Integrated Review Plan for the 

Primary National Ambient Air Quality 

Standards for Nitrogen Dioxide 

 

 
[This page intentionally left blank.]

 
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

 
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. 
 i 

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 
 ii 

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 the NAAQS 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
 iii 

LIST OF ACRONYMS/ABBREVIATIONS

AADT Annual Average Daily Traffic 

AERMOD EPA’s Air Dispersion Model 

ANPR Advanced notice of proposed rulemaking 

APEX EPA’s Air Pollutants Exposure model 

AQI Air Quality Index 

AQS EPA’s Air Quality System 

CAA Clean Air Act 

CAPS Cavity attenuated phase shift 

CASAC Clean Air Scientific Advisory Committee 

CBSA Core Based Statistical Area 

CFR Code of Federal Regulations 

CO Carbon monoxide 

C-R Concentration-response 

EPA Environmental Protection Agency 

E-R Exposure-response 

FEM Federal Equivalent Method 

FEV1 Forced expiratory volume in one second, volume of air exhaled in first 

second of exhalation 

FR Federal Register 

FRM Federal Reference Method 

HA Hospital admissions 

HERO Health and Environmental Research Online 

HONO Nitrous acid 

HNO3 Nitric acid 

IRP Integrated Review Plan 

ISA Integrated Science Assessment 

μg/m3 micrograms per cubic meter 

m Meters 

ME Microenvironmental 

MSA Metropolitan Statistical Area 

NAAQS National Ambient Air Quality Standards 

NCEA National Center for Environmental Assessment 

NCore National Core Monitoring Network 

NO Nitric oxide 

NO2 Nitrogen dioxide 

NO3

- Nitrate 

NOX NO+NO2 

NOY Total oxides of nitrogen (NOX + NOZ) 

NOZ Reactive oxides of nitrogen (e.g., HNO3, HONO, PAN, particulate 

 nitrates) 

O3 Ozone 

OAQPS Office of Air Quality Planning and Standards 

OAR Office of Air and Radiation 
 iv 

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 (μm); a measurement of fine 

particles 

ppb Parts per billion 

ppm Parts per million 

QA Quality assurance 

QMP Quality Management Plan 

REA Risk and Exposure Assessment 

RIA Regulatory Impact Analysis 

RTP Research Triangle Park 

SES Socioeconomic status 

SO2 Sulfur dioxide 

TBD To be determined
 1-1 

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 (NO2). 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 NO2 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 NO2 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 (NO2) 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 NO2 standard is the 

three-year average of the 98th percentile of the annual distribution of 1-hour daily maximum NO2 concentrations. 

4

 The “level” defines the allowable concentration of the criteria pollutant in the ambient air. 
 1-2 

[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)(1) defines a primary standard as one “the 

attainment and maintenance of which in the judgment of the Administrator, based on such 

criteria and allowing an adequate margin of safety, 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 NO2 standards. The 

secondary NO2 standard will be separately reviewed in conjunction with review of the secondary sulfur dioxide 

(SO2) standard. 

6

The legislative history of section 109 indicates that a primary standard is to be set at “the maximum 

permissible ambient air level . . . which will protect the health of any [sensitive] group of the population,” and that 

for this purpose “reference should be made to a representative sample of persons comprising the sensitive group 

rather than to a single person in such a group.” S. Rep. No. 91-1196, 91st Cong., 2d Sess. 10 (1970). 

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); and Association of Battery Recyclers v. EPA, 604 F. 3d 613, 617-18 (D.C. Cir. 2010). 
 1-3 

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, “[a]ttainability and technological feasibility are not 

relevant considerations in the promulgation of national ambient air quality standards.”12

Section 109(d)(1) requires that “not later than December 31, 1980, and at 5-year intervals 

thereafter, the Administrator shall complete a thorough review of the criteria published under 

section 108 and the national ambient air quality standards . . . and shall make such revisions in 

such criteria and standards and promulgate such new standards as may be appropriate . . . ” 

Section 109(d)(2) requires that an independent scientific review committee “shall complete a 

review of the criteria . . . and the national primary and secondary ambient air quality standards. . . 

