EPA United States

Environmental

Protection Agency

Draft Plan for the 

Development of the Integrated 

Science Assessment for 

Nitrogen Oxides – Health 

Criteria

Draft - May 2013

NOTICE

This information is distributed solely for the purpose of pre-dissemination peer review under 

applicable information quality guidelines. It has not been formally disseminated by EPA. It does 

not represent and should not be construed to represent any Agency determination or policy.

U. S. Environmental Protection Agency

Office of Research and Development; National Center for Environment Assessment

Office of Air and Radiation; Office of Air Quality Planning and Standards

Research Triangle Park, North Carolina
Draft – May 2013 ii

DISCLAIMER

This document serves as a planning tool for the U.S. Environmental Protection Agency's National 

Center for Environmental Assessment and the Office of Air Quality Planning and Standards. The 

approach described in this plan may be modified to reflect information developed during this review and 

to address advice and comments received from the Clean Air Scientific Advisory Committee and the 

public throughout this review. Mention of trade names or commercial products does not constitute 

endorsement or recommendation for use.
Draft – May 2013 iii

TABLE OF CONTENTS

1. INTRODUCTION...............................................................................................................1

1.1 OVERVIEW OF THE PROCESS...........................................................................1

Figure 1.1 Overview of Process for Reviewing the NAAQS ..................................2

1.2 HISTORY OF REVIEWS OF THE PRIMARY NAAQS FOR NO2 .......................2

1.3 Scope of the CURRENT review..............................................................................3

2. REVIEW SCHEDULE........................................................................................................4

Table 2-1. Anticipated Schedule for the Development of the Integrated Science 

Assessment for NOX – Health Criteria ..................................................4

3. DEVELOPMENT of the INTEGRATED SCIENCE ASSESSMENT..................................5

3.1 SCOPE AND ORGANIZATION............................................................................5

3.2 Assessment Approach.............................................................................................6

Figure 3.1. General process for development of Integrated Science Assessments 

(ISAs)...................................................................................................7

4. SCIENTIFIC AND PUBLIC REVIEW.............................................................................18

5. REFERENCES..................................................................................................................19

APPENDIX A........................................................................................................................ A-1

LEGISLATIVE REQUIREMENTS ............................................................................... A-1

U.S. EPA SCIENCE ADVISORY BOARD CLEAN AIR SCIENTIFIC ADVISORY 

COMMITTEE MEMBERS............................................................................... A-3

Draft Outline for Integrated Science Assessment for Nitrogen Oxides – Health Criteria . A-5
Draft – May 2013 1

1. INTRODUCTION

1.1 OVERVIEW OF THE PROCESS

1 The U.S. Environmental Protection Agency (EPA) is conducting a review of the air quality 

2 criteria for the health effects of nitrogen oxides (NOX) and the primary (health-based) national ambient air 

3 quality standards (NAAQS) for nitrogen dioxide (NO2). Figure 1.1 illustrates the four major phases of the 

4 NAAQS review process: (1) planning, (2) science assessment, (3) risk/exposure assessment, as 

warranted1 5 , and (4) policy assessment and rulemaking. An Integrated Review Plan (IRP) is being 

6 developed for this NAAQS review, and a draft IRP will be released for review by the Clean Air Scientific 

7 Advisory Committee (CASAC) and the public later in 2013. The IRP will characterize the review of the 

8 primary NAAQS for NO2, including discussion of the four major phases listed above, the schedule for the 

9 entire review, the process for conducting the review, and the key policy-relevant science issues that will 

10 guide the review.

11 The purpose of this document is to communicate the draft plan for the development of the 

12 Integrated Science Assessment (ISA) for NOX health criteria which will comprise the science assessment 

13 phase for the review of the primary NAAQS for NO2. An ISA is intended to provide a concise review, 

14 synthesis, and assessment of the most policy-relevant science, including key science judgments that are 

15 important to the design and scope of exposure and risk assessments, as well as other aspects of the 

16 NAAQS reviews. An ISA is intended to provide a comprehensive assessment of the current scientific 

17 literature pertaining to known and anticipated effects on public health and welfare associated with the 

18 presence of the pollutant in the ambient air, emphasizing information that has become available since the 

19 last air quality criteria review in order to reflect the current state of knowledge. As such, an ISA provides

20 the scientific foundation for each NAAQS review and is intended to provide information useful in 

21 forming judgments about the air quality indicator(s), form(s), averaging time(s) and level(s) for the 

22 NAAQS. The current review process generally includes production of a first and second draft ISA, both 

23 of which undergo CASAC and public review prior to completion of the final ISA.

24 The plan for development of an ISA usually is included as part of the IRP. However, a separate 

25 draft plan for ISA development is being released for CASAC and public consultation prior to completion 

26 of the draft IRP so that EPA may benefit from advice and comments as the first draft ISA is developed.

27 EPA intends to release the first draft NOX health effects ISA for CASAC and public review in August 

 1

EPA staff will consider the extent to which information and conclusions presented in the ISA support the 

development of quantitative estimates of NO2 risks and/ or exposures for the current review.
Draft – May 2013 2

1 2013. This draft plan for ISA development includes discussion of the history of the primary NAAQS for 

2 NO2 and relevant legislative requirements as background material.

1.2 HISTORY OF REVIEWS OF THE PRIMARY NAAQS FOR NO2

3 The establishment and revision of the NAAQS is governed by two sections of the Clean Air Act, 

4 as described in more detail in the Appendix. On April 30, 1971, EPA promulgated identical primary and 

5 secondary NAAQS for NO2, under section 109 of the Act, set at 0.053 parts per million (ppm), annual 

6 average (36 FR 8186). EPA concluded the first review of the NAAQS with a final decision to retain these 

7 standards published on June 19, 1985 (50 FR 25532). The next review was initiated in 1987 and 

8 culminated October 8, 1996 in a final determination by the Administrator not to revise the NAAQS for 

9 NO2 (61 FR 52852).

10 EPA initiated the most recent review of the air quality criteria for the health effects of NOX and 

11 the NO2 primary NAAQS on December 9, 2005 (70 FR 73236) with a general call for information. Upon 

12 completion of the Integrated Science Assessment for Oxides of Nitrogen-Health Criteria and the Risk and 

13 Exposure Assessment to Support the Review of the NO2 Primary National Ambient Air Quality Standard 

14 (Risk and Exposure Assessment), EPA proposed to supplement the existing annual primary standard for 

Figure 1.1 Overview of Process for Reviewing the NAAQS
Draft – May 2013 3

1 NO2 by establishing a new short-term standard on July 15, 2009 (74 FR 34404). On February 9, 2010, 

2 EPA finalized a new short-term primary NO2 standard with a level of 100 parts per billion (ppb), based on 

the 3-year average of the 98th 3 percentile of the yearly distribution of 1-hour daily maximum 

4 concentrations. In that rulemaking, EPA also retained the existing annual primary standard, with a level of 

53 ppb2 5 (75 FR 6474). The Administrator signed a notice of final rulemaking on January 22, 2010.

