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> **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON D.C. 20460**

> **OFFICE OF THE ADMINISTRATOR**
>
> **SCIENCE ADVISORY BOARD**

November 29, 2007

EPA-CASAC-08-002

Honorable Stephen L. Johnson

Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW

Washington, DC 20460

> Subject: Clean Air Scientific Advisory Committee's (CASAC) Peer Review
> of EPA's Integrated Science Assessment (ISA) for Oxides of Nitrogen --
> Health Criteria (First External Review Draft, August 2007)

Dear Administrator Johnson:

The Clean Air Scientific Advisory Committee (CASAC or Committee),
augmented by subject-matter-experts to form the CASAC Oxides of Nitrogen
Primary NAAQS Review Panel (hereafter referred to as the panel)
completed its review of EPA's *Integrated Science Assessment (ISA) for
Oxides of Nitrogen -- Health Criteria* (First External Review Draft,
August 2007, EPA/600/R-07/093) on October 24-25, 2007. The ISA for
oxides of nitrogen (NO~x~) is the first ISA produced for EPA's new
process for reviewing and revising National Ambient Air Quality
Standards (NAAQS). Done properly, the ISA should be an informative,
succinct, and useful summary of the evidence for consideration of the
NAAQS. Overall, the panel found that the first draft ISA did not fully
meet its objective. CASAC panel members have provided individual
recommendations to strengthen the next draft (Attachment B) and the
panel responded to charge questions submitted to CASAC by EPA's National
Center for Environmental Assessment. While there is some redundancy in
the responses to different charge questions (because the charge
questions overlap in their areas of concern), the responses to the
different charge questions are consistent with each other. Finally, the
CASAC offers general comments related to a multiple-pollutant approach
for air quality management.

**Charge Question 1. To what extent are the atmospheric chemistry and
air quality characterizations clearly communicated, appropriately
characterized, and relevant to the review of the primary NO~2~ NAAQS?**

The panel advises EPA to expand its discussion of sources and
atmospheric chemistry in Chapter 2, Source to Tissue Dose (and later in
Chapter 5, the Findings and Conclusions), and throughout the document to
relate assessment of information to the review of the NAAQS. There needs
to be more quantitative information provided on the sources of oxides of
nitrogen (NOx) and the speciation of NOx, both indoors and out. These
findings should be related to where the monitors tend to be, including
their vertical elevation and the co-pollutants being emitted and
monitored. How these findings relate to exposure and health studies need
to be addressed later in the discussion of atmospheric processing and
exposure.

CASAC recognizes that the current monitors are susceptible to
interferences and may include oxidized nitrogen species other than
nitrogen dioxide (NO~2~) in the signal, leading to a potentially high
bias. As such, it is important to provide quantitative information on
the extent or level of likely bias in specific metrics of ambient NO~2~
levels/air concentrations, e.g., the expected uncertainty/bias in annual
averages, daily maximum(s), etc., and how they vary by time of day and
season. The ISA should be careful to provide a balanced assessment of
possible issues involved in use of monitoring data, taking into account
the likely relevance of these issues to monitors across the United
States and the likely impact of those issues on human health assessment.

Given that the health literature suggests that NO~2~ is at least likely
to be the pollutant of concern \[*vis à vis*, e.g. nitric acid,
peroxyacyl nitrate (PAN), nitrous acid (HONO), or other oxides of
nitrogen\], developing a method that has less interference would be
preferred over a method that captures all oxidized nitrogen species
without identifying the concentrations of specific species. The
monitoring method used, however, should be consistent with the method
used in key epidemiological studies or an appropriate correction factor
used (see response to Charge Question 2).

The panel advises EPA to present a series of maps that show spatial
trends as well as figures or tables that show temporal trends in ambient
concentrations in various parts of the country, ideally from some time
before the establishment of the existing health standard in 1971. It
would be helpful to relate trends to major economic, transportation,
technological, or other historical events that may have some relevancy
to emissions of oxides of nitrogen events since 1971. Information is
needed about the location of NO~2~, NO~x~, and NO~y~ \[the sum of all
oxydized nitrogen compounds including those listed in Section 108(c) of
the Clean Air Act\] monitors. The ISA or its appendices should include
information about monitor location in terms of proximity to roadways,
size of roadways. The ISA should provide a list of NO~x~, particulate
matter (PM), ozone, and other pollutants measured at these same
monitoring sites.

**Charge Question 2. Are the properties of ambient oxides of nitrogen
appropriately characterized, including policy-relevant background,
spatial and temporal patterns, and relationships between ambient oxides
of nitrogen and human exposure?**

The discussion of nitrogen oxides species needs to be made clearer and
more complete. For example, the relative importance of the various
nitrogen oxides \[NO, NO~2~, nitric acid (HNO~3~), PAN, etc.\] as a
function of location and time should be discussed. In addition, a more
accurate depiction of PM nitrate species (both inorganic and organic) is
needed in Figure 2.2.1.

A better description of the spatial and temporal variability of NO~2~
and other nitrogen oxides is needed. In particular, the ISA should
discuss the spatial variability of nitrogen oxides near roadways since
spatial variability is directly relevant to the discussion of
high-exposure individuals in Chapter 4 (Susceptible and Vulnerable
Populations).

The discussion of the ambient monitoring needs to be more focused,
keeping in mind that the objective of the monitoring network should be
consistent with the NAAQS. If the NAAQS is based in part on
epidemiological studies that used a certain monitoring technique for
ambient NO~2~ concentrations, the designation of attainment or
non-attainment should be based on the same or a similar monitoring
technique. If a significantly different technique were to be used, then
some correction may be needed.

The panel advises that NO, as well as NO~2~, should be reported by the
states since the measurement is available from current monitoring. If NO
were reported, scientists could better understand the atmospheric
chemistry and spatial and temporal patterns of the related nitrogen
species.

The siting of monitors will be critical for future attainment
designations and exposure assessments because of the strong horizontal
and vertical gradients in nitrogen oxides concentrations near roadways,
and their effects on human exposure. The difference in NO~2~
concentrations between measurements made near the ground and those made
at 10 m above ground level should be taken into account in exposure and
health effects studies.

**Charge Question 3. Does the information in Chapter 2 provide a
sufficient atmospheric science and exposure basis for the evaluation of
human health effects presented in later chapters?**

The panel finds that information in Chapter 2 is insufficiently
integrated for purposes of evaluating human health effects and lacks key
information. The ISA would be improved if it were revised to incorporate
changes identified by the panel. The ISA should integrate information
about the current standard in order to give perspective to the ambient
exposure data cited in graphs and tables.

The emissions of NO~2~ and related species from both indoor and outdoor
sources need to be discussed both in general and specifically in the
context of the correlation of ambient NO~2~ levels with other
co-pollutants, including ultrafine and carbon-containing particles. The
relationships between personal, indoor, and outdoor levels of NO~2~
deserve more discussion, particularly with respect to the parameter
"alpha" (the ratio of ambient exposure to ambient concentration) and in
the context of specific epidemiological study designs.

The ISA should address the complex nature of spatial variability of
NO~2~ within urban areas in more detail. Important topics to address
include potential exposure misclassification due to siting of monitors
away from busy roads, the presence or absence of street canyons,
in-vehicle exposures, and the effect of atmospheric dilution with height
above ground. The panel recognizes, however, that many of these issues
cannot be addressed in detail, given the current state of information.

The panel advises EPA to revise the ISA to include some discussion of
the biological activity of inhaled NO, particularly with respect to
cardiovascular function. The ISA should also include some discussion of
the dosimetry associated with that activity.

**Charge Question 4. To what extent is the discussion and integration of
evidence from the animal toxicology and controlled-exposure human
experimental studies and epidemiologic studies, technically sound,
appropriately balanced, and clearly communicated?**

Chapter 3 was a multi-author effort and, for balance, the
inconsistencies in integration and level of discussion across the
sections should be rectified. The chapter is quite long and should be
greatly reduced in size. Ideally, only the key studies that support a
NAAQS should be discussed in detail. In addition, the document should
identify the relevant chemical species of concern and clearly discuss
how the processes involved in NO~x~ production result in additional air
pollutants that confound study findings. For communication purposes, it
is important to have an integrated analysis that draws key conclusions
from the available data sets and includes the magnitude of the
concentration response for the different health endpoints. Providing the
concentration response information is not only the key to Chapter 3,
Health Effects, but also to the overall quality of the ISA. The ISA
would be improved if a plan or process for integration and study
selection was clearly laid out and followed throughout the document.
Such an approach would facilitate integration across the three study
types of epidemiology, clinical, and animal toxicology. In particular,
the toxicological studies should be evaluated with respect to their
support or inconsistency with the biological plausibility of health
effects related to NOx exposures.

**Charge Question 5. To what extent does the integration of health
evidence focus on the most policy-relevant studies or health findings?**

The panel advises EPA to revise Chapter 3 to explicitly relate
discussion of the health evidence to a detailed explanation early in the
document concerning the search strategy for identifying literature, the
criteria for selecting studies for the ISA, and the criteria for
evaluating studies for health effect. Adding discussion of such a
comprehensive framework for the assessment of studies at the start of
the document would allow a more consistent evaluation of the various
study evidences for relevance and help with integration across chapters.

The panel also called for more integrated assessment of the health
evidence presented in Chapter 3. The panel advises the ISA to be revised
to evaluate the interaction between animal toxicology studies, dosimetry
studies, and epidemiological investigations. In particular, there is a
need to cross-compare the separate evidence (e.g., toxicology vs.
epidemiology) in order to see which health results are coherent or
inconsistent with each other. The panel also advises EPA to ensure a
balance in reporting both negative and positive studies and to take
steps to avoid publication bias. Panel members noted at the October
25^th^ consultation that several studies with negative findings that
merited inclusion were missing from the ISA (see list below for examples
of studies discussed[^1]). The panel advises EPA to review panel
members' written comments in detail for additional discussion of studies
that should be examined for the ISA. Finally, examining the epidemiology
results as a function of exposure concentration, the consideration of
study environment (indoor/outdoor, near/way from roadway), and the
consideration of other pollutants would help future decisions related to
the NAAQS. The panel noted that the emphasis given to the indoor and
intervention studies in Chapter 5 was generally felt to be appropriate.
A more comprehensive and consistent evaluation of possible PM-NO~x~
interactions is needed throughout the ISA.

**Charge Question 6. What are the views of the Panel on the conclusions
drawn in the draft ISA regarding the strength, consistency, coherence
and plausibility of NO~2~-related health effects?**

Since the 1993 Air Quality Criteria Document for Oxides of Nitrogen, a
substantial body of evidence has been developed that documents adverse
health effects associated with exposures to ambient or near ambient
levels of NO~2~ and its oxidative reaction products. These include
epidemiologic studies demonstrating relationships between oxides of
nitrogen and hospital admissions, emergency department visits, and
mortality. There is evidence of adverse health responses in sensitive
populations such as children, asthmatics, and those living and working
near roadways. Field and panel studies have demonstrated relationships
between NO~2~ exposure and both respiratory symptoms and pulmonary
function impairment. The relationships between these health responses
and NO~x~ exposure appear to be robust and to maintain significance when
corrected for confounding variables.

In spite of the robust relationships with NO~x~ levels, CASAC recognizes
that the primary associations are between products of combustion and
adverse health impacts. NOx levels may partly be a surrogate for
combustion product exposures. However, the consistent finding of strong
associations with NO~x~ levels across studies of diverse designs,
including indoor exposures, suggests that NO~x~ can be a significant
factor in the causation of the observed adverse health impacts.
Epidemiological findings discussed in the draft ISA indicate that
current ambient NO~2~ exposures are associated with adverse impacts to
the public health. CASAC advises EPA to revise the ISA to better
document that these findings are plausible, consistent and coherent. In
revising Chapter 3, the Agency should explicitly relate discussion of
the health evidence to a detailed explanation early in the document of
the search strategy for identifying literature and an exposition of the
criteria for selecting studies for health effect, based on A. B. Hill's
criteria (Hill 1965).

In addition, the panel notes that the ISA strongly benefits from the
creation of tables that integrate the complex data from studies of
multiple designs. If possible, tables should also consider co-pollutant
effects and confounding. The Agency should choose a reliable method in
the tables to standardize the metric used for comparison between
studies.

**Charge Question 7. What are the views of the Panel on the
appropriateness of public health impact and the characterization of
groups likely to be susceptible or vulnerable to NO**~2~**?**

The panel advises EPA to revise the ISA to define "susceptible"
populations with regard to the extent of response relative to the
general population. It would be helpful to reorganize the discussion of
susceptible populations under the umbrellas of biological
susceptibility, socioeconomic susceptibility, and susceptibility related
to geographic locale. The ISA treatment of susceptibility would be
strengthened by: 1) including discussions of potential mechanisms of
action that relate specifics of NO~2~ biology to pathobiological
perturbations; and 2) defining susceptible populations more clearly and
systematically examining how different toxicological, clinical, and
epidemiological data relate to these populations, reporting results as a
function of concentration, and considering both relative risks and
absolute attributable risks in such at-risk sub-populations. With these
changes, the ISA discussion of susceptibility will better address
biological plausibility with regard to specific populations and allow
attribution of health outcomes to direct causal actions of NO~2~.

The panel notes that the lung growth studies from the California
Children\'s Health Study are particularly important in identifying
children as a distinctive and probably susceptible population with
respect to NO~2~ exposure. Children offer the opportunity to observe the
whole spectrum of injury, growth, and repair in response to NO~2~
exposure, if it occurs. Some discussion of dosimetric differences
between adults and children would be useful and the panel notes that
there are at least two peer-reviewed papers related to this subject.[^2]

**Charge Question 8. What are the Panel's views on the adequacy of this
first external review draft ISA to provide support for future risk,
exposure and policy assessments?**

While Charge Question 8 calls for a consideration of whether the entire
ISA document provides adequate support for \"future risk, exposure and
policy assessments,\" the panel considers it essential that Chapter 5
summarize all of this support succinctly and rigorously so readers can
understand how EPA is drawing scientifically sound conclusions from the
previous chapters. Chapter 5 does not currently meet this goal. The most
significant problems are that: 1) the bulleted conclusions in Chapter 5
are not always the most relevant findings from the earlier chapters; 2)
most of these items provide little quantitative support for the kinds of
risk assessment and policy decisions that will eventually need to be
made on population risk, form of the standard, dose-response, etc.; 3)
the authors have not applied - or at least have not specified clearly -
a transparent set of criteria in drawing the conclusions presented in
the face of at times conflicting data (for more insight into this, see
the criteria supplied by Dr. Ellis Cowling in his individual comments);
and 4) the conclusions drawn do not adequately address the uncertainties
in slope factors, the judgment on causal associations, and the efficacy
of control measures targeting NO~2~ introduced by confounding exposures
in the epidemiological studies that play such a strong role in the
assessment. This Chapter needs significant work before it will provide a
good synthesis for the updated science assessment of NO~x~.

**Summary**

In summary, the CASAC review of this first draft ISA raises concerns
about the approach used by the Agency for this important assessment,
which will serve as a template for future assessments within EPA's new
NAAQS process. The draft NO~x~ ISA inadequately describes the NAAQS
review process, including EPA's approach to literature identification
and evidence evaluation. The ISA does not appear to have been developed
by a process that approaches the current "state-of-the-art" around the
development of systematic reviews for decision-making purposes. A
replicable approach is needed that presents a clear statement of
principles for evidence evaluation and that presents standardized
language for characterizing the strength of evidence. Additionally,
CASAC found that a clear framework was not established in the draft ISA
for considering potential causal effects and non-causal associations of
NOx with human health effects.

**General Comments Related to a Multiple-Pollutant Approach for Air
Quality Management**

In addition to the responses provided above to the charge questions, the
panel felt strongly that a major issue that needs to be addressed more
fully is the multiple pollutant aspect of the ISA for oxides of
nitrogen. The August 2007 draft *Integrated Science Assessment* for
oxides of nitrogen contains many references to:

1)  the role of gaseous NO and NO~2~ in the formation and accumulation
    of ozone and other photochemical oxidants,

2)  the role of NO and NO~2~ in the formation of nitrate-containing
    secondary aerosols,

3)  the co-occurrence of any two or all three of these pollutants in the
    same air parcel near the ground,

4)  the possibility that the respiratory functions of many susceptible
    populations of people will be affected differently when their lungs
    are exposed to mixture of these pollutants than when exposed to any
    one of these pollutant when occurring alone; and

5)  the possible interaction of NO~x~ and PM in association with health
    effects.

These five possibilities are part of the reasons why the National
Research Council's recent report on *Management of Air Quality in the
United States* recommended that the EPA consider development of a
multiple-pollutant approach in air quality management -- this as an
addition or alternative to the Agency's long-established tradition of
dealing with one pollutant at a time by establishing separate National
Ambient Air Quality Standards for CO, ozone, sulfur dioxide, oxides of
nitrogen, PM, and lead. The EPA is currently considering a
multiple-pollutant approach to air quality management in addition to the
present "one-pollutant-at-a-time" approach. CASAC strongly recommends
that EPA seriously consider developing a multiple-pollutant,
multiple-effects approach to air quality management.

In closing, the CASAC Oxides of Nitrogen Primary NAAQS Review Panel was
pleased to review the first draft of the ISA for oxides of nitrogen. We
look forward to review of the second draft and wish you well in this
important endeavor.

