# EPA United States

Environmental Protection Agency



# Draft Plan for the
Development of the Integrated

Science Assessment for
Nitrogen Oxides

– Health

Criteria

Draft

- May 2013

NOTIC E

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 Tri angle Park, North CarolinaDraft

– 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 Pla nning and Standards

. The

approach described in this plan may be modified to reflect i nformation 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 NO 2

....................... 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 NO X

– 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. RE FERENCES

................................ ................................ ................................ .................. 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

- 5Draft

– May 2013 1 

## 1. INTRODUCTION

1.1 OVERVIEW OF THE PROC ESS

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

criteria for the health effects of nitrogen oxides ( NO X ) and the primary (health

- based) national ambient air 2

quality standards (NAAQS) for nitrogen dioxide (NO 2 ). Figure 1.1 illustrates the four major phases of the 3

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

warranted 1

, a nd (4) po licy assessment and rulemaking. An Integrated Review Plan (IRP) is being 5

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

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

primary NAAQS for NO 2 , including discussion of the four major phases listed above, the schedule for the 8

entire review, the process for conducting the review, and the key policy

- relevant science issues that will 9

guide the rev iew

. 10

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

Integrated Science Assessment (ISA) for NO X health criteria which will comprise the scien ce assessment 12

phase for the review of the primary NAAQS for NO 2

. An ISA i s intended to provide a concise review, 13

synthesis, and assessment of the most policy

- relevant science, including key science judgments that are 14

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

NAAQS review s

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

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

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

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

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

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

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

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

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

draft plan for ISA development is being released for CASAC and public consul t ation prior to completion 25

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

EPA intends to release the first draft NO X health effects ISA for CASAC and public review in August 27

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

development of quantitative estimates of NO 2 risks and/ or exposures for the current review.Draft

– May 2013 2 2013. This draft pla n for ISA development includes discussion of the history of the primary NAAQS for 1

NO 2 and relevant legislative requirements as background material

. 2



### 1. 2 HISTORY OF REVIEWS O F THE PRIMARY NAAQS FOR NO 2

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

as described in more detail in the A ppendix

. On April 30, 1971, EPA promulgated identical primary and 4

secondary NAAQS for NO 2 , under section 109 of the Act, set at 0.053 parts per million (ppm), annual 5

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

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

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

NO 2 (61 FR 52852). 9

EPA initiated the most recent review of the air quality criteria for the health effects of NO X and 10

the NO 2 primary NAAQS on December 9, 2005 (70 FR 73236) with a general call for information. Upon 11

completion of the Integrated Science Assessment for Oxides of Nitrogen

- Health Criteria and the Risk and 12

Exposure Assessment to Support the Review of the NO 2 Primary National Ambient Air Quality Standard 13

(Risk and Exposure Assessment )

, EPA proposed to supplement the existing annual primary standard for 14 Figure 1.1 Overview of Process for Reviewing the NAAQSDraft

– May 2013 3 NO 2 by establishing a new short

- term standard on July 15, 2009 (74 FR 34404). On February 9, 2010, 1

EPA finalized a new short

- term primary NO 2 standard with a level of 100 parts per billion ( ppb ), based on 2

the 3

- year average of the 98 th percentile of the yearly distribution of 1

- hour daily maximum 3

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

53 ppb 2 (75 FR 6474) . T he Administrator signed a notice of final rulemaking on January 22, 2010

. 5



### 1. 3 SCOPE OF THE CURRENT REVIEW

As noted above, in reviewing the NO 2 NAAQS, EPA has historically focused its review of 6

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

specify the indicator of the standard specifically in terms of NO 2

. As specifie d in Section 108(c) of the 8

Clean Air Act, EPA cons iders t he term nitrogen oxides to refer to all forms of oxidized nitrogen includ ing 9

multiple gaseous (e.g., NO 2 , nitric oxide [ NO ] ) and particulate (e.g., nitrate) species

. 42 U.S.C. 21 10

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

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

review of the NAAQS for particulate matter

. Thus, the current review of the NO 2 NAAQS will focus on 13

the gaseous species of nitrogen oxides , which in this document are abbreviated as NO X 3

. 14

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

, 15

particularly with regard to human exposures and health effects, will be specifically for NO 2 , evidence on 16

