or population?
• What evidence is available regarding populations at increased risk because of co-
occurring risk factors (e.g., young age, residence near major roads, lower SES, and
asthma; older age and pre-existing cardiovascular disease)?
Public Health Impact
The integrative synthesis chapter at the beginning of the ISA will present concepts that
integrate evidence on health effects and consequent public health significance to aid in the
assessment of the public health implications of exposure to short- and long-term exposure to
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oxides of nitrogen. The discussion will include evaluation of the adversity of the health effects
potentially associated with exposure to oxides of nitrogen. The assessment of public health
impact also may include, as appropriate, an estimation of the sizes of potential at-risk lifestages
and populations and discussion of the public health significance of the magnitudes of change in
health outcomes characterized to result from ambient air exposure to oxides of nitrogen. Further,
to the extent that evidence is available, the integrative synthesis chapter of the ISA will discuss
what evidence is available regarding interrelationships among risk factors in a particular lifestage
or population as described in the preceding section that may add to the understanding of the
public health impact of exposure to oxides of nitrogen.
4.5 SCIENTIFIC AND PUBLIC REVIEW OF THE ISA
Drafts of the ISA will be made available for review by the CAS AC and the public as
indicated in Figures 1-1 and 4-1 and Table 2-1 above. Availability of draft documents will be
announced in the Federal Register. The CAS AC will review the draft ISA documents and
discuss its comments in public meetings that will be announced in the Federal Register. The
EPA will take into account comments, advice, and recommendations received from the CASAC
and from the public in revising the draft ISA documents. The EPA has established a public
docket for the development of the ISA.50 After appropriate revision based on comments received
from the CASAC and the public, the final document will be made available on an EPA website.
A notice announcing the availability of the final ISA will be published in the Federal Register.
50The ISA docket can be accessed at www.regulations.gov using Docket ID number EPA-HQ-ORD-2013-
0232.
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5 QUANTITATIVE RISK AND EXPOSURE
ASSESSMENT
Within the context of NAAQS reviews, a quantitative risk and exposure assessment
(REA) is designed to estimate human exposure and health risks associated with existing and
potential alternative standards. The appropriate scope of any REA will be informed by the
availability of scientific information from the ISA as well as air quality information and
information on data and models that may help to address important uncertainties or provide
additional insights beyond those provided by previous REAs. As a result, the first step in the
REA planning process is an assessment of the appropriate scope of the REA, which includes a
determination of whether a distinct REA document is needed. As part of this planning process,
we evaluate the 2008 REA in the context of the extent to which important uncertainties may be
addressed by new information available since the previous review and the extent to which new
information may change results of the 2008 REA in important ways or may allow for additional
analyses that can address important gaps in our understanding of the exposures and risks
associated with NCh.
This phase of the NAAQS review begins with the preparation of a REA Planning
Document and considers the extent to which newly available scientific evidence and
tools/methodologies provide support for conducting quantitative risk and exposure assessments.
To the extent warranted, the scope and methods for components of exposure/risk assessments
will be described. As outlined in Table 2-1 above, the EPA plans to issue this REA Planning
Document in November 2014. This document will be the subject of a CASAC consultation and
will be made available to the public for review and comment. CASAC advice and public
comments on the draft IRP (Frey, 2014) will be considered in developing the REA Planning
Document. If warranted, one or more drafts of an REA will then be prepared and released for
CASAC review and public comment prior to completion of a final REA.
The information newly available in this review will be considered in light of the
comprehensive, complex and resource-intensive quantitative assessments of human exposure and
health risks documented in the 2008 REA as discussed in section 5.1 below. As discussed in
section 5.2 below, the REA Planning Document will consider the available scientific evidence,
tools, and methodologies in light of areas of uncertainty identified in the 2008 REA and the
potential for new analyses to provide notably different exposure and risk estimates, with lower
associated uncertainty. The timeline for collection of ambient NCh measurement data within
near-road environments under the recently revised monitoring requirements is recognized as an
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important consideration for the REA Planning Document. CAS AC advice (Frey, 2014) and
comments from the public on the draft IRP, as well as the availability of resources, will inform
the development of the REA Planning Document.
5.1 OVERVIEW OF RISK AND EXPOSURE ASSESSMENT FROM
PRIOR REVIEW
In the last review, as summarized in sections 5.1.1, 5.1.2, and 5.1.3 below, the EPA
designed and developed three approaches to estimating exposures and health risks associated
with a number of ambient air quality scenarios (i.e., recent air quality unadjusted, air quality
adjusted to simulate just meeting the then-existing annual standard (i.e., annual average of 53
ppb), and air quality adjusted to simulate just meeting several potential alternative daily
maximum 1-hour standards). Briefly, in the first approach ambient NCh concentrations
(measured and modeled) were compared to 1-hour health effect benchmark levels derived from
the controlled human exposure literature. In the second approach, modeled estimates of human
exposures in an urban study area were compared to these same health effect benchmark levels. In
the third approach, concentration-response relationships from an epidemiological study were
used to estimate health impacts associated with ambient NCh concentrations in an urban study
area. An overview of these approaches used and results generated in characterizing health risks is
provided below.
The 2008 REA's health risk estimates were, in part, based on pre-2010 ambient monitor
concentrations. Those monitors primarily measured NCh concentrations that were representative
of a broad geographic area (e.g., area-wide ambient measurements)51 rather than concentrations
at specific locations where the highest concentrations of NCh were likely to be found (e.g.,
maximum or peak ambient measurements including near major roadways).
5.1.1 Ambient Air Quality Characterization
In the first approach, we compared 1-hour ambient NCh concentrations (1995 to 2006)
with short-term health effect benchmark concentrations of 100, 150, 200, 250, and 300 ppb
51 Area-wide monitors are defined as those sited at neighborhood, urban, and regional scales, as well as
those monitors sited at either a micro- or middle-scale that are representative of many such locations in the same
Core Based Statistical Area (CBSA) (40 CFR 58.1). The introduction and first use of the term "area-wide" was in
the final rule for the last primary NO2 NAAQS review as part of the NO2 minimum monitoring requirements (75 FR
6504, February 9, 2010). The term was formally defined in the final rule for the most recent PM NAAQS review (78
FR 3235 and 3281 to 3282, January 15, 2013). The underlying spatial scales are defined in 40 CFR part 58
Appendix D, section 1.2(b).
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NCh52 in order to identify the number of days a particular benchmark concentration was
exceeded per monitor per year. All U.S. monitoring sites where NCh data had been collected
were included in this analysis, and, as such, the results generated were considered a broad
characterization of national air quality and potential human exposures that might be associated
with these concentrations.53 The available NCh air quality for 18 Core Based Statistical Areas
(CBSAs) named study areas54 and two aggregate study areas were separated into two six-year
groups; one contained data from years 1995-2000, representing an historical data set; the other
contained the monitoring years 2001-2006, representing recent ambient monitoring (U.S. EPA,
2008b, section 7.2.2).
Each of these monitoring year groups and study areas were evaluated considering the
ambient NCh concentrations as they were reported and representing the conditions at that time
(termed in that assessment "as is"). This served as the first air quality scenario evaluated as part
of the air quality characterization. Further, within each year group and study area we categorized
the monitors using their sited distance from a road: at or within 20 meters (< 20 m), between 20
and 100 meters (> 20 m to < 100 m), and at least 100 meters from a road (> 100 m).55 These
ambient monitor data were categorized in this manner to account for the potential influence of
vehicle emissions on NCh concentrations measured at the monitors within close proximity to
roadways (U.S. EPA, 2008b, section 7.2.3). There was potential for different concentration
levels measured at each of these locations (i.e., near-road monitors versus those sited away from
roadways) and thus potentially different exposure concentrations experienced by those persons
52 The 1-hour NOa health effect benchmark levels were based on NCh exposure concentrations associated
with increased airway responsiveness in asthmatics and determined from 1 to 2 hour duration controlled human
exposure studies. These benchmark values were used for the evaluation of both the NOa air quality concentrations
and estimated NOa exposures.
53 After applying a 75% data completeness criterion the final analytical data base included 627 monitors
collecting ambient concentrations for 4,177 site-years of data (a valid monitoring day had>18 hourly measurements;
monitors included in the analysis had >75% valid monitoring days in a year).
54 At the time the assessment was conducted, we used the terms CMSA/MSA to describe the monitors
associated with metropolitan statistical areas. We replaced that terminology here with CBS A to reflect current
terminology. An initial pool of monitors was subset from the total set of monitors based on their belonging to
specific CBS A. Then we selected study areas having annual mean NCh concentrations occurring at a minimum of
one monitor at or above 25.7 ppb (i.e., the 90th percentile concentrations across all study areas and site-years) and/or
had at least one reported 1-hour NCh level greater than or equal to 200 ppb (i.e., the lowest level of the potential
health effect benchmarks indicated by the ISA at the time these study areas were identified for investigation in the
2008 REA). All remaining not included in this collection of named study areas were aggregated into either one of
two groups: all other CBS A or all other non-CBS A.