> Sincerely,
>
> /Signed/
>
> Dr. Rogene Henderson, Chair
>
> Clean Air Scientific Advisory Committee

**Attachments**

Attachment A: Roster of CASAC Oxides of Nitrogen Primary NAAQS Review
Panel

Attachment B: Compilation of Individual Panel Member Comments on EPA's
*Integrated Science Assessment (ISA) for Oxides of Nitrogen -- Health
Criteria* (First External Review Draft, August 2007, EPA/600/R-07/093)

Attachment A: Roster of CASAC Oxides of Nitrogen Primary NAAQS Review
Panel

**U.S. Environmental Protection Agency**

**Clean Air Scientific Advisory Committee**

**Oxides of Nitrogen Primary NAAQS Review Panel**

**CHAIR**

**Dr. Rogene Henderson**, Scientist Emeritus, Lovelace Respiratory
Research Institute, Albuquerque, NM

**CASAC MEMBERS**

**Dr. Ellis B. Cowling**, University Distinguished Professor At-Large,
Emeritus, Colleges of Natural Resources and Agriculture and Life
Sciences, North Carolina State University, Raleigh, NC

**Dr. James Crapo**, Professor of Medicine, Department of Medicine,
National Jewish Medical and Research Center, Denver, CO

**Dr. Douglas Crawford-Brown**, Professor and Director, Department of
Environmental Sciences and Engineering, Carolina Environmental Program,
University of North Carolina at Chapel Hill, Chapel Hill, NC

**Dr. Donna Kenski**, Data Analyst, Lake Michigan Air Directors
Consortium, Des Plaines, IL

**Dr. Armistead (Ted) Russell**, Professor, Department of Civil and
Environmental Engineering , Georgia Institute of Technology, Atlanta, GA

**Dr. Jonathan M. Samet**, Professor and Chair of the Department of
Epidemiology, Bloomberg School of Public Health, Johns Hopkins
University, Baltimore, MD

**CONSULTANTS**

**Mr. Ed Avol**, Professor, Preventive Medicine, Keck School of
Medicine, University of Southern California, Los Angeles, CA

**Dr. John R. Balmes**, Professor, Department of Medicine, Division of
Occupational and Environmental Medicine, University of California, San
Francisco, CA

**Dr. Terry Gordon**, Professor, Environmental Medicine, NYU School of
Medicine, Tuxedo, NY

**Dr. Dale Hattis**, Research Professor, Center for Technology,
Environment, and Development, George Perkins Marsh Institute, Clark
University, Worcester, MA

**Dr. Patrick Kinney**,\* Associate Professor, Department of
Environmental Health Sciences, Mailman School of Public Health ,
Columbia University, New York, NY

**Dr. Steven Kleeberger**, Professor, Lab Chief, Laboratory of
Respiratory Biology, National Institute of Environmental Health
Sciences, National Institutes of Health, Research Triangle Park, NC

**Dr. Timothy V. Larson**, Professor, Department of Civil and
Environmental Engineering, University of Washington, Seattle, WA, USA

\*Unable to participate in the ISA Review.

**Dr. Kent Pinkerton**, Professor, Regents of the University of
California, Center for Health and the Environment, University of
California, Davis, CA

**Dr. Edward Postlethwait**, Professor and Chair, Department of
Environmental Health Sciences, School of Public Health, University of
Alabama at Birmingham, Birmingham, AL

**Dr. Richard Schlesinger**, Associate Dean, Department of Biology,
Dyson College, Pace University, New York, NY

**Dr. Christian Seigneur**, Vice President, Atmospheric & Environmental
Research, Inc., San Ramon, CA

**Dr. Elizabeth A. (Lianne) Sheppard**, Research Professor,
Biostatistics and Environmental & Occupational Health Sciences, Public
Health and Community Medicine, University of Washington, Seattle, WA

**Dr. Frank Speizer**, Edward Kass Professor of Medicine, Channing
Laboratory, Harvard Medical School, Boston, MA

**Dr. George Thurston**, Professor, Environmental Medicine, NYU School
of Medicine, New York University, Tuxedo, NY

**Dr. James Ultman**, Professor, Chemical Engineering, Bioengineering
Program, Pennsylvania State University, University Park, PA

**Dr. Ronald Wyzga**, Technical Executive, Air Quality Health and Risk,
Electric Power Research Institute, Palo Alto, CA

**SCIENCE ADVISORY BOARD STAFF**

**Dr. Angela Nugent**, Designated Federal Officer, 1200 Pennsylvania
Avenue, NW

1400F, Washington, DC, Phone: 202-343-9981, Fax: 202-233-0643,
(nugent.angela@epa.gov)

Attachment B: Comments from CASAC Oxides of Nitrogen Primary NAAQS
Review Panel on EPA's *Integrated Science Assessment for Oxides of
Nitrogen -- Health Criteria* (First External Review Draft)
(EPA/600/R-07/093, August 2007)

**[Comments Received]{.underline}**:

[Comments from Professor Ed Avol 11](#__RefHeading___Toc184090826)

[Comments from Dr. John Balmes 11](#__RefHeading___Toc184090827)

[Comments from Dr. Ellis Cowling 11](#__RefHeading___Toc184090828)

[Comments from Dr. Douglas Crawford Brown
11](#__RefHeading___Toc184090829)

[Comments from Dr. Terry Gordon 11](#__RefHeading___Toc184090830)

[Comments from Dr. Dale Hattis 11](#__RefHeading___Toc184090831)

[Comments from Dr. Donna Kenski 11](#__RefHeading___Toc184090832)

[Comments from Dr. Steven Kleeberger 11](#__RefHeading___Toc184090833)

[Comments from Dr. Timothy Larson 11](#__RefHeading___Toc184090834)

[Comments from Dr. Kent Pinkerton 11](#__RefHeading___Toc184090835)

[Comments from Dr. Edward Postlethwait 11](#__RefHeading___Toc184090836)

[Comments from Dr. Armistead Russell 11](#__RefHeading___Toc184090837)

[Comments from Dr. Jonathan Samet 11](#__RefHeading___Toc184090838)

[Comments from Dr. Richard Schlesinger 11](#__RefHeading___Toc184090839)

[Comments from Dr. Christian Seigneur 11](#__RefHeading___Toc184090840)

[Comments from Dr. 'Lianne' Elizabeth Sheppard
11](#__RefHeading___Toc184090841)

[Comments from Dr. Frank Speizer 11](#__RefHeading___Toc184090842)

[Comments from Dr. George Thurston 11](#__RefHeading___Toc184090843)

[Comments from Dr. James Ultman 11](#__RefHeading___Toc184090844)

[Comments from Dr. Ronald Wyzga 11](#__RefHeading___Toc184090845)

[]{#__RefHeading___Toc184090826 .anchor}[Comments from Professor Ed
Avol]{.underline}

Integrated Science Assessment for Oxides of Nitrogen: Health Criteria

EPA/600/R-07/093, August 30, 2007

First External Review Draft

Comments By Ed Avol

General Comments:

This document represents a heroic compendium of information, and Staff
are to be congratulated for pulling this substantial set of diverse
information together. It is clear from the assembled document that a
great deal of additional information has become available since the
previous document review (which last occurred almost 15 years ago). The
current compilation will be useful and critical in deliberations
concerning possible revisions to the standards.

That said, I have several concerns with the layout and presentation of
the document. The logic behind the organizational layout eludes me.
Although it presumably is focused on published relevant research since
the previous NO2 review document (ca. 1993), there are numerous
references, discussions about, and consideration of data from 1965-1992.
It seems that Staff could have summarized this previous data more
efficiently, provided some summary tables in a chapter essentially
describing how we got to this level of understanding NO2, or referred to
the previous document, and moved on. There is too much discussion,
review, and emphasis on pre-1993 research.

Within the health chapter, the order of topical presentations seemed to
circle and re-circle around topics presented again and again in the
chapter, in a sort of ever-decreasing (downward) spiral, re-visiting (at
least two or three times) each topic under a slightly different heading
in a slightly different manner. The document is unduly repetitive and
could be significantly re-compiled and shortened. The chapter that is
entitled "Integrated Health Effects of NO2 Exposure", for example, is
over 150 pages long and often re-visits and re-visits more than it
integrates.

In the Health Chapter, I found the separation of US research from
research performed in other countries to be unwarranted, inconsistent,
and counter-productive. Quality research does not have borders; the
relevance of well-performed research should dictate the weight given in
determining the value of each contribution. The separation of research
by country in the text seemed to be inferring some diminution in
quality, consideration, or relevance, which (for the most part is not
warranted).

Organizationally, the document is inconsistent (possibly reflecting
multiple chapter contributions from different authors). Sometimes there
are summaries following major sections reporting the research data,
sometimes sections are completed by an integration section, and
sometimes one or both are missing (for example, see P3-94 \[no
integration\], P3-118 \[no summary\], or P4.13 \[missing both\]).
Summary and integration in this document is critical (isn't that
supposed to be one of the benchmarks of the "new" process?), but the
document seems to reflect a transitional state between the former
compendium-of-complete-results approach and a more-streamlined
distillation of recent research with an emphasis on integration.

The Chapter 3 summary figures and tables are especially
well-constructed, very useful, and much appreciated. Document staff are
to be commended for the practical utility of the summary figures,
allowing readers to visually review a number of study results easily and
effectively. Similarly, the provided tables contain a large amount of
concentrated information that were useful to review, and will be useful
as summary reference material.

Specific Comments:

CHAPTER 3

P3-4, Sec 3.2.1.1 Lung Host Defenses and Immunity, line 1 -- the word
"new" should be replaced with "recent"

P3-4, Sec 3.2.1.1 Lung Host Defenses and Immunity, lines 8 & 9 -- This
section is ostensibly about human research data, but these references
all cite animal work.

P3-5, Sec 3.2.1.1 Lung Host Defenses and Immunity, lines 7 & 8 --
"...mucociliary clearance is not affected by NO2 exposure as low as
3ppm..." is an awkward way to phrase this; recommend re-wording, such as
"...mucociliary clearance effects have not been reported below 3ppm..."

P3-5, Sec 3.2.1.1 Lung Host Defenses and Immunity, line 29 -- should be
"...body *[of]{.underline}* evidence..."

P3-6, Sec 3.2.1.1 Lung Host Defenses and Immunity, line 6 --
"...confounding with ultrafine emissions remains a concern..." comes
unsupported and out of nowhere in the discussion. This should be
supported by a sentence or removed.

P3-11, Sec 3.2.1.1 Lung Host Defenses and Immunity, line 1 -- Reference
to a study involving an exposure of 29ppm NO2 is unnecessary, given the
unrealistic level of the exposure and the general guidelines to only
refer to relevant study concentrations (in the less than 5ppm range).

P3-14, Sec 3.2.1.2 Effects of Short-Term NO2 Exposure on Lung Function,
lines 26 & 27 -- "...spirometry...is not generally used for large-scale
studies..." This is incorrect and should be removed; the document itself
contains numerous references to "large-scale" studies utilizing
spirometry.

Additionally, why are the California Children Health Study citations
(Gauderman, Peters, McConnell, Avol) not in this section?

P3-19, Sec 3.2.1.2 Effects of Short-Term NO2 Exposure on Lung Function,
lines 20 thru 22 -- Most of these references precede the previous NO2
review document and were already previously discussed in the earlier
document. This approach (reviewing earlier work that has already been
reported in the previous document, is repeated *ad nauseum* throughout
this chapter.

P3-44, Sec 3.2.1.6 Hospital Admissions and Emergency Department...,
lines 30 thru 32 -- This discussion of morbidities that can result in
Emergency Department visits is all true and completely irrelevant.

P3-45, Sec 3.2.1.6 Hospital Admissions and Emergency Department..., line
5 -- "Asthma visits typically dominate the daily incidence counts..."
*(in the Emergency Department and hospital admissions for respiratory
disease)* may be true, but still is not especially germane (unless an
argument is going to be made that most asthma admissions are somehow
related to NO2 exposure).

P3-45, Sec 3.2.1.6 Hospital Admissions and Emergency Department..., line
6 thru 8 -- "...Chronic bronchitis...is a prominent diagnosis among
older adults..." is another true statement that is irrelevant to the
discussion.

P3-46, Sec 3.3.1.6.1 All Respiratory Outcomes..., line 4 -- A calculate
relative risk of 1.0027 is really pushing the edges of credulity; this
may indeed be statistically significant, but as a practical matter, is
it likely to be important?

P3-49, Sec 3.2.1.6.2 Asthma..., line 19 -- in two places, the wrong
reference appears; it should be Lin, not Linn.

P3-49, Sec 3.2.1.6.2 Asthma..., line 30 -- The differences in study
results could also be related to the analytical power of the respective
studies (differing subject population sizes).

P3-51, Sec 3.2.1.6.2 Asthma..., lines 18 and 19 -- should be replace to
read "...models show*[ed]{.underline}* that the addition
*[of]{.underline}* O3, smoke, or SO2 into the model
result*[ed]{.underline}* in..."

P3-67, Sec 3.2.2.1 Studies of Hospital Admissions..., line 5 -- delete
the word "been".

P3-68 and 3-69, Sec 3.2.2.1 Studies of Hospital Admissions..., Figures
3.2-15 and 3.2-16 -- Check relationships, units, and conversions between
what is stated in the text reports of percent changes and what appears
as relative risk plots in the figures; for ease of reading and following
the discussion, these should be consistent.

P3-79, Sec 3.2.2.3 Integration for Effects of Short-Term NO2..., line 15
-- insert "NO2" between "ambient" and "(Peters...".

P3-82, Sec 3.3.1.2 Canadian Multi-City Studies -- Why are these broken
out as a separate group for discussion? Why are they not a part of the
discussion under multi-city studies? Throughout the previous
presentations, studies from Europe and Australia and elsewhere have been
cited and discussed, so it is not the case that studies are presented in
the text by country of origin?

P3-84, Sec 3.3.1.3 Air Pollution and Health... -- similar comment as
above; what is this European study set separately presented from the
previous data?

P3-88, Sec 3.3.1.5 Other European MultiCity Studies -- same comment

P3-89, Sec 3.3.1.6 Australian Four Cities Study -- same comment

P3-112, Sec 3.4.1.3 Asthma Prevalence..., line 27 -- phrasing of
"...reported positive associations for girls to both NO2 and NOx..." is
awkward and a bit confusing; change to "...reported associations with
both NO2 and NOx for girls..."

P3-130, Sec 3.4.4.1 Integration and Biological Plausibility..., line 31
-- insert a space between "Nitrogen" and "deemed".

P3-144, Sec 3.6 Studies of NO, HONO, and HNO3, line 8 and line 13 -- As
mentioned previously, studies are referred to here with exposure
concentrations of 16ppm, 50ppm, and even 80ppm; these are not especially
relevant to ambient health concerns, and violate the boundary condition
that studies utilizing exposures in the realm of ambient (\<5ppm NO2)
would be the focus.

P3-152, Table 3.2-2, need to specify the units of Age, ***in years***.

CHAPTER 4

P4-2, Section 4.1.1 Pre-existing Disease as a Potential Risk Factor,
line 8 -- delete "...and some nonasthmatic individuals do..."; this is
assumed in the phrasing of the statement.

P4-13, Sec 4.2.2 Estimation of Potential Numbers of Persons in At-Risk
Susceptible Population Groups...- Why is there no summary section on
genetic susceptibility? It has been discussed as a risk factor, there
are published articles about it, and we do know something about the
penetration of certain genes of interest in the general population.

P4-13, Sec4.2.2 Estimation of Potential Numbers of Persons in At-Risk
Susceptible Population Groups...- Why is there no summary statement
about those subpopulations considered to be susceptible (asthmatics,
children, those with certain genetic profiles, cardiovascular disease
patients)?

P4-15, Table 4.1 -- Re-write the third and fourth sentences in the
second paragraph (the ones that refer to the Islam et al work). These
are inconsistent with the summary perspective of the table. (Just state
the findings, don't introduce the study).

CHAPTER 5

P5.1, Sec 5.1 Introduction, line 8 -- delete "this" from "...(1) this
introduction..."

P5.1, Sec 5.1 Introduction, lines 10 thru 12 -- delete this first
sentence; it is unnecessary.

P5-3, Sec 5.2 Atmospheric Sciences, line 3 -- "...motor vehicles are a
large source of urban NO2..." -- more correctly, aren't motor vehicles a
large source of NO, which is quickly converted (in the presence of
oxygen) to NO2?

P5-3, Sec 5.2 Atmospheric Sciences, line 13 -- replace the words "a few"
with "some", since across the country, there will be more than "a few".

P5-11, Sec 5.5.2.4 Morbidity and Long-Term Exposure..., line 20 -- Why
is it necessary to specify that two studies were from Europe? If the
studies are valid, they should be discussed on their merits.

P5-12, Sec 5.5.2.6 Concentration-Response Relationships..., lines 29
thru 32 -- what are these studies being referenced and discussed here?
This chapter is supposed to be a summary of findings presented in the
previous chapters, in an integrated presentation.

P5-14, Sec 5.5.2.7 Susceptible and Vulnerable Populations, line14 -- Why
is there not a section on Genetic Susceptibility?

P5-17 onward... - What are all these tables doing here? They should be
in Chapter 3, where the data is presented.

[]{#__RefHeading___Toc184090827 .anchor}[Comments from Dr. John
Balmes]{.underline}

Charge 4 To what extent is the discussion and integration of evidence
from the animal toxicology and controlled human exposure studies and
epidemiologic studies technically sound, appropriately balanced, and
clearly communicated?

GENERAL COMMENTS

Chapter 3 on Health Effects is long (over 150 pages) and overly detailed
in certain parts. There should be less detail about experimental design
and specific results in the chapter text; these details are best left to
the annex. By trimming this detail and endeavoring to present the
information in a more thematically clear manner, a revised chapter will
better support whatever recommendations for an air quality standard
emerge from the review process. The chapter as currently written reads
too much like a mini-criteria document rather than an integrated
synthesis.

In general, the presentation of the results of the animal toxicologic,
controlled human exposure, and epidemiologic studies that have been
reviewed is technically sound, although I am concerned about the
selection of studies based on the observation that two relevant but
negative studies from my own lab are not included (see specific comments
below). The criteria for selection of specific studies in all three
categories should be clearly stated. In addition, the criteria for
judging the strength of findings from specific studies as well as those
used to assess aggregate findings of studies on a relevant research
question should also be clearly stated.

In my view, the epidemiologic data are relatively consistent and
coherent with regard to the association of daily ambient NO2 and
exacerbations of asthma. In addition, the data from a single
well-designed and conducted study, the Children's Health Study, that
show an association between annual average NO2 and decreased rate of
growth of lung function provide strong evidence of a chronic effect on
lung development in children. The toxicologic evidence in Chapter 3 is
not presented in a way that convincingly supports potential mechanisms
for either of these two health outcomes.