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

relevant to the review of the NO 2 NAAQS. In addition, evidence will be considered o n the possible 18

influence of atmospheric pollutants other than the NO X (e.g., sulfur oxides, carbon monoxide, ozone, 19

particulate matter) on the role of the NO X in health effects

. 20

2 At standard temperature (25 o C) and pressure (1 atm), 53 ppb NO 2 is equivalent to 100 micrograms per cubic meter
of air ( μ g/m 3 ), and 100 ppb NO 2 is equivalent to 188 μ g/m 3

. 3 In the fields of air pollution res earch and control, the term NO X can refer more narrowly to the sum of NO and NO 2

.Draft

– May 2013 4 

## 2. REVIEW SCHEDULE

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

Triangle Park, NC (NCEA

- RTP) announced the initiation of the current periodic review of the air quality 2

criteria for the health effects of NO X and the primary NO 2 NAAQS and issued a call for information in 3

the Federal Register (7 7 FR 7 149 ). EPA held a workshop February 29 to March 1, 2012 , to discuss with 4

invited scientific experts, key science and policy issues relevant to the review of the health effects of NO X 5

( 77 FR 7149)

. Table 2

- 1 outlines the anticipated schedule for development of the ISA

. The anticipated 6

schedule for the remainder of the review of the primary NO 2 NAAQS will be included in the draft IRP, 7

which will be released later in 2013. 8

Table 2

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

for NO X
– Health Criteria

Major Milestone Pro jected 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 2014Draft

– May 2013 5 

## 3. DEVELOPMENT OF THE INTEGRATED SCIENCE

ASSESSMENT

3 .1 SCOPE AND ORGANIZATI ON

T he ISA comprises t he science assessment phase of the NO 2 NAAQS review. The ISA may be 1

s upplement ed with additional materials if additional documentation is required to support information 2

contained within the ISA

. These supplementar y materials may include more detailed and comprehensive 3

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

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

( http://hero.epa.gov/ )

. Supplementary information available in the HERO database will be presented as 6

electronic links in the ISA. 7

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

effects associated with NO X in ambient air in the discipline areas of atmospheric science

, human 9

exposure

, epidemiology, controlled human exposure, toxicology, and dosimetry

. 4 The purpose of the 10

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

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

review of the NAAQS for NO 2

. The ISA discussions will be designed to focus on the key policy

- relevant 13

questions described in S ection 3.2

. 14

The focus of the ISA will be on literature published since the 2008 NO X ISA

. Key findings and 15

conclusions from the 2008 ISA for NO X will be briefly summarized at the beginning of the ISA and of 16

individual sections

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

studies revi e wed in previous assessments will be discussed in greater detail if they are open to 18

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

literature

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

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

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

conducted at or near NO X concentrations that represent the range of human exposures in the ambient 23

environment across various microenvironments

. However, in recognition of the fact that contr olled 24

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

4 Note that evidence related to environmental effects of NO X will be considered separately in the science assessment
conducted as part of the review of the secondary NAAQS for NO 2 and SO 2

.Draft

– May 2013 6 populations, studies at higher exposure concentrations will be included when they provide information 1

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

effect, or information on exposure

- response relationships

. 3



### 3. 2 ASSESSMENT APPROACH

Introduction

The NC EA

- RTP is responsible for preparing the ISA for NO X health criteria

. In each NAAQS 4

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

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

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

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

development of an ISA (i.e., the development process ) are presented in Figure 3 .1 and are described in 9

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

2013 )

. How the IS A fits into the larger NAAQS review p rocess is briefly described in Section 1.1 , the 11

Overview of the Review Process. 12Draft

– 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

. G eneral process for development of Integrated Science Assessments (ISAs)Draft

– May 2013 8 Important aspects of the development of the ISA are described in the sections below, including the 1

approach for searching the literature and identifying relevant publications and forming specific policy

2

relevant questions that are intended to guide the assessment. These responsibilities are undertaken by 3

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

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

scien tific and public review of drafts of the ISA is described in Section 3.3

. 6

Literature Search and Identification of Relevant Studies

The NCEA

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

inclusion in the ISA

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

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

by EPA through a recurrent multi

- tiered literature search process that inc ludes extensive manual and 10

computer

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

as keywords terms such as NO X , NO 2 , NO, nitric acid, p eroxyacytyl nitrate

, or total reactive nitrogen. Th e 12

search strateg ie s are iteratively modified to optimize identification of pertinent published papers. P apers 13