55 In our assessment, road distances to each monitor were generally determined using a Tele-Atlas roads
database in a GIS application. The road types used to identify near-road monitors were those defined as: l=primary
limited access or interstate, 2=primary US and State highways, 3=Secondary State and County, 4=freeway ramp,
5=other ramps. Note only the monitors falling within the 18 identified study areas had estimated distances to these
identified roads types, all other monitors (either characterized as 'other CMSA/MSA' or 'all other non-
CMSA/MSA') were assumed to be > 100 m from a road.
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spending time in these locations. Then, for each ambient monitor, we summed the number of
days per year that monitor recorded a daily maximum 1-hour concentration at or above the health
effect benchmark levels and summarized this metric for each study area, year group, and
roadway distance group, using descriptive statistics (e.g., means, maximums) (U.S. EPA, 2008b,
section 7.2.5).
A second air quality scenario in the air quality characterization used the as is ambient
monitoring data obtained from monitors sited >100 m from a road combined with an on-road
concentration adjustment factor to estimate on-roadNO2 concentrations for each of the year-
groups and study areas. This scenario was developed by recognizing that motor vehicles are
important emission sources of NOx and NCh and that people spend time inside vehicles while
travelling on roadways. At that time, a strong relationship had been reported between NCh
concentrations measured on roadways and NCh concentrations measured at increasing distance
from the road, generally in the form of a first-order exponential decay (e.g., Cape et al., 2004).
We derived an empirical distribution of on-road adjustment factors using data from published
studies that reported on- and near-road NCh concentrations and NCh concentrations occurring at
greater distances from a road (> 100 m).56 Then, we probabilistically applied these on-road
adjustment factors to NCh concentrations reported at monitors sited > 100 meters from a road
(and generally assumed to be at a background non-roadway influenced concentration) to
approximate on-road NCh concentrations for each study area and monitor year. As described
above, for the area-wide ambient monitor data, we counted the number of days per year an
estimated daily maximum 1-hour on-road concentration exceeded the health effect benchmark
levels and summarized these data using simple descriptive statistics (U.S. EPA, 2008b, section
7.2.4).
Additional summaries of exceedances of health effect benchmark levels were generated
for the above two air quality scenarios (i.e., using the complete set of ambient monitoring
concentrations at each of the three roadway distance categories and the simulated on-road NCh
concentrations), though they differed in that the ambient concentrations were first adjusted to just
meet the then-existing annual standard or alternative daily maximum 1-hour standards. Because
the annual average 2001 to 2006 ambient concentrations57 were below the level of the existing
annual standard (i.e., < 53 ppb) as well as most of the potential daily maximum 1-hour standards
56 See Table 7-10 of the 2008 REA for the specific values of distributions that were used and Appendix A,
section 8 for the studies used and the derivation methodology (U.S. EPA, 2008b).
57 Only the 2001 to 2006 ambient concentrations were used to evaluate the existing and alternative standard
levels, the historical air quality data set with measurements from 1995 to 2000 was not used in this part of the
assessment.
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being evaluated, ambient concentrations were primarily adjusted upwards to reflect these
additional air quality scenarios. A simple proportional adjustment approach was selected to
simulate concentrations to meet a particular standard level, an approach supported by within-
monitor comparisons of low and high NCh concentration years that largely demonstrated
characteristics of a proportional relationship.58 We note also that the as is air quality could be
characterized in all study areas as falling within the evaluated alternative standard levels of 50
and 100 ppb (either a 98th or 99th percentile daily maximum 1-hour concentration); thus
simulating these particular air quality scenarios required the smallest proportional adjustment.
Simulations of just meeting an alternative standard level of 50 ppb required a downward
adjustment (U.S. EPA, 2008b, section 6.3.1). That said, the number of benchmark exceedances
for as is air quality scenarios in each study area also fell within the range of that estimated
considering the 50 and 100 ppb daily maximum 1-hour alternative standard scenarios.
5.1.1.1 Key Observations
• Ambient monitoring NOi concentrations: When considering any of the air quality
scenarios, NCh concentrations and estimated number of exceedances of health effect
benchmark levels were typically higher for monitors that were within 20 meters (m) of a
roadway than when monitors were sited farther from a roadway (i.e., between 20 m and
100 m or >100 m from a road) (U.S. EPA, 2008b, section 7.3.1). As expected, fewer
health effect benchmark exceedances were estimated to occur at the highest health effect
benchmark level (300 ppb) when compared with the lowest health effect benchmark level
(100 ppb). While results were generated for health effect benchmark levels ranging from
100 to 300 ppb in 50 ppb increments, the discussion in the 2008 REA focused only on the
health effect benchmark levels of 100, 200, and 300 ppb.
o 100 ppb health effect benchmark level: When air quality was adjusted to simulate
just meeting the then-existing annual standard (i.e., 53 ppb, annual average), most
study areas were estimated to have, on average, 50 days or more per year with daily
maximum 1-hour ambient NCh concentrations > 100 ppb, while about 1/3 were
estimated to have 100 days or more per year with daily maximum 1-hour ambient
NCh concentrations > 100 ppb. When air quality was adjusted to simulate just
meeting alternative daily maximum 1-hour standard levels of 50 and 100 ppb (98th or
99th percentile in a year), far fewer days per year were estimated to have, on average,
daily maximum 1-hour ambient concentrations > 100 ppb (i.e., <10 days per year, on
average) than compared with just meeting higher alternative daily maximum 1-hour
standard levels of 150 and 200 ppb (generally tens to hundreds of days per year with
58 Linear regressions were performed using the daily maximum 1-hour concentration distributions of each a
low and high concentration year measured at the same ambient monitor and evaluated for model linearity and
presence of statistically significant regression intercepts. Statistically significant linear regression slopes and model
R2 values strongly supported features of linearity. On a few occasions however, the presence of statistically
significant regression intercepts and deviation from linearity at upper percentile concentrations tends to obfuscate a
conclusion of proportionality existing at all monitors (Rizzo, 2008; U.S. EPA, 2008b, section 7.4.5).
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daily maximum 1-hour ambient NCh concentrations > 100 ppb) (U.S. EPA, 2008b,
section 7.5).
o 200 ppb health effect benchmark level: When air quality was adjusted to simulate
just meeting the then-existing annual standard, only two study areas were estimated,
on average, to have 10 or more days per year with daily maximum 1-hour ambient
NCh concentrations > 200 ppb. When air quality was adjusted to simulate just
meeting alternative daily maximum 1-hour standard levels of 50 and 100 ppb (98th or
99th percentile in a year), only four study areas were estimated, on average, to have at
least one day per year with daily maximum 1-hour ambient NCh concentrations > 200
ppb.
o 300 ppb health effect benchmark level: When air quality was adjusted to simulate
just meeting the then-existing annual standard, only five study areas were estimated,
on average, to experience any days with daily maximum 1-hour ambient NCh
concentrations at central site monitors > 300 ppb, and none of those study areas were
estimated to experience more than 2 such days per year, on average. When air quality
was adjusted to simulate just meeting alternative daily maximum 1-hour standard
levels of 50 and 100 ppb (98th or 99th percentile in a year), only three study areas were
estimated, on average, to have at least one day per year with daily maximum 1-hour
ambient NCh concentrations > 300 ppb.
Simulated on-road NCh concentrations: Simulated on-road annual average NCh
concentrations, estimated using an on-road adjustment factor, were on average, 80
percent higher than the respective ambient concentrations measured at distances >100 m
from a road; thus, there were a greater number of days per year where estimated daily
maximum 1-hour concentrations on roads exceeded the health effect benchmark levels.
o 100 ppb health effect benchmark level: In the majority of study areas, exceedances
of the 100 ppb health effect benchmark level were estimated to occur on roadways for
most days of the year when air quality was adjusted to simulate just meeting the then-
existing standard. Most study areas were estimated, on average, to have between 100
and 300 days per year with daily maximum 1-hour on-road NCh concentrations > 100
ppb. The mean number of days per year where estimated on-road concentrations were
> 100 ppb was always greater than that estimated using concentrations at ambient
monitoring locations (e.g., up to 18 days per year for a standard level of 50 ppb, 257
for a standard level of 100 ppb, 343 for a standard level of 150 ppb, and 351 for a
standard level of 200 ppb, based on the 98th percentile of daily maximum 1-hour
concentrations, averaged over three years).
o 200 and 300 ppb health effect benchmark levels: Even considering the higher
health effect benchmark levels, most study areas were estimated, on average, to
exceed these benchmark levels on roadways when air quality was adjusted to simulate
just meeting the then-existing annual standard. Most study areas were estimated, on
average, to have between 25 and 100 days per year with daily maximum 1-hour on-
road NCh concentrations > 200 ppb. All study areas evaluated, except one, were
estimated to have on-road NCh concentrations > 300 ppb. Four of these study areas
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were estimated, on average, to experience an average of greater than 20 days per year
with on-road NCh concentrations > 300 ppb.