The toxicologic data that are best presented in the chapter are those
which indicate that NO2 exposure increases risk of bacterial and viral
respiratory infection in experimental animal models. While these data do
provide some plausibility for the epidemiologic studies that find an
association between ambient NO2 and total respiratory hospitalizations
or emergency department visits, they do not illuminate how NO2 exposure
might induce exacerbations of asthma not related to respiratory
infections. The controlled human exposure data on NO2 and non-specific
airway responsiveness in asthmatic subjects are mixed and on aggregate
do not show an exposure-response relationship. The animal toxicologic
data show an effect of sub-chronic but not acute exposure on
non-specific airway responsiveness. Enhancement by NO2 of airway
responses to specific allergen challenge is perhaps the potential
mechanism of asthma exacerbation best supported by the combined
controlled human exposure and animal toxicologic data. While these data
are presented well in Chapter 3, they are not included in either the
integration of evidence and biological plausibility for respiratory
effects in Chapter 3 or the summary of respiratory health effects and
short-term exposure in Chapter 5.

There are really no controlled human exposure data that support a
mechanism for the decreased rate of growth of lung function in children
observed in the Children's Health Study. Because the animal toxicologic
studies that have demonstrated lung structural changes with chronic NO2
exposures used much higher than ambient concentrations, these studies
also do not really provide much support for the effect observed in the
Children's Health Study. In my view, the relative lack of both human and
animal toxicologic data to support the strong epidemiologic evidence
that ambient NO2 is associated with asthma exacerbations and decreased
growth of lung function in children should be clearly stated in the ISA.
The issue of dose-response in comparison of animal toxicologic data with
those from human studies also should be addressed directly in Chapter 3.
Rodents are likely less sensitive to the effects of a given
concentration of NO2, but no quantitative discussion of this issue is
included in the current draft.

Regarding the question of appropriate balance, this can be best handled
by the provision of clear criteria for the inclusion of studies and
rating of quality of the evidence as noted above.

In terms of clear communication, Chapter 3 as currently drafted falls
short. The text in Chapter 3 needs to be tighter, less redundant, and
more thematically organized (i.e., each section should have a story
line). In particular, the summary/integration subsections should provide
an overview of the quantity and quality of the evidence for the health
outcome(s) of interest as well as evaluation of how well the toxicologic
data support the epidemiologic findings.

SPECIFIC COMMENTS

Chapter 3 would be easier for the reader to follow if the NO2 exposure
metric noted for each study discussed was the same (i.e., either all
μg/m3 or ppb or ppm). Although the point is mentioned here and there, it
would probably also be easier for the reader if there was a discussion
early in the chapter about NO2 often being correlated with CO and PM in
epidemiologic studies, suggesting a common origin from combustion
sources.

p\. 3-5, line 29 ...the body [of]{.underline} evidence...

p\. 3-6, line 29 The experimental protocol used in the Solomon et al.
study actually involved three consecutive days of exposure, not four.

p\. 3-21, lines 10-22 Two recent controlled human exposure studies
provide relevant data for this paragraph. The paper of Barck et al.
(2002) cited later in the chapter reported the results of a study of 13
asthmatic subjects exposed to 0.26 ppm for 30 min. A second paper by
Witten A, et al. (J Occup Environ Med 2005; 47:1250-9) reported the
results of a study of 15 asthmatic subjects exposed for 3 h to filtered
air or 0.4 ppm NO~2~ with intermittent exercise. No effect of NO2 on
FEV1 was noted in either of these papers. Brief discussion of these
papers in this paragraph would strengthen basis for the subsequent
statement on p. 3-22 that "For asthmatics, the effects of NO2 on
pulmonary function have also been inconsistent at exposure
concentrations of less than 1 ppm NO2."

p\. 3-33 The Solomon et al. study (2000) cited earlier in the chapter
also showed increased PMNs in the bronchial fraction of BAL 18 h after
the third consecutive day of exposure to 2.0 ppm NO2 for 4 h with
intermittent exercise and could be easily cited here as well.

p\. 3-35 , lines 22-25 The first sentence of this paragraph appears to
refer to the studies in rats and mice mentioned in the previous
paragraph. If that is the case, then the second sentence of the
paragraph is superfluous.

p\. 3-41, line 1 The study by Witten et al. noted above is a study that
did not confirm the findings of Barck et al. and thus should be
discussed here. In the Witten et al. study inflammatory cells and
molecules were measured in sputum induced at 6h and 26h post-house dust
mite allergen challenge after both NO2 and filtered air exposures. After
NO2 exposure, eosinophil concentration decreased significantly in the
6-h post-allergen sputum. No significant NO2-related difference was
observed for other variables. In this study, multi-hour exposure to a
high ambient concentration of NO2 did not enhance the inflammatory
response to subsequent inhaled allergen as assessed by cell distribution
in induced sputum.

p\. 3-43, line 17 Should be airways responsiveness here, not
hyperresponsiveness.

p\. 3-45, lines 21-27 As written these two sentences are confusing
because the first sentence states that there were no significant
associations between NO2 and hospital admissions found for children 1 to
4 years, and then the next sentence notes a 2.8% increase in respiratory
admissions for a 9-ppb increment in the daily maximum 1-h concentration
of NO2 was observed. That this increase was not statistically
significant needs to be made more clear.

p\. 3-49, line 19 Should be Lin et al., not Linn et al. for both
citations.

p\. 3-50, line 3 Both the mean 24-h and maximum daily 1-h concentrations
of NO2 in this study should be given here.

p\. 3-51, line 19 ...addition [of]{.underline} O3, smoke or SO2...

p\. 3-51, line 23 ...working day[s]{.underline} shows...

p\. 3-54, lines 5-6 This sentence would be clearer if it read as
follows: "...showed increased risks in each quartile [for the summer
months]{.underline}, although the increase was not monotonic." Figure
3.2-11 does not show increased risks in each quartile for the winter
months.

p\. 3-57, line 15 "there" should be deleted from this line.

p\. 3-57, lines 16-17 It might be better to state "In [many]{.underline}
of these studies, there was evidence of correlations between NO2 and CO
[or]{.underline} PM measures."

p\. 3-58, lines 12-13 Ibid.

p\. 3-62, lines 11-19 This paragraph in the "Integration with a Focus on
Asthma" section should include some discussion of the effect of NO2 to
enhance the airways responses to inhaled allergen because this could be
a mechanism by which asthmatic individuals develop exacerbations after
exposure to high ambient levels.

p\. 3-63, lines 28-29 I would delete the first sentence of this
paragraph; it is an unnecessary distraction here. Cerebrovascular
disease is discussed later.

p\. 3-67, line 3 ...a 4.2-ppb increase [in]{.underline} NO2...

p\. 3-67, lines 16-17 For clarity, I would modify this sentence as
follows: "An effect of NO2 on hospitalization for IHD was observed only
during the cold season (Jalaludin et al., 2006)."

p\. 3-70, line 32 Should it be PAH here rather than PIH?

p\. 3-72, line 5 ...Barnett et al. (1997a) report[ed]{.underline} robust
estimates...

p\. 3-76, line 1 The citation here should be Rich et al., 2006b).

p\. 3-76, line 7 There are two separate papers by the same team of
investigators, but I do not think it is correct to say that this
represents two separate analyses.

p\. 3-76, lines 14-17 For clarity, this sentence should be revised as
follows: "Rich et al. (2005, 2006[b]{.underline}) examined associations
between ambient pollution levels and [PAF episodes as well]{.underline}
as ventricular arrythmias." In addition, the Rich et al. (2006a) study
of ventricular arrythmias in St. Louis is not actually discussed as the
paragraph is currently written.

p\. 3-79, lines 13-14 It is inappropriate to cite a German paper as a
secondary reference regarding the leading causes of hospital admissions
for CVD in the U.S in a U.S. federal agency document. Primary U.S. data
should be cited.

p\. 3-79, line 15 ...ambient [NO2]{.underline} (Peters...

p\. 3-79, line 18 I suggest this sentence be revised as follows: "A
study of repolarization changes and air pollution [in
Germany]{.underline}..."

p\. 3-86, Figure 3.3-2 I suggest that the figure legend be revised as
follows: "Shape of the association of total mortality with NO2 over 6
days (lags 0 through 5) [in the APHEA2 study]{.underline} summarized..."

p\. 3-92, lines 13-14 For clarity, I suggest this sentence be revised as
follows: "The combined estimate for total mortality was 0.8% (95% CI:
0.2, 1.5) per 20-ppb increase in the [24-h]{.underline} average NO2 from
the single-pollutant models, and 0.4% (95% CI: -0.2, 1.1[) per 20-ppb
increase in the 24-h average from the multipollutant
models]{.underline}."

p\. 3-95, lines 5-6 I suggest this sentence be revised as follows: "Risk
estimates for specific causes of death [are]{.underline} useful in
evaluating consistency of the association [for]{.underline} causal
inference."

p\. 3-104, line 17 ...new cells in the [bronchioli]{.underline} are
derived...

p\. 3-111, line 19 In each community [studied]{.underline}, NO2 was...

p\. 3-112, lines 1-4 There is insufficient information in Figure 3.2-4
for the reader to understand how these graphs show a protective effects
from better lung function regarding risk of new-onset asthma.

p\. 3-113, Figure 3.4-2 The figure legend needs to include a better
explanation of what the graphs actually show (i.e., that HR = hazard
ratio for new-onset asthma and that the two letter abbreviations are for
the 12 communities of the Children's Health Study and that these
communities are arrayed by annual average of the pollutant shown on the
X axis of each graph).

p\. 3-116, Figure 3.4-3 I would add the following words to the figure
legend: "...for two-pollutant models [for the 12 communities of the
Children's Health Study]{.underline}."

pp. 3-118-119 This integration section is problematic. The first
paragraph discusses both respiratory illness in children associated with
long-term exposure to NO2 in children and the decreased rate of growth
in lung function observed in the Children's Health Study. The next six
paragraphs then discuss the human and animal toxicological data on
altered immune responses and lung defenses. The section then concludes
with a paragraph on possible mechanisms by which chronic exposure to NO2
might affect lung growth. For greater clarity, I would suggest that the
discussion of the epidemiologic and toxicologic evidence be treated
separately for each of the two health outcomes (i.e., epi-tox for
respiratory illness followed by epi-tox for decreased growth of lung
function).

p\. 3-118, lines 17-19 Because the Children's Health Study was a
prospective study, multiple papers reporting the results of the
longitudinal analysis of lung function at various time points during the
course of the study were published. However, it is not correct to
describe these results as "recent evidence from cohort *studies* from
California." There was really only one cohort studied, albeit for a long
follow-up period.

p\. 3-120, line 29 Ibid.

p\. 3-120, lines 12-16 This is a confusing sentence as written and needs
to be revised for clarity.

pp. 3-149-150 This section on Nitric Acid does not include discussion of
a relevant controlled human exposure study (Aris R, et al. Am Rev Respir
Dis 1993; 148:965-973).

3-151, Table 3.2-1 I would add the following to the first proposed
mechanism under the Lower Airways, Allergens category: "...and ↑
epithelial permeability"

p\. 3-156, Tables 3.4-1 and 3.4-2 The Titles for both of these tables
should include "in the Children's Health Study"

[]{#__RefHeading___Toc184090828 .anchor}[Comments from Dr. Ellis
Cowling]{.underline}

**Very General Comments on these NAAQS Review Processes**

Before dealing with the details of my specific assignment during the
September 24, 2007 Peer Review of the *Integrated Science Assessment for
Oxides of Nitrogen*, I would like to offer the following very general
comments about these periodic NAQQS Review processes -- and thus our
responsibilities during Peer Reviews of *Integrated Science Assessment
documents* in general.

In a May 12 2006 summary letter to Administrator Johnson, CASAC Chair,
Dr. Rogene Henderson, provided the following statement of purpose for
these periodic NAAQS review processes.

> "CASAC understands the goal of the NAAQS review process is to answer a
> critical scientific question: *"What evidence has been developed since
> the last review to indicate if the current primary and/or secondary
> NAAQS need to be revised or if an alternative level or form of these
> standards is needed to protect public health and/or public welfare?"*

During the past 18 months, CASAC has participated in reviews of three of
the existing six criteria pollutants -- particulate matter, ozone, and
lead. CASAC has also joined with senior EPA administrators in a
"top-to-bottom review" and the resulting recently-completed revision of
the NAAQS review processes. These two experiences have led to a
seemingly slight but important need for rephrasing and refocusing of
this very important "critical scientific question:"

> *"What scientific evidence and/or scientific insights have been
> developed since the last review to indicate if the current
> public-health based and/or the current public-welfare based NAAQS need
> to be revised or if alternative levels, indicators, statistical forms,
> or averaging times of these standards are needed to protect public
> health with an adequate margin of safety and to protect public
> welfare?"*

With this rephrasing held carefully in mind, I offer the following
general comment with regard to one very important part of my assigned
Charge Question on Air Quality aspects of the ISA for Oxides of
Nitrogen:

**What is the major "pollutant of concern" in the case of the**

**public-health-based standard for "oxides of nitrogen?"**

It appears (but is not stated clearly anywhere that I can find in
Chapter 2 or any other part of this ISA) why nitrogen dioxide (NO~2~)
was chosen by the USEPA as the "indicator" of choice in the case of the
NAAQS for "oxides of nitrogen." Much attention is given in both Chapters
1 and 2, as well as other chapters in this ISA, to the many different
oxidized forms of nitrogen (including nitric and nitrous acids,
nitrites, nitrates, nitrosamines and other carcinogenic and potentially
carcinogenic derivatives of oxides of nitrogen, as well as NO, NOx, NOy,
and NOz) that have been shown to have significant effects on public
health. But the specific rational for choosing NO~2~ among all these
different oxides of nitrogen as the "indicator" of choice for a National
Ambient Air Quality Standard is not described in this *Integrated
Science Assessment for Oxides of Nitrogen*. The present ISA does include
some discussion of using NO~y~ rather than NO~2~ as the "indicator" for
oxides of nitrogen \-- See especially the "Key Fingings" statements on
lines 17 and 18 on page 5-3 and lines 9-16 on page 5-4.

**My Assignment in this Peer Review for Oxides of Nitrogen**

My specific assignment in preparation for the October 24, 2007 CASAC
Peer Review of EPA's First (August 2007) External Review Draft of the
*Integrated Science Assessment for Oxides of Nitrogen* is the first
Charge Question asked by Mary Ross in her transmittal note to Fred
Butterfield on August 31, 2007:

> To what extent are the atmospheric chemistry and air quality
> characterizations clearly communicated, appropriately characterized,
> and relevant to the review of the primary NO~2~ NAAQS?

These topics are covered in detail mainly in Chapter 2 and in summary
form in the "Atmospheric Sciences" part (section 5.2) in Chapter 5. I
found the brief summary in chapter 5 much more clear and relevant to the
existing primary standard than the much more detailed information
contained in Chapter 2.

Chapter 2 is filled with detailed analyses of specific topics that are
relevant to indoor and outdoor exposures, to personal vs community
exposures, to the strengths and limitations of monitoring instruments
for oxides of nitrogen, and analyses of the strengths and limitations of
specific health-effects research studies on nitrogen oxides in this
country and abroad. But there is not a single place in all 67 pages of
Chapter 2 where this large body of information is discussed in the
context of the existing primary NAAQS standard for oxides of nitrogen!

In fact, I could find only eight places in this ISA document where the
existing primary standard is mentioned -- in the Preface on pages iv and
v, on line 17 on page 1-2 of the Introduction, and on lines 11 and 12 on
page 5.3, lines 7-9 on page 5.8, lines 10-12 on page 5-11, lines 17-18
on page 5-12, and lines 21-24 on page 5-14 in Chapter 5.

I was pleased, however, to find a carefully annotated presentation of
the "*History of Review of the Primary NAAQS for* NO2" on pages iv and v
of the Preface. But even here there was no discussion of the rational
behind the original (1971) selection of NO~2~ as the "indicator" of
choice for "oxides of nitrogen."

It was also surprising to find that the last sentence in the Preface is
the only place in this ISA document in which all four essential parts of
a National Ambient Air Quality Standard -- level, indicator, statistical
form, and averaging time -- are discussed -- and then only in the
context of the identical primary (public health based) and secondary
(public welfare based) standards that were established in 1971 and have
never been changed since that time. The staff and administrator of the
USEPA in 1971 must have been very wise indeed to have created identical
primary and secondary standards for oxides of nitrogen that did not
require any science-based or other modification during the past 36
years!

**More specific Comments and Suggestions for Improvement of Chapter 2**

[Title of the Chapter]{.underline}:

"Chapter 2 highlights key concepts or issues relevant to understanding
the atmospheric chemistry, sources, exposure and dosimetry of oxides of
nitrogen, following a "source to dose" paradigm." The idea of dealing
with atmospheric chemistry all the way from emissions sources to
dosimetry in the lung is a good one; but titling the chapter "Source to
Tissue Dose" is a little too "cute" to be taken seriously. In my
opinion, "Chemistry and Dosimetry of Nitrogen Oxides" would be better as
a title for this important chapter.

[Organization within Chapter 2]{.underline}

Distributing all the Figures within the text so that the text
descriptions of the figures is near the figures themselves is a good
one, but the distributing all the tables to the end of Chapter 2 makes
reading and checking back and for the between text descriptions and the
important data and information in the tables very tedious, time
consuming, and needlessly challenging. I got lost more often than I
succeeded in finding my way through the information contained in most
parts of chapter 2.

[Design and Content of Figure and Table Captions]{.underline}

In my opinion, every figure and table in an Integrated Science
Assessment document \--that is clearly to be used for policy purposes
\-- should "stand alone" to the maximum extent possible and not be any
more dependent on descriptions in the text than absolutely necessary for
understanding by the reader.

Some specific examples of these difficulties that lead to confusion,
lack of clarity, or, worse yet, communication of disinformation include
the following:

The caption for Figure 2.2-1 implies incorrectly that the "reactive
nitrogen species" in the atmosphere include only oxidized forms of
nitrogen and do not include any reduced forms of nitrogen. In fact, the
total amount of ammonia emissions from animal agriculture on both a
global scale and a national scale are considerably larger than the total
emissions of nitrogen oxides from all the power plants on these same
scales! See paper by Galloway et al in AMBIO 31(2):63-71.