and shall recommend to the Administrator any new . . . standards and revisions of existing 

criteria and standards as may be appropriate . . . .” Since the early 1980s, this independent review 

function has been performed by the Clean Air Scientific Advisory Committee (CASAC).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.51, 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 CASAC members and of members of the CASAC Oxides of Nitrogen Primary NAAQS Review 

Panel are available at: 

http://yosemite.epa.gov/sab/sabproduct.nsf/WebCASAC/CommitteesandMembership?OpenDocument. 
 1-4 

Figure 1-1. Overview of the NAAQS review process. 

Integrated Review Plan (IRP): timeline and key

policy-relevant issues and scientific 

questions 

Integrated Science Assessment (ISA): evaluation and 

synthesis of most 

policy-relevant studies

Risk/Exposure Assessment (REA): quantitative assessment, as warranted, focused on key results, observations, and uncertainties

Workshop on science-policy issues

Public hearin

gs and comments 

on 

proposal

EPA 

decisi

stand

Intera

gency review

Intera

gency review Agency decision making and draft 

proposal notice

Agency decision making and draft final notice

Pub

Clean 

Adviso

(CA

Policy Assessment (PA): staff anal

ysis of policy options based on integration and interpretation of information in the ISA and REA

EPA 

proposed decisions on 

standards

Peer-reviewed 

scientific studies
 1-5 

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 CASAC 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 policyrelevant 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 over time (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 NO2 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 NO2, 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. 
 1-6 

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 NO2. 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. 
 1-7 

elements of national ambient air quality standards: indicator, averaging time, form, and level. 

One or more drafts of a PA are released for CASAC 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)(1) of the CAA and issued the initial air quality criteria (36 FR 1515, January 30, 1971; 

U.S. EPA, 1971). Based on these air quality criteria, the EPA promulgated NAAQS for nitrogen 

oxides using NO2 as the indicator (36 FR 8186, April 30, 1971). Both primary and secondary 

standards were set at 100 micrograms per cubic meter (μg/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. 
 1-8 

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 ppb20 Annual arithmetic average 

1985 

50 FR 25532 

Jun 19, 1985 

Primary annual NO2 standard retained, without revision. 

1996 

61 FR 52852 

Oct 8, 1996 

Primary annual NO2 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 NO2 standard retained, without revision. 

The EPA retained the primary and secondary NO2 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 shortterm NO2 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 NO2 standard was 100 μg/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). 
 1-9 

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 NO2 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 NO2 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 shortterm 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). 
 1-10 

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 NO2 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 NO2 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 NO2 in the air 

and the exposure and risk information, the Administrator determined that the existing primary 

NO2 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 NO2. 

In so doing, the Administrator particularly noted the potential for adverse health effects to occur 

following exposures to elevated NO2 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 NO2 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 NO2 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 NO2 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. 
 1-11 

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 NO2 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 NO2 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 NO2

standards.28 The gaseous oxides of nitrogen include NO2 and nitric oxide (NO) as well as their 

gaseous reaction products. Total oxides of nitrogen include these gaseous species as well as 

particulate species (e.g., nitrates). Collectively, we refer to the total set of species as NOY (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 NO2 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 NO2 monitoring network requirements are specified in 40 

CFR part 58, Appendix D, section 4.3. The EPA revised the AQI for NO2 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. 
 1-12 

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 NO2 standard in conjunction 

with a review of the secondary SO2 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 NO2 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. 
 2-1 

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 NO2 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 NO2 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 policyrelevant science issues identified as key to guiding the evaluation of the air quality criteria for 

oxides of nitrogen and the review of the primary NO2 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 NO2 measurement data 

 31 Workshop materials are available in the rulemaking docket accessible through 

http://www.regulations.gov, Docket ID number EPA-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). 
 2-2 

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. 

 
 2-3 

Table 2-1. Anticipated schedule for the current review. 