1.3 SCOPE OF THE CURRENT REVIEW

6 As noted above, in reviewing the NO2 NAAQS, EPA has historically focused its review of 

7 relevant scientific information on a broad category of nitrogen oxides, while finding it appropriate to 

8 specify the indicator of the standard specifically in terms of NO2. As specified in Section 108(c) of the 

9 Clean Air Act, EPA considers the term nitrogen oxides to refer to all forms of oxidized nitrogen including

10 multiple gaseous (e.g., NO2, nitric oxide [NO]) and particulate (e.g., nitrate) species. 42 U.S.C. 21 

11 7408(c). EPA has evaluated the atmospheric chemistry, exposure, and health effects associated with 

12 nitrogen compounds present as particulate matter within the context of ambient particles in the Agency’s 

13 review of the NAAQS for particulate matter. Thus, the current review of the NO2 NAAQS will focus on 

the gaseous species of nitrogen oxides, which in this document are abbreviated as NOX

3 14 . 

15 Although it is likely that the majority of the information available to inform the current review, 

16 particularly with regard to human exposures and health effects, will be specifically for NO2, evidence on

17 the other gaseous nitrogen oxides will be considered to the extent that information is available and 

18 relevant to the review of the NO2 NAAQS. In addition, evidence will be considered on the possible 

19 influence of atmospheric pollutants other than the NOX (e.g., sulfur oxides, carbon monoxide, ozone, 

20 particulate matter) on the role of the NOX in health effects.

 2

At standard temperature (25oC) and pressure (1 atm), 53 ppb NO2 is equivalent to 100 micrograms per cubic meter 

of air (μg/m3

), and 100 ppb NO2 is equivalent to 188 μg/m3. 3

In the fields of air pollution research and control, the term NOX can refer more narrowly to the sum of NO and NO2.
Draft – May 2013 4

2. REVIEW SCHEDULE

1 On February 10, 2012, EPA’s National Center for Environmental Assessment in Research 

2 Triangle Park, NC (NCEA-RTP) announced the initiation of the current periodic review of the air quality 

3 criteria for the health effects of NOX and the primary NO2 NAAQS and issued a call for information in 

4 the Federal Register (77 FR 7149). EPA held a workshop February 29 to March 1, 2012, to discuss with 

5 invited scientific experts, key science and policy issues relevant to the review of the health effects of NOX

6 (77 FR 7149). Table 2-1 outlines the anticipated schedule for development of the ISA. The anticipated 

7 schedule for the remainder of the review of the primary NO2 NAAQS will be included in the draft IRP, 

8 which will be released later in 2013.

Table 2-1. Anticipated Schedule for the Development of the Integrated Science Assessment 

for NOX – Health Criteria

Major Milestone Projected Target Dates

CASAC/public consultation on draft plan for ISA development June 2013

Final plan for ISA development (to be incorporated into draft IRP) August 2013

First draft of ISA August 2013

CASAC/public review of first draft ISA and draft IRP November 2013

Second draft of ISA April 2014

CASAC/public review of second draft ISA July 2014

Final ISA November 2014
Draft – May 2013 5

3. DEVELOPMENT OF THE INTEGRATED SCIENCE 

ASSESSMENT

3.1 SCOPE AND ORGANIZATION

1 The ISA comprises the science assessment phase of the NO2 NAAQS review. The ISA may be 

2 supplemented with additional materials if additional documentation is required to support information 

3 contained within the ISA. These supplementary materials may include more detailed and comprehensive 

4 coverage of relevant publications and may accompany the ISA or be available in electronic form as output 

5 from the Health and Environmental Research Online (HERO) database developed by EPA 

6 (http://hero.epa.gov/). Supplementary information available in the HERO database will be presented as 

7 electronic links in the ISA.

8 The ISA will critically evaluate and integrate the scientific information on exposure and health 

9 effects associated with NOX in ambient air in the discipline areas of atmospheric science, human 

exposure, epidemiology, controlled human exposure, toxicology, and dosimetry.

4 10 The purpose of the 

11 discussions within the ISA is not to provide a detailed literature review but to draw upon the existing 

12 body of evidence to synthesize the current state of knowledge on the most relevant issues pertinent to the 

13 review of the NAAQS for NO2. The ISA discussions will be designed to focus on the key policy-relevant

14 questions described in Section 3.2.

15 The focus of the ISA will be on literature published since the 2008 NOX ISA. Key findings and 

16 conclusions from the 2008 ISA for NOX will be briefly summarized at the beginning of the ISA and of 

17 individual sections. The results of recent studies will be integrated with previous findings. Important 

18 studies reviewed in previous assessments will be discussed in greater detail if they are open to 

19 reinterpretation in light of newer data or if they provide the most informative evidence in the available 

20 literature. Generally, only information that has undergone scientific peer review and that has been 

21 published (or accepted for publication) in the open literature will be considered. In evaluation of 

22 controlled human exposure and animal toxicological studies, emphasis will be placed on studies 

23 conducted at or near NOX concentrations that represent the range of human exposures in the ambient 

24 environment across various microenvironments. However, in recognition of the fact that controlled 

25 human exposure and animal toxicological studies do not necessarily reflect effects in the most sensitive 

 

4

Note that evidence related to environmental effects of NOX will be considered separately in the science assessment 

conducted as part of the review of the secondary NAAQS for NO2 and SO2.
Draft – May 2013 6

1 populations, studies at higher exposure concentrations will be included when they provide information 

2 relevant to previously unreported effects, evidence of the potential biological mechanism for an observed 

3 effect, or information on exposure-response relationships.