The caption for Figure 2.4-2 contains no units of measurement for any of
the three different panels in this complex figure. The data displayed in
this figure are much too important to require that readers must see the
"text in Annex Section nAX2.9 for details."

The data in Table 2.5-1 is simply impossible to understand without
reading and rereading lines 25-32 on page 2-17 and lines 1-31 on page
2-18.

Neither the text on lines 10-22 on page 2-19 nor the caption for Figure
2.5-2 make clear whether the data displayed in this figure are from the
South Bronx, New York City, or a wide variety of urban areas throughout
the state of New York. It also would be very helpful to know for sure
what averaging time was used in calculating and plotting the data shown
in this figure and to show the present NAAQS standard in this same
figure.

I recommend that essentially every figure and table (and the
corresponding text descriptions) in Chapter 2 be revised to conform to
the principal that all figures and tables should "stand alone" to the
maximum extent possible. This principal will greatly facilitate
comprehension by readers and facilitate the accumulation of carefully
crafted statements of scientific findings as was accomplished to a very
useful extent in Chapter 5 of this ISA for oxides of nitrogen.

[Inclusion of carefully crafted Statements of Findings and Conclusion in
Chapter 2]{.underline}

My understanding of much of the useful information contained in Chapter
2 was increased substantially after reading the nine "Key Findings"
listed on lines 10 through 31 on page 5-2 and on lines 1-18 on page 5-3.

In reading these nine "Key Findings" statements listed in the
Atmospheric Chemistry part (section 5.2) in Chapter 5, however, I was
surprised and disappointed to recognize that all nine of these "Key
Findings" were relevant to "measuring nitrogen oxides" and that there
were no statements of "Key Findings" that were relevant to the other
major topics covered in Chapter 2: including indoor and outdoor
exposures, personal vs community exposures, and analyses of the
strengths and limitations of specific health-effects research studies on
nitrogen oxides in this country and abroad.

Please note that the "Key Findings" outlined on lines 11-13 on page 5-3,
lines 7-9 on page 5-8, lines 10-12 on page 5-11, lines 17-18 on page
5-12, and lines 21-14 on page 5-14 are the only places I can find in
this ISA where conclusions are reached that are relevant to the adequacy
or inadequacy of the existing primary standard for health effects of
oxides of nitrogen. Maybe these six statements are sufficient to provide
a scientific foundation for evaluation of the adequacy or inadequacy of
the existing health-based standard for oxides of nitrogen. It is not
clear to me, however, if these relatively few conclusionary statements
cover all the bases that base that are necessary for final decisions by
Administrator Johnson. Thus I look forward to the further discussions we
will have on Octiber 24 and 25 during this peer review of the First
External Review Draft Integrated Science Assessment for the health-based
NAAQS for oxides of nitrogen.

For this reason and many others, I call attention once again to the
attached "*Guideline for Formulation of Statements of Scientific
Findings to be Used for Policy Purposes.*" These guidelines were
developed and published in 1991 by the Oversight Review Board for the
National Acid Precipitation Assessment Program. These guidelines will
also be very useful as we examine all 47 of the "Key Findings"
statements presented in Chapter 5.

**GUIDELINES FOR FORMULATION OF SCIENTIFIC FINDINGS**

###### TO BE USED FOR POLICY PURPOSES

The following guidelines in the form of checklist questions were
developed by the NAPAP Oversight Review Board to assist scientists in
formulating presentations of research results to be used in policy
decision processes.

1\) **IS THE STATEMENT SOUND?** Have the central issues been clearly
identified? [Does each statement contain the distilled essence of
present scientific and technical understanding of the phenomenon or
process to which it applies]{.underline}? Is the statement consistent
with all relevant evidence -- evidence developed either through NAPAP
research or through analysis of research conducted outside of NAPAP? Is
the statement contradicted by any important evidence developed through
research inside or outside of NAPAP? Have apparent contradictions or
interpretations of available evidence been considered in formulating the
statement of principal findings?

2\) **IS THE STATEMENT DIRECTIONAL AND, WHERE APPROPRIATE,
QUANTITATIVE?** Does the statement correctly quantify both the direction
and magnitude of trends and relationships in the phenomenon or process
to which the statement is relevant? When possible, [is a range of
uncertainty given for each quantitative result]{.underline}? Have
various sources of uncertainty been identified and quantified, for
example, does the statement include or acknowledge errors in actual
measurements, standard errors of estimate, possible biases in the
availability of data, extrapolation of results beyond the mathematical,
geographical, or temporal relevancy of available information, etc. In
short, [are there numbers in the statement? Are the numbers correct? Are
the numbers relevant to the general meaning of the
statement]{.underline}?

3\) **IS THE DEGREE OF CERTAINTY OR UNCERTAINTY OF THE STATEMENT
INDICATED CLEARLY?** [Have appropriate statistical tests been applied to
the data used in drawing the conclusion]{.underline} set forth in the
statement? If the statement is based on a mathematical or novel
conceptual model, has the model or concept been validated? Does the
statement describe the model or concept on which it is based and the
degree of validity of that model or concept?

4\) **IS THE STATEMENT CORRECT WITHOUT QUALIFICATION?** [Are there
limitations of time, space, or other special circumstances in which the
statement is true]{.underline}? If the statement is true only in some
circumstances, are these limitations described adequately and briefly?

5\) **IS THE STATEMENT CLEAR AND UNAMBIGUOUS?** [Are the words and
phrases used in the statement understandable by the decision makers of
our society]{.underline}? Is the statement free of specialized jargon?
Will too many people misunderstand its meaning?

6\) **IS THE STATEMENT AS CONCISE AS IT CAN BE MADE WITHOUT RISK OF
MISUNDERSTANDING?** Are there any excess words, phrases, or ideas in the
statement which are not necessary to communicate the meaning of the
statement? Are there so many caveats in the statement that the statement
itself is trivial, confusing, or ambiguous?

7\) **IS THE STATEMENT FREE OF SCIENTIFIC OR OTHER BIASES OR
IMPLICATIONS OF SOCIETAL VALUE JUDGMENTS?** Is the statement free of
influence by specific schools of scientific thought? Is the statement
also free of words, phrases, or concepts that have political, economic,
ideological, religious, moral, or other personal-, agency-, or
organization-specific values, overtones, or implications? [Does the
choice of how the statement is expressed rather than its specific words
suggest underlying biases or value judgments]{.underline}? Is the tone
impartial and free of special pleading? If societal value judgments have
been discussed, have these judgments been identified as such and
described both clearly and objectively?

8\) **HAVE SOCIETAL IMPLICATIONS BEEN DESCRIBED OBJECTIVELY?**
Consideration of alternative courses of action and their consequences
inherently involves judgments of their feasibility and the importance of
effects. For this reason, it is important to ask if a reasonable range
of alternative policies or courses of action have been evaluated? Have
societal implications of alternative courses of action been stated in
the following general form?:

\"[If this]{.underline} \[particular option\] were adopted [then
that]{.underline} \[particular outcome\] would be expected.\"

9\) **HAVE THE PROFESSIONAL BIASES OF AUTHORS AND REVIEWERS BEEN
DESCRIBED OPENLY?** Acknowledgment of potential sources of bias is
important so that readers can judge for themselves the credibility of
reports and assessments.

**Two Additional General Concerns**

As an ecologist, who is aware of the many different and important
adverse public-welfare effects of both oxidized and reduced forms of
reactive nitrogen, I was pleased to find that Annex 2 is described on
page 1-6 of the Introduction to this ISA as containing "evidence related
to the physical and chemical processes controlling the production,
destruction, and levels of reactive nitrogen compounds in the
atmosphere, including both oxidized and reduced species."

When I looked through Annex 2, however, I was glad to see that this
Annex does indeed deal with both gaseous and particulate matter forms of
ammonia and ammonium ion and their short and long-distance transport.

But it was also disappointing to find that there was little or no
discussion in Annex 2 about the important adverse effects of both
reduced and oxidized forms of reactive nitrogen on visibility in urban,
rural, and wilderness areas, on the productivity and stability of
aquatic and terrestrial ecosystems in lakes, streams, fields, forests,
and coastal regions of this country.

Many of us in the ecological community continue to believe that the US
and other developed countries of the world need to consider the
establishment of an integrated total reactive nitrogen approach in
air-quality management. Such an integrated total nitrogen idea was
considered in a 1997 EPA report titled "Nitrogen Oxides: Impacts on
Public Health and the Environment." This document was prepared by a team
of scientists and engineers led by Doug Grano in EPA's Office of Air and
Radiation. Such an integrated approach was also recommended in a more
recent review paper titled "Optimizing air quality management in Europe
and North America: Justification for integrated management of both
oxidized and reduced forms of nitrogen" by Cowling et al (Environmental
Pollution 102 S1 (1998) 599-608).

Such an Integrated Total Reactive Nitrogen approach in air quality
management ideally will include both reduced and organic as well as
oxidized forms of reactive nitrogen and would be aimed at decreasing
adverse effects on both public welfare and public health. These ideas
are also currently under study by an Integrated Nitrogen Committee
established within EPA's Science Advisory Board in 2006 under the
leadership of Dr. James Galloway of the University of Virginia and with
additional advice and counsel from me as a CASAC-liaison representative.

[]{#__RefHeading___Toc184090829 .anchor}[Comments from Dr. Douglas
Crawford Brown]{.underline}

**Comments on Chapter 5: The Integrated Science Assessment for Oxides of
Nitrogen: Health Criteria**

Doug Crawford-Brown

My comments here focus largely on Chapter 5: Findings and Conclusions,
although material from other chapters used to form the conclusions in
Chapter 5 will be mentioned as needed. These comments should be paired
with those of Dale Hattis, who is charged with reviewing the same
chapter.

The charge question concerns the "adequacy of this first external review
draft ISA to provide support for future risk, exposure and policy
assessments". As a broad statement, I will begin by noting that Chapter
5 could not be used as the basis for a risk assessment on oxides of
nitrogen. It is a largely qualitative discussion of, and summary of, the
findings in the earlier chapters. It does draw the conclusions that U.S.
populations are currently exposed to NOx concentrations both above and
below the existing NAAQS; that there are adverse health effects
associated with short term exposures both above and below the existing
NAAQS, and adverse health effects associated with long term exposures at
levels slightly above the existing NAAQS; that the exposure-response
relationship is approximately linear with no evident threshold for
effect; and that NOx produces both direct adverse effects and probably
makes individuals susceptible to the effects of other pollutants and to
exposure to microbes such as viruses. In each of these conclusions,
Chapter 5 represents an accurate summary of the information provided in
the earlier chapters.

The authors have adopted a scale of causality from "inconclusive" to
"suggestive" to "likely causal". This was helpful throughout the
chapter. It was a good way to summarize the strength of the conclusions
for both short and long term exposures. The one caveat I would place on
my support for this system is the curious omission of the judgment
"demonstrates (weakly or strongly) that there is NO adverse effect".
This is a problem throughout the chapter, and remains a weakness of EPA
risk assessment methodologies (especially the Hazard Identification
stage). The current chapter follows an EPA tendency to present the
evidence as if one were building a legal case in which evidence FOR a
belief is what matters most. Throughout the chapter, and throughout the
report, there is a focus on the studies that are suggestive of an
adverse effect, with the conflicting studies providing a kind of
counter-evidence that lowers a judgment from "likely causal" down to
"suggestive" or down to "inconclusive". What is needed instead is a
methodology that examines ALL studies, supportive and
counter-supportive; considers the potentially conflicting findings from
these studies; weighs these findings systematically by trying to
determine why there are conflicting results; and then yields a final
judgment of causality that reflects this full range. I realize the
authors probably feel they did that, but it is not evident in the
report. If this were done, there would naturally be the fourth category
of judgment I mentioned: the judgment that existing evidence suggests
that there is in fact no adverse effect (and yes, I do realize the issue
of proving a negative!).

To be useful in a quantitative risk assessment, the EPA needs to develop
some sort of system of describing -- for epidemiological, clinical and
animal studies -- the Minimum Detection Limit and Minimum Quantitation
Limit for a study. This could be based on some sort of power
calculation. If the chapter is intended only as a kind of Hazard
Identification, then it is useful to know whether a study that finds no
effect would have detected any effects at some level of odds ratio (i.e.
could it have found an effect with an odds ratio of 2 if one had been
present?). But if Chapter 5 is to be used for quantitative risk
assessment, one needs information on the minimal effects level (minimal
odds ratio) that could be quantified from the study. This MQL is always
above the MDL, and often quite far above the MDL.

There are some places in the chapter in which the terminology is poor,
or perhaps some part of the text is missing. Instances are:

-   On page 5-10, line 15, the statement is that effects estimates
    ranged from "0.5 to 3.6% excess risk". More context is needed here.
    The statement should be that this level of excess risk is the
    difference between exposure at X and Y, but X and Y are not
    provided. And it is not clear whether this is a relative or absolute
    risk model (i.e. whether a person has a 0.5 to 3.6% risk of
    developing the effect above and beyond the background probability of
    effect - an absolute risk model -, or whether this percentage is to
    be multiplied by the natural incidence to obtain the probability of
    effect - a relative risk model.

-   On page 5-20, the final bullet needs to be reworked. There is
    something missing on line 27. In addition, the authors state that
    the "range of mortality risk estimates is smaller", but no insight
    is given as to what is meant by a "mortality risk estimate". Is this
    referring to some sort of slope factor?

-   On page 5-11, line 6, the authors state that "results were similar
    for boys compared to girls" without stating WHICH results (perhaps
    they mean ALL results?).

-   On page 5-12, line 25, the authors are considering the issue of
    linearity in exposure-response, and include a reason based in the
    "additivity of pollutant-induced effects to the naturally occurring
    background disease processes". Even if the pollutant-induced effects
    are additive, this does not imply that the curve will be linear. It
    is possible for the effect to be additive and yet non-linear if the
    modes of action are not the same.

-   On page 5-13, line 2, the authors state that "effects are weaker at
    low concentrations". They don't state what they mean by "weaker".
    Weaker in the sense that the effect in a diseased individual is not
    as pronounced? Weaker in the sense of a more shallow
    exposure-response curve?

-   On page 5-14, lines 10-12, the authors suggest there is an adverse
    effect related to a shift towards greater sensitivity to illness.
    While I agree that the data on NOx make this a reasonable
    possibility, this chapter provides no evidence to support that
    claim. This raises for a me a more general critique of the chapter.
    All conclusions drawn in the chapter should reference the findings
    in earlier chapters, and explain why the BODY of evidence (both
    supporting and counter to the conclusion) presented in those
    chapters leads on balance to the claim being made. As currently
    written, readers are left to their own devices to determine which
    results from previous chapters are being invoked, and to determine
    how the often conflicting results are being reconciled or weighted.
    A typically vague example is on page 5-14, lines 24-25, in which the
    authors state "These conclusions are supported by evidence from
    toxicological and controlled human exposure studies". This is a much
    too subjective approach to forming conclusions, especially because
    there is no way for a reader to determine the basis for the claim
    and, therefore, to find any points around which a discussion might
    begin. The reader is left with nothing other than a claim rooted in
    some unknown reasoning process, or emotive process, in the writer,
    and some unknown body of actual data presented in earlier chapters.

This then brings me to the largest issue with the chapter, which is
related to the charge question. This chapter is intended to "provide
support for future risk, exposure and policy assessments". I can see no
way in which it can serve in that role. The conclusions drawn in the
chapter are too qualitative to form the basis for a risk assessment. The
chapter doesn't provide any guidance or insights into the existing
ambient levels of NOx for the exposed populations. It does not provide a
summary exposure-response relationship, other than to suggest it is
linear. It correctly identifies the sensitive subpopulations, but does
not express this increased sensitivity quantitatively. It would not be
possible to use this chapter as a basis for any sort of quantitative
risk assessments or benefits assessment.

And even if the goal is only to assist in setting a safe exposure limit,
or establishing the form, etc for a NAAQS, rather than calculating
actual risks and benefits, the chapter falls short. There is no way to
use the results in the chapter to determine where there is a NOAEL or
LOAEL, or where the probability of adverse effect drops below any target
level of risk. The authors conclude (on page 5-15) with the statement
that "it is plausible, consistent and coherent that current ambient NO2
exposures directly result in adverse impacts to public health below the
current NAAQS for NO2", but there is no systematic support for even this
qualitative claim (although I personally agree with the claim).

Overall, I don't feel this chapter is adequate "to provide support for
future risk, exposure and policy assessments".

[]{#__RefHeading___Toc184090830 .anchor}[Comments from Dr. Terry
Gordon]{.underline}

Comments from Terry Gordon

[Major Comments]{.underline}:

There is a chapter-to-chapter difference in the level of detail and
integration provided to the reader. For example, the title of Chapter 3
states "Integrated" but there are several sections, particularly in the
animal toxicology studies, where the text does not integrate the science
but reports on individual studies in too much detail. This is a key
chapter and should have better balance between providing the details of
essential data/studies and the overall integration.

[Minor Comments]{.underline}:

Chapter 2

Figure 2.2-2 -- ppbv or pptv?

page 2-17 -- Why are tables at the end of each chapter and the figures
are inserted where appropriate in the text?

page 2-23, line 10-12 -- Does this sentence apply to NOx? Similarly, the
rest of the para provided more info on other pollutants than it does on
NOx without integrating how these confounding pollutants should be
considered.

page 2-24, lines 11-12 -- Because all of this data on NO3 is modeling
data (i.e., not real data), does the conclusion that NO3, in ppt, "may
be meaningful confounders"?

pages 2-24, lines 23 and on -- This entire section presents a lot of
chemistry w/o much 'scientific assessement'.

page 2-30, lines 6-18 -- After stating that more weight would be given
to North American studies, and referencing a ton of literature in the
previous para, why was this one European study discussed in detail? The
same comment applies to the second para on page 2-31.

page 2-38 -- Why is this a separate subtitle when it's almost identical
to 2.5.3.2? Also, lines 18-32 and some of the next page don't appear to
provide correlations as stated in the subtitle.