Stage of Review Major Milestone Target Date 

Integrated Review 

Plan (IRP) 

Literature Search Ongoing 

Federal Register Call for Information February 10, 2012 

Workshop on science/policy issues February 29 – March 1, 2012 

Draft plan for developing ISA 

CASAC consultation on draft ISA plan 

Draft IRP 

May 2013 

June 5, 2013 

February 2014 

CASAC review of draft IRP March 12-13, 2014 

Final IRP June 2014 

Integrated Science 

Assessment (ISA) 

First draft ISA November 2013 

CASAC public meeting for review of first draft ISA March 12-13, 2014 

Second draft ISA October 2014 

CASAC/public review of second draft ISA December 2014 

Final ISA April 2015 

Risk/Exposure 

Assessment (REA) 

REA Planning Document November 2014 

CASAC consultation/public review of REA Planning 

Document December 2014 

If warranted, 

First draft REA 

CASAC/public review of first draft REA 

Second draft REA 

CASAC/public review of second draft REA 

Final REA 

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. 
 2-4 

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 3-1 

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 NO2 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 NO2 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 NO2. 

3.1 CONSIDERATIONS AND CONCLUSIONS IN LAST REVIEW 

The last review of the primary NO2 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 
 3-2 

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 NO2

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 NO2 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 NO2 and effects potentially associated with long-term 

exposures. As discussed further in section 6.2 below, in conjunction with the revised primary 

NO2 NAAQS, the EPA also established a two-tiered monitoring network composed of (1) nearroad monitors which would be placed in locations of expected maximum 1-hour NO2

concentrations near heavily trafficked roads in urban areas and (2) monitors located to 

characterize areas with the highest expected NO2 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 NO2 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 NO2 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 CASAC (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. 
 3-3 

hyperresponsiveness in asthmatics following short-term exposures to NO2 concentrations as low 

as 100 ppb and epidemiological studies reporting associations between short-term NO2 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 NO2 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) NO2 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 NO2 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 NO2 but additionally noted that ISA analyses of co-pollutants 

generally found that NO2 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 NO2

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). 
 3-4 

studies (U.S. EPA, 2008a, sections 3.1.3 and 5.4). The EPA drew two broad conclusions 

regarding airway responsiveness in asthmatics following NO2 exposures. First, NO2 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 to NO2 concentrations as low as 260 ppb. (U.S. EPA, 2008a, section 5.3.2.1, Figure 3.1-2). 

Second, exposure to NO2 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 NO2 (U.S. EPA, 2008a, sections 

3.1.3.2; 5.3.2.1). The EPA further concluded that the majority of asthmatics may experience 

NO2-related airway hyperresponsiveness following short-term NO2 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 NO2 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 NO2

standard. Estimates were developed for (1) an “as-is” scenario which estimated the health risks 

associated with short-term exposure to NO2 at actual recent air-quality concentrations, which 

were lower than what was permitted by the then-current annual NO2 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). 
 3-5 

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 NO2 exposures; most 

asthmatics in Atlanta could be exposed on multiple days per year to NO2 concentrations at or 

above 300 ppb, and most locations evaluated could experience on-/near-road NO2 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 NO2 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 shortterm NO2 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 NO2 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 NO2 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). 
 3-6 

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 NO2 as the most appropriate indicator for oxides 

of nitrogen because the available scientific information regarding health effects was largely 

indexed by NO2. In the review completed in 2010, controlled human exposure studies and animal 

toxicological studies provided specific evidence for health effects following exposures to NO2. 

In addition, epidemiological studies typically reported effects associated with NO2

concentrations though the degree to which monitored NO2 reflected actual NO2 concentrations, 

as opposed to NO2 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 NO2 as the indicator for a standard that was intended to address effects associated 

with exposure to NO2, 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 NO2

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 NO2 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) NO2 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) 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) (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 NO2. 
 3-7 

As had been done in previous reviews of the NO2 NAAQS, the Administrator next noted 

that it was instructive to evaluate the potential for a standard based on annual average NO2

concentrations, as was the existing standard at the time of the 2010 review, to provide protection 

against short-term NO2 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) 