3.2 ASSESSMENT APPROACH

Introduction

4 The NCEA-RTP is responsible for preparing the ISA for NOX health criteria. In each NAAQS 

5 review, development of the science assessment begins with a “Call for Information” published in the 

6 Federal Register. This notice announces EPA’s initiation of activities in the preparation of the ISA for the 

7 specific NAAQS review and invites the public to assist through the submission of research studies in the 

8 identified subject areas. This and subsequent key components of the process currently followed for the 

9 development of an ISA (i.e., the development process) are presented in Figure 3.1 and are described in 

10 greater detail in the Preamble to the ISA for Ozone and Related Photochemical Oxidants (U.S. EPA, 

11 2013). How the ISA fits into the larger NAAQS review process is briefly described in Section 1.1, the 

12 Overview of the Review Process.
Draft – May 2013 7

(Modified from Figure III of the Preamble to the ISA for Ozone and Related Photochemical Oxidants, 

U.S. EPA, 2013).

Literature Search and

Study Selection

Integrated Science Assessment Development Process

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. Develop initial conclusions as 

appropriate.

Development of 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, potential at-risk populations 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 epidemiologic study findings for particular health outcome. Evaluate evidence for groups of related endpoints or 

outcomes to draw conclusions for 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 expert authors in the fields of 

atmospheric science, exposure, dosimetry, animal toxicology, controlled human exposure, epidemiology, ecology, and environmental effects, considering the design, methods, conduct, and documentation of each study. Strengths 

and limitations of individual studies that may affect the interpretation of study results are considered. 

Peer Input Consultation

Review of initial draft materials by scientists 

from both outside and within EPA in public 

meeting or public teleconference.

Figure 3.1. General process for development of Integrated Science Assessments (ISAs)
Draft – May 2013 8

1 Important aspects of the development of the ISA are described in the sections below, including the 

2 approach for searching the literature and identifying relevant publications and forming specific policy3 relevant questions that are intended to guide the assessment. These responsibilities are undertaken by 

4 expert authors of the ISA chapters which include EPA staff with extensive knowledge in their respective 

5 fields and extramural scientists solicited by EPA for their expertise in specific fields. The process for 

6 scientific and public review of drafts of the ISA is described in Section 3.3.

Literature Search and Identification of Relevant Studies

7 The NCEA-RTP uses a structured approach to identify relevant studies for consideration and 

8 inclusion in the ISA. A Federal Register Notice is published to announce the initiation of a review and 

9 request information, including relevant literature, from the public. In addition, publications are identified 

10 by EPA through a recurrent multi-tiered literature search process that includes extensive manual and 

11 computer-aided citation mining of computer databases on specific topics in a variety of disciplines using 

12 as keywords terms such as NOX, NO2, NO, nitric acid, peroxyacytyl nitrate, or total reactive nitrogen. The

13 search strategies are iteratively modified to optimize identification of pertinent published papers. Papers 

14 are identified for inclusion in several additional ways: searches for recent publications that have cited 

15 references included in the previous ISA, independent review of tables of contents for journals in which 

16 relevant papers may be published or reference lists from key publications, independent identification of 

17 relevant literature by external expert authors, and identification of relevant publications by both the public 

18 and CASAC during the external review process. The studies identified will include research published or 

19 accepted for publication from January 2008, which was the publication end date for studies reviewed in 

20 the 2008 NOX ISA, through approximately two months before the release of the second external review 

21 draft of the ISA (target of February 2014, see Table 2-1). Once identified, studies are reviewed with 

22 regard to inclusion criteria described below before including them in the ISA. Publications considered for 

23 inclusion in the ISA are added to the HERO database; the references in the ISA include a hyperlink to the 

24 database. The combination of approaches described above is intended to produce the comprehensive 

25 collection of pertinent studies needed to address the key scientific issues that form the basis of the ISA.

26 Studies that have undergone scientific peer review and have been published or accepted for 

27 publication and reports that have undergone review are considered for inclusion in the ISA. Analyses 

28 conducted by EPA using publicly available data, for example, air quality and emissions data, are also 

29 considered for inclusion in the ISA. 
Draft – May 2013 9

Evaluation of Individual Study Quality

1 The ISA will emphasize studies published since the 2008 NOX ISA; however, evidence from 

2 previous studies will be included to integrate with results from recent studies, and in some cases, 

3 characterize the key policy-relevant evidence in a particular subject area. Several general benchmarks are 

4 used to evaluate the quality and policy-relevance of studies included in the ISA. Policy-relevant and 

5 informative studies include those that provide a basis for or describe the relationship between the criteria 

6 pollutant and effects, such as studies that offer innovation in method or design and studies that reduce 

7 uncertainty on critical issues, for example, analyses of potential confounding or effect modification by 

8 copollutants or other variables, analyses of concentration-response or dose-response relationships, or 

9 analyses related to time between exposure and response. In assessing the scientific quality and relevance 

10 of studies, the following parameters are considered:

11 • To what extent are the air quality data, exposure, or dose metrics of adequate quality and sufficiently 

12 representative to serve as credible exposure indicators?

13 • Were the study populations, subjects, or animal models adequately selected, and are they sufficiently 

14 well defined to allow for meaningful comparisons between study or exposure groups?

15 • Are the statistical analyses appropriate, properly performed, and properly interpreted?

16 • Are likely covariates (i.e., potential confounding factors, effect modifiers) adequately controlled for or 

17 taken into account in the study design or statistical analyses?

18 • Are the health endpoint measurements meaningful, valid, and reliable?

19 • Are the reported findings internally consistent, biologically plausible, and coherent in terms of 

20 consistency with other known facts?