Chapter 3

page 3-1, line 11 -- Is the discussion of studies at 5 ppm NOx
warranted?

page 3-4, lines 15-30 -- This section is redundant and described again
on pages 3-7 and 3-8.

page 3-5, lines 28-29 -- These first 2 sentences are confusing. First it
states the evidence is "coherent" and then it states it "lacks
consistency and robustness".

page 3-6, line 1 -- The Pilotto study (2004) is referenced but no
description of it is given previous to this mention.

page 3-6, line 8 -- Why is this subtitle different or even used? The
same words are used in the sentence in line 10, page 3-4. Combine?

page 3-6, lines 10-17 -- The authors should consider cutting the Goings
study in a final 'integrated science assessment' if the findings were
"inconclusive"?

page 3-6, lines 21 and on -- As mentioned above in the Major Comments,
this paragraph provides too much detail for an 'integrated' chapter.
Maybe it should be cut and summarized/referenced as is nicely done in
the following paragraph.

page 3-7, lines 21 and on -- Some of this work was already described
(same comment for top of page 3-8).

page 3-8 -- Starting here, there are too many study details and not
enough integration. Also, many pre-1993 studies are described rather
than referencing the 1993 CD as done in other sections/chapters.

page 3-14, line 9 -- 20 ppm NO2?

page 3-16, lines 20-28 -- As in the animal tox section, there is too
much detail in describing this study, whereas the last couple sentences
give an excellent assessment.

Figure 3.2-1 -- Is this figure important enough for inclusion?

Figure 3.2-2 -- Possible typo: should it be [ppb]{.underline} on the
Y-axis?

page 3-19, lines 1-5 -- Too much detail for a study for which
"quantitative results not provided".

page 3-20, lines 11-13 -- Unclear: No change in spirometry but a change
in airway resistance? Some labs measure airway resistance by what they
consider 'spirometry'.

page 3-21, lines 5-7 -- Redundant

page 3-21, lines 10 and on -- Integrate and shorten?

page 3-22 -- The summary is very good and more of this integration
should be used in this chapter.

Figure 3.2-5 -- The legend need to be rewritten to clarify the figure.

Figure 3.2-7 -- The boxed legend in the graph (giving ages) is not
described in the legend text.

page 3-32, line 8 -- Unclear as to how a significant association could
exist if the 95% CI of ln(CC16) was 0.1 to 18.3.

page 3-38 -- Here is an example of the kind of excellent level of
integrated text that should be used throughout this Chapter.

page 3-51, line 19 -- Add 'of' after addition?

Figure 3.2-9 -- Describe gray boxes in this and the following figure.

Figure 3.2-11 -- The boxed legend doesn't match the legend text (authors
vs. city/country).

page 3-61, line 2 -- what is 'attache'?

page 3-61, line 16 -- Are the NO2 effects on macrophages 'especially
relevant' at 1 ppm?

page 3-61, line 26 -- Cut 'strong' as the animal effects are typically
at much higher concentrations.

page 3-62, lines 12-15 -- Slightly confusing to say airway
responsiveness is most sensitive response at 0.2 to 0.5 ppm and then say
other studies found nothing up to 4 ppm.

page 3-62, line15 -- Be more specific on what is meant by lung function
-- in some ways airway responsiveness describes the function of the
lung.

page 3-67, line 5 -- delete 'been'.

page 3-70, line 2 -- 95% CI for the OR of 1.08?

page 3-75, lines 14-26 -- condense

page 3-78, line 7 -- Please reference these 'subsequent studies'.

page 3-79, line 15 -- 'exposure to ambient'.... what?

page 3-80, lines 28-32 -- Switch the order of the first 2 sentences?

page 3-97 -- Why the different sub-headings (e.g., Confounding)?

Figure 3.4-1 -- Figure legend text: 'average' is daily or hourly or
yearly?

page 3-106, line 29 -- 10 to 20 ppm data? too much detail; same goes for
Barth studies on next page.

page 3-108, lines 3-26 -- Why not summarize from 1993 CD? same for page
3-110.

page 3-121, line 17 -- 2.0 plus or minus?

page 3-124 -- If 0.05 ppm was a LOAEL for NO2 in this unreferenced study
(lines 23-31), this should be described more clearly here and elsewhere
as to its importance. Similarly, an increase in post-implantation
lethality at 0.5 ppm should be discussed. Neither of these findings are
mentioned in the Integration section on pages 3-125-126.

page 3-145, lines 23-27 -- An 'older' 10 ppm study like this could be
cut unless this is a relevant concentration for NO.

Chapter 4

page 4-9, line 4-5 -- PCR and time are too much detail.

page 4-9, line 25 -- typo: suggestive?

page 4-11 -- This is a good summary but why are the next 2 or 3
subheadings included yet not related directly to interpreting the data
for NOx?

Chapter 5

page 5-4, lines 14-15 -- Is this sentence comparing ambient to ambient?

page 5-6, lines 4-5 -- Unclear.

page 5-8, lines 19-28 -- These 2 paragraphs/bullets seem to contradict
each other. The first says "Few recent epidemiological evaluations..."
and the second section says "provide key support..."

page 5-14, lines 10-12 -- I understand what this is saying if I read it
enough times, but it should be made more clear.

[]{#__RefHeading___Toc184090831 .anchor}[Comments from Dr. Dale
Hattis]{.underline}

**Comments on the ISA**

Charge Question 2: Ref p. 2-19, lines 15-22. It is important for
eventual risk assessments that may be based on absolute measurement data
(e.g. the data from the Australian intervention study) to characterize
not just that there is a verticle bias in NO2 concentrations measured at
regulatory montiors, and how large it is on average with height, but the
distributional aspects of how much correction is needed to convert the
distribution of concentrations measured at existing monitor heights to
concentrations that would approximate breathing level concentrations.
This can only be done by combining information about how many sampling
stations are at what height with data on the verticle gradients. Ideally
there should also be information on the relationship between the slope
of the verticle gradient in concentrations and the absolute level of NO2
measured at the monitoring station.

In cases where the health concentration-response data are implicitly
based on measurements at monitoring stations with the same height
distribution as those used for exposure analysis, such a correction may
not be needed, as a general matter, but it is still important to keep
track of the biases that may exist in the determination of exposures in
different studies used for the concentration-response analysis and
ultimate projection of the likely incidences of different types of
adverse health effects.

Charge Question 3: Ref p. 2-22, lines 9-10. It is not technically
correct that "shorter term average concentrations tend to be much higher
than longer-term averages". Real averages---arithmetic means---must be
the same independent of averaging time. What is true is that higher
percentile values---e.g. 90^th^ or 99^th^ percentiles, will tend to be
higher for shorter averaging times because of regression to the mean
effects.

Charge Question 4: As a general matter the integrated analyses do a
reasonable job of bringing together relevant data sets of the same kind,
but do not do enough to draw key conclusions from the available data on
the forms and magnitude of concentration response for different
endpoints, associated uncertainties, and the need for correction of
individual data sets for the vertical bias in between regulatory
monitors and breathing zone concentrations in assessing exposure levels.

Charge Question 8: I think the authors of the ISA have generally done a
good job in analyzing information within specific data types and showing
the comparisons and contrasts between studies of the same endpoints.
What they have not generally done is to provide overall uncertainty
weighted quantitative conclusions that reflect the combined implications
of all reasonably decent studies for specific adverse effects. They have
not come to definite quantitative conclusions about the extent of
interindividual variability in susceptibility among different people
within and among different putatively susceptible subgroups, and they
have not done quantitative evaluations of the uncertainty in overall
measures of relative potency for causing effects of different types and
severities. Shapes of dose response relationships have generally not
been subject to critical statistical analyses informed by mechanistic
theories of likely relevant causal mechanisms.

In my reading of the ISA I came across one example of an apparent missed
opportunity to do the kind of reanalysis that can shed light on
implications for the forms of dose response relationships. Figure 2.7-3
on page 2-47 shows plots of data of van Strien et al. (2004) on
confounder-adjusted relative risks of persistent cough and shortness of
breath in relation to quartiles of NO2 concentrations for a large number
of infants (762) in the first year of life. Plotting by quartiles where,
as is usual, exposures are approximately lognormally distributed,
implicitly introduces a log transformation into the dose scale that is
known to give rise to an impression of threshold like behavior, even for
dose response relationships that are in fact linear when plotted with an
untransformed x-axis. I therefore first did a lognormal probability plot
of the quartile data and found that, as is usual, the exposures appear
to be reasonably well described as lognormal, as indicated by the
adherence of the points in Figure 1 (next page) to the straight
regression line. Using the lognormal distribution of individual
exposures derived in Figure 1, I then calculated mean levels of NO2
within each of the quartile groups and replotted the relationships with
a linear x axes (Figure 2). It can be seen that, viewed in this way, the
suggested form of the relationship for shortness of breath appears to
have a saturation-like convex shape; and the relationship for persistent
cough may well be similar.

**Figure 1**

![](media/image2.wmf){width="6.490277777777778in"
height="4.555555555555555in"}

**Figure 2**

**Replot of the Concentration Response Data of van Strien et al (2004)
On Linear Axes Based on Estimates of Mean Concentrations for the Four
Quartile Groups**

![](media/image3.wmf){width="6.79375in" height="5.780555555555556in"}

I have done log probability plots (see Figure 3) analyzing the amount of
lognormal variability for different averaging times, based on the data
from a particular table in Annex 3.

**Figure 3**

![](media/image4.jpeg){width="6.0in" height="4.5in"}

[]{#__RefHeading___Toc184090832 .anchor}[Comments from Dr. Donna
Kenski]{.underline}

Review of Integrated Science Assessment for Oxides of Nitrogen -- Health
Criteria

Donna Kenski

October 19, 2007

Charge question 2: *Are the properties of ambient oxides of nitrogen
appropriately characterized, including policy-relevant background,
spatial and temporal patterns, and relationships between ambient oxides
of nitrogen and human exposure? (Sec. 2.5)*

One overarching observation: A huge amount of research is gathered and
described in this document and that is commendable. But the integration
of that research is sorely lacking synthesis. It seems that no
significant attempt has been made to summarize and pull common threads
from the many studies. Rather, the authors have been much too careful to
keep any semblance of interpretation out of this document, especially in
Chapter 2, making it difficult for readers/reviewers to pull all the
pieces together into a coherent picture.

Section 2.2: Needs to discuss the relative importance of the various NOz
species, at least by giving average concentration data where available.
More discussion of the formation of particle nitrate and removal
mechanisms would be helpful. The information on NOz species
concentrations given in AX3.2 should be summarized in a table or figure
and included here.

Sections 2.3-2.4: Since our ability to find health effects due to NO2
depends partly on accurate measurements, this section should be much
more comprehensive in describing and quantifying the accuracy of the FRM
and the degree of interference from various NOz species. The single
paragraph on interference on p.2-8 is not adequate. Again, it could be
more useful if this information were summarized graphically, including
the diurnal differences in interferences. The document seems to be of
two minds on measurements -- in some instances leaning toward NOy
measurements as somehow better than the current NOx, and in some
instances implying that more specific NO2 measurements are to be
preferred. At some point the two should be explicitly compared to the
FRM and the merits of each measurement approach noted for various
applications (epi studies, atmospheric chemistry, etc.). Both NOy and
'true' NO2 are useful measurements in certain situations, but it is not
clear to me whether a change in the FRM is being encouraged, or whether
there is any need for such a change. In addition, the challenges of
making both of these measurements are significantly underestimated in
this document, particularly in the context of a state or local agency
being asked to undertake them.

Section 2.4.1 is woefully lacking adequate information on US NO2
concentrations. At the very least this section needs to include a map of
the distribution of sites (instead of stashing it in the Annex) and
visually make the point that there just aren't very many NO2 sites
providing data for health studies or NAAQS comparisons. A brief
discussion and enumeration of the number of sites by type (i.e.,
roadside monitors, population-oriented, point-source-oriented, suburban,
urban, etc) should be here. Figure 2.4-1 is helpful, but it should be
accompanied by similar figures showing diurnal, day-of-week, and
seasonal variation in NO2. Most of these are already in the Annex AX3.2
and in Section 2.5.3.2. The discussion of spatial variability from Sec.
2.5.2.2 should be moved here, and expanded to include a discussion of
the extreme gradients in NOx found near roadways. The vertical
variability section 2.5.2.2.2 should include some information about the
monitoring probe heights in the current network -- how many are at 4 m
vs 15 m? How significant might the bias be when estimating human
exposures?

Section 2.4.2 is generally adequate in describing background
concentrations. The caption for Fig. 2.4-2 should be concentrations in
pptv, rather than ppbv.

Section 2.5 needs some reorganizing, as mentioned above. The variables
in Eqns 2.5-1 thru 2.5-5 need to be defined immediately, not as they are
now, 13 pages later in section 2.5.2.3.3.

Section 2.5.2.3 needs a summary. Throughout Chapter 2, summaries were
used only sporadically. At least each major subsection should
incorporate a 1-2 paragraph summary. On page 2-30, the summary paragraph
(together with the one that follows) seem like they were written for the
section 2.5.2 as a whole, and should be moved to the end.

The description of diurnal cycles of NO2 and its link to motor vehicle
emissions belongs in Sec. 2.4.

The ISA needs a section devoted to a discussion of confounding. I'm not
sure where this should go -- probably in Chapter 2. Section 2.5.3 seems
like it was intended to cover this but doesn't quite accomplish that
goal. Similarly, Annex section AX3.6 ostensibly discusses confounding
but almost exclusively by describing correlations among copollutants.
Rather than just summarizing these correlations, a more thoughtful
discussion of the impacts of confounding would be useful. Implications
and estimates of impacts from confounding are mentioned in Chapter 3 in
part of the discussion of individual summaries, but again not treated
comprehensively.

Chapter 3; Much better presentation and summarization of studies than
Chap 2. Figures are very helpful. Summaries at the end of each
subsection were careful, fair, and thoughtful. This chapter was
impressively comprehensive -- perhaps a bit too long or too
comprehensive? More reliance on figures and less discussion of
individual studies would make it more manageable.

Chapter 4: The last half of this chapter had a lot of typos and
grammatical errors and needs a careful proofreading. The section on
traffic exposure seems more suited to discussion in Chapter 2.

Chapter 5: Conclusions in section 5.2 seem to be advocating a move to
NOy rather than NOx. While the previous chapters did demonstrate that
this is preferable in terms of understanding atmospheric chemistry,
there was no supporting information given to show that this would be a
better measurement in terms of understanding the health effects of NO2
or supporting epidemiological studies. That link (between ambient NOy or
NOy-NO and health effects) must be made explicitly. The last bullet on
p. 5-2 is true, existing NOx monitors can be converted to NOy monitors
fairly easily, but the subsequent calibration, operation, and
maintenance of those NOy monitors is considerably more complex and must
not be ignored. Finally, the last paragraph is odd. Yes, NO2 is an
indicator of traffic pollutants. But since estimates of its health
effect are confounded by other traffic pollutants, wouldn't it be more
reasonable to state that the health effects we attribute to NO2 may be
partly due to other pollutants? In any event, the abrupt introduction of
multipollutant mixtures as the last point of this conclusion seems out
of place and inappropriate without more supporting information.

The following were typos or minor wording changes:

+-----------+----------+-----------------------------------------------+
| Page no.  | Line no. |                                               |
+-----------+----------+-----------------------------------------------+
| 2-5       | 2        | Nitro-patts should be nitro-PAHs              |
+-----------+----------+-----------------------------------------------+
| 2-17      | 4        | "...tube measurements were *not* likely to    |
|           |          | be..." ?? Doesn't seem right as written.      |
+-----------+----------+-----------------------------------------------+
| 2-31      | 17       | An r~s~ of 1 seems extraordinary -- typo?     |
+-----------+----------+-----------------------------------------------+
| 2-36      | 13-14    | Rephrase: '\...between ambient NO2 and        |
|           |          | *pollutants other than those* presented       |
|           |          | above.'                                       |
+-----------+----------+-----------------------------------------------+
|           |          | Make lines 13-24 all one paragraph. Rephrase: |
|           |          | "Table 2.5-8 shows correlations between NOx   |
|           |          | and traffic pollutants measured in ambient    |
|           |          | air *for the Kim 2005 study and several       |
|           |          | others.*" Move this sentence to follow the    |
|           |          | one beginning 'Leaded gasoline\...'           |
+-----------+----------+-----------------------------------------------+
| 2-38      | 18+      | This description of diurnal concentration     |
|           |          | variations belongs in Sec. 2.4 rather than    |
|           |          | here.                                         |
|           |          |                                               |
|           |          | There certainly needs to be a description of  |
|           |          | seasonal variability in NO2 here (i.e., in    |
|           |          | Sec. 2.4) rather than relegating it to the    |
|           |          | Annex.                                        |
+-----------+----------+-----------------------------------------------+
| 2-38      | 23       | For clarification, add: Motor vehicle         |
|           |          | emissions *of NOx* consist mainly\...         |
+-----------+----------+-----------------------------------------------+
| 2-39      | 10       | Why '*still* show positive correlation with   |
|           |          | CO'? Since both pollutants tend to peak       |
|           |          | during the winter in most places, isn't this  |
|           |          | the expected relationship?                    |
+-----------+----------+-----------------------------------------------+
| 2-40      | 1-2      | Since \~50% of NO2 is emitted from power      |
|           |          | plants, which do have a strong seasonal       |
|           |          | cycle, there certainly *is* good reason to    |
|           |          | suspect seasonal variations in its emissions. |
+-----------+----------+-----------------------------------------------+
| 2-42      | 9        | Indoor NO2 *concentrations* or *exposures*    |
|           |          | are not likely confounded, rather than        |
|           |          | sources                                       |
+-----------+----------+-----------------------------------------------+
| 2-42      | 18+      | Isn't the Pilotto 2004 study still subject to |
|           |          | possible confounding from other pollutants    |
|           |          | emitted from the heaters? I.e., ultrafines?   |
+-----------+----------+-----------------------------------------------+
| 2-46      | Fig.     | between children *within* classrooms          |
|           | caption  |                                               |
+-----------+----------+-----------------------------------------------+
| 2-51      | 11-14    | It seems more accurate to say that these      |
|           |          | studies did not measure other pollutants that |
|           |          | could have confounding effects.               |
+-----------+----------+-----------------------------------------------+
|           | 25       | What exactly is meant by "evidence of         |
|           |          | coherence for respiratory effects"? That the  |
|           |          | evidence is consistent? Not clear. But unlike |
|           |          | most of the previous sections, which          |
|           |          | desperately need a summary, this was a nice   |
|           |          | summary.                                      |
+-----------+----------+-----------------------------------------------+
| 2-52      |          | This table would benefit from some            |
|           |          | explanatory information (mostly for P90) in a |
|           |          | footnote.                                     |
+-----------+----------+-----------------------------------------------+
| 3-61      | 2        | Triggering asthma *attacks,* not attache?     |
+-----------+----------+-----------------------------------------------+
| 4-11      | 18       | Item (2) needs rewording to be meaningful     |
+-----------+----------+-----------------------------------------------+
| 5-2       | 25       | Measuring NOy would perhaps be more           |
|           |          | meaningful in terms of atmospheric chemistry, |
|           |          | but the implications of that measurement for  |
|           |          | health studies aren't at all clear. It may    |
|           |          | just lead to further confounding.             |
+-----------+----------+-----------------------------------------------+
| AX3-88    | 30-31    | Sentence beginning 'Stronger correlations..'  |
|           |          | needs rewording                               |
+-----------+----------+-----------------------------------------------+
| AX3-93-94 |          | These pages have a number of typos and        |
|           |          | grammar problems that need to be fixed.       |
+-----------+----------+-----------------------------------------------+

[]{#__RefHeading___Toc184090833 .anchor}[Comments from Dr. Steven
Kleeberger]{.underline}

**Chapter 4 Comments.**

The document focuses on susceptibility factors that include preexisting
disease (e.g. asthma, COPD, cardiovascular disease), age (e.g. neonates,
children, and the elderly), high exposure occupational groups, and
genetic background. IS GENDER CONSIDERED SUFFICIENTLY?