NO2 concentrations to annual average concentrations, suggesting that a standard based on annual 

average NO2 concentrations would not likely be an effective or efficient approach to focus 

protection on short-term NO2 exposures. For example, these analyses indicated that in some 

areas the existing annual standard could allow 1-hour daily maximum NO2 concentrations of 

about 400 ppb, while in other areas the annual standard could limit 1-hour daily maximum NO2

concentrations to about 150 ppb. Thus, for purposes of protecting against the range of 1-hour 

NO2 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 NO2 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 NO2 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 NO2 concentrations. Based on REA 

analyses of ratios between 1-hour and 24-hour NO2 concentrations (U.S. EPA, 2008b, section 

10.4.2), she further concluded that a standard based on 1-hour daily maximum NO2

concentrations could also be effective at protecting against effects associated with 24-hour NO2

exposures. 

Based on the above, the Administrator judged that it was appropriate to set a new NO2

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 
 3-8 

decisions were consistent with CASAC advice to establish a primary short-term standard for 

oxides of nitrogen based on using 1-hour maximum NO2 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 NO2 standard at 

100 ppb. This standard was focused on limiting the maximum 1-hour NO2 concentrations in 

ambient air, including in locations near major roadways where the highest ambient NO2

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 NO2, such as those that can occur around major roadways. Available evidence and 

information suggested that roadways account for the majority of exposures to peak NO2

concentrations and, therefore, are important contributors to NO2-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 NO2-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 NO2-

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 NO2 concentrations (see section 6.2 below). 
 3-9 

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 NO2

epidemiological studies. She noted that a new standard focused on protecting against maximum 

1-hour NO2 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 NO2

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 NO2 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 NO2 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 NO2 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 NO2 concentrations well below those in 

locations where key U.S. epidemiological studies had reported that ambient NO2 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 

NO2 concentrations below 100 ppb and/or associated with area-wide NO2 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). 
 3-10 

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 NO2 standard. The 

focus on the upper percentiles of the distribution was based, in part, on evidence of health effects 

associated with short-term NO2 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 NO2

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 NO2 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. 
 3-11 

standard (75 FR 6493). Given that the EPA set a new primary 1-hour NO2 standard that focused on 

limiting the maximum allowable NO2 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 NO2 concentrations are expected (e.g., including near major 

roads). 

Given the limited available information on the variability in peak NO2 concentrations near 

important sources of NO2 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 NO2 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 NO2 in the complex ambient mixture which 

includes a range of co-occurring pollutants (e.g., PM2.5, ozone (O3), CO, SO2, other trafficrelated pollutants); (2) understanding the extent to which monitored ambient NO2 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 NO2-induced respiratory effects reported in controlled human exposures studies can 

be characterized; (4) understanding the NO2 concentration gradients around important sources, 

such as major roads, and relating those gradients to broader ambient monitoring concentrations; 

and (5) improving the characterization of NO2 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 
 3-12 

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 policyrelevant 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 

NO2 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. 
 3-13 

Figure 3-1. Overview of General Approach for Review of Primary NO2 Standards 

 
 3-14 

The initial overarching question in reviewing the adequacy of the current suite of primary 

NO2 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., NO2, 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 NO2

standards? 

 To what extent are health effects associated with exposures to oxides of nitrogen, 

including NO2, 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? 
 3-15 

 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 atrisk 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 NO2

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 NO2 concentrations or with concentrations that just 

meet the current primary NO2 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 NO2 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 NO2 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: 
 3-16 

 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 NO2? 

 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. 
 4-1 

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 NO2 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 NO2, 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 NO2 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 NO2, 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. 
 4-2 

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 NO2, 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 policyrelevant 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. 
 4-3 

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/. 
 4-4 

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.

Literature Search and

Study Selection

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., toxicological studies of lung 

function. 

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.

Final Integrated Science Assessment

Evaluation, Synthesis and Integration of Evidence 

Integrate evidence from scientific disciplines – for example, toxicological, 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.

Public Comments

Comments on draft ISA solicited by EPA

Evaluation of Individual Study Quality

After study selection, the quality of individual studies is evaluated 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. 