21 In evaluating epidemiologic studies for the present assessment, EPA also will consider whether a 

22 given study contains information on (1) short- or long-term exposures that represent ambient 

23 concentrations of NOX across various microenvironments; (2) health effects of specific NOX species; (3) 

24 lifestages or populations that potentially are at increased risk of NOX-related health effects; (4) potential 

25 copollutant interactions (e.g., are there synergistic effects of NOX with other pollutants) or confounding 

26 (e.g., are associations observed between NOX and health endpoints biased by the effects of copollutants);

27 and/or (5) important methodological issues (e.g., lag or time period between exposure and effects, model 

28 specifications, thresholds, mortality displacement) related to the health effects of NOX exposure. Among 

29 the epidemiologic studies, particular emphasis will be given to those relevant to standard setting in the 

30 U.S. Specifically, studies conducted in the U.S. or Canada generally will be accorded more text 

31 discussion than those from other geographic regions because of the greater relevance of the population 

32 sociodemographic characteristics and air pollution mixture. In addition, emphasis will be placed on 
Draft – May 2013 10

1 discussion of (1) multicity studies that employ standard methodological analyses for evaluating NOX

2 effects, provide overall estimates for effects based on combined analyses of information pooled across 

3 cities, and examine results for consistency across cities; (2) studies that provide quantitative effect 

4 estimates for populations of interest; and (3) studies that regard NOX as a component of a complex 

5 mixture of air pollutants by considering the concentrations of copollutants, correlations of NOX with these 

6 copollutants, and results of copollutant analyses.

7 A set of additional explicit criteria also will be used to evaluate the quality and relevance of

8 experimental studies included in the ISA. The discussion of research evaluating controlled exposures of

9 laboratory animals will focus primarily on those studies conducted with NOX exposures representative of

10 exposure concentrations and durations that humans experience across various ambient 

11 microenvironments. In animal models, relevant exposures will depend on the toxicokinetics and 

12 biological sensitivity of the particular laboratory animal examined. With respect to the mechanisms of 

13 NOX toxicity, studies conducted under environmentally-relevant conditions will be emphasized, but 

14 studies at higher concentrations also will be considered, because of species-to-species differences and 

15 potential differences in sensitivity between humans or animals included in experimental studies and at16 risk human lifestages and populations. Other considerations for the evaluation of animal toxicological 

17 studies include: (1) investigation of animal models of disease that can provide information on human 

18 lifestages and populations potentially at increased risk of NOX-related health effects; (2) examination of

19 concentration-response or time-course of responses; and (3) demonstration of sufficient statistical power 

20 to assess responses to exposures. Results from in vitro studies also may be included if they provide 

21 mechanistic insight or further inform effects demonstrated in vivo. For research evaluating controlled 

22 human exposures to NOX, emphasis will be placed on studies that (1) examine NOX exposures that 

23 approximate the range of human exposure concentrations and durations across various ambient 

24 microenvironments; (2) compare responses following NOX exposure and control or filtered air exposure 

25 and thus have subjects serve as their own controls; (3) investigate effects in potential at-risk populations 

26 such as people with asthma and compare to responses in age-matched healthy subjects; (4) address issues 

27 such as concentration-response or time-course of responses; (5) investigate exposure to NOX separately 

28 and in combination with other pollutants such as ozone and sulfur dioxide; and (6) have sufficient 

29 statistical power to adequately assess responses to NOX exposures. 

30 NCEA participates in the Agency-wide Quality Management System, which requires the 

31 development of a Quality Management Plan (QMP). Implementation of the NCEA QMP ensures that all 

32 data generated or used by NCEA scientists are “of the type and quality needed and expected for their 

33 intended use” and that all information disseminated by NCEA adheres to a high standard for quality 

34 including objectivity, utility, and integrity. Quality assurance (QA) measures detailed in the QMP are 
Draft – May 2013 11

1 being employed for the current NOX review, including the development of the ISA for NOX health 

2 criteria. The NCEA QA staff is responsible for the review and approval of quality-related documentation.

3 NCEA scientists are responsible for the evaluation of all inputs to the ISA, including primary (new) and 

4 secondary (existing) data, to ensure their quality is appropriate for their intended purpose. NCEA adheres 

5 to Data Quality Objectives, which identify the most appropriate inputs to the science assessment and 

6 provide QA instruction for researchers citing secondary information. The approaches utilized to search 

7 the literature and criteria for study selection and evaluation were detailed in the two preceding 

8 subsections. Generally, NCEA scientists rely on scientific information found in peer-reviewed journal 

9 articles, books, and government reports. Where information is integrated or reduced from multiple 

10 sources to create new figures, tables, or summation, the data generated are considered to be new and 

11 subject to rigorous quality assurance measures to ensure their accuracy.

Content and Organization of the ISA

12 The organization of the ISA for NOX health criteria will be consistent with that used in the recent 

13 assessments for other criteria pollutants (e.g., ISA for Ozone and Related Photochemical Oxidants, U.S. 

14 EPA, 2013). Development of the ISA will be guided by policy-relevant questions that frame the entire 

15 review of the primary NO2 NAAQS. These policy-relevant questions will be discussed in more detail in 

16 the IRP but are related to two overarching issues. The first issue is whether new evidence reinforces or 

17 calls into question the evidence presented and evaluated in the last NAAQS review with respect to factors 

18 such as the concentrations of NOX exposure associated with health effects and plausibility of health 

19 effects caused by NOX exposure. The second issue is whether uncertainties from the last review have been 

20 reduced and/or whether new uncertainties have emerged. Specific questions that will be addressed in the 

21 ISA are listed subsequently by topic area.
Draft – May 2013 12

1 A. Air Quality and Atmospheric Chemistry: The ISA will present and evaluate data related to 

2 ambient concentrations of NOX; sources leading to the presence of NOX in the atmosphere; 

3 and chemical reactions that determine the formation, degradation, and lifetime of NOX in 

4 the atmosphere. 

5 • What progress has been made in improving measurements and reducing 

6 interference problems in measuring NOX? What limitations still remain?

7 • Based on recent air quality and emissions data, what are current concentrations 

8 and emissions of NOX? How have emissions and concentrations of NOX and of 

9 NO2 changed since the 2008 NOX ISA? To what extent can satellite data be used 

10 to improve the characterization of NOX concentrations?

11 • What spatial and temporal patterns can be seen in the air quality data for NOX? In 

12 particular, what patterns can be seen on a micro-scale for near road environments 

13 and on a national scale based on satellite data?

14 • Based on air quality and emissions data on NOX and atmospheric chemistry 

15 models, what are likely policy relevant background concentrations of NOX in the 

16 absence of anthropogenic emissions?