5.1.1.2 Key Uncertainties
An advantage of this approach to estimating potential health risk is its relative simplicity;
however, there were a number of important uncertainties identified (US EPA, 2008b, section
7.4). One of the most important uncertainties overall was related to the spatial representation of
the ambient monitors, hence part of the reasoning to revise ambient monitoring networks at the
conclusion of the last primary NCh NAAQS review to include monitoring near roadways. To
overcome this lack of near-roadway measurement data in the 2008 REA, and as briefly described
above, we developed a simple statistical model using measurement data reported in a limited
number of peer-reviewed studies to estimate on-road NCh concentrations. In doing so, this
statistical model was characterized as having moderate or greater uncertainty in estimating on-
road NO2 concentrations, both in potentially under- and over-estimating the number of
exceedances of health effect benchmark levels. In addition, the proportional adjustment applied
to ambient air quality measurements to simulate just meeting the existing and alternative
standards was characterized as another important uncertainty, particularly when adjusting
concentrations upwards to meet or approach concentrations reflecting the existing primary
annual NCh standard. Further, the selection of health effect benchmark levels used to
characterize risk was based on controlled human exposure studies that used mild asthmatics. In
the absence of information regarding the potential health response of persons characterized as
having moderate or severe asthma, we characterized the health effect benchmark level selection
as an important uncertainty.
5.1.2 Human Exposure Assessment
In the second approach, we used an inhalation exposure model to generate more realistic
estimates of personal NCh exposure concentrations and compared those estimates of personal
exposure to the health effect benchmark levels. The EPA's Air Pollutants Exposure model
(APEX) probabilistically estimated individual exposures considering the time people spend in
different microenvironments and the variable NCh concentrations that occur within these
microenvironments across time, space, and microenvironment type, including estimation of on-
and near-roadway exposure concentrations (U.S. EPA, 2008b, section 8.2). The EPA's air
dispersion model (AERMOD) was used to estimate hourly NCh concentrations occurring at a
census tract level and at roadway receptors, considering emissions from stationary, area-wide,
and on-road mobile sources (U.S. EPA 2008b, section 8.4). This approach to assessing exposures
at that time was more resource intensive than using ambient measurements as a surrogate for
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exposure as discussed in section 5.1.1 above; therefore, only one specific study area was selected
for analysis (four counties comprising the core Atlanta, GA metropolitan statistical area, or
MSA). Although the geographic scope of this analysis was restricted, the approach provided
realistic estimates of NCh exposures, particularly those exposures associated with important
emission sources of NOx and NCh, and served to complement the results of the broad Mh air
quality characterization.
For the characterization of risks in the exposure modeling analysis, staff used the same
range of short-term potential health effect benchmark levels described above in the air quality
characterization summarized in section 5.1.1 (i.e., 1-hour NCh concentrations of 100, 150, 200,
250, and 300 ppb) and considered the same air quality scenarios (recent "as is" ambient
concentrations and ambient concentrations adjusted to just meet the existing and potential
alternative standards, though using only years 2001-2003).59 Asthmatic school-age children (5 to
17 years of age) and all asthmatics (0 to 99 years of age) were considered the most important
exposure study groups in this assessment based on their having potentially increased health risk
toNCh exposure concentrations (U.S. EPA, 2008a, section 4.3). Exposure estimates for
asthmatic school-age children were segregated from that estimated for the broader asthmatic
population group because of their potential to have greater participation rate and time engaged in
outdoor activities, thus possibly increasing their NCh exposures. When personal exposures for
either exposure study group were simulated, the output of the analysis was an estimate of the
number of individuals at risk for experiencing daily maximum 1-hour levels of NCh
concentrations of ambient origin that exceeded particular health effect benchmark levels. An
advantage of using potential health effect benchmark levels based on evidence from controlled
human exposure studies to characterize health risks in this exposure modeling approach was that
the effects observed in these studies clearly resulted from Mh exposure. This was in contrast to
using health effects associated with ambient NCh concentrations in epidemiological studies (as
discussed in the third approach described in section 5.1.3 below), which can also be associated
with pollutants that co-occur with NCh in the ambient air.
5.1.2.1 Key Observations
• Estimated daily maximum 1-hour exposures at or above potential health effect
benchmark levels using APEX were largely a function of roadway-related exposure
concentrations (greater than 99 percent). Of these exposures, approximately 70 percent
resulted from in-vehicle exposures, with the remainder associated with outdoor near-road
exposures. Overall, when simulating air quality that just meets the then-existing annual
59 This three-year period was selected to bound the most recent year of NOX emissions data available (i.e.,
2002) and used to model ambient concentrations at the time our exposure assessment was conducted (U.S. EPA,
2008b)
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standard, virtually all asthmatics in Atlanta were estimated to experience six or more
daily maximum 1-hour exposures per year to NCh concentrations above the highest
health effect benchmark level evaluated (i.e., >300 ppb), indicating the extremely limited
ability of the then-existing annual standard at that time to protect against daily maximum
1-hour exposures at or above any of the selected health effect benchmark levels (U.S.
EPA, 2008b, section 8.10).
o 100 ppb health effect benchmark level: For all air quality scenarios considered,
more than 90 percent of all asthmatics in Atlanta were estimated to be exposed to
concentration > 100 ppb at least one time per year. Of the daily maximum 1-hour
alternative standard levels evaluated, 50 ppb was the only standard level estimated to
reduce repeat daily maximum 1-hour NCh exposures above 100 ppb compared to
recent air quality concentrations.
o 200 ppb health effect benchmark level: Of all the air quality scenarios considered,
only the 98th and 99th percentile daily maximum 1-hour alternative standards set at 50
ppb were estimated to reduce the percent of asthmatics exposed at least one time per
year to concentrations > 200 ppb (by approximately 40 to 50 percent) relative to
recent air quality concentrations.
o 300 ppb health effect benchmark level: Of all the air quality scenarios considered,
only alternative standard levels set at 50 ppb or 100 ppb were estimated to reduce the
percent of asthmatics exposed at least one time per year to concentrations > 300 ppb
(by approximately 80 percent and 15 percent, respectively) relative to recent air
quality concentrations.
5.1.2.2 Key Uncertainties
The same important uncertainties exist for the exposure modeling results as described in
section 5.1.1.2 above for the air quality characterization where similar approaches were used
(i.e., proportional air quality adjustment approach and selection of health effect benchmark
levels). One important uncertainty identified as specific to the exposure assessment was the
AERMOD estimated concentrations used to represent the air quality surface across the Atlanta
study area (U.S. EPA, 2008b, section 8.12). An evaluation with limited ambient monitor
measurement data suggested a potential bias in overestimating ambient concentrations,
potentially associated with uncertainty in mobile source emissions and/or diurnal profiles used as
input (among other sources of uncertainty) (U.S. EPA, 2008b, section 8.4.8). Given the few
monitors available and overall confidence in the AERMOD system and other input data, it was
difficult to reasonably justify adjusting all estimated concentrations across the entire 4-county
modeling domain based on the differing concentrations observed at the few monitor locations,
thus they were used without adjusting for this observed difference. An additional uncertainty,
though not specifically identified as an exposure uncertainty in the prior assessment, was the
similar factors approach used to adjust 1-hour AERMOD ambient concentrations to estimate on-
and near-roadways concentrations. While AERMOD estimated l-hourNO2 concentrations
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occurring on roadway link-based receptors, these on-road concentrations could not be used
directly as an input to APEX based on its existing configuration. Thus, an on-road adjustment
factor was developed from the AERMOD estimated on-road and census tract level
concentrations (U.S. EPA, 2008b, section 8.7.2.5). These new on-road adjustment factor
distributions used by APEX, along with the number of estimated on-road peak concentrations,
were compared with those used for the air quality characterization (U.S. EPA, 2008b, section
8.4.8.3). The two similar, though independently developed, concentration adjustment approaches
were found to be comparable across a wide range of estimated values, though they diverged at
the upper percentiles of the distribution.60 And finally, in a limited set of targeted exposure
analyses, exposures were also modeled considering indoor source emissions (U.S. EPA, 2008b,
section 8.7.2.1).61 The characterization of indoor source emissions of NCh and estimated air
exchange rates used to simulate indoor microenvironments was considered an important
uncertainty.