Peer Input Consultation

Review of initial draft materials by scientists 

from both outside and within EPA in public 

meeting or public teleconference.
 4-5 

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, NO2, 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, 

toxicological, 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 
 4-6 

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 policyrelevant 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: 
 4-7 

 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 
 4-8 

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, timeactivity 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). 
 4-9 

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 NO2 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 NO2 are particularly informative if conducted in 

anatomically relevant cells such as lung epithelium or other airway cells. 
 4-10 

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 pollutantinduced pathophysiological alterations from laboratory animals to humans; confounding by coexposure 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 
 4-11 

concentrations of oxides of nitrogen defined to be relevant to ambient concentrations (e.g., up to 

5,000 ppb NO2). 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 NO2 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 NO2 standards. Decisions on the specific 

content of the ISA will be guided by policy-relevant questions that frame the entire review of the 

primary NO2 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 
 4-12 

question the evidence presented and evaluated in the last primary NO2 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 NO2 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 NO2 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 CASAC 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 

NO2 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 NO2 are strongly influenced by volatile 

organic compounds and O3. The relationships among these pollutants are critical to the 

understanding of ambient NO2 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? 
 4-13 

 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 NO2 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 NO2 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 NO2 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 NO2

concentrations obtained from central site monitors as measures of short-term exposure in 

epidemiological studies tended to bias the magnitude of associations between ambient NO2 and 

health effects toward the null (U.S. EPA, 2008a, section 5.2.2). The ISA will describe sources of 
 4-14 

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, timeactivity 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 

NO2 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 NO2 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? 
 4-15 

 To what extent is information available characterizing how well the current area-wide 

and near-road NO2 monitoring sites represent exposures to populations living near major 

roads? 

 What new information exists regarding characterization of error in assessment of shortterm and long-term exposure of oxides of nitrogen and how it influences personalambient 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 NO2 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 NO2 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 NO2? 

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 NO2 and/or NO. These topic areas will 
 4-16 

be evaluated using both human and animal data. The 2008 ISA concluded that inhaled NO2, 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 NO2 exposure. Additionally, findings 

of NO2-induced changes in airway responsiveness, airway inflammation, and lung host defenses 

were described as key mechanistic support for NO2-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 NO2 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 NO2 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 to NO2 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 
 4-17 

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 policyrelevant 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 longterm 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 
 4-18 

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., NO2, 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? 
 4-19 

 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 NO2 exposures and respiratory effects 

(U.S. EPA, 2008a, sections 3.1.7 and 5.3.2.1). In looking at a broader 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 shortterm NO2 exposures and premature mortality and between long-term NO2 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 NO2 exposures and cardiovascular effects as well as 

between long-term NO2 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 reevaluate the causal determinations made for relationships between NO2 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: 
 4-20 

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 NO2 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 NO2 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 NO2

concentrations to represent personal ambient NO2 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. 
 4-21 

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 NO2 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 NO2 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 NO2 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 NO2 serve not only as an indicator for oxides of nitrogen but as a 

surrogate for exposure to other vehicle exhaust gaseous and particulate 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 NO2, 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 
 4-22 

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 

NO2 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 NO2-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 preexisting 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, preexisting disease). 
 4-23 

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 atrisk 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 cooccurring 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 
 4-24 

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 CASAC 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 CASAC 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. 
 5-1 

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 NO2. 

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 NO2 measurement data within 

near-road environments under the recently revised monitoring requirements is recognized as an 
 5-2 

important consideration for the REA Planning Document. CASAC 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 NO2 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 NO2 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 NO2 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 NO2 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 NO2 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). 
 5-3 

NO2

52 in order to identify the number of days a particular benchmark concentration was 

exceeded per monitor per year. All U.S. monitoring sites where NO2 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 NO2 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 NO2 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 NO2 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 NO2 health effect benchmark levels were based on NO2 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 NO2 air quality concentrations 

and estimated NO2 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 CBSA to reflect current 

terminology. An initial pool of monitors was subset from the total set of monitors based on their belonging to 

specific CBSA. Then we selected study areas having annual mean NO2 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 NO2 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 CBSA or all other non-CBSA. 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: 1=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 nonCMSA/MSA’) were assumed to be ≥ 100 m from a road. 
 5-4 