The document adequately discussed the existing literature regarding
differential responsivity to NOx. My overall impression of the chapter
is that, while some studies do address susceptibility factors, the
critical issue is the relative dearth of systematic investigations that
sufficiently evaluate each of the potential modulators of response.
Therefore, it will be difficult to come to hard conclusions regarding
the relative risk due to the susceptibility risk factors described
above.

Specific comments:

Page 4-5. It is not clear to me that new evidence since 1993 "raises
concerns" for increased severity and frequency of respiratory
infections, decreased lung function growth, increased onset of asthma
and allergy, etc. Does the new evidence truly raise concern or simply
indicate that these questions are now being pursued and suggest that
these factors could be important? The lack of consistent findings within
investigations, and between investigations, suggests that additional
investigations need to be performed before attributing risk of exposure
to NO2 among the susceptible subgroups.

Page 4-10. In particular, the lack of investigations on the role of
genetic background on susceptibility to NO2 exposure is evident. The
studies performed to date are focused on candidate genes (e.g. GSTM1,
GSTP1) which, while defensible, are "looking under the lightpost".
Multiple genes could be examined in this manner without obtaining a
clear understanding of the role of genetic background on responsivity to
NO2. Investigations that systematically approach the importance of
genetic variation in experimental models with translational or
extrapolation potential are clearly necessary. This information could
lead to explanations regarding the inter-individual variation observed
in many of the clinical investigations in healthy individuals and those
with pre-existing disease.

It is not clear that "understanding a basis for susceptibility to
asthma, will facilitate/improve the precision of future studies of air
pollution and health". In fact, it is probable that understanding the
basis of susceptibility to environmental exposures (such as NO2) and
interaction between asthma susceptibility genes will facilitate
understanding asthma and other chronic diseases. It is understood that
we are not making recommendations regarding the research that should be
done, but the literature available currently does not inform adequately
on genetic susceptibility to enable firm conclusions.

Page 4-12. It is not clear that section 4.2.2 is informative.
Documentation of estimates of the number of individuals with asthma
and/or heart disease does not seem meaningful if there are no clear
indications that these diseases are predisposing to the effects of
exposure to NOx. Furthermore, it is also not clear that all individuals
with asthma (or other chronic lung disease) will respond similarly to
exposures to air pollutants. The variation in responses to pollutants
among diseased individuals may be as great as that found among healthy
individuals.

GENERAL COMMENT

With respect to Question 5: "to what extent does the integration of
health evidence focus on the most policy-relevant studies or health
findings".

"integration of health evidence" was not as clearly delineated as
probably should have been to enable evaluation of its focus on
policy-relevant studies or health findings. To enable this interaction,
we must have a more comprehensive evaluation of the integration between
animal toxicology studies, dosimetry studies, and epidemiological
investigations. This leads to question whether integration is possible
with the existing literature or whether the studies do not exist and
should be proposed as recommendations.

[]{#__RefHeading___Toc184090834 .anchor}[Comments from Dr. Timothy
Larson]{.underline}

*General Comments*

*Charge Question 3:* I would agree with the conclusion on p. 5-14 that
epidemiological studies are potentially confounded by other traffic
related pollutants, although I would qualify this to say that the
evidence suggests that CO is not one of these. The ISA relies more
heavily on the intervention study of Pilotto to argue for the
independent effects of NO2 in real world exposures. However, as
mentioned in Chapter 2, this study is also potentially confounded by
other combustion related products (c.f. page 2-42). This issue deserves
more elaboration if possible. For instance, the recent survey of
Canadian homes by Weichenthal et al (JESEE 17(3) 288-297, 2007)
indicates that heating sources including natural gas are not significant
sources of ultrafine particles, but cooking is. Given that indoor
heating by natural gas is an important source of NO2it may be possible
to argue more persuasively that indoor ultrafine particle exposures are
not correlated with NO2 exposures. I have had a hard time finding any
direct studies on this topic. At a minimum I would suggest more research
in this area.

*Charge Question 1:* In Chapter 2, the discussion about the spatial
variability of NO2 concentrations needs to be prefaced by a brief
discussion of the EPA siting criteria for NO2 monitors. These siting
criteria include proximity to traffic and are an important determinant
of the observed spatial variability as summarized in Table 2-5-1 and
related tables. One could also show the distribution of distance to
major roads for both the EPA NO2 monitors and the population in general,
and the relationship between NO2 levels at monitors less than xx meters
from major roads vs all others.

*Charge Question 1:* The decision to exclude the European data in
Chapter 2 is understandable, but misses the opportunity to compare
networks based on near road monitoring of NO2 with the U.S. networks
sited away from roads. Some European networks have at least one NO2
monitor at an 'urban background' location for contrast. This location
would be comparable to the majority of U.S. locations. The importance of
street canyons in many is also worth discussing in more detail, given
that this is a very important determinant of spatial variability in
urban areas. Again, most of this work has been done in the European
context and clearly shows this effect. However, it is generally
applicable to parts of many U.S. cities.

*Specific Comments*

p\. 2-14 As presented, its not clear how the physical factors
determining exposure are in turn determined by the exposure factors.
Some are obvious, but others are not. How do the indoor sources affect a
person's exposure to the ambient component of a given pollutant? If this
were generally true, then the assumption that these are independent
(which I think is generally true) is brought into question.

p\. 2-16 line 26 For clarity, add "tube-type TEA passive sampler.."
Presumably it is the this type of sampler that has demonstrated
significant artifacts.

p\. 2-17 line 19 The fact that passive samplers cannot currently provide
hourly information should be stated at the beginning of this section.
The statements about health effects should be put in Chapter 3.

p\. 2-52 Table 2-5-1 might also include the NO2 data from Vancouver,
B.C., a relatively dense regulatory monitoring network with similar
siting criteria to the U.S. (c.f. Henderson et al Environmental Science
& Technology 41 (7): 2422-2428 Apr 1 2007).

p\. 2-21 line 9 A reference is needed for the statement about the
importance of indoor sources on outdoor NO2 levels. I am not aware of
this literature.

p\. 2-33 line 22 Although it may be true that susceptible populations
have different levels of protection, a reference is needed. I am aware
of the work sponsored by the EPA PM Centers that showed no differences
in PM2.5 as a function of susceptibility.

p\. 2-34 line 11 The error here would probably not be a fixed
difference, but rather proportional to the average level. This would be
consistent with spatial variations during a given sampling period being
proportional to the spatial distribution of emissions and spatially
averaged levels over the sampling period being determined by
meteorology.

p\. 2-34 line 22 Is this true even if there is significant
spatio-temporal interaction?

Page 2-38 What information is there on the correlation of NO2 with the
ultrafine fraction?

p\. 2-42 line 7 This caveat is not mentioned much in other discussions
in Chapter 3 about the importance of the intervention studies (e.g.
Pilotto et al.) in elucidating the effects of NO2 alone. The conclusion
in the following sentence is not clear, i.e., isn't CO a combustion
product of unflued gas heaters? (c.f. the summary statement on page 51,
line 11)

p\. 3-1 line 27 I think it is better to say that these estimates
represent the exposure to other oxidized species rather than the
effects.

p\. 3-4 line 4 Although these concentrations are lower, the CxT may not
be.

p\. 3-6 line 6 If confounding with ultrafine particles is a concern, why
wasn't it discussed in Chapter 2? I suggest expanding the discussion of
this potential confounding in the exposure section. This qualifying
statement is not included later in Chapter 3. On page 3-58 line 28 the
Chauhan et al study is interpreted without mention of potential
confounding, as are the short term mortality studies on page 3-97, line
10.

p\. 5-2 line 15 "roughly 20 to 25%" overestimate implies a relative
amount of certainty whereas the previous sentence implies a lot of
uncertainty.

p\. 5-2 line 27 suggest wording as " total oxidized nitrogen" to be more
consistent with "physically meaningful"

p\. 5-3 line 18 why is this by itself an additional benefit? It might be
if we also were to measure NO and NO2 as this would provide information
on NOz that may have different effects.

p\. 5-4 line 8 The biases are a function of sampler type and some are
better than others as discussed in chapter 2.

p\. 5-5 line 11 Or one could suggest doing both, i.e., pursue better NO2
measurement methods and also measure NOy.

p\. 5-6 line 5 The findings refer to studies that looked at the daily
1-hr max, not the actual relevant 1 hr values with comparable health
outcomes on this time scale. Therefore the conclusion should more
precisely state that "differences between daily 1-h max and 24-h
exposures...."

[]{#__RefHeading___Toc184090835 .anchor}[Comments from Dr. Kent
Pinkerton]{.underline}

Review comments for the draft Integrated Science Assessment (ISA) for
Oxides of Nitrogen: Health Criteria

Kent E. Pinkerton, Ph.D.

University of California, Davis

Center for Health and the Environment

Charge #4: To what extent is the discussion and integration of evidence
from the animal toxicology and controlled-exposure human experimental
studies and epidemiologic studies, technically sound, appropriately
balanced and clearly communicated?

REPLY: Outstanding work has been done to address this charge in Chapters
3 and 4. However, the integration of animal toxicology,
controlled-exposure human experimental studies and epidemiologic
findings would benefit from further efforts to address disparities. For
example, the levels of NO~2~ needed to observe health effects in animals
are much higher than those used for NO~2~ to observe effects in human
studies. To observe toxic effects in animals, most toxicology studies
appear to require concentrations of NO~2~ well above (by at least an
order of magnitude) those implemented in human controlled studies. In a
similar manner, are the levels of NO~2~ used in human experimental
studies an appropriate reflection of ambient levels under which
epidemiologic studies are observed. It is also critical to address
whether the current standard (set 36 years ago) which is associated with
only a rare occurrence of exceeding or violating the current NO~2~
standard is justified, while epidemiological studies show clear health
(respiratory) effects of NO~2~ exposure in both children and adults
(particularly in the case of asthma) defined by a 10 to 20 ppb change in
NO~2~ levels. The document certainly does a reasonable job to review the
new literature, but does not provide for a clear interpretation of what
data we should be used as relevant and important in the decision-making
process to determine if a change should be made for the next NAAQS
standard for NO~2~. Finally, it is critical to further elucidate if
health effects attributed to NO~2~ are confounded by co-pollutants or
whether NO~2~ is simply serving as a surrogate for other pollutants.

Chapter 1

This introductory chapter does a nice job to identify the purpose of the
ISA with a series of questions to be addressed. Perhaps these bullet
points could be better implemented by referring to given sections found
in each chapter where they will be addressed using page numbers and/or
the section location in the document. Efforts to further revise the
document will be critical in order to reach the goal stated in the first
sentence of the chapter to formulate "a concise synthesis and evaluation
of the most policy-relevant science". Although some chapter sections are
approaching this goal, others appear to be plagued with excessive
findings presented in a somewhat rambling fashion. Some sections also
deal with the dilemma of being forced to discuss literature that is
quite dated.

Chapter 2

This chapter is excellent with up-to-date studies that are nicely
discussed. The vast majority of the references for this chapter are new
since the publication of the last criteria document. The figures
throughout the chapter and tables at the end of the chapter are
extremely useful in providing a nice summary of the most salient points
for this portion of the document.

Page 2-3: This figure (2.2-1) provides a nice summary of the cycle of
reactive nitrogen species.

Page 2-13: This figure (2.5-1) is an excellent reminder of the time
spent in different environments in the U.S. This is an important issue
to consider in evaluating the potential for exposure to NO~2~ that
should be emphasized in the document.

Page 2-36: The fact that NO~2~ behaves similarly to CO and PM~2.5~ as
well as the fact that NO~2~ may be a surrogate for ultrafine particles
emphasizes the potential for confounding effects in the interpretation
of health effects due to NO~2~. This is a fact that needs to be clearly
stated throughout the document.

Chapter 3

This chapter makes a heroic effort to bring together all the available
information on the health effects of NO~2~ exposure. The chapter is
organized into sections to cover potential mechanisms of injury,
morbidity and mortality associated with short-term exposure driven in
large measure by impacts on the respiratory system, followed by
short-term effects on the cardiovascular system and finally the
long-term effects of NO~2~ exposure on morbidity and mortality. The
chapter ends with a brief discussion on other chemical derivations of
NO~2~, namely, NO, HONO and HNO~3~.

Although all the appropriate points are covered in this chapter, there
remain concerns regarding some of the contents. This includes 1)
repetition of the data, 2) data that describes health effects of NO~2~
exposure at levels well above 1 ppm and 3) the need to further
disentangle the confounding effects of NO~2~ from that of other
co-pollutants, especially PM. It will also be important to further
address the potential for NO~2~ to simply be a surrogate for ultrafine
particles.

Pages 3-2 to 3-6: Excellent recent studies to demonstrate NO~2~
exposures at or below the current NAAQS lead to increases in respiratory
symptoms and exacerbation of asthma. The issue of confounding with
ultrafine particles needs to be addressed.

Pages 3-6 to 3-8: The impact of NO~2~ exposure on systemic effects of
immune function should be further elaborated. The primary target of
NO~2~ effects resides in the respiratory tract. However, it is unclear
how much evidence exists for systemic effects as well.

Pages 3-8 to 3-14: This is the section of the current document that
provides some degree of concern. Many of the studies quoted were done
well before the last criteria document was published. Why are these
studies still present in this document? A second concern are the levels
of NO~2~ used in many of these studies which clearly exceed the 1 ppm
level originally stated would represent the maximal level for
consideration. Some justification for the inclusion of these older
studies needs to be made.

Pages 3-12 to 3-13: Infectivity models add credibility to susceptibility
to NO~2~ exposure. A concern is the use of quite high levels of NO~2~
exposure well above ambient levels to document toxic infective effects
in publications that are fairly dated.

Pages 3-14 to 3-31: Lung function measures in children in this section
appear to provide excellent data to demonstrate significant effects of
NO~2~ exposure. How do we interpret unsupervised peak flow measurements
in children? Spirometric studies in adults also suggest decrements in
lung function with exposure to ambient levels of NO~2~. However, a
critical question is whether studies (SAPALDIA and Lagario et al, 2006)
controlled for the co-pollutant PM?

Page 3-21, lines 5 to 7 were also discussed on page 3-20, lines 14-16.
Is this redundancy necessary?

Page 3-26: The impact of NO~2~ exposure on childhood asthma management
seems to indicate mixed results. How should this material be interpreted
relative to previously mentioned studies suggesting strong NO~2~
exposure effects in children with a history of asthma?

Pages 3-31 to 3-36: Measurements of airways inflammation have made
dramatic advances since the approval of the current NAAQS. New studies
in controlled human clinical experiments (Frampton et al., 2002) suggest
effects, but only at high (1.5 ppm) NO~2~ levels. Toxicology studies in
animals use even higher levels of NO~2~ exposure. Since none of these
levels of NO~2~ exposure represent levels to simulate ambient
concentrations, how should we interpret these findings? Do these
represent plausible mechanisms that may play a role in airway effects of
exposure to NO~2~ at lower, more relevant ambient concentrations? In
this respect, it would seem the existing controlled human clinical
studies are more relevant than the toxicity studies in animals for
interpretation in risk assessment evaluations.

Pages 3-31 and 3-44: The summary provided for each of these sections is
a nice idea. It is important in the document to take the next step to
integrate or synthesize this summary into what information can be used
to help better evaluate the current NAAQS standard for NO~2~ and whether
a change in the standard is needed.

Pages 3-45 to 3-57: Recurring evidence for small, but significant health
impacts on respiratory outcomes is presented in a number of new studies
reviewed. Emergency department admissions also show mixed findings that
may be based on location (US versus Europe). However, a recurring
concern remains the question of whether these findings are based on the
effects of NO~2~ directly or whether NO~2~ simply serves as a surrogate
for other pollutants. It is critical to disentangle these confounding
factors.

Pages 3-60 to 3-62: The section on integration with a focus on asthma is
a nice summary of the literature to date. The section provides a nice
amalgamation of the literature to provide greater credibility for these
in terms of biologic plausibility. This type of integration greatly
facilitates interpretation of the existing literature.