5.1.3 Epidemiological-based Human Health Risk Assessment
In the third approach, respiratory-related 1 emergency department visits were estimated as
a function of short-term ambient NCh concentrations measured at a fixed-site monitor
representing ambient air quality for an urban area (U.S. EPA, 2008b, chapter 9). This health
endpoint was selected because the 2008 ISA reported several epidemiological studies with
observed positive associations between ambient Mh concentrations and emergency department
visits and hospitalizations for all respiratory diseases and asthma (U.S. EPA, 2008a, section
3.1.6). In this type of risk estimation approach, concentration-response functions were based on
findings from NCh epidemiological studies that relied on fixed-site, population-oriented, ambient
monitors as a surrogate for actual ambient NCh exposures and were used to estimate the impact
of daily maximum 1-hour ambient NCh concentrations, as measured at a single fixed-site
monitor, on emergency department visits (U.S. EPA, 2008b, section 9.3). By focusing on a
different health endpoint from the first two approaches described above, this epidemiological-
60 See Figure 8-8 and Table 8-7 of the 2008 REA (U.S. EPA, 2008b, pp. 175 to 176). While the divergence
between the two on-road concentration estimations was noteworthy, particularly at the upper percentiles of the
distribution, important differences in the data used to develop the two approaches were likely a highly influential
contributing factor. For example, the on-road adjustment factor used in the exposure modeling approach used 1-hour
concentrations, while the on-road adjustment factor used in air quality characterization approach was developed
from measurement data time averaged over 7 to 14 days. It is likely that the latter approach smoothes the
distribution of possible concentration ratios by using the long-term time-averaged concentrations, though we believe
it is reasonable to still highlight this issue here as an important uncertainty in the exposure assessment conducted for
the last review.
61 While potentially important in understanding health effects and the total exposure/health risk from NO2,
exposures resultant from indoor sources of NO2 have limited relevance in understanding health risk associated with
ambient concentrations.
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based approach provided additional perspective on the potential public health impacts resulting
from NCh exposures.
Because of the limited number of epidemiological studies reporting concentration-
response (C-R) functions and the limited availability of other data needed for a quantitative risk
assessment (e.g., baseline incidence rates), this type of health risk assessment was only
conducted in one study area (Atlanta, GA) using C-R functions extracted from one study
(Tolbert et al., 2007). The same general air quality scenarios described in section 5.1.1 above
were evaluated (i.e., ambient concentrations as is and those adjusted to just meeting the then-
existing annual and potential alternative daily maximum 1-hour standard levels), using ambient
air quality data from 2005 to 2007, the most recent ambient monitoring data available at the time
the assessment was conducted and similar to the years of air quality used in the epidemiological
study in determining C-R functions (1993 through 2004) (Tolbert et al., 2007).
5.1.3.1 Key Observations
• Health risks associated with just meeting the then existing annual standard: Central
estimates of annual NCh-related respiratory emergency department visits associated with
air quality adjusted upward to simulate just meeting the then-existing annual standard
(based on 2006 to 2007 air quality data) range from 8.1 to 9.0 percent of total incidence
(or 9,800 to 10,900 NCh-related incidences per year) based on single-pollutant models
and from 1.7 to 7.7 percent (or 3,100 to 9,400 NCh-related incidences per year) based on
two-pollutant models that included either CO, Os, particulate matter 10 micrometers or
less in diameter (PMio), or a three pollutant model that included both Os and PMio.
• Health risks associated with just meeting alternative daily maximum 1-hour
standards: Central estimates of annual NO2-related respiratory emergency department
visits associated with air quality adjusted to simulate just meeting a 100 ppb, 1-h daily
maximum, 98th percentile standard (based on 2005 to 2007 air quality data) ranged from
3.9 to 4.3 percent of total incidence based on single-pollutant models and from 0.8 to 3.7
percent based on co-pollutant models. Central estimates of annual NO2-related
respiratory emergency department visits associated with air quality adjusted to simulate
just meeting a 50 ppb, 1-h daily maximum, 98th percentile standard (based on 2005 to
2007 air quality data) ranged from 2.0 to 2.2 percent based on single-pollutant models
and from 0.4 to 1.9 percent based on the same above mentioned co-pollutant models.
5.1.3.2 Key Uncertainties
A few of the same important uncertainties exist for the health risk modeling results as
described in sections 5.1.1.2 and 5.1.2.2 above for the air quality characterization and exposure
modeling assessments where similar approaches were used (i.e., uncertainties related to the
proportional air quality adjustment approach and the spatial representativeness of air quality
data, in general). In addition, two uncertainties unique to the epidemiological-based health risk
assessment approach recognized as important included (1) the appropriateness of the selected
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risk model (i.e., overall form for concentration-response functions and the presence or not of a
threshold) and (2) the adequacy of the ambient NCh monitors to serve as a surrogate for
population exposure (U.S. EPA, 2008b, section 9.6).
5.2 CONSIDERATION OF QUANTITATIVE ASSESSMENTS FOR THIS
REVIEW
This discussion is focused particularly on considering the extent to which newly available
scientific evidence and tools/methodologies are available to inform our understanding of the key
areas of uncertainty identified in the 2008 REA as discussed in sections 5.1.1.2, 5.1.2.2 and
5.1.3.2 above. As outlined in Table 2-1 above, the EPA plans to release an REA Planning
Document for consultation with CAS AC and for public comments in November 2014 that will
consider the extent to which new quantitative risk and exposure assessments will be appropriate
to conduct in the current review. CASAC review and public comments on the draft IRP will be
considered in developing the REA Planning Document (Frey, 2014).
Some key areas being considered by staff, including types of data, methodologies and
tools, are identified and summarized below. Building upon each of the three approaches used to
estimate exposure or health risk in the previous review, we summarize the potential areas where
additional information, if available, would provide reasonable substance to address key
uncertainties identified in the previous review. We then discuss the potential utility and impacts
of this new information to improve upon the assessments performed in the prior review.
In evaluating the appropriateness of conducting new assessments, it is worth mentioning
a few overarching considerations. For each of the three approaches used in the 2008 REA, the
EPA staff used a mainly qualitative characterization of uncertainty that was supplemented with
information generated from a number of targeted sensitivity analyses. Where appropriate data
and methodologies are identified in the current review, it could be informative to conduct new
sensitivity analyses of important model input variables (e.g., generate a broader range of risk
estimates using alternative concentration-response functions) and perhaps better characterize
uncertainty through quantitative analyses (e.g., propagate and evaluate uncertainties of varied
model inputs through estimated exposure concentrations). Further detailed discussions regarding
the types of analyses, data needed, and methods to be used, all taken in context with available
resources, will be described in the REA Planning Document.
5.2.1 Air Quality Characterization
Table 5-1 summarizes the potentially important uncertainties where additional
information, if available, would provide reasonable substance to the discussion of improving the
air quality characterization performed in the prior review (U.S. EPA, 2008b, section 7.4).
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Table 5-1. Information (data, methods, models, etc.) identified as potentially important and/or newly available to inform the
air quality characterization for the current review.
Major
Uncertainty or
Limitation
Uncertainty/Limitation Remaining from 2008 REA
Sub-group
Description
Consideration of Potential Utility and Impact of
Information Newly Available in This Review Could
Have on Assessment
Near-Road Ambient
Monitoring Data
Ambient Monitor
Spatial and
Temporal
Representativeness
Long-term
Exposures
There is a general lack of existing ambient monitoring data
near-roads in most U.S. urban areas. This, combined with
the potential for short-term high NOa concentrations
occurring in these locations creates a significant
uncertainty regarding how often on- and near-road NCh
concentrations may exceed exposure levels of concern.
This uncertainty served as a driver for revising ambient
monitor siting.
The near-road monitoring network is to be developed
in three phases: the first set of 52 monitors to begin
measuring near-road NOa concentrations starting
January 1, 2014, followed by the addition of 23
monitors by January 1, 2015, and phase III adding 51
monitoring sites (see section 5.2 of this IRP). Given
this schedule, it is possible that there will be a lag in
the availability of the newest near-road ambient
monitor concentration data due to quality assurance
reviews, potentially delaying the utilization of this
new and important data in this NCh review.
The annual average standard of 53 ppb was retained in the
last review due to some evidence suggesting NOa
concentrations had a causal relationship with respiratory-
related health effects. Newly identified for this review
would be the consideration of how long-term, though
spatially variable, ambient NOa concentrations could
adversely affect health.
Model and data fusion techniques could improve the
estimation of the spatial and temporal distribution of
NOa concentrations across urban areas (not simply
area-wide and on-road distinctions), generally
accounting for increased emission sources and other
influential factors within a defined spatial sector.
There could be utility in estimating screening level
long-term NO2 concentrations if there were a newly
defined long-term health effect benchmark level of
interest.
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Major
Uncertainty or
Limitation
Uncertainty/Limitation Remaining from 2008 REA
Sub-group
Description
Consideration of Potential Utility and Impact of
Information Newly Available in This Review Could
Have on Assessment
Approach Used to
Estimate On-Road
NO2
Concentrations
Exponential
Relationship Used
to Characterize
Concentration
Decline with
Increasing Distance
from Roads
Based on a literature review of all available studies (both
U.S and non-U.S.) that measured both near- and away
from road NC>2 concentrations conducted by OAQPS staff
at the time of the last review, our analysis indicated that
NO2 concentrations decline with distance from a roadway;
thus, an exponential relationship was used to derive our
on-road adjustment factors. Variability in the form of the
relationship could result in the derivation of different
factors and potentially influence estimated on-road NO2
concentrations, though of course any estimates will be
dependent on the form and parameters describing the
relationship.