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-road NO2 concentrations for each of the yeargroups and study areas. This scenario was developed by recognizing that motor vehicles are 

important emission sources of NOX and NO2 and that people spend time inside vehicles while 

travelling on roadways. At that time, a strong relationship had been reported between NO2

concentrations measured on roadways and NO2 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 NO2 concentrations and NO2 concentrations occurring at 

greater distances from a road (≥ 100 m).56 Then, we probabilistically applied these on-road 

adjustment factors to NO2 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 NO2 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 NO2

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. 
 5-5 

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 withinmonitor comparisons of low and high NO2 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 maximum1-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 NO2 concentrations: When considering any of the air quality 

scenarios, NO2 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 NO2 concentrations ≥ 100 ppb, while about 1/3 were 

estimated to have 100 days or more per year with daily maximum 1-hour ambient 

NO2 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). 
 5-6 

daily maximum 1-hour ambient NO2 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 

NO2 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 NO2 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 NO2

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 NO2 concentrations ≥ 300 ppb. 

 Simulated on-road NO2 concentrations: Simulated on-road annual average NO2

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 thenexisting standard. Most study areas were estimated, on average, to have between 100 

and 300 days per year with daily maximum 1-hour on-road NO2 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 onroad NO2 concentrations ≥ 200 ppb. All study areas evaluated, except one, were 

estimated to have on-road NO2 concentrations ≥ 300 ppb. Four of these study areas 
 5-7 

were estimated, on average, to experience an average of greater than 20 days per year 

with on-road NO2 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 NO2 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 NO2 concentrations. In doing so, this 

statistical model was characterized as having moderate or greater uncertainty in estimating onroad 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 NO2 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 NO2 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 NO2 concentrations that occur within these 

microenvironments across time, space, and microenvironment type, including estimation of onand near-roadway exposure concentrations (U.S. EPA, 2008b, section 8.2). The EPA’s air 

dispersion model (AERMOD) was used to estimate hourly NO2 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 
 5-8 

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 NO2 exposures, particularly those exposures associated with important 

emission sources of NOX and NO2, and served to complement the results of the broad NO2 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 NO2 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 

to NO2 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 NO2 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 NO2

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 NO2 exposure. This was in contrast to 

using health effects associated with ambient NO2 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 NO2 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) 
 5-9 

standard, virtually all asthmatics in Atlanta were estimated to experience six or more 

daily maximum 1-hour exposures per year to NO2 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 NO2 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 onand near-roadways concentrations. While AERMOD estimated 1-hour NO2 concentrations 
 5-10 

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 NO2 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 l emergency department visits were estimated as 

a function of short-term ambient NO2 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 NO2 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 NO2 epidemiological studies that relied on fixed-site, population-oriented, ambient 

monitors as a surrogate for actual ambient NO2 exposures and were used to estimate the impact 

of daily maximum 1-hour ambient NO2 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. 
 5-11 

based approach provided additional perspective on the potential public health impacts resulting 

from NO2 exposures. 

Because of the limited number of epidemiological studies reporting concentrationresponse (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 thenexisting 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 NO2-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 NO2-related incidences per year) based on single-pollutant models 

and from 1.7 to 7.7 percent (or 3,100 to 9,400 NO2-related incidences per year) based on 

two-pollutant models that included either CO, O3, particulate matter 10 micrometers or 

less in diameter (PM10), or a three pollutant model that included both O3 and PM10. 

 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 
 5-12 

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 NO2 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 CASAC 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). 
 5-13 

Table 5-1. Information (data, methods, models, etc.) identified as potentially important and/or newly avail

air quality characterization for the current review. 

Major 

Uncertainty or 

Limitation 

Uncertainty/Limitation Remaining from 2008 REA Consideration of Poten

Information Newly Avai

Sub-group Description Have on 

Ambient Monitor Spatial and Temporal Representativeness

Near-Road Ambient Monitoring Data 

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 NO2 concentrations 

occurring in these locations creates a significant uncertainty regarding how often on- and near-road NO2

concentrations may exceed exposure levels of concern. This uncertainty served as a driver for revising ambient monitor siting. 