Pages 3-62 to 3-80: The section on cardiovascular effects is a nice
summary of possible short-term effects of NO~2~ exposure. A summary for
this section would be helpful. From this section, it would be concluded
that NO~2~ exposure has minimal cardiovascular impact.

Pages 3-80 to 3-98: The literature on mortality effects of NO~2~
exposure are nicely reviewed with excellent summary and integration
sections. The conclusions made suggest a consistent increased risk of
mortality risk associated with NO~2~ exposure. These significant effects
associated with small incremental increases in NO~2~ levels provide
strong arguments for a change in the current NO~X~ standard. However,
again it is critical that the influence for potential confounding due to
co-pollutants must be considered and discussed to place this in the
proper perspective.

Pages 3-99 to 3-102: Morbidity associated with long-term exposure to
NO~2~ review on new data in lung function growth from the Southern
California Children's Health Study. This study is particularly
compelling, but must separate NO~2~ effects from PM. Figure 3.4-1 is
very helpful as it appears in this draft.

Pages 3-104 to 3-107: Animal toxicology studies provide a summary of
morphological effects of NO~2~ exposure. Again, many of these studies
were conducted using very high levels of NO~2~ that are one to two
orders of magnitude above ambient levels. How should these findings be
interpreted for this document?

Pages 3-111 to 3-120: This section seems to be repetitious on asthma
prevalence and incidence in children. Although it may be important to
distinguish between acute and chronic effects of NO~2~ exposure, perhaps
the presentation of issues regarding asthma could be better addressed in
a single location for the document.

Pages 3-126 to 3-131: The positive relationship of cancer incidence to
chronic NO~2~ exposure based on case control studies is a fascinating
observation. However, it is important to assess whether this is a NO~2~
effect or more an air pollution effect. The recent study of the American
Cancer Society cohort study based in New York City demonstrates a small,
but significant increased risk for cancer, but the air pollutant
implicated is PM rather than NO~2~.

Pages 3-143 to 3-150: The discussion of oxides of nitrogen other than
NO~2~ is good.

Final thoughts for chapter 3: Based on the current measured annual level
of NO~X~ today that is well below the current NAAQS, yet health effects
have been noted in children and adults with ambient exposures to NO~X~,
it is absolutely critical to explain why such health outcomes can be
justified without changing the current NAAQS for NO~2~.

Chapter 4

I like the format for this chapter to discuss susceptible and vulnerable
populations. The writing is well done and stresses key points such as
pre-existing respiratory disease, children, the elderly, folks who live
in proximity to high volume traffic, as well as genetic factors related
to susceptibility (oxidant and inflammatory damage). However, it is not
clear how we should consider the findings in susceptible and vulnerable
populations in addressing the current NAAQ for NO~2~.

Chapter 5

This chapter on findings and conclusions is a good start. The question
of how nitrogen oxides should be defined is relevant. Is NO~2~ a
reasonable measure (reflection) for the presence of other forms of
nitrogen oxides? Toxicology and controlled human clinical studies
clearly demonstrate a health effect associated with only NO~2~ to
provide justification for this part of the NO~X~. To emphasize
conclusions based on new findings since 1993 should be a critical part
of this chapter.

[]{#__RefHeading___Toc184090836 .anchor}[Comments from Dr. Edward
Postlethwait]{.underline}

Comments on Chapter 4: Appropriateness of public health impact and the
characterization of groups likely to be susceptible or vulnerable to
NO~2~.

To form a more solid basis for the subsequent discussions, it is
suggested to first open the chapter by defining "susceptibility" and
making note that while all populations may be susceptible, the
objectives are to help identify those populations that may be especially
susceptible, ie., it's a matter of degree and range of biological
responses. Subsequently, the paragraphs (section 4.2) on public health
impacts and the definitions of adverse health effects should be moved up
before addressing the individual factors and populations. In general,
the selection of sensitive populations appeared to be more intuitive
rather than quantifiable. It may also be useful to categorize
susceptible populations under the general headings of biological (e.g.,
genetic, age, underlying disease, etc), socioeconomic, and geographic
(including proximity to traffic zones). It would also be useful to
estimate the magnitude of especially susceptible population responses
relative to the population at large to demonstrate the extent of
enhanced responses. As with other aspects of the ISA, this topical area
would be strengthened by including integration among disease states,
measured outcomes, exposure, and potential mechanisms of action that
related specifics of NO~2~ biology to pathobiological perturbations. The
chapter did not address biological plausibility with regard to specific
populations and thus it is a challenge to attribute health outcomes to
direct causal actions of NO~2~. On page 4-8 were very specific criteria
for characterizing causal associations between genetics and health
outcomes that appeared to be significantly more robust conditions than
the evaluation criteria applied to other portions of the document.
Consideration should be given regarding the correlations between the
intrapulmonary distribution of inhaled NO~2~ (dosimetry) relative to the
anatomic sites of the specific disease processes. Finally, some overlap
among the identified groups (e.g., children and asthma) may serve to
amplify responsiveness and may categorize specific individuals into
multiple susceptible groups.

[]{#__RefHeading___Toc184090837 .anchor}[Comments from Dr. Armistead
Russell]{.underline}

Review of NOx Primary ISA

Armistead Russell

First, some kudos to the team putting this together on a few fronts:

1.  Having a greatly trimmed down report was great.

2.  The title of Chapter 2 was spot on, as well as the approach to
    condensing what used to be multiple chapters in to one nice, more
    concise chapter providing just what was needed.

That being said, there are a number of areas that need to be
strengthened and refocused, both in the chapters and then again in the
summary.

Chapter 1: Good introduction.

Page 1-4, line 2 (1-4:2), include studies showing a lack of effect as
well.

1-5: 25, Add a comma between epidemiologic and controlled.

Chapter 2: Again, I like the title and the idea that the report should
quickly move to discussing when the pollutants get to where some effect
will be found. However, at present, the road it has taken could be
straightened.

If I might, I would recommend the following outline for Chapter 2:

1.  Introduction

2.  Sources (provide magnitudes in a table)

    1.  Outdoor

        1.  Note that industrial and EGU emissions are often elevated
            and usually distant so their impact on exposure is usually
            reduced and there is a change in speciation.

    2.  Indoor

        1.  Note that while smaller, this is where people are, and there
            is drastically less dispersion.

3.  Atmospheric and indoor processing

    1.  Dispersion

    2.  Chemistry (or the other way around... don't care)

4.  Measurement methods

5.  Ambient and Indoor concentrations

    1.  Ambient

        1.  PRB

    2.  Indoor

6.  Exposure (this section is broken apart pretty well... no changes
    suggested)

It is not radically different, but adds a few key pieces in areas that
provide needed information and in a way that such can be compared to
other relevant pieces of information.

In regards to their discussion of sources, it is a bit short and also (I
think) misleads the reader. The Annex also is light on detail. There
should be a table of sources emissions, with emission estimates. This
should include indoor sources as well. Also, it should include estimates
of the fraction that is NO2. Some in Europe are making a big deal out of
how changing technologies will change the fraction of NO2 in emissions,
hence changing NO2 exposure. In this section, one should note that the
location of source is quite important and why, noting that indoor
sources will have a greatly enhanced impact on exposure, while upper
level, distant sources may have a relatively minor impact, and that
speciation will be different. The inventory used should be for 2008, and
it would be good to have a forecast inventory for, say, 2020 to show how
the relative source makeup will change. Having the actual numbers will
negate the need to have much commentary about the relative size of
sources.

The section on chemistry was sufficient, and about the right length. I
might add more emphasis on that most of the NOx comes out as NO, and is
then transformed to NO2 by O3 and other odd-oxygen species. Thus, after
much transport, most of the NOx is NO2, but in the near field, exposure
can be dominated by NO, and that the transformation of NO to NO2 is
dependent on the amount of ozone running around.

In the section on measurement techniques, measurement uncertainty should
be addressed quantitatively. The piece on the following page on
interferences in Mexico City should be brought up here and removed from
the next section, AND significantly de-emphasized, and studies conducted
in the US given. Mexico City results are not overly relevant to the
conditions here, and that was one study. If one considers the total
amount of interfering species in a typical US urban atmosphere, one
comes to the conclusion that the interferences will not be that large.
It is interesting that in the conclusions the document suggests (maybe
even rails on about) getting an NOy monitor as that might be more
appropriate, but the current monitor sort of does that, though with some
uncertainty. My view is that it would be good to have a pure NO2
monitor, but we can live with the level of uncertainty we currently
have, and if we want to better understand other oxides, we should
measure them specifically. This section should also discuss how indoor
measurements and personal exposure is also done. When this is done, the
section on 2-16 needs to be made more clear, and the sentence starting
on 2-16:9 ("Briefly, ...") needs to be cleaned up.

The ambient measurement section should be expanded to include indoor and
other related species for comparison. Further, they quickly focus on
NO2, though really should keep NOx and NO2 more together as an NO
molecule is just an NO2 molecule waiting for an ozone to come along.
Yes, they have different effects, but when one looks at controls, and
considers spatial variabilities, one can not understand NO2 without
understanding NOx. This whole section should give more of an overall
oxidized nitrogen understanding followed by speciation. A figure with
observed NO2 at monitors throughout the US should be presented as a PDF,
showing both the mean as well as the maximum levels, and how the former
compares to the current NAAQS. This section should also discuss how NOx
species correlate to related species that have health effects, e.g.,
ultrafine particles and Primary OC/EC.

The first part of the General Concepts part of the Exposure section is a
bit scattered, and also is not very exacting in presenting EQ's 2.5-2
and 2.5-4. All variables should be provided either before, or
immediately after, the equation is presented.

The section on Spatial Variability does something that just adds bulk, A
whole paragraph is devoted to saying what is in a Table, then the
following paragraphs discuss each topic. The first paragraph is not
needed. Also, I was baffled by the whole section on vertical
variability. It was overly long, a bit biased, and when one got done,
you wondered why it was even provided as it is not really used, and
further, one can not say how representative it might be. Further,
vertical variability is going to be very location and time dependent.
One also needs to expound on what Restrapo et al., says, in that one has
to be specific about exposure to ambient NO2 and monitor location. It is
quite easy to envision cases when using ambient NO2 measurements near a
road would lead to over estimates of exposure to ambient NO2.

The two paragraphs starting at the bottom of 2-20 (2-20:7) and going
over to the next page are scattered and repeat some earlier discussion.
Breathing should be included as a source in the table discussed above.
(Note, this section also talks about emitting NO2, not NOx, and the two
must be reconciled and both discussed given the possible rapid
conversion.) Much of the discussion of indoor NOx species being
converted to other things comes on 2-23. This should go up in the
chemistry part.

Chapter 2 Specific Comments:

2-1:8: NRC, 1998 not in reference list

2-1:19: Should be (VOCs: anthro...

2-4:6: add HNO3 to list

2-5:2: nitro-patts ?

2-5:9: Very weak sentence

Fig. 2.4-1: Clarify figure caption and add detail as to what is being
shown.

2-8:12...: The SEARCH monitoring network is probably more complete.

2-9: 9 NOx in **[non-surface level]{.underline}** unpolluted air.

2-10:1 Sentence is awkward, try: "Contributors to PRB concentrations
include natural emissions of ..."

Fig. 2.4-2: Add units ON THE FIGURES themselves. Also, I think the
figure caption is wrong in that regard. How did they treat lightening
NOx?

2-12: Again, define all variables immediately upon use.

2-16:9 This sentence is awkward, and it is not just Fician diffusion at
work. The last part of that paragraph is awkward.

2-16: 26 Remove "cost-effective"

2-17:1 Appears to contradict prior paragraph.

2-17: 18 Awkward.

2-18: 1 COD... provide the mathematical definition somewhere.

2-20: 7 Probably use "Penetration of outdoor NO**[x]{.underline}** and
**[indoor]{.underline}** combustion in ..."

2-21: top paragraph is awkward and repetitive.

2-21: 19. Remove length of monitoring period as a cause. (This paragraph
is also quite awkward).

2-22:9: They need to be more precise in the working of this sentence. It
makes no sense as currently given.

2-22:21: "... of **[indoor]{.underline}** NO2..."

Fig. 2.5-3: Add the range of slopes as well.

2-27:10. Obvious...

2-30, last paragraph: Doesn't this repeat 2-25 a bit much.

2-36: 25. This reminds me, discuss the co-occurrence of NO2 and
particles in both the source and ambient concentration sections, and how
this confounds epidemiologic analyses.

The Findings and Conclusions Chapter is still rather rough, and appears
to have picked up some pieces from the prior parts without consideration
of balance and importance. Interestingly, this Chapter, at the beginning
of the second paragraph, has the phrase "at the outset". Chapter
5/Conclusions is no longer the outset. This Chapter might have one
section on sources, long. In the summary on Atmospheric Sciences, I
thought it was unbalanced and did not adequately characterize what was
said. I was immediately put off by the first bullet being on
interferences. This, I doubt, is a major issue in terms of policy
making, and they need to do a better job of figuring out how important
this is in a typical US urban atmosphere. Taking results from one study
in the Mexico City area is a bit extreme. They also bring up an issue
that really is not well explored beforehand, e.g., monitoring total
oxides. Why? How different would this be in practice? How can you
criticize the current method when, in essence, that is almost what it
does? One gets the feeling this is a pet issue. Indeed, the "Atmospheric
Science" part of the Conclusion has four separate bullets related to the
monitoring device when my guess is that that issue will have little
impact on standard setting. The conclusions section should look back and
consider the important pieces in a balanced fashion.

[]{#__RefHeading___Toc184090838 .anchor}[Comments from Dr. Jonathan
Samet]{.underline}

**Comments: NO~x~ Integrated Science Assessment (ISA)**

**Jonathan M. Samet, M.D., M.S.**

**General Comments**

As the first of the Integrated Science Assessment's (ISA) of the Agency,
the general approach and form of the NO~x~ ISA merits careful and
thorough evaluation. Done properly, the ISA should be an informative,
succinct, and useful summary of the evidence for consideration of the
NAAQS. I have long advocated for more critical synthesis of the evidence
in evaluation of the need for NAAQS revision; the limitations of prior
documents, including the Criteria Document and Staff Paper, have long
been evident. Unfortunately, this draft ISA has not accomplished the
anticipated and needed level of synthesis.

***Inadequate development of the review process:*** On reading the
draft, there is no clear statement of the methodology; the ISA does not
meet the widely applied standards for evidence-based reviews that at a
minimum include a clear and replicable strategy for evidence evaluation,
criteria for evidence evaluation, and agreed to and uniform language for
specifying conclusions. There are abundant models: reports of the
Surgeon General and reviews of the Agency for Health Care Research and
Quality and the Cochrane Collaboration, for example. In reviewing the
draft ISA, the following can be identified:

-   Only a general approach is described for literature identification.
    How do the Agency and authors move from literature identification to
    inclusion of specific studies?

-   The criteria for inclusion of epidemiological studies are vague and
    not replicable.

-   Terms for evidence evaluation are introduced but without clear
    definition or uniform application. There is no clear statement of
    how strength of evidence is evaluated and there is a patchwork of
    discussion of this critical issue across the ISA.

-   In considering the epidemiological information, no consideration is
    given to the possibility of publication bias, a serious concern,
    given the number of epidemiological studies that have been carried
    out and the high potential for selective reporting of positive
    findings.

***Failure to develop an underlying set of conceptual models:*** In many
ways, NO~2~ represents an ideal starting point for carrying out an
integrated assessment of the literature. There are multiple ways by
which sources of NO~2~ might cause or be associated with adverse health
effects: 1) a direct causal effect; 2) an indirect causal effect
mediated by secondary pollutants, including PM and O~3~; and 3) by
standing in as a surrogate for emissions from the same sources that are
actually responsible for the adverse health effects observed (see
figure). These possibilities are not necessarily exclusive. Confounding,
as usually defined, would refer to the production of association between
NO~2~ and adverse health effects, by the actions of one or more other
exposures, themselves associated with NO~2~ in a particular study.
Multipollutant approaches are the mostly widely used strategy to address
confounding in epidemiological studies, but such models are not readily
interpreted when the potential "confounders", e.g., PM, are potentially
mediating effects attributable to NO~2~.

These complexities speak to the need for a far more thoughtful approach
to the development of the ISA and particularly to far more specificity
in considering the indicators used in the epidemiological studies. The
ISA nicely lays out a foundation on the complex atmospheric chemistry
related to NO~x~ but this information is largely ignored in the
remainder of the document. Similarly issues of dosimetry are largely
overlooked. At the least, the document needs to bring far greater
specificity to the types of exposures considered.

A fundamental issue for the NAAQS is the causal attribution of effects
to NO~x~. Implicit in the specification of the NAAQS is the assumption
that achieving the specified level(s) brings health benefits; the risk
assessment also implicitly assumes causation.

Overall, the ISA does not meet the standards used elsewhere for a
systematic review of evidence that has the purpose of reaching judgments
on a body of evidence in a clear, replicable and transparent process.

**Charge Questions**

1.  In general, the ISA does an adequate job on covering atmospheric
    chemistry (extensively covered elsewhere) and air quality.

2.  Chapter 2 succeeds to an extent in addressing the issues in this
    question. It does not adequately consider, however, the
    relationships of NO~2~, as measured at ambient sites, and the
    various species that may be relevant to health. It needs to set a
    better context for interpreting the epidemiological evidence
    particularly in view of considering the alternative models of
    causation that were set out above.

3.  See above.

4.  The integrated discussions only partially succeed. One problem with
    the present approach is replicative discussion of pathogenetic
    issues. Since the focus is largely on respiratory outcomes, with
    lesser concern with cardiovascular effects, there should be one
    in-depth discussion. The issue of dose in the toxicological studies
    needs greater discussion; there is no attempt to consider doses to
    key target sites at ambient concentrations and the relationship of
    such doses to those in the experimental research.

5.  The health effects considered are encyclopedic, rather than focused
    on those most relevant to the NAAQS. For example, literature on
    reproductive effects is only emerging now, and not readily
    interpreted. The studies on cancer are problematic in their
    interpretation. A review process that offered criteria for selecting
    the most relevant outcomes would have avoided a chapter as unfocused
    as Chapter 3.