Distribution of On-
road Adjustment
Factors
Two distributions of NCh on-road adjustment factors were
derived and used in their empirical form, one for summer
months ranging from 1.5 to 3.7 (median 1.9), the other
non-summer months ranging from 1.2 to 2.5 (median
1.75).
Effect of Using
Longer-term
(weekly) Data
versus Hourly Data
to Estimate On-road
Adjustment Factors
Data used to derive on-road adjustment factors were all
from data collected over 1-week or longer term
measurements. It is possible that there is variability in the
derived relationship over different time-averaging periods
and concentrations. Thus, there is uncertainty in
application of the time-averaged derived distribution to
accurately estimate variability in hourly
concentrations.
Definition of
monitors minimally
influenced by
roadway emissions
to use in the
calculation of on-
road concentrations
We used any ambient monitor that was > 100 meters from
a road to estimate on-road concentrations. At that time,
this distance alone was considered a reasonable criterion
given the literature reviewed and patterns noted in the
then-existing ambient monitoring data. As stated in the
prior REA section 7.4.6, it is possible that some of the
ambient monitors used to estimate on-road concentrations
We could use air quality models, e.g., AERMOD
dispersion model combined with output from the
photochemical model CMAQ, to characterize near-
source gradients (roadways and combustion sources).
In addition, we could evaluate alternative relationships
(e.g., linear, biphasic, etc.), better characterize the
distributions of on-road adjustment factors, and
consider other factors used to define ambient monitors
if there are studies newly available (modeling and/or
measurement) that indicate alternative relationships
exist outside of the range already considered in the
2008 REA. Further, in the absence of new data from
the complete near-road monitoring network, additional
information regarding near-road concentration
gradients could be characterized from existing and
new published literature and/or current ambient
monitoring databases.
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Major
Uncertainty or
Limitation
Uncertainty/Limitation Remaining from 2008 REA
Sub-group
Description
could have been influenced by emissions from a non-road
NOx source.
Consideration of Potential Utility and Impact of
Information Newly Available in This Review Could
Have on Assessment
Approach Used to
Simulate Just
Meeting Potential
Air Quality
Standard Scenarios
N/A
Six study areas (Los Angeles, Atlanta, New York,
Philadelphia, Denver, and Chicago) were used to evaluate
existence of a proportional relationship between high
concentration and low concentration years. The
proportional adjustment factors derived from the area
design monitor was similarly applied to adjust all ambient
monitors within a given study area. Deviation from
proportionality (where it exists) at any monitor could
result in either over or under-estimation of concentrations.
New, adjusted ambient air quality data sets could be
developed if there are studies newly available that
indicate alternative approaches to adjusting air quality
exist that would generate demonstrably different data
sets outside of those already considered in the 2008
REA. This could include additional analysis of
ambient monitor data trends and air quality model
based approaches.
Selection of Health
Effect Benchmark
Levels
N/A
A generally common and important uncertainty in
controlled human exposure studies is the limited number
of study subjects as well as limits to the type of pre-
existing health conditions subjects may have, particularly
if the health condition affords the subject with heightened
effects sensitivity to the pollutant exposure. Further, there
is a lack of exposure data from study groups at potentially
at-risk lifestages (e.g., pregnant women, children).
New estimates of benchmark exceedances could be
developed if there are studies newly available that
indicate alternative health effect benchmark levels
should be considered outside of the range already
evaluated in the 2008 REA. This would also apply
where any new health endpoints are identified beyond
those associated with respiratory effects due to short-
term exposures. Further, additional analysis of
existing human exposure study data sets and an
improved characterization of adversity could be
possible using newly identified approaches or
information.
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The major uncertainties identified in section 5.1 above based on the 2008 REA were related to
(1) ambient monitoring representativeness, (2) the approach used to estimate on-road NCh
concentrations, (3) the approach used to estimate the existing and alternative air quality standard
scenarios, and (4) the selection of health effect benchmark levels.
5.2.2 Human Exposure Assessment
In addition to some of the uncertainties identified and described above in section 5.2.1,
three additional uncertainties were identified as specific to the exposure assessment conducted
for the 2008 REA. The major uncertainties identified in section 5.1.2.2 above that warrant
additional discussion here include (1) the use of unadjusted AERMOD estimated ambient NCh
concentrations as input to APEX, (2) the factors approach used to estimate in-vehicle and near-
road NCh concentrations, and (3) the limited input data used to estimate the contribution of a
single source emission (indoor gas stoves) to a simulated person's total NCh exposure (Table 5-
2).
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Table 5-2. Information (data, methods, models, etc.) identified as potentially important and/or newly available to inform the
exposure assessment for the current review.
Major Uncertainty
or Limitation
Uncertainty/Limitation Remaining from 2008 REA
Description
Consideration of Potential Utility and Impact of
Information Newly Available in This Review Could Have
on Assessment
Use of Unadjusted
AERMOD
Estimated
Concentrations as
Input to APEX
AERMOD was used to reasonably represent spatial variability in
ambient NO2 concentrations across an urban area where using limited
monitor data alone cannot. Even though comparisons made with limited
ambient monitoring data suggest AERMOD estimated ambient NO2
concentrations may have been systematically over-estimated,
concentrations were not adjusted for this potential upward bias.
We could further evaluate existing data generated for the 2008
REA (both the modeled exposures and ambient concentrations)
to approximate the potential impact of developing a newly
modeled alternative ambient concentration data set. In addition,
we could use AERMOD, with recent improvements by EPA, to
improve the quality and characterization of the ambient
concentration data set for input to APEX.
Approach Used to
Estimate In-Vehicle
and Near-Road
Microenvironmental
(ME)
Concentrations in
APEX
In-vehicle and near-road NO2 concentrations were estimated using a
similar concentration adjustment approach described above for the air
quality characterization, only differing in that the relationship between
on-road and away-from-road receptor concentrations were estimated
using AERMOD and that penetration/decay inside motor vehicles was
accounted for by APEX. While the distribution of adjustment factors
was stratified by time-of-day (11PM-6AM, 6AM-7PM, 7PM-11PM)
and seasons (summer and not-summer) (U.S. EPA, 2008b, Table B-42),
it is possible that use of a factors approach and randomly sampling from
distributions occasionally leads to a mismatching of on-road adjustment
factors and the away from road census block concentrations, leading to
either over or under estimated on-road NO2 concentrations. In addition,
near-road NO2 concentrations were considered at the same level as the
estimated on-road concentrations without additional adjustment for
their occurring at a given distance from the road. Note also, APEX
estimated ME concentrations that varied across the study area based on
workplace commutes of simulated individuals.
APEX has been recently modified to allow for a time series of
on-road concentrations, and can be stratified by a geographic
identifier, as an input to estimating in-vehicle exposure
concentrations. Thus, APEX is capable of utilizing the
AERMOD on-road concentrations themselves rather than using
a factors-based approach. In the absence of having a time-series
of on-road concentrations for potential study areas of interest, it
is possible that new factors or concentration distributions could
be developed and used to estimate near-road
microenvironmental concentrations, where newly published
data are identified.
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Major Uncertainty
or Limitation
Uncertainty/Limitation Remaining from 2008 REA
Description
Consideration of Potential Utility and Impact of
Information Newly Available in This Review Could Have
on Assessment
Limited Input Data
Used to Estimate
Contribution of
Indoor Source
Emissions of NC>2 to
Total Exposures
For a few APEX simulations, we estimated exposures associated with
ambient NCh concentrations along with those associated with a single
indoor emission source (gas stoves). The estimation was based on
limited input data readily available to represent variability in the source
emissions, population prevalence of gas stoves, frequency of source use
per cooking event and times of occurrence, and indoor removal rates.
Estimation of total exposure to NCh (i.e., that arising from
combined ambient, personal, and indoor sources) is an
important consideration in understanding total NCh-related
health risk. However, the role and relevance of understanding
the contribution of personal and indoor source emissions to
exposures when setting ambient air quality standards would
need to be further evaluated considering resource availability
and in addressing other key assessment priorities.
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5.2.3 Controlled Exposure-based Human Health Risk Assessment
One question to be raised for this review is whether or not there are newly identified
controlled human exposure studies in addition to the studies previously considered in the 2008
REA that substantially expand our understanding of respiratory-related (or other) adverse health
effects associated with short-term NCh exposures. If new studies are identified and adequate data
are available to develop exposure-response (E-R) relationships, these functions could be
combined with NCh exposures (e.g., output from a population-based exposure model) and thus,
warrant conducting a quantitative risk assessment based on the controlled human exposure
evidence. In addition, having new human exposure study data would not necessarily preclude a
comparison of earlier approaches (e.g., meta-analyses) used to develop the health effect
benchmark levels with any newly identified or alternative approaches identified in this review.