The near-road monitoring in three phases: the first semeasuring near-road NO2 

January 1, 2014, followed monitors by January 1, 20monitoring sites (see sectithis schedule, it is possiblthe availability of the newmonitor concentration datreviews, potentially delaynew and important data in 

Long-term Exposures 

The annual average standard of 53 ppb was retained in the last review due to some evidence suggesting NO2

concentrations had a causal relationship with respiratoryrelated health effects. Newly identified for this review would be the consideration of how long-term, though spatially variable, ambient NO2 concentrations could 

adversely affect health. 

Model and data fusion tecestimation of the spatial aNO2 concentrations acrosarea-wide and on-road disaccounting for increased einfluential factors within a There could be utility in elong-term NO2 concentrat

defined long-term health einterest. 
 5-14 

Major 

Uncertainty or 

Limitation 

Uncertainty/Limitation Remaining from 2008 REA Consideration of Poten

Information Newly Avai

Sub-group Description Have on 

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 NO2 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. 

We could use air quality mdispersion model combinephotochemical model CMsource gradients (roadwayIn addition, we could eval(e.g., linear, biphasic, etc.distributions of on-road adconsider other factors useif there are studies newly measurement) that indicatexist outside of the range 2008 REA. Further, in the the complete near-road minformation regarding neagradients could be charactnew published literature amonitoring databases. 

Distribution of Onroad Adjustment Factors 

Two distributions of NO2 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 NO2

concentrations. 

Definition of monitors minimally influenced by roadway emissions to use in the calculation of onroad 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 
 5-15 

Major 

Uncertainty or 

Limitation 

Uncertainty/Limitation Remaining from 2008 REA Consideration of Poten

Information Newly Avai

Sub-group Description Have on 

could have been influenced by emissions from a non-road NOx source. 

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 developed if there are studindicate alternative approaexist that would generate sets outside of those alrea

REA. This could include aambient monitor data trenbased 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 preexisting 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 benchmdeveloped if there are studindicate alternative health should be considered outs

evaluated in the 2008 REAwhere any new health endthose associated with respterm exposures. Further, aexisting human exposure improved characterization possible using newly ideninformation. 
 5-16 

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 NO2

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 NO2

concentrations as input to APEX, (2) the factors approach used to estimate in-vehicle and nearroad NO2 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 NO2 exposure (Table 5-

2). 
 5-17 

Table 5-2. Information (data, methods, models, etc.) identified as potentially important and/or newly avail

exposure assessment for the current review. 

Major Uncertainty 

or Limitation 

Uncertainty/Limitation Remaining from 2008 REA Consideration of Potential 

Information Newly Available in 

Description on Assessm

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 REA (both the modeled exposures to approximate the potential impacmodeled alternative ambient concewe could use AERMOD, with receimprove the quality and characterizconcentration data set for input to A

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 on-road concentrations, and can be identifier, as an input to estimating concentrations. Thus, APEX is capAERMOD on-road concentrations a factors-based approach. In the abof on-road concentrations for potenis possible that new factors or concbe developed and used to estimate microenvironmental concentrationdata are identified. 
 5-18 

Major Uncertainty 

or Limitation 

Uncertainty/Limitation Remaining from 2008 REA Consideration of Potential 

Information Newly Available in 

Description on Assessm

Limited Input Data Used to Estimate Contribution of Indoor Source Emissions of NO2 to 

Total Exposures

For a few APEX simulations, we estimated exposures associated with ambient NO2 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 NO

combined ambient, personal, and inimportant consideration in understa

health risk. However, the role and rthe contribution of personal and indexposures when setting ambient air need to be further evaluated considand in addressing other key assessm
 5-19 

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 NO2 exposures. If new studies are identified and adequate data 

are available to develop exposure–response (E-R) relationships, these functions could be 

combined with NO2 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 NO2 monitors to serve as a surrogate for population exposure. The 

risk assessment conducted in the last review focused on one health endpoint (i.e., respiratoryrelated 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. 
 5-20 

 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 Consideration of Potential Utility and Impact 

that Information Newly Available in this Review 

Description 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 loglinear form assuming no threshold 

was selected, and both single and copollutant 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 areawide 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 
 5-21 

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. 