17 B. Exposure: The ISA will evaluate the factors that influence exposure to ambient NOX and 

18 the uncertainties associated with extrapolation from ambient concentrations to personal 

19 exposures to NOX of ambient origin, particularly in the context of interpreting results from 

20 epidemiologic studies. The issues of uncertainty differ by the exposure period of interest as 

21 most short-term exposure studies (e.g., population-level studies using time-series analyses, 

22 field/panel studies) rely on temporal variation in exposure while long-term exposure 

23 studies (e.g., longitudinal cohort studies) rely on spatial variability of exposure.

24 • What are the relationships between NOX measured at stationary monitoring sites

25 and personal exposure to NOX? What evidence is available regarding these 

26 relationships in environments near roads or other sources?

27 • What new information exists regarding characterization of error in NOX exposure 

28 assessment and how it influences personal-ambient exposure relationships?

29 • What information is available regarding differences in NOX exposure patterns and 

30 personal-ambient exposure relationships among various lifestages and 

31 populations?

32 • What new information exists regarding NOX measurements in a multipollutant 

33 context? To what extent do NO2 measurements serve as surrogates of exposure to 
Draft – May 2013 13

1 other gaseous pollutants (including carbon monoxide and nitrous acid) and 

2 particle phase pollutants generated by traffic or other combustion sources?

3 • What new information is available about the interaction of NOX with organic 

4 compounds that may influence human exposure?

5 C. Dosimetry and Modes of Action: The ISA will evaluate literature focusing on dosimetry 

6 and modes of action that may underlie the health outcomes associated with exposure to 

7 NOX. These topic areas will be evaluated using both human and animal data.

8 • What information is available to discern the relative contributions to internal 

9 NOX compounds of NOX derived exogenously from ambient exposures and NOX

10 derived from pathways such as diet or biological processes?

11 • What NOX reaction products can be found in the respiratory tract cells, tissues, or 

12 fluids that may serve as markers of NOX exposure and effect?

13 • What are the potential biological mechanisms underlying responses to NOX at or 

14 near environmentally-relevant exposures, with a focus on response pathway(s) 

15 and exposure-dose-response relationships?

16 • What new information is available related to the modes of action for health 

17 effects associated with exposure to NOX?

18 • What mechanisms can be qualitatively compared across species?

19 • Do interactions between inhaled NOX and other inhaled pollutants influence the 

20 mechanisms underlying the toxic potential of NOX?

21 • What are the effects of host factors such as age, sex, pre-existing disease, and 

22 genetic background on NOX uptake and cellular and tissue responses?

23 D. Health Effects: The ISA will evaluate the literature related to respiratory, cardiovascular, 

24 reproductive, and developmental health effects, mortality, and cancer associated with NOX

25 exposure. Other health effects also may be evaluated, for example, those related to the 

26 central nervous system or gastrointestinal system. Health effects that occur following both

27 short- and long-term exposures will be evaluated in epidemiologic, controlled human 

28 exposure, and animal toxicological studies. Efforts will be directed at identifying the lower 

29 concentrations at which effects are observed, including those in potential at-risk lifestages 

30 and populations.

31 Short-Term Exposure:

32 • What do controlled human exposure, animal toxicological, and epidemiologic 

33 studies indicate regarding the relationship between short-term (i.e., hours to 
Draft – May 2013 14

1 weeks) exposures to NOX and health effects of concern (e.g., altered lung 

2 function, respiratory symptoms, inflammation, heart rate variability, cardiac 

3 arrhythmias, emergency department visits, hospital admissions, mortality), 

4 including the nature and time course, in healthy individuals and in those with pre5 existing disease states (e.g., people with asthma or cardiovascular disease) or 

6 other potential at-risk factors (e.g., lifestage, genetic, nutritional)?

7 • How do results of recent studies expand current understanding of the relationship 

8 between short-term exposure to NOX and airway hyperresponsiveness or other

9 lung function changes?

10 • What is the influence of NOX on host defense against infectious disease?

11 • What are the effects of NOX exposure on cardiovascular health in humans (e.g., 

12 heart rate variability, arrhythmias, vasomotor function, risk of myocardial 

13 infarction)?

14 • How do results from recent population-level time-series studies expand 

15 understanding of relationships between exposure to NOX and mortality (all-cause, 

16 respiratory, cardiovascular), hospital admissions, or emergency department visits?

17 • To what extent does exposure to NOX contribute to health effects beyond the 

18 respiratory and cardiovascular systems?

19 • What do results from studies conducted in environments near roads or other 

20 sources indicate about the health effects of short-term NOX exposure?

21 • How are observed responses such as changes in lung function, airway

22 hyperresponsiveness, heart rate variability, and vasomotor function related to 

23 more overt health effects? What other biomarkers of early effect may be used in 

24 the assessment of health effects?

25 • What evidence is available regarding the shape of concentration-response 

26 relationships between short-term NOX exposure and health effects?

27 • What evidence is available regarding the nature of health effects from interactions

28 between NOX and other ambient air pollutants in comparison to health effects 

29 following exposure to NOX alone?

30 • What are the potential effects of exposure measurement error on epidemiologic 

31 results?

32 • To what extent does information on the pattern of NOX exposure (e.g., peak, 

33 repeated peak, average) influence interpretation of the health effects evidence?
Draft – May 2013 15

1 • To what extent do data provide information on health effects related to various

2 NOX exposure indices or averaging times relevant to the 1-hour standard? What

3 data exist comparing associations of health effects among various short-term NOX

4 exposure metrics (e.g., 1-hour versus 24-hour)?

5 Long-Term Exposure:

6 • To what extent does the scientific evidence support the occurrence of health 

7 effects from long-term NOX exposure (e.g., months to years) at ambient 

8 concentrations that are lower than those previously observed? If so, what 

9 uncertainties are related to these associations and are the health effects in question 

10 important from a public health perspective?

11 • How do results of recent studies expand current understanding of the relationships 

12 between long-term exposure to NOX and chronic respiratory effects manifested as 

13 permanent lung tissue damage, a reduction in baseline lung function, or a 

14 reduction in lung function development?

15 • To what extent does long-term NOX exposure promote exacerbation and 

16 development of asthma or other chronic lung diseases, cardiovascular diseases, 

17 and other conditions? What is the relationship between long-term NOX exposure 

18 and all-cause mortality and cause-specific mortality?