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

references included in the previous ISA

, independent review of tables of contents for journals in which 15

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

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

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

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

the 2008 NO X ISA

, through approximatel y two month s before the release of the second external review 20

draft of the ISA ( target of February 2014, see Table 2

- 1)

. Once identified, studies are reviewed with 21

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

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

database

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

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

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

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

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

considered for inclusion in the ISA

. 29Draft

– May 2013 9 Evaluation of Individual Study Quality

The IS A will emphasize studies published since the 2008 NO X ISA; however, evidence from 1

previous studies will be included to integrate with results from recent studies

, and in some cases, 2

characterize the key policy

- relevant evidence in a particular subject area

. Several general benchmarks are 3

used to evaluate the quality and policy

- relevan ce of studies inclu ded in the ISA. Policy

- relevant and 4

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

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

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

copollutants or other variables, analyses of concentration

- response or dose

- response relationships, or 8

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

of studies, the following parameters are considered : 10

• T o what ext ent are the air quality data

, exposure , or dose metrics of adequate quality and sufficiently 11

representative to serve as credible exposure indicators ? 12

• W ere the study populations , subjects, or animal models adequately selected

, and are they sufficiently 13

wel l defined to allow for meanin gful comparisons between study or exposure groups ? 14

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

• A re likely covariates (i.e., potential confound ing factors, effect modifiers) adequately controlled for or 16

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

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

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

consistency with other known facts ? 20

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

given study contains information on (1) short

- or long

- term exposures that represent ambient 22

concentration s of NO X across various microenvironments ; (2) health effects of specific NO X species; ( 3 ) 23

lifestages or populations that potentially are at increased risk of NO X - related health effects ; ( 4 ) potential 24

copollutant interactions (e.g., are there synergistic effects of NO X with other pollutants ) or confoun ding 25

(e.g., are associations observed between NO X and health endpoints biased by the effects of copollutants ) ; 26

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

specifications, thresholds, mortality di splacement) related to the health effects of NO X exposure. Among 28

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

U

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

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

sociodemographic characteristics and air pollution mixture

. In addition, emphasis will be placed on 32Draft

– May 2013 10 discussion of (1) multicity studies that e mploy standard methodological analyses for evaluating NO X 1

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

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

estimates for populations of interest; and (3) studies that regard NO X as a component of a complex 4

mixture of air pollutants by consider ing the concentration s of copollutants, correlations of NO X with these 5

copollutants, and results of co pollutant analyses. 6

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

experimental studies included in the ISA

. The discussion of research evaluating controlled exposures of 8

laboratory animals will focus primarily on those studies conducted with NO X exposures representative of 9

exposure con centrations and durations that humans experience across various ambient 10

micro environment s . In animal models

, relevant exposures will depend on the toxicokinetics and 11

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

NO X toxicity, studies conducted under environmentally

- relevant conditions will be emphasized, but 13

studies at highe r concentration s also will be considered, because of species

- to

- species differences and 14

potential differences in sensitivity between humans or animals included in experimental studies and at

15

risk human lifestages and populations. Other considerations for t he evaluation of animal toxicological 16

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

lifestages and populations potentially at increased risk of NO X - related health effects ; (2) examination of 18

concentrat ion

- response or time

- course of responses; and (3) demonstration of sufficient statistical power 19

to assess responses to exposures

. Results from in vitro studies also may be included if they provide 20

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

human exposures to NO X , emphasis will be placed on studies that (1) examine NO X exposures that 22

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

microenvironments ; (2) compare responses following NO X exposure and control or filtered air exposure 24

and thus have subjects serve as their own control s; (3) investigate effects in potential at

- risk populations 25

such as people with asthma and compare to responses in age

- matched he althy subjects ; ( 4 ) address issues 26

such as concentration

- response or time

- course of responses; ( 5 ) investigate exposure to NO X separately 27

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

statistical power t o adequately assess responses to NO X exposures

. 29

NCEA participates in the Agency

- wide Quality Management System, which requires the 30

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

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

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

including objectivity, utility

, and integrity. Quality assurance (QA) measures detailed in the QMP are 34Draft

– May 2013 11 being employed for the current NO X review, including the development of the ISA for NO X health 1

criteria

. The NCEA QA staff is responsible for the review and approval of quality

- related documentation. 2

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

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

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

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

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

subsections. Generally, NCEA scientists rely on scientific information found in peer

- reviewed journal 8

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

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

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

Content and Organization of the ISA

The organization of the ISA for NO X health criteria will be consistent with that used in the recent 12

assessments for other criteria pollutants (e.g.