 
 5-22 

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 6-1 

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 NO2. 

6.1 CONSIDERATION OF SAMPLING AND ANALYSIS METHODS 

Generally, in order to be used for regulatory purposes, ambient NO2 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, NO2 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 NO2 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 NO2. 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 

NO2 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. 
 6-2 

oxidized nitrogen species such as nitric acid (HNO3) or peroxyacetyl nitrate (PAN) make it to the 

converter, where they can be reduced by some degree to NO and subsequently counted as NO2. 

While similar in the use of a two-step process of indirectly determining NO2 concentrations as 

the chemiluminescent FRM, the photolytic-chemiluminescence FEM carries out the reduction of 

NO2 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. 
 6-3 

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 NO2 monitoring network and data was performed as part of the 

primary NO2 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 NO2 standard. The minimum requirements 

consisted of the following: (1) near-road monitors which would be placed in locations of 

expected maximum 1-hour NO2 concentrations near heavily trafficked roads in urban areas; (2) 

monitors located to characterize areas with the highest expected NO2 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 NO2 concentrations that have the potential to approach or 

exceed the standards (75 FR 6509). The near-road NO2 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 NO2 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 NO2 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 NO2 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 nearroad NO2 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 NO2

 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. 
 6-4 

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 NO2 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 NO2 monitoring network was estimated to have 391 NO2

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 NO2 monitors. We anticipate 126 

near-road sites will be operational on or before January 1, 2017, potentially resulting in more 

than 500 NO2 monitors nationwide when the NO2 network is fully operational. 
 6-5 

Figure 6-1. NO2 Monitoring Network: Active monitors as of September 2013. 

In the last review, there was limited near-road ambient NO2 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 

NO2 monitors would be required. In particular, the 2008 REA considered estimates of on- or 

near-roadway exceedances in 17 urban areas associated with CBSA populations ranging from 

approximately 540,000 to 19,000,000 persons. Those analyses indicated that the areas under 

explicit consideration were estimated to experience NO2 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 

NO2 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 NO2 concentrations 

are in the near-road environment, with the continued understanding that factors including traffic 
 6-6 

counts, fleet mix, congestion patterns, roadway design, terrain, and meteorology all play a major 

role in measured roadside NO2 concentrations. The EPA plans to summarize the meta-data of 

near-road NO2 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 NO2 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 CBSA (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 NO2 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. 
 7-1 

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 CASAC’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/exposurebased 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 

NO2 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 
 7-2 

scientific evidence and analyses. Staff’s 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 CASAC 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. 
 7-3 

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 NO2 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 NO2 NAAQS review is identified as EPA-HQ-OAR2013-0146. 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). 
 7-4 

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8-1 

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Samet J (2008a). Letter form Dr. Jonathan M. Samet, Chair, Clean Air Scientific Advisory Committee to EPA 

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2574F00069D45E/$File/EPA-CASAC-09-001-unsigned.pdf. 

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52575210074A7AE/$File/EPA-CASAC-09-003-unsigned.pdf. 
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A-1 

APPENDIX A 

DRAFT OUTLINE FOR INTEGRATED SCIENCE ASSESSMENT FOR OXIDES OF 

NITROGEN – HEALTH CRITERIA 

Preamble Process of ISA Development 

(will be available online) 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 

Preface 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 

Executive Summary 

Chapter 1 Integrative Summary 

1.1 ISA Development and Scope 

1.2 Organization of the ISA 

1.3 Sources of Oxides of Nitrogen to Human Exposure 

1.4 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 

1.5 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 

1.6 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 
A-2 

 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. 
A-3 

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 Genetic Factors 

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 
United States 

Environmental Protection Agency

Office of Air Quality Planning and Standards 

Health and Environmental Impacts Division 

Research Triangle Park, NC 

Publication No