5.2.4 Epidemiological-based Human Health Risk Assessment
In addition to a few relevant uncertainties identified in section 5.2.1 above, two additional
uncertainties were identified as unique to the epidemiological-based human health risk
assessment conducted for the 2008 REA. The major uncertainties identified in section 5.1.3.2
above that warrant additional discussion here include (1) the selection of the C-R function and
(2) the ability of the ambient NCh monitors to serve as a surrogate for population exposure. The
risk assessment conducted in the last review focused on one health endpoint (i.e., respiratory-
related emergency department visits) in one urban study area (Atlanta). An important issue in
this review is whether or not additional information is available to consider conducting a
quantitative risk assessment that would include additional health effect endpoints and/or
additional urban study areas. The EPA's decisions regarding the conduct of and associated scope
of an REA for this review can be informed by the ISA causality determinations,62 in addition to
the availability of appropriate data for quantitative analyses (e.g., availability of C-R functions,
baseline incidence data, etc.). General criteria to be evaluated in identifying potential candidate
studies to inform a quantitative risk assessment include the following:
• the study was a published, peer-reviewed study that had been evaluated in the ISA for the
pollutant of interest and judged adequate by the EPA staff for purposes of inclusion in the
risk assessment based on that evaluation;
• it directly measured, rather than estimated, the pollutant of interest on a reasonable
proportion of the days in the study; and
62 The strength of the ISA causal determinations serves as a preliminary screen in identifying health
endpoints to consider in conducting our health assessments; historically, we have generally focused these
assessments on health endpoints having either 'causal' or 'likely to be causal' determinations.
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• it preferably included both single- and co-pollutant models.
Table 5-3 summarizes the potentially important uncertainties where additional
information, if available, would provide reasonable substance to the discussion of improving the
epidemiological-based human health risk assessment performed in the prior review.
Table 5-3. Information (data, methods, models, etc.) identified as potentially important
and/or newly available to inform the epidemiological-based risk assessment for
the current review.
Major
Uncertainty or
Limitation
Uncertainty/Limitation Remaining
From 2008 REA
Description
Consideration of Potential Utility and Impact
that Information Newly Available in this Review
Could Have on Assessment
Form of
Concentration -
Response
Functions
In the epidemiological-based health
risk assessment, a single short-term
NO2 epidemiological study was used
to estimate respiratory-related health
risk (emergency department visits) in
Atlanta (Tolbert et al., 2007). A log-
linear form assuming no threshold
was selected, and both single and co-
pollutant models were employed. An
additional study by Ito et al. (2007)
conducted in New York City was also
identified but due to time and
resource constraints, was not included
in the 2008 REA.
It is possible that new epidemiological-based health
risk assessments in additional study areas could be
performed using new or alternative C-R functions
and potentially assuming alternative model
specifications if such published studies are available.
Adequacy of the
Ambient NO2
Monitors to
Serve as a
Surrogate for
Population
Exposure
For the epidemiological-based health
risk assessment developed from data
reported in Tolbert et al. (2007),
concentrations from a single ambient
monitor were used to represent area-
wide exposures.
While this is a common approach used in these types
of assessments, it is possible that the effect of using
a single monitor could be further evaluated where
new studies have employed additional or alternative
monitors in estimating health risk.
5.3 SCIENTIFIC AND PUBLIC REVIEW
The REA Planning Document will be distributed to the CASAC for their consideration
and provided to the public for review and comment. The document will be the subject of a
consultation with the CASAC at a public meeting or teleconference that will be announced in the
Federal Register.
If, upon consideration of CASAC recommendations and public comments, the EPA
concludes that development of a new REA, or updating or expanding the last assessment, is
warranted, staff will take into account comments received from CASAC and the public in
designing and conducting the assessment. In such a case, staff would prepare at least one draft of
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the assessment for CASAC review and public comment. Review would be conducted by CASAC
and discussed at a public meeting that would be announced in the Federal Register. Based on
past practice by CASAC, the EPA expects that key advice and recommendations for revision of
the document would be summarized in a letter to the EPA Administrator. In revising the draft
REA document, the EPA would take into account any such recommendations and also consider
comments received from the public, both at the meeting itself and directly in writing. A final
document would then be made available on an EPA website, with its public availability
announced in the Federal Register.
If upon consideration of CASAC and public comments on the REA planning document,
the EPA concludes that development of a new REA is not warranted, a REA will not be
developed and the PA for this review will draw from the REA developed in the last review in
light of analyses or assessments made in the REA planning document with regard to the current
evidence pertaining to exposure and risk, as well as the evidence presented in the ISA and other
documents prepared for the review. Review steps for the PA are described in section 7.1 below.
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6 AMBIENT AIR MONITORING
In the course of NAAQS reviews, aspects of the methods for sampling and analysis of the
NAAQS pollutant, and the current network of monitors, including their physical locations and
monitoring objectives, are reviewed. The methods for sampling and analysis of each NAAQS
pollutant are generally reviewed in conjunction with consideration of the indicator element for
each NAAQS. Consideration of the ambient air monitoring network generally informs the
interpretation of current data on ambient air concentrations, and helps identify if the monitoring
network is adequate to determine compliance with the existing or, as appropriate, a potentially
revised NAAQS. This chapter describes plans for considering these aspects of the ambient air
monitoring program for oxides of nitrogen which includes the indicator NCh.
6.1 CONSIDERATION OF SAMPLING AND ANALYSIS METHODS
Generally, in order to be used for regulatory purposes, ambient NCh concentration data
must be obtained using federal reference methods (FRMs) or federal equivalent methods (FEMs)
which are designated by the Agency in accordance with 40 CFR part 53. As described in section
1.3 above, NCh is the indicator for the oxides of nitrogen NAAQS and has been routinely
measured by chemiluminescent FRMs since the early 1980s.63 However, in 2012 a photolytic
chemiluminescent method became commercially available and was approved by the Agency as
an FEM (77FR 32632, June 1, 2012). This new FEM is expected to be used to some degree in
the ambient NCh monitoring network but is not expected to displace a majority of traditional
chemiluminescence FRMs.
Both the chemiluminescent FRM and the photolytic chemiluminescent FEM are indirect
measurement techniques for NCh. In the chemiluminescent FRM, the analyzer can only detect
NO in the sample stream and therefore utilizes a two-step process in determining the amount of
NCh in ambient air. First, the analyzer determines the amount of NO in the sample air. Second,
the analyzer re-routes air flow so that the sample air stream passes over a heated molybdenum
oxide catalytic converter reducing a large majority (if not all) of the oxidized nitrogen species
present in the sample stream to NO, before again measuring the amount of NO in the sample.
The analyzer then subtracts the measured, actual ambient NO, determined in the first step, from
the amount measured in the second step, allowing for the determination of NO, NO2, and NOx
(where NOx = NO + NO2). This long-standing method is subject to interference (U.S. EPA,
2013b, section 2.4.1). This documented interference can produce a positive bias if higher
63
See 40 CFR part 50, Appendix F.
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oxidized nitrogen species such as nitric acid (HNCb) or peroxyacetyl nitrate (PAN) make it to the
converter, where they can be reduced by some degree to NO and subsequently counted as NCh.
While similar in the use of a two-step process of indirectly determining NCh concentrations as
the chemiluminescent FRM, the photolytic-chemiluminescence FEM carries out the reduction of
NCh to NO in a photolytic converter with a known converter efficiency rate. This method is
more specific to NO2 and, thus, is not subject to the same positive bias potential as the
chemiluminescent FRM. Data produced by both of these FRM and FEM analyzers include NO,
NO2, and NOx measurements which are all routinely logged by state and local agencies whom
typically report the hourly average values to the EPA's Air Quality System (AQS).
The Agency is aware of a number of recent technological advances for direct
measurements of NO2 which are now or may become commercially available as FEMs (e.g.,
cavity attenuated phase shift (CAPS) spectrometry and cavity ring-down spectroscopy). The first
of these new methods, CAPS spectrometry, had two models approved recently as FEMs (78 FR
67360, November 12, 2013; 79 FR 34734, June 18, 2014).64 These new direct measurement
techniques are specific to NO2. This would create a notable, anticipated difference with the
traditional chemiluminescent FRMs in that these direct measurement methods will only provide
NO2 data and will not provide NO or NOx data. The Agency recognizes the advantages of these
new direct measurement technologies including: (1) increased accuracy, via a lack of potential
positive bias in measured values, and (2) increased confidence in monitored NO2 values.
However, there may also be potential drawbacks if these new methods largely replace the current
network of FRMs and photolytic-chemiluminescent FEMs as there would potentially be a loss of
monitored NO. As a result, the Agency seeks to determine what might be an appropriate balance
between the use of the "old" and "new" methods. More specifically, the sampling and analysis
issues to be considered during the current review include the following:
• To what extent are additional direct NO2 measurements available for consideration as an
FEM?
• If new, direct NO2 measurement methods become available and integrated into the
ambient network, what would be the anticipated impact to subsequent air quality data
analyses by potentially losing NO and NOx measurements?