19 • To what extent does long-term exposure to NOX contribute to other health effects, 

20 e.g., cognitive, behavioral, reproductive, developmental effects?

21 • What evidence is available regarding the shape of concentration-response 

22 relationships between long-term NOX exposure and health effects?

23 • What do results from studies conducted in environments near roads or other 

24 sources indicate about the health effects of long-term NOX exposure?

25 • What evidence is available regarding the nature of health effects from interactions

26 between NOX and other ambient air pollutants in comparison to health effects 

27 attributable to specifically to exposure to NOX?

28 • What information is available regarding the effect of long-term, low29 concentration exposure to NOX on an individual’s sensitivity to short-term but 

30 higher concentration exposures?

31 • What evidence is available regarding health effects related to long-term exposure 

32 windows other than annual or lifetime average (e.g., preconception, pregnancy 

33 average, pregnancy trimester average)? What data are available comparing 
Draft – May 2013 16

1 associations of health effects among various long-term NOX exposure metrics

2 (e.g., annual, seasonal, pregnancy average)?

3 E. Causality: The ISA will evaluate the evidence for and against causal relationships between 

4 observed health outcomes and NOX exposures. EPA has developed a framework to provide 

5 a consistent and transparent basis for drawing such conclusions. In the framework, key 

6 considerations in drawing conclusions about causality include consistency of findings for 

7 an endpoint across studies, biological plausibility, and coherence of the evidence across 

8 disciplines and across related endpoints, including those related to modes of action (see 

9 Table II in Preamble to the ISA for Ozone and Related Photochemical Oxidants, U.S. 

10 EPA, 2013). The ISA will place emphasis on studies conducted with NOX concentrations

11 representative of those across various ambient microenvironments, with the exception of 

12 evidence for biological plausibility and modes of action, which in animal or controlled 

13 human exposure study groups with shorter duration (e.g., 2 to 8 hour periods) exposures

14 may be observed with higher exposure concentrations than those (e.g., lower, 24-hour 

15 average concentrations) typically associated with the health effects and human populations

16 examined in epidemiologic studies.

17 • Does the evidence base from recent studies contain new information to support or 

18 re-evaluate the causal determinations made for relationships between NOX

19 exposure and various health effects in the 2008 NOX ISA? 

20 • What information is available regarding the health impacts of a decrease in 

21 ambient concentrations of NOX? 

22 F. Uncertainties: The ISA will evaluate uncertainty in the scientific data, particularly in 

23 relation to observed epidemiologic findings.

24 • How does confounding by co-exposure to other ambient pollutants (e.g., ozone, 

25 particulate matter, sulfur dioxide, carbon monoxide) or meteorological factors 

26 influence relationships observed between health effects and both short- and long27 term NOX exposures? To what extent do other factors serve as potential 

28 confounding factors in epidemiologic studies (e.g., demographic and lifestyle 

29 attributes)?

30 • To what extent are the observed health effect associations attributable to ambient 

31 NOX or to the pollutant mixtures that NOX may be representing? For example, the 

32 possibility that ambient concentrations of NO2 serve as a surrogate for exposure to 

33 vehicle exhaust pollutants, including various other gases and particles, will be 

34 considered.
Draft – May 2013 17

1 • How does exposure measurement error contribute to uncertainty in epidemiologic 

2 study results?

3 G. At-risk Lifestages and Populations: The ISA will examine exposure and health outcome

4 data to draw conclusions about specific lifestages or populations that potentially are at 

5 increased risk of NOX-related health effects. Potential at-risk lifestages or populations can

6 be characterized by a variety of factors: intrinsic factors (biological factors such as age, 

7 pre-existing disease, genetic variants), extrinsic factors (nonbiological factors such as diet, 

8 lower socioeconomic status), and/or factors affecting dose or exposure (age, outdoor 

9 activity or work, lower socioeconomic status). As noted above, some factors (e.g., age) 

10 may influence risk through multiple mechanisms. EPA has developed a framework to

11 provide a consistent and transparent basis for drawing conclusions about at-risk lifestages 

12 or populations (see Table 8-1 of ISA for Ozone and Related Photochemical Oxidants, U.S. 

13 EPA, 2013). In the framework, key considerations in drawing such conclusions include 

14 consistency of findings for a factor within a discipline and coherence of the evidence 

15 across disciplines.

16 • What conclusions can be drawn about at-risk lifestages and populations based on 

17 evidence integrated across disciplines regarding factors that may increase risk of 

18 NOX-related health effects?

19 • How does new information augment that evaluated in the 2008 NOX ISA 

20 regarding people with pre-existing respiratory disease or genetic variants as 

21 potential at-risk populations and children or older adults as potential at-risk 

22 lifestages?

23 • What information is available that characterizes whether a factor influences risk

24 of NOX-related health effects by increasing NOX exposure or dose or by 

25 increasing biological response given a specific dose of NOX?

26 • What is the extent of the coherence of evidence regarding potential at-risk 

27 lifestages or populations for both short- and long-term exposures to NOX?

28 H. Public Health Impact: The ISA will evaluate what conclusions can be drawn about public 

29 health impacts related to short- and long-term exposure to NOX. This will include 

30 evaluation of the potential for health effects of NOX exposure to be considered adverse.

31 Development of these concepts may include, as appropriate, an estimation of the sizes of 

32 potential at-risk lifestages and populations and discussion of the public health significance 

33 of the magnitude of change in health outcomes characterized to result from ambient air 

34 NOX exposure.
Draft – May 2013 18

4. SCIENTIFIC AND PUBLIC REVIEW

1 Drafts of the ISA will be made available for review by the CASAC NOX primary NAAQS review 

2 panel and public as indicated in Figure 3.1 above; availability of draft documents will be announced in the 

3 Federal Register. The CASAC panel will review the draft ISA documents and discuss their comments in 

4 public meetings that will be announced in the Federal Register. EPA will take into account comments, 

5 advice, and recommendations received from the CASAC panel and from the public in revising draft ISA 

6 documents. EPA has established a public docket for the development of the ISA. After appropriate 

7 revision based on comments received from CASAC and the public, the final document will be made 

8 available on an EPA website and in hard copy. A notice announcing the availability of the final ISA will 

9 be published in the Federal Register.
Draft – May 2013 19

5. REFERENCES

U.S. Environmental Protection Agency. (2013) Integrated Science Assessment for Ozone and Related 

Photochemical Oxidants (Final Report). U.S. EPA, Washington, DC. EPA/600/R-10/076F. Available at:

http://www.epa.gov/ttn/naaqs/standards/ozone/s_o3_2008_isa.html; 
Draft – May 2013 A-1

APPENDIX A.