, ISA for Ozone and Related Photochemical Oxidants, U.S. 13

EPA, 2013 ). D evelopment of the ISA will be guided by policy

- relevant questions that frame the entire 14

review of the primary NO 2 NAAQS. These policy

- relevant questions will be discussed in more detail in 15

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

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

such as the concentrations of NO X exposure associated with health effects and plausibility of health 18

effects caused by NO X exposure. The second issue is whether uncertainties from the last review have been 19

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

ISA are listed subsequently by topic area

. 21Draft

– May 2013 12 A. Air Quality and Atmospheric Chemistry : The ISA will pre sent and evaluate data related to 1

ambient concentrations of NO X ; sources leading to the presence of NO X in the atmosphere; 2

and chemical reactions that determine the formation, degradation, and lifetime of NO X in 3

the atmosphere. 4

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

interference problems in measuring NO X ? What limitations still remain? 6

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

and emissions of NO X ? How have emissions and concentrations of NO X and of 8

NO 2 changed since the 2008 NO X ISA ? To what extent can satellite data be used 9

to improve the characterization of NO X concentrations ? 10

• What spatial and temporal patterns can be seen in the air quality data for NO X ? In 11

particular, what patterns can b e seen on a micro

- scale for near road environments 12

and on a national scale based on satellite data ? 13

• Based on air quality and emissions data on NO X and atmospheric chemistry 14

models, what are likely policy relevant background concentrations of NO X in the 15

absence of anthropogenic emissions ? 16

B. Exposure : The ISA will evaluate the factors that influence exposure to ambient NO X and 17

the uncertainties associated with extrapolation from ambient concentrations to personal 18

exposures to NO X of ambient origin, particularly in the context of interpreting results from 19

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

most short

- term exposure studies (e.g., population

- level studies using time

- series analyses, 21

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

- term exposure 22

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

• What are the relationships between NO X measured at stationary monitoring sites 24

and personal expo sure to NO X ? W hat evidence is available regarding these 25

relationships in environment s near road s or other sources ? 26

• What new information exists regarding characterization of error in NO X exposure 27

assessment and how it influences personal

- ambient exposure relationships? 28

• What information is available regarding differences in NO X exposure patterns and 29

personal

- ambient exposure relationships among various lifestages and 30

populations? 31

• What new information exists regarding NO X measurements in a multipollutant 32

context? To what extent do NO 2 measurements serve as surrogates of exposure to 33Draft

– May 2013 13 other gaseous pollutants (including carbon monoxide and nitrous acid ) and 1

particle phase pollutants generated b y traffic or other combustion sources? 2

• What new information is available about the interaction of NO X with organic 3

compounds that may influence human exposure ? 4

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

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

NO X

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

. 7

• W hat information is available to discern the relative contributions to internal 8

NO X compounds of NO X derived exogenously from ambient exposures and NO X 9

derived from pathways such as diet or biological processes ? 10

• What NO X reaction products can be found in the respiratory tract cells, tissues, or 11

fluids that may serve as markers of NO X exposure and effect ? 12

• What are the potential biological mechanisms underlying responses to NO X at or 13

near environmentally

- relevant exposure s , with a focus on response pathway(s) 14

and exposure

- dose

- response relationships? 15

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

effects associated with exposure to NO X ? 17

• What mechanisms can be qualitatively compared across species? 18

• Do interactions between inhaled NO X and other inhal

e d p ollutants influence the 19

m echanisms underlying the toxic potential of NO X ? 20

• What are the effects of host factors such as age, sex, pre

- existing diseas e, and 21

genet ic background on NO X uptake and cellular and tissue responses? 22

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

reproductive

, and developmental health effects

, mortality, and cancer associated with NO X 24

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

central nervous system or gastrointestinal system

. Health effects that occur following both 26

short

- and long

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

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

concentration s at which effects are observed

, including those in potential at

- risk lifestages 29

and populations

. 30

Short

- Term Exposure : 31

• What do controlled human exposure, animal toxicologic al , and epidemiologic 32

studies indicate regarding the relationship between short

- term (i.e., hours to 33Draft

– May 2013 14 weeks) exposures to NO X and health effects of concern (e.g., altered lung 1