6.2 CONSIDERATION OF AIR MONITORING NETWORK
REQUIREMENTS
The majority of data used to determine compliance with the NO2 NAAQS are obtained
from monitors operated by state, local, and tribal air monitoring agencies. These monitors are
64 For a complete list of designated reference and equivalent methods,
seehttp://www.epa.gov/ttn/amtic/files/ambient/criteria/reference-equivalent-methods-list.pdf.
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required due to either federal regulation contained in 40 CFR Part 58, Appendix D, state
implementation plans, industrial permits, other state or local based requirements, or voluntary
actions. The monitoring networks support three major objectives: (1) to provide air pollution data
to the general public in a timely manner; (2) to support compliance with NAAQS and emissions
strategy development; and (3) to support air pollution research studies.
A review of the available NCh monitoring network and data was performed as part of the
primary NCh NAAQS review completed in 2010. In conjunction with revising the primary
standards in that review, the Agency promulgated minimum monitoring requirements to support
the implementation of a new primary 1-hour NCh standard. The minimum requirements
consisted of the following: (1) near-road monitors which would be placed in locations of
expected maximum 1-hour NCh concentrations near heavily trafficked roads in urban areas; (2)
monitors located to characterize areas with the highest expected NCh concentrations at the
neighborhood and larger spatial scales (also referred to as "area-wide" monitors) (75 FR 6505 to
6506, February 9, 2010); and (3) a specific set of monitors in areas with susceptible and
vulnerable65 communities exposed to NCh concentrations that have the potential to approach or
exceed the standards (75 FR 6509). The near-road NCh monitoring requirements were novel at
the time of promulgation and stemmed from findings that roadway-associated exposures account
for a majority of exposures to peak NCh concentrations (75 FR 6514). The area-wide and the
susceptible and vulnerable communities monitoring requirements each minimally required
approximately 52 and 40 monitors, respectively, and were consistent with traditional monitoring
approaches. This meant the existing network did not require significant modification in order to
satisfy these two requirements. Sites satisfying these two monitoring network requirements were
identified and documented or became fully operational on or before January 1, 2013. Conversely,
the near-road NCh monitoring network did not exist at the time of promulgation, and the Agency
acknowledged that it would have to be designed, funded, and installed in its entirety.
One near-road NCh monitor is required in each Core Based Statistical Area (CBSA)
having 500,000 or more persons, per 40 CFR part 58, Appendix D, section 4.3.2. A second near-
road NCh monitor is required in those CBSAs having either (a) 2,500,000 persons or more or (b)
any CBSA having 500,000 or more persons that also has one or more road segments carrying
250,000 or greater Annual Average Daily Traffic (AADT) counts. At each of the near-road NCh
65 The terms susceptible, vulnerable, sensitive, and at-risk are commonly used to characterize population
groups or lifestages at greatest risk for experiencing health effects associated with exposure to a specific pollutant(s).
In finalizing revisions to the NO2 monitoring network in 2010, the EPA required that an additional forty monitors,
nationally, be sited to focused "primarily on communities where susceptible and vulnerable populations are located"
(75 FR 6510). In this review, the Agency will use the term "at-risk populations and lifestages" for those groups with
characteristics that increase the risk of pollutant-related health effects.
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sites, the monitors are subject to all requirements in 40 CFR part 58 and its appendices, which
include specific siting criteria such as having the monitor probe placed ".. .as near as practicable
to the outside nearest edge of the traffic lanes of the target segment; but shall not be located at a
distance greater than 50 meters, in the horizontal, from the outside nearest edge of the traffic
lanes of the target road segment" and having the monitor probe placed between 2 and 7 meters
above the ground.
The near-road NCh monitors are required to be installed in three phases (78 FR 16184,
March 14, 2013). The first phase required one monitor in any CBSA of 1,000,000 or more
persons to be operational by January 1, 2014. We anticipate that 52 near-road sites will be added
in Phase 1. The second phase is for any second monitor required in a CBSA (those having
2,500,000 or more persons or those having 500,000 or more persons that also have one more
road segments carrying 250,000 or greater AADT counts) to be operational by January 1, 2015.
We anticipate 23 near-road sites will be added in Phase II. The third phase is for those monitors
in CBSAs having between 500,000 and 1,000,000 persons, which are to be operational by
January 1, 2017. We anticipate 51 near-road sites will be added in Phase III.
By the end of 2013, the ambient NCh monitoring network was estimated to have 391 NCh
monitors in operation nationwide (see Figure 6-1). This estimate does not reflect the impending
additions of the three-phased implementation of the near-road NCh monitors. We anticipate 126
near-road sites will be operational on or before January 1, 2017, potentially resulting in more
than 500 NCh monitors nationwide when the NCh network is fully operational.
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Legend
• Active NO2 Monitors- Sept2013 (-391)
Note: Hawaii has two NO2 sites in operation (not shown).
These active monitors do not include the anticipated near-road NO2 monitors
which are expected to phase into operation at the start of 2014.
Figure 6-1. NOi Monitoring Network: Active monitors as of September 2013.
In the last review, there was limited near-road ambient NCh monitoring data. Analyses
conducted as part of the 2008 REA (U.S. EPA, 2008b) along with public comment on the
proposed rule were considered in reaching final decisions on how many and where near-road
NCh monitors would be required. In particular, the 2008 REA considered estimates of on- or
near-roadway exceedances in 17 urban areas associated with CBS A populations ranging from
approximately 540,000 to 19,000,000 persons. Those analyses indicated that the areas under
explicit consideration were estimated to experience NCh concentrations on or near roads that
exceeded health benchmark levels.
In this review, the EPA will have the benefit of monitored near-road data for
consideration in analyzing potential exposures and exceedances. Although the new near-road
NCh monitoring network is not yet fully installed, data from newly operational monitors, plus
data from more recent research efforts, may provide a clearer picture of what NCh concentrations
are in the near-road environment, with the continued understanding that factors including traffic
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counts, fleet mix, congestion patterns, roadway design, terrain, and meteorology all play a major
role in measured roadside Mh concentrations. The EPA plans to summarize the meta-data of
near-road NCh monitoring sites (e.g., location, distance to road, probe height, target road AADT)
to aid in the broad understanding of what the new near-road monitor data represent. The EPA
also notes that many near-road NCh monitoring sites are expected to become multi-pollutant
monitoring sites. For those CBSAs having 1,000,000 or more persons, both CO and PM2.5
monitoring are required to be phased in from 2015 through 2017, at one site per CBS A (40 CFR
part 58, Appendix D, sections 4.2.1 and 4.7.1). Further, the EPA has strongly encouraged state,
local, and tribal air agencies to conduct multi-pollutant monitoring at near-road sites beyond
those parameters that are required. Pollutants and metrics such as black carbon, ultrafine
particles, toxics, ozone, meteorological parameters, and traffic counters and cameras have all
been suggested for consideration (U.S. EPA, 2012). It is expected that many sites will have one
or more of these additional measurements, which will increase the understanding of
pollutant/traffic correlations, pollutant chemistry and fate, and provide information to improve
our understanding of the role of oxides of nitrogen as a component of a complex mixture of air
pollutants in the near-road environment.
Finally, with increasing availability of new near-road NCh monitoring data, the EPA
anticipates that it may be in a position to re-evaluate the analyses underlying the minimum
monitoring requirements promulgated in the 2010 revisions in this review. Any such analysis
would be predicated on some framework or criteria to aid in the determination of whether a
network design change is warranted and what modifications might be considered.
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7 POLICY ASSESSMENT AND RULEMAKING
As outlined in section 1.2 above, the fourth and final stage of the NAAQS review is the
preparation of a Policy Assessment (PA) and rulemaking notices. These two steps are described,
respectively, in sections 7.1 and 7.2 below.
7.1 POLICY ASSESSMENT
The PA provides a transparent OAQPS staff analysis and staff conclusions regarding the
adequacy of the current standards and potential alternatives that are appropriate to consider prior
to the issuance of proposed and final rules. The PA integrates and interprets the information from
the ISA and, if available, REA(s) to frame policy options for consideration by the Administrator.
The PA is also intended to facilitate CAS AC's advice to the Agency and recommendations to the
Administrator on the adequacy of the existing standards or revisions that may be appropriate to
consider, as provided for in the CAA. Staff conclusions in the PA are based on the information
contained in the ISA; the REA, as available; and any additional staff evaluations and assessments
discussed in the PA. In so doing, the discussion in the PA is framed by consideration of a series
of policy-relevant questions drawn from those outlined in section 3.2 above, including the
fundamental questions associated with the adequacy of the current standards and, as appropriate,
consideration of alternative standards in terms of the specific elements of the standards:
indicator, averaging time, level, and form.