6.  See general comments above.

7.  See comments above. Chapter 4 is satisfactory.

8.  My general concerns are set out above. The ISA does not adequately
    establish the causal relationships that should underlie the risk
    assessment.

**Comments on Specific Chapters**

**[Chapter 2]{.underline}**

This should be a critical chapter but it does not achieve the goal
implied by its title: "Source to tissue dose". The material reviewed in
the chapter's first portion nicely establishes that ambient NO~x~
contributes to the generation of a heterogeneous group of gaseous and
particulate compounds. There is the potential for effects associated
with ambient NO~x~ to be consequent to either exposure to NO~x~ itself
or to be mediated by the many potentially toxic compounds generated
through chemical and physical transformations of the
combustion-generated NO~x.~ The paths from source to dose(s) may well be
different and sites of deposition in the respiratory track differ for
the different compounds. Unfortunately, the chapter fails almost
entirely in the needed integrative function. Additionally some of the
material seems out of place: should the studies of indoor NO~x~ be in
Chapter 3? Some of the discussion of exposure measurement error and
misclassification might also be better placed in Chapter 3.

**[Chapter 3]{.underline}**

This chapter is lengthy, difficult to read, and reminiscent of the style
of the Criteria Documents. Its sections offer lengthy descriptions of
individual studies, generally only brief and non-informative summaries
of the evidence, and duplication of mechanistic discussions. In part,
the chapter fails because an adequate framework was not provided; there
is clear variation in approach across its segments.

**[Chapter 4]{.underline}**

This is a "pro-forma" discussion of the issue of susceptibility that
offers a relatively "standard" review of the various populations that
might be susceptible to NO~2~. It is not well linked to Chapter 3.

**[Chapter 5]{.underline}**

My expectations for this chapter were much higher than what I found,
which is largely a set of bulleted findings of prior chapters with
limited integration.

**Figure**

**Potential Relationships of NO~2~ With Adverse Health Effects**

[Direct Causal Effect]{.underline}

> NO~x~ Risk for outcome

[Mediated Effect]{.underline}

PM

NO~x~ Risk for outcome

0~3~

[Surrogate]{.underline}

NO~x~

> Source
>
> Other Pollutants Risk for outcome

[Confounding]{.underline}

NO~x~

Risk for outcome

> Confounder

Summary of Comments on 1

Page: 1-1

Author: JSAMET

Subject: Sticky Note

Date: 10/20/2007 8:59:43 AM

This is not a matter of definition for the research committee, but what
has actually been studied, whether in the laboratory or the community.

Page: 1-2

Date: 10/16/2007 11:36:35 PM

There needs to be a sharp discussion of use of terms such as
\"interaction\" which has multiple definitions and meanings depending on
the domain. Here for example, NOx is a contributor to PM, not the same
as \"interaction\".

Page: 1-3

Date: 10/16/2007 11:40:03 PM

What does this mean? Is this a documented process?

Date: 10/16/2007 11:42:09 PM

Date: 10/16/2007 11:42:05 PM

What does this mean? Accurate?

Date: 10/16/2007 11:43:55 PM

What does credible mean? accurate? and meaningful?

Page: 1-4

Date: 10/16/2007 11:45:37 PM

This is very ambiguous. Ambient levels where and when?

Page: 2-15

Date: 10/16/2007 11:58:34 PM

NO2 or NOx?

Isn\'t another issue whether NO2 measured by an ambient monitor is an
adequate surrogate for the various compounds produced from NO2?

Page: 2-19

Date: 10/20/2007 9:14:56 AM

This paragraph seems off the mark in the comparison to PM and O3.

Page: 2-20

Date: 10/20/2007 9:16:42 AM

Not clear what is meant by alter. Indoor sources contribute to total
exposure but why modify?

Page: 2-21

Date: 10/20/2007 9:18:23 AM

These variables are not confounders but exposure determinants or
determinants of concentration. The document needs to be precise in its
use of language.

Page: 2-22

Date: 10/20/2007 9:21:53 AM

Not in reference list. Are these European data?

Page: 2-25

Date: 10/20/2007 9:25:04 AM

How does this discussion relate to outdoor NOx? What is its relevance to
interpreting the evidence on health related to outdoor NOx?

Page: 2-27

Date: 10/20/2007 9:27:32 AM

speculation---

Page: 2-32

Date: 10/20/2007 9:30:43 AM

Undoubtedly, ambient monitors do not capture personal exposure to NO2
with complete accuracy.

Page: 2-33

Date: 10/17/2007 12:09:13 AM

A very confused paragraph

Page: 2-35

Date: 10/17/2007 12:13:45 AM

Confounding by what? It is critical for this document to carefully
specify the relationship of NOX and NO2 with other pollutants.

Page: 2-47

Date: 10/20/2007 9:38:06 AM

In what way? are they studying the same pollutant mix as is associated
with ambient NOx?

Page: 3-1

Date: 10/20/2007 9:58:16 AM

What do these terms mean? Presumably, \"strength\" means strength of
association? What about consistency? How do coherence

and plausibility differ?

Page: 3-3

Author: JSAMET

Date: 10/20/2007 10:01:02 AM

This discussion would benefit by clear linkages to a stronger Chapter 2
that gave greater specificity to discussion of \"doses\" of various
compounds.

Page: 3-5

Date: 10/20/2007 10:03:11 AM

Is this where bacteria and viruses deposit? what is the reference for
this?

Page: 3-6

Date: 10/20/2007 10:05:29 AM

The issue of dose and dose-response needs to be addressed. Some of the
studies involve quite high doses.

Date: 10/20/2007 10:06:36 AM

This is not clear at all. Confounding under what circumstances? for what
health effects?

Page: 3-14

Date: 10/20/2007 10:24:40 AM

reliable means repeatable

Page: 3-27

Date: 10/20/2007 10:30:06 AM

Not a correct statement about the advantage of GEE

Date: 10/20/2007 10:31:07 AM

plausibility?

Page: 3-38

Date: 10/20/2007 10:34:53 AM

Would be careful to not include research recommendations

Page: 3-43

Date: 10/20/2007 6:32:16 PM

Tachypnea is very nonspecific.

Page: 3-44

Date: 10/20/2007 6:33:29 PM

A comment is needed here on the dose range in these studies.

Page: 3-45

Date: 10/20/2007 6:34:48 PM

The problem of interpreting multivariable models with NO2 needs far
deeper discussion.

Page: 3-57

Date: 10/20/2007 6:40:19 PM

This paragraph is illustrative of the need to have some unifying
approach to sorting out potential causal, from mediating, from
confounding effects.

Date: 10/20/2007 6:40:51 PM

same problem here

Page: 3-58

Date: 10/20/2007 6:43:19 PM

What are the criteria for coherence applied here?

Date: 10/20/2007 6:42:38 PM

The issue of publication bias needs to be addressed. This is a major
concern in interpreting the time-series results as there is a high
likelihood that positive responses were selectively reported.

Date: 10/20/2007 6:44:24 PM

More \"frank effects\"? What is intended here?

Page: 3-60

Date: 10/20/2007 6:45:21 PM

Plausibility of this lag structure?

Page: 3-61

Date: 10/20/2007 6:46:27 PM

This paragraph offers a very weak discussion of plausibility.

Page: 3-62

Date: 10/20/2007 6:47:32 PM

In what way are these strong associations?

Page: 3-72

Date: 10/20/2007 6:51:43 PM

And what is the view of the ISA\'s authors on this critical issue?

Page: 3-78

Date: 10/20/2007 7:16:34 PM

support for this comment?

Page: 3-87

Date: 10/20/2007 7:21:36 PM

Another example of an inadequate conceptual framework.

Page: 3-91

Date: 10/20/2007 7:23:50 PM

Interpretation is far more than a matter of addressing confounding.

Page: 3-95

Date: 10/20/2007 7:26:27 PM

very poorly phrased and indicative of the lack of an underlying,
unifying approach. Presumably, the authors refer to disease specific
associations that would be consistent with an underlying causal effect.

Page: 3-97

Date: 10/20/2007 7:27:37 PM

A far deeper discussion of this sort is needed up front.

Page: 3-112

Date: 10/20/2007 7:40:07 PM

Needs more careful explanation.

Page: 3-115

Date: 10/20/2007 7:42:30 PM

A poorly phrased and somewhat erroneous set of statements. Chronic
symptoms, core to many respiratory questionnaires, are presumed to
reflect chronic exposures. Symptoms are an outcome by themselves, as
well as possibly being indicators of the presence of a disease.

Page: 3-118

Date: 10/20/2007 7:46:19 PM

This section has yet another discussion of underlying mechanisms of
respiratory effects. Emphasis and interpretation differ across these
sections. One thoughtful discussion is needed. Not multiple reviews of
the same range of evidence. This one, for example, does not carefully
consider dose range.

Page: 3-119

Date: 10/20/2007 7:47:17 PM

Isn\'t this statement overly confident, given the concentrations of most
of the toxicological work?

Page: 3-127

Date: 10/20/2007 7:51:10 PM

A further example of failure to link the atmospheric chemistry
discussion to the health effects.

Page: 3-139

Date: 10/20/2007 7:55:10 PM

By no means is this a correct characterization of the origins of these
studies.

Page: 3-141

Date: 10/20/2007 7:56:57 PM

Needs more complete discussion.

Page: 4-1

Date: 10/20/2007 7:59:42 PM

Not a very useful or informed discussion of this key issue.

Page: 5-1

Date: 10/20/2007 8:09:54 PM

This is a mis-characterization. Much of the reviewed material is
extraneous to the policy objective.

Page: 5-5

Date: 10/20/2007 8:11:09 PM

Far too sweeping. What is a reasonable proxy?

Page: 5-7

Date: 10/20/2007 8:12:42 PM

The ISA has never set up a framework for application of the criteria
offered in this paragraph.

[]{#__RefHeading___Toc184090839 .anchor}[Comments from Dr. Richard
Schlesinger]{.underline}

CHAPTER 2

GENERAL COMMENT: Overall, the document needs to be reorganized as
indicated in a number of comments below. There is much repetition in
different sections that often make it difficult for the reader to
determine what is new material or what has already been discussed but
within a different context. More summaries within certain sections are
also needed so as to clearly indicate the conclusions from each of these
sections regarding health outcomes from NOx.

CHAPTER 2

Section 2.7 is misplaced in the draft document. It should be integrated
earlier in the chapter where ambient outdoor exposures are discussed.
Also, discussion of health outcomes in this section should be avoided.
The real purpose of the chapter is to provide the reader with a
perspective on the relative exposure levels of NOx; this information
will then be evaluated in light of the exposure atmospheres used in the
health effects studies discussed in Chapter 3.

CHAPTER 3

This chapter is not very well organized. There are sections that are
separate that should be integrated, which would make it easier to
evaluate the significance of the health outcomes from NOx.

This document is supposed to discuss material since the previous AQCD,
yet it seems to also discuss studies that were included in that prior
document but does not do so in a manner which will allow the reader to
understand why some early studies were selected for inclusions and
others were not. Perhaps each section should have a brief summary of the
conclusions from the previous document and then go into the newer data
followed by a summary to indicate whether these new studies change or
support the earlier conclusions or make some that were not possible due
to a sparse dataset in the earlier document.

p.3-1, line 11. Here it is noted that the document concentrates on NO2
levels at or below 5 ppm. This appears to contadict the statement on
page 1-5, line 9 that limits evaluation of studies to those using levels
\< 1 ppm. In fact, some of the sections in the document discuss studies
at levels \> 5ppm.

Section 3.2 There is no consistency in the integration of health data in
the different sections. Some provide a summary of the effects on the
outcomes while others are merely a description of a number of studies.

p.3-5, lines 28-31. It is confusing to be told that the evidence for
altered defense is coherent and plausible, and then be told that the
evidence for such effects is not consistent and not robust. How can it
be plausible if it is not consistent or robust?

p.3-22, lines 20-21. High variability does not necessarily mean
increased susceptibility. One subgroup could be more variable than
another, yet be within the normal range. Thus, this seems to be an
overstatment.

p.3-32, line 20. Clinical Studies of Airway Inflammation. This section
provides an example of the need to better integrate related material.
The topic discussed here is also discussed in the host defense section
and could be incorporated there.

p.3-34, lines 19-21. On page 3-2, lines 16-18, it is noted that effects
seem to be dependent upon the concentration, duration and exposure
profile rather than simply the product of C x T. However, both here on
page 3-34 and in other places in the document, a simple C x T value is
given to indicate some threshold of response. This seems to conflict
with the earlier comment.

p.3-37, lines 7-11. The degree of increased airway responsiveness is not
always a good marker of the severity of asthma. Furthermore, it is
stated on p. 4-2, lines 7-9, that not all asthmatic show increased
airway responsivity. Therefore, the comments about responsiveness and
asthma need to be corrected and made consistent in the various sections
of the document.

p.3-39, line 5-7. This last sentence should be deleted. It really does
not add anything to the previous discussion.

p.3-39, line 11. Remove "allergic" from airways inflammation.

p.3-44, Summary. This is a summary of clinical studies but does not
integrate them with the animal toxicology studies.

p.3-59, line 3. The sentence should read "...evidence for airways
HYPERresponsiveness..."

p.3-61, line 15. It is not clear how alterations in mucociliary
clearance can be a mechanisms underlying asthma exacerbation in
children. It is most likely that NOx induced changes in mucociliary
clearance may be an independent effect that is not causally related to
any effect on asthma.

p.3-80, lines 13-14. What is the biological rationale for the comment
that changes in hemoglobin and hematocrit could account for the
cardiovascular effects in certain groups of people? One does not seem to
be the cause of the other, except perhaps for changes in blood
viscosity.

p.3-99, lines 1-2. Expand this sentence to indicate time frame for the
cellular changes in relation to the lag times.

p.3-105, line 4. Perhaps the lesser sensitivity of rats is due to their
ability to produce ascorbic acid.

p.3-108, line 28. Factors affecting susceptibility... This section
should be in Chapter 4 or wherever the main discussion of suspectible
populations is eventually located.

p.3-119, line 18. Insert "may be" after systems and delete "is."

p.3-119, lines 23-25. This supports the earlier comment that it is not
just C x T that is responsible for effects.

p.3-125, line 22. Wording error here.

p.3-125, lines 29-30. The sentence should be reworded as follows, "The
small body of toxicological literature examining the effects of NO2 on
birth outcomes is inconclusive as to whether NO2 is a reproductive
toxicant." The rest of the original sentence should be left out since it
makes a summary statement without adequate supporting evidence.

p.3-126, line 7-11. The comment made here that there is a weak
association between NO2 exposure and adverse birth outcomes contradicts
the statement on page 3-125, line 30 that NO2 is not a reproductive
toxicant.

p.3-129, line 22. If statistics were inappropriate, then why discuss the
study. Alternatively, indicate why they were inappropriate.

p.3-130, line 24. Reword as follows: "...the main source of NO2- in the
body is endogenously formed NO2-..."

p.3-131, line 1. The statement that NO2 is a tumor promoter at the site
of contact is too strong.

p.3-131, line 19. Parallel to what?

p.3-144, lines 13-14. NO is a bronchodilator, so the comment that NO2 is
a bronchoconstrictor is not needed.

p.3-144, line 19. A study from 1995 is not recent.

p.3-146, line 27. Effects of short term exposure. It is not clear
whether this section is a summary of presented material or is presenting
new material. It should be integrated in another section, perhaps that
beginning on p.3-144 line 6.

p.3-149. Nitric Acid. Since this section discusses a number of early
studies, then the ones below should be included.

> Schlesinger, RB, HAN El-Fawal, JT Zelikoff, JE Gorczynski, T McGovern,
> CE Nadziejko and LC Chen. Pulmonary effects of repeated episodic
> exposures to nitric acid vapor alone and in combination with ozone.
> Inhalation Toxicology. 6: 21-41 (1994)
>
> Chen, LC and RB Schlesinger. Considerations for the respiratory tract
> dosimetry of inhaled nitric acid vapor. Inhalation Toxicology 8:
> 639-654 (1996)

CHAPTER 4

This is a weak chapter in its present iteration. It would be better to
integrate the material within Chapter 3 since it would make a more
coherent picture of the effects of NOx. The repeating of material is
especially evident in Section 4.1.2.

The public health impacts section should also be in Chapter 3.

This chapter discussed drivers as potentially susceptible populations
but does not seem to include general population living near major
freeways.

p.4-3, line 13. The sentence should be changed to read, "...and have
higher minute ventilation compared to adults..."

p.4-3, line 18. Add "and/or to a decline in immune system surveillance
or response."

Section 4.1.3. The description of exposure levels should be in Chapter
2. This section should just have the relevant toxicology and
epidemiology that shows that such exposure levels as may occur result in
increased mortality/morbidity.

p.4-8, line 20. Change"respiratory" to "health". This makes it more
general.

p.4-10, lines 19-21. The logic behind this sentence is not clear.

p.4-13, line 16. West Virginia reported the highest prevalence of heart
disease is what comparison?

CHAPTER 5

The title should be changed to SUMMARY AND CONCLUSIONS.

[]{#__RefHeading___Toc184090840 .anchor}[Comments from Dr. Christian
Seigneur]{.underline}

**Comments on the Integrated Science Assessment for Oxides of Nitrogen:
Health Criteria -- First External Review Draft, EPA/600/R-07/093, August
30, 2007.**

Christian Seigneur

Atmospheric & Environmental Research, Inc.

San Ramon, CA

**Chapter 2. Source to tissue dose**

*Charge question 1:* It is important to note in the introduction that
the term "oxides of nitrogen" has a different meaning in the NAAQS
context (all oxides of nitrogen except N~2~O) and in atmospheric
chemistry (only NO and NO~2~). To that end, the first paragraph of
Section 2.1 and Figure 2.2.1 are very helpful. However, more precise
definitions of NO~y~ and NO~z~ are needed. For example, in the list of
abbreviations and acronyms (p. xxix), NO~y~ is defined as the sum of
NO~x~