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

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

including the nature and time course, in healthy ind ividuals and in those with pre

4

existing disease states (e.g., people with asthma or cardiovascular disease) or 5

other potential at

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

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

between short

- term exposure to NO X and airway hyperresponsiveness or other 8

lung function changes? 9

• What is the influence of NO X on host defense against infectious disease? 10

• What are the effects of NO X exposure on cardiovascular health in humans (e .g., 11

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

infarction) ? 13

• How do results from recent population

- level time

- series studies expand 14

understanding of relationships between exposure to NO X and mortality ( all

- cause

, 15

respiratory

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

• To what extent does exposure to NO X contribute to health effects beyond the 17

respiratory and cardiovascular systems? 18

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

sources indicate about the health effects of short

- term NO X exposure ? 20

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

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

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

the assessment of health effects ? 24

• What evidence is available regarding the shape of concentration

- response 25

relationships between short

- term NO X exposure and health effects? 26

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

between NO X and other ambient air pollutants in comparison to health effects 28

following exposure to NO X alone ? 29

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

results? 31

• To what extent does information on the pattern of NO X exposure (e.g., peak, 32

repeated peak, average) influence interpretation of the health effects evidence ? 33Draft

– May 2013 15 • To what extent d o data provide information on health effects related to various 1

NO X exposure indices or averaging times relevant to the 1

- hour standard ? What 2

data exist comparing associations of health effects among various short

- term NO X 3

exposure metrics (e.g., 1

- hour versus 24

- hour)? 4

Long

- Term Exposure : 5

• To what extent d oes t he scientific evidence support the occurrence of health 6

effects from long

- term NO X exposure (e.g., months to years) at ambient 7

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

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

important from a public health perspective? 10

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

between long

- term exposure to NO X and chronic respiratory effects manifested as 12

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

reduction in lung function development? 14

• To what extent does long

- term NO X exposure promote exacerbation and 15

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

and other conditions? What is the relationship between long

- term NO X exposure 17

and all

- cause mortality and cause

- specific mortality ? 18

• To what extent does long

- term exposure to NO X contribute to other health effects, 19

e.g., cognitive

, behavioral

, reproductive

, developmental effects? 20

• What evidence is available regarding the shape of concentration

- response 21

relationships between long

- term NO X exposure and health effects? 22

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

sources indicate about the health effects of long

- term NO X exposure? 24

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

between NO X and other a mbient air pollutants in comparison to health effects 26

attributable to specifically to exposure to NO X ? 27

• What information is available regarding the effect of long

- term, low

28

concentration exposure to NO X on an individual’s sensitivity to short

- term but 29

higher concentration exposures? 30

• W hat evidence is available regarding health effects related to long

- term exposure 31

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

average, pregnancy trimester average)? What data are available comparing 33Draft

– May 2013 16 associations of health effects among various long

- term NO X exposure metrics 1

(e.g., annual

, seasonal , pregnancy average ) ? 2

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

observed health outcomes and NO X exposure s

. EPA has developed a framework to provide 4

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

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

an endpoint across studies

, biological plausibility

, and coherence of the evidence across 7

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

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

. S

. 9

EPA, 2013 )

. The ISA will place emphasis on studies conducted with NO X concentration s 10

representative of those across various ambient microenvironments

, with the except ion of 11

evidence for biological plausibility and m odes of action

, which in animal or controlled 12

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

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

- hour 14

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

examined in epidemiologic studies

. 16

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

re

- evaluate the causal determinations made for relationships between NO X 18

exposure and various health ef fects in the 2008 NO X ISA ? 19

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

ambient concentration s of NO X ? 21

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

relation to observed epidemiologic findings. 23

• How does confounding by co

- exposure to other ambient pollutants (e.g., ozone, 24

particulate matter, sulfur dioxide

, carbon monoxide ) or meteorological factors 25

influence relationships observed between health effects and both short

- and long

26

term NO X exposures? To what extent d o other factors serve as potential 27

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

attributes)? 29

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

NO X or to the pollutant mixtures that NO X may be representing? For example, the 31

possibility that ambient concentrations of NO 2 serve as a surrogate for exposure to 32