The PA for the current review will identify conceptual evidence-based and risk/exposure-
based approaches for reaching public health policy judgments. It will discuss the implications of
the science and quantitative assessments for the adequacy of the current primary standards and
for any alternative standards under consideration. The PA will also describe a broad range of
policy options for standard setting, identifying the range for which the staff identifies support
within the available information. In so doing, the PA will describe the underlying interpretations
of the scientific evidence and risk/exposure information that might support such alternative
policy options that could be considered by the Administrator in making decisions for the primary
NCh standards. Additionally, the PA will identify key uncertainties and limitations in the
underlying scientific information and in our assessments. The PA will also highlight areas for
future health-related research, model development, and data collection.
In identifying a range of primary standard options for the Administrator to consider, it is
recognized that the final decision will be largely a public health policy judgment. A final
decision must draw upon scientific information and analyses about health effects and risks, as
well as judgments about how to deal with the range of uncertainties that are inherent in the
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scientific evidence and analyses. Staffs approach to informing these judgments recognizes that
the available health effects evidence generally reflects a continuum consisting of ambient
concentrations at which scientists generally agree that health effects are likely to occur, through
lower concentrations at which the likelihood and magnitude of the response become increasingly
uncertain. This approach is consistent with the requirements of the NAAQS provisions of the
CAA and with how the EPA and the courts have historically interpreted the CAA. These
provisions require the Administrator to establish primary standards that are requisite to protect
public health and are neither more nor less stringent than necessary for this purpose. As
discussed in section 1.1 above, the provisions do not require that primary standards be set at a
zero-risk level, but rather at a level that avoids unacceptable risks to public health, including the
health of at-risk populations.66
Staff will prepare at least one draft of the PA document for CAS AC review and public
comment. The draft PA document will be distributed to the CASAC Oxides of Nitrogen Primary
NAAQS Review Panel for their consideration and provided to the public for review and
comment. Review by the CASAC will be discussed at a public meeting that will be announced in
the Federal Register. Based on past practice by CASAC, the EPA expects that CASAC will
summarize key advice and recommendations for revision of the document in a letter to the EPA
Administrator. In revising the draft PA document, OAQPS will take into account any such
recommendations and also consider comments received, from CASAC and from the public, at
the meeting itself, and any written comments received. The final document will be made
available on an EPA website, with its public availability announced in the Federal Register.
7.2 RULEMAKING
Following issuance of the final PA and the EPA management consideration of staff
analyses and conclusions presented therein, and taking into consideration CASAC advice and
recommendations, the Agency will develop a notice of proposed rulemaking. The proposed
rulemaking notice conveys the Administrator's proposed conclusions regarding the adequacy of
the current standards and any revision that may be appropriate. The EPA will submit a draft
notice of proposed rulemaking to the Office of Management and Budget (OMB) for interagency
review, to provide OMB and other federal agencies the opportunity for review and comment.
66 The at-risk population groups identified in a NAAQS review may include low income or minority
groups. Where low income/minority groups are among the at-risk populations, the rulemaking decision will be based
on providing protection for these and other at-risk populations and lifestages (e.g., children, older adults, persons
with pre-existing heart and lung disease). To the extent that low income/minority groups are not among the at-risk
populations identified in the ISA, a decision based on providing protection of the at-risk lifestages and populations
would be expected to provide protection for the low income/minority groups.
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After the completion of interagency review, the EPA will publish the notice of proposed
rulemaking in the Federal Register. Monitoring rule changes associated with review of the
primary NCh standards, and drawing from considerations outlined in Chapter 6 above, will be
developed and proposed, as appropriate, in conjunction with this NAAQS rulemaking.
At the time of publication of the notice of proposed rulemaking, all materials on which
the proposal is based are made available in the public docket for the rulemaking.67 Publication of
the proposal notice is followed by a public comment period, generally lasting 60 to 90 days,
during which the public is invited to submit comments on the proposal to the rulemaking docket.
Taking into account comments received on the proposed rule, the Agency will then develop a
notice of final rulemaking, which again undergoes OMB-coordinated interagency review prior to
issuance by the EPA of the final rule. At the time of final rulemaking, the Agency responds to all
significant comments on the proposed rule.68 Publication of the final rule in the Federal Register
completes the rulemaking process.
67 The rulemaking docket for the current primary NC>2 NAAQS review is identified as EPA-HQ-OAR-
2013-0146. This docket has incorporated the ISA docket (EPA-HQ-ORD-2013-0232) by reference. Both dockets
are publicly accessible at www.regulations.gov.
68 For example, Agency responses to all substantive comments on the 2009 notice of proposed rulemaking
in the last review were provided in the preamble to the final rule and in a document titled Responses to Significant
Comments on the 2009 Proposed Rule on the Primary National Ambient Air Quality Standards for Nitrogen Dioxide
(July 15, 2009; 74 FR 34404) (U.S. EPA, 2010).
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APPENDIX A
DRAFT OUTLINE FOR INTEGRATED SCIENCE ASSESSMENT FOR OXIDES OF
NITROGEN - HEALTH CRITERIA
Preamble
(will be available online)
Preface
Executive Summary
Chapter 1
1.1
1.2
1.3
1.4
1.5
1.6
Process of ISA Development
Literature Search
Study Selection
Evaluation of Individual Study Quality
Evaluation, Synthesis, and Integration across Disciplines and
Development of Scientific Conclusions and Causal
Determinations
EPA Framework for Causal Determinations
Public Health Impact
Approach to Classifying At-risk Factors
Concepts in Evaluating Adversity of Health Effects
Legislative Requirements for the Primary NAAQS Review
History of the Review of the Air Quality Criteria for the Oxides
of Nitrogen and NAAQS for Nitrogen Dioxide
Integrative Summary
ISA Development and Scope
Organization of the ISA
Sources of Oxides of Nitrogen to Human Exposure
Health Effects of Oxides of Nitrogen
Causal determinations and key evidence for evaluated
health effects including information related to
dosimetry, modes of action, exposure assessment,
and potential confounding factors
Evaluation of the Independent Effects of Nitrogen Dioxide
Potential confounding by time-varying and individual- or
population-level characteristics
Potential confounding by copollutant exposures -
multivariable models, indoor NO2, traffic proximity
and intensity, pollutant interactions or
mixtures with oxides of nitrogen
Policy-Relevant Considerations
NO2 Exposure Metrics
Lag Structure of NO2-related Morbidity and Mortality
Associations
Concentration-Response Relationships and Thresholds
Public Health Significance - Adversity of Effects, At-risk
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Lifestages and Populations
1.7 Conclusions
Chapter 2 Atmospheric Chemistry and Air Quality
2.1 Introduction
2.2 Atmospheric Chemistry and Fate
2.3 Sources
2.4 Measurement Methods
2.5 Ambient Concentrations of Oxides of Nitrogen
2.6 Summary and Conclusions
Chapter 3 Assessment of Human Exposure
3.1 Introduction
3.2 Methodological Considerations for Application in
Epidemiological Models
3.3 Exposure Data and Distributions
3.4 Exposure Assessment and Epidemiological Inference
3.5 Conclusions
Chapter 4 Dosimetry and Modes of Action of Inhaled Nitrogen Oxides
4.1 Introduction
4.2 Dosimetry of Inhaled Oxides of Nitrogen
Dosimetry of Nitrogen Dioxide
Dosimetry of Nitric Oxide
Metabolism, Distribution, and Elimination of
Products Derived from Inhaled Oxides of Nitrogen
Summary
4.3 Modes of Action for Inhaled Oxides of Nitrogen
Introduction
Nitrogen Dioxide
Nitric Oxide
Metabolites of Nitric Oxide and Nitrogen
Dioxide
Summary
4.4 Summary
Chapter 5 Integrated Health Effects of Short-term Exposure to Oxides
of Nitrogen69
5.1 Introduction
5.2 Respiratory Effects
5.3 Cardiovascular Effects
5.4 Total Mortality
69Sections for each of the major health effect outcome categories will include a review of the available evidence and
conclude with the causal determination and summary of contributing evidence.
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Chapter 6 Integrated Health Effects of Long-term Exposure to Oxides
of Nitrogen60
6.1 Introduction
6.2 Respiratory Effects
6.3 Cardiovascular Effects
6.4 Reproductive and Developmental Effects
Fertility, Reproduction, and Pregnancy
Birth Outcomes
Postnatal Development
6.5 Total Mortality
6.6 Cancer
Chapter 7 Lifestages and Populations Potentially at Increased Risk for
Health Effects Related to Exposure to Oxides of Nitrogen
7.1 Introduction
7.2 Proximity to and Time Spent Near Major Roads
7.3 Geneti c F actors
7.4 Pre-existing Disease/Conditions
7.5 Sociodemographic Factors (lifestage, socioeconomic status,
race/ethnicity, sex)
7.6 Behavioral and Other Factors (diet, obesity, smoking, residential
location)
7.7 Summary
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United States Office of Air Quality Planning and Standards Publication No. EPA-452/R-14-003
Environmental Protection Health and Environmental Impacts Division June 2014
Agency Research Triangle Park, NC
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