LEGISLATIVE REQUIREMENTS

1 Two sections of the Clear Air Act govern the establishment and revision of the National Ambient 

2 Air Quality Standards (NAAQS). Section 108 of the Act directs the Administrator to identify and list air 

3 pollutants that meet certain criteria, including that the air pollutant “in [her] judgment, cause[s] or 

4 contribute[s] to air pollution which may reasonably be anticipated to endanger public health and welfare” 

5 and “the presence of which in the ambient air results from numerous or diverse mobile or stationary 

6 sources.” 42 U.S.C. 21 7408(a)(1)(A) & (B). For those air pollutants listed, section 108 requires the 

7 Administrator to issue air quality criteria that “accurately reflect the latest scientific knowledge useful in 

8 indicating the kind and extent of all identifiable effects on public health or welfare which may be 

9 expected from the presence of [a] pollutant in ambient air . . .” 42 U.S.C. 7408(2).

10 Section 109(a) of the Act directs the Administrator to promulgate “primary” and “secondary” 

NAAQS for pollutants for which air quality criteria have been issued. 42 U.S.C. 7409(1).

5 11 Section 

12 109(b)(1) defines a primary standard as one “the attainment and maintenance of which in the judgment of 

13 the Administrator, based on [the air quality] criteria and allowing an adequate margin of safety, are 

requisite to protect the public health.”6 14 42 U.S.C. 7409(b)(1). A secondary standard, in turn, must 

15 “specify a level of air quality the attainment and maintenance of which, in the judgment of the 

16 Administrator, based on [the air quality] criteria, is requisite to protect the public welfare from any known 

or anticipated adverse effects associated with the presence of such pollutant in the ambient air.”7 17 42 

18 U.S.C. 7409(b)(2).

19 The requirement that primary standards include an adequate margin of safety is intended to 

20 address uncertainties associated with inconclusive scientific and technical information available at the 

21 time of standard setting. It is also intended to provide a reasonable degree of protection against hazards 

22 that research has not yet identified. Lead Industries Association v. EPA, 647 F.2d 1130, 1154 (D.C. Cir 

23 1980), cert. denied, 449 U.S. 1042 (1980); American Petroleum Institute v. Costle, 665 F.2d 1176, 

24 1186 (D.C. Cir. 1981), cert. denied, 455 U.S. 1034 (1982). Both kinds of uncertainties are components 

25 of the risk associated with pollution at concentrations below those at which human health effects can be 

26 said to occur with reasonable scientific certainty. Thus, in selecting primary standards that include an 

 5

EPA notes that as the promulgation of a NAAQS is identified in section 307(d)(1) of the Clean Air Act, all of the 

provisions of this rulemaking are subject to the requirements of section 307(d) of the Clean Air Act. 

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

EPA will conduct a separate review of the secondary NO2 NAAQS jointly with a review of the secondary SO2

NAAQS.
Draft – May 2013 A-2

1 adequate margin of safety, the Administrator is seeking not only to prevent pollution concentrations that 

2 have been demonstrated to be harmful but also to prevent lower pollutant concentrations that may pose an 

3 unacceptable risk of harm, even if the risk is not precisely identified as to nature or degree.

4 In addressing the requirement for a margin of safety, EPA considers such factors as the nature and 

5 severity of the health effects involved, the size of the at-risk population(s), and the kind and degree of the 

6 uncertainties that must be addressed. The selection of any particular approach to providing an adequate 

7 margin of safety is a policy choice left specifically to the Administrator’s judgment. Lead Industries 

8 Association v. EPA, supra, 647 F.2d at 1161-62.

9 In setting standards that are “requisite” to protect public health and welfare, as provided in section 

10 109(b), EPA’s task is to establish standards that are neither more nor less stringent than necessary for 

11 these purposes. In so doing, EPA may not consider the costs of implementing the standards. Whitman v. 

12 American Trucking Associations, 531 U.S. 457, 471, 475-76 (2001).

13 Section 109(d)(1) of the Act requires the Administrator to periodically undertake a thorough 

14 review of the air quality criteria published under section 108 and the NAAQS and to revise the criteria 

15 and standards as may be appropriate. 42 U.S.C. 7409(d)(1). The Act also requires the Administrator to

16 appoint an independent scientific review committee composed of seven members, including at least one 

17 member of the National Academy of Sciences, one physician, and one person representing State air 

18 pollution control agencies, to review the air quality criteria and NAAQS and to “recommend to the 

19 Administrator any new ... standards and revisions of existing criteria and standards as may be appropriate 

20 under section 108 and subsection (b) of this section." 42 U.S.C. 7409(d)(2). This independent review 

21 function is performed by the Clean Air Scientific Advisory Committee of EPA’s Science Advisory Board.
Draft – May 2013 A-3

U.S. EPA SCIENCE ADVISORY BOARD

CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE MEMBERS

FISCAL YEAR 2013

1 The Clean Air Scientific Advisory Committee (CASAC) has a statutorily mandated responsibility 

2 to review and offer scientific and technical advice to the Administrator on the air quality criteria and 

3 regulatory documents that form the basis for the National Ambient Air Quality Standards (NAAQS), 

4 which currently include standards for lead, particulate matter, ozone, carbon monoxide, nitrogen dioxide,

5 and sulfur dioxide. To perform such reviews, in each case the Committee forms a review panel consisting 

6 of CASAC members augmented by selected consultants with expertise in scientific or technical areas 

7 pertinent to the given pollutant or pollutant class under review. 

CHAIR

Dr. H. Christopher Frey, North Carolina State University, Raleigh, NC

CHARTERED MEMBERS

Dr. H. Christopher Frey, North Carolina State University, Raleigh, NC

Mr. George A. Allen, Northeast States for Coordinated Air Use Management, Boston, MA

Dr. Ana Diez-Roux, University of Michigan, Ann Arbor, MI

Dr. Jack Harkema, Michigan State University, East Lansing, MI

Dr. Helen Suh, Northeastern University, Boston, MA

Dr. Kathleen Weathers, Cary Institute of Ecosystem Studies, Millbrook, NY

Dr. Ronald Wyzga, Electric Power Research Institute, Palo Alto, CA

OXIDES OF NITROGEN PRIMARY NAAQS PANEL

Dr. H. Christopher Frey, Chair, North Carolina State University, Raleigh, NC

Mr. George A. Allen, Northeast States for Coordinated Air Use Management, Boston, MA

Dr. Matthew Campen, University of New Mexico, Albuquerque, NM

Dr. Ronald Cohen, University of California, Berkeley, CA

Dr. Douglas Dockery, Harvard University, Boston, MA

Dr. Philip Fine, South Coast Air Quality Management District, Diamond Bar, CA

Dr. Panos Georgopoulos, UMDNJ – Robert Wood Johnson Medical School, Piscataway, NJ

Dr. Jack Harkema, Michigan State University, East Lansing, MI

Dr. Michael Jerrett, University of California, Berkeley, CA

Dr. Joel Kaufman, University of Washington, Seattle, WA

Dr. Patrick Kinney, Columbia University, New York, NY

Dr. Michael T. Kleinman, University of California, Irvine, CA

Dr. Timothy V. Larson, University of Washington, Seattle, WA

Dr. Jeremy Sarnat, Emory University, Atlanta, GA

Dr. Richard Schlesinger, Pace University, New York, NY

Dr. Elizabeth A. (Lianne) Sheppard, University of Washington, Seattle, WA
Draft – May 2013 A-4

Dr. Helen Suh, Northeastern University, Boston, MA

Dr. Ronald Wyzga, Electric Power Research Institute, Palo Alto, CA

Dr. Junfeng (Jim) Zhang, University of Southern California, Los Angeles, CA

SCIENCE ADVISORY BOARD STAFF

Mr. Aaron Yeow, Designated Federal Officer, U.S. Environmental Protection Agency, Science Advisory 

Board (1400R), 1200 Pennsylvania Avenue, NW, Washington, D.C. 20460-0001, Phone: 202-564-2050, 

Fax: 202-565-2098, (yeow.aaron@epa.gov)
Draft – May 2013 A-5

DRAFT OUTLINE FOR INTEGRATED SCIENCE ASSESSMENT FOR 

NITROGEN OXIDES – HEALTH CRITERIA

ISA Section Section Title

Preamble Process of ISA Development

(will be available online) EPA Framework for Causal Determination

Public Health Impact

Concepts in Evaluating Adversity of Health Effects

Preface Legislative Requirements for the NAAQS Review

History of the Primary NAAQS for Nitrogen Dioxide

Executive Summary

Chapter 1 Integrative Summary

Section 1.1 Policy-relevant Questions for Nitrogen Dioxide NAAQS Review

Section 1.2 ISA Development and Scope

Section 1.3 Nitrogen Oxides Sources, Ambient Concentrations, Exposure

Section 1.4 Health Effects Evidence

Exposure, Dosimetry, and Modes of Action

Comparison of 2008 ISA and Current Conclusions

Key Evidence for Evaluated Health Effects

Section 1.5 Policy-Relevant Considerations

Concentration-Response and Thresholds

Exposure Averaging Times and Lags

At-risk Populations

Adverse Health Effects, Public Health Significance

Section 1.6 Summary

Chapter 2 Atmospheric Chemistry and Exposure to Nitrogen Oxides

Section 2.1 Introduction

Section 2.2 Atmospheric Chemistry and Fate

Section 2.3 Sources

Section 2.4 Measurement Methods

Section 2.5 Atmospheric Concentrations of Nitrogen Oxides

Section 2.6 Spatial Modeling

Section 2.7 Exposure Assessment

Section 2.8 Summary and Conclusions
Draft – May 2013 A-6

ISA Section Section Title

Chapter 3 Dosimetry and Modes of Action of Inhaled Nitrogen Oxides

Section 3.1 Dosimetry of Inhaled Nitrogen Oxides

Dosimetry of Inhaled Nitric Oxide

Reaction with Epithelial Lining Fluid Water

Mechanisms of Absorption of Nitrogen Dioxide

Epithelial Lining Fluid Interactions with Nitrogen Dioxide

Regional and Total Respiratory Absorption of Nitrogen Dioxide

Experimental Studies of Nitrogen Dioxide Uptake

Endogenous Generation, Metabolism, Distribution, and Elimination of 

Nitrogen Dioxide

Section 3.2 Modes of Action for Exposure to Nitrogen Oxides

Introduction

Formation of Secondary Oxidation Products or Reactive Nitrogen 

Species

Activation of Neural Reflexes

Initiation of Inflammation

Alteration of Epithelial Barrier Function

Sensitization of Bronchial Smooth Muscle

Modification of Innate/Adaptive Immunity

Remodeling of Airways and Alveoli

Extrapulmonary Effects

Nitric Oxide

Nitric Oxide and Nitrogen Dioxide Metabolites

Interindividual Variability in Response

Chapter 4 Integrated Health Effects of Short-term Exposure to Nitrogen Oxides

Section 4.1 Introduction

Section 4.2 Respiratory Effects

Section 4.3 Cardiovascular Effects

Section 4.4 Mortality

Section 4.5 Other Health Effects Related to Short-term Exposure
Draft – May 2013 A-7

ISA Section Section Title

Chapter 5 Integrated Health Effects of Long-term Exposure to Nitrogen Oxides

Section 5.1 Introduction

Section 5.2 Respiratory Effects

Section 5.3 Cardiovascular Effects

Section 5.4 Reproductive and Developmental Effects

Section 5.5 Mortality

Section 5.6 Central Nervous System Effects

Section 5.7 Other Noncancer Health Effects Related to Long-term Exposure

Section 5.8 Cancer

Chapter 6 Potential At-risk Lifestages and Populations

Introduction and Summary of 2008 ISA Key Findings

Review of Evidence for Specific Lifestages or Factors

Influencing Health Effects of Nitrogen Oxides such as:

Children, Older Adults, Socioeconomic Status, Diet, Sex,

Pre-existing Disease, Genetic Variants

Summary and Conclusions