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

considered. 34Draft

– May 2013 17 • How do es exposure measurement error contribute to uncertainty in epidemiologic 1

study results? 2

G. At

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

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

increased risk of NO X - related health effects

. Potential at

- risk lifestages or populations can 5

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

pre

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

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

activity or work, lower socioeconomic status )

. As noted above, s ome factors (e.g., age) 9

may influence risk through multiple m echanisms. EP A has developed a framework to 10

provide a consistent and transparent basis for drawing conclusions about at

- risk lifestages 11

or populations (see Table 8

- 1 of ISA for Ozone and Related Photochemical Oxidants

, U

. S

. 12

EPA, 2013 )

. In the framework, k ey considerations in drawing such conclusions include 13

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

across disciplines

. 15

• What conclusions can be drawn about at

- risk lifestages and populations based on 16

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

NO X - related health effects? 18

• How does new information augment that evaluated in the 2008 NO X ISA 19

regarding people with pre

- existing respiratory disease or genetic variants as 20

potential at

- risk population s and children or older adults as potential at

- risk 21

lifestages? 22

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

of NO X - related health effects by increasing NO X exposure or dose or by 24

increasing biological response given a specific dose of NO X ? 25

• What is the extent of the coherence of evidence regarding potential at

- risk 26

lifestages or populations for both short

- and long

- term exposure s to NO X ? 27

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

heal t h impacts related to short

- and long

- term exposure to NO X . This will include 29

evaluation of the potential for health effe cts of NO X exposure to be considered adverse

. 30

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

potential at

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

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

NO X exposure

. 34Draft

– May 2013 18 

## 4. SCIENTIFIC AND PUBLI C REVIEW

Drafts of the ISA will be made available for review by the CASAC NO X primary NAAQS review 1

panel and public as indicated in Figure 3 .1 above ; availability of draft documents will be announced in the 2

Federal Register

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

public meeting s that wi ll be announced in the Federal Register. EPA will take into account comments, 4

advice

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

documents

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

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

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

be published in the Federal Register. 9Draft

– 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 REQUIREM ENTS

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

Air Quality Standards ( NAAQS )

. Section 108 of the Act directs the Administrator to identify and list air 2

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

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

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

sources

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

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

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

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

. 9

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

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

. 5 Section 11

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 represent ative 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 NO 2 NAAQS jointly with a review of the secondar y SO 2 NAAQS.Draft

– May 2013 A

- 2 adequate margin of safety, the Adminis trator is seeking not only to prevent pollution concentrations that 1

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

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

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

severity of the health effects involved, the size of the at

- risk population(s), and the kind and degree of the 5

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

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

Association v. EPA

, supra , 647 F.2d at 1161

- 62. 8

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

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

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

American Trucking Associations , 531 U.S. 457, 471, 475

- 76 (2001). 12

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

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

and standards as may be appropriate

. 42 U.S.C. 7409(d)(1). The Act also requires the Administrator to 15

appoint an independent scientific review committee composed of seven members

, including at least one 16

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

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

Administrator any new

... standards and revisions of existing criteria and standard s as may be appropriate 19

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

function is performed by the Clean Air Scientific Advisory Committee of EPA’s Science Advisory Board. 21Draft

– May 2013 A

- 3 

### U.S. EPA SCIENCE ADV ISORY B OAR D

CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE MEMBERS

FISCAL YEAR 20 1 3

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

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

regulatory documents that form the basis for the N ational A mbient A ir Q uality S tandards (NAAQS), 3

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

, 4

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

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

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

CHAIR

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

CHARTERED MEMBERS

D r. 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. C hristopher 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 Georgopo u los, 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. Kleinm an, 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, WADraft

– 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 IN T EGRATED SCIENCE ASSE SSMENT 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 ConclusionsDraft

– 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 I ntroduction

Section 4.2 Respiratory Effects

Section 4. 3 Cardiovascular Effects

Section 4. 4 Mortality

Section 4. 5 Other Health Effects Related to Short

- term ExposureDraft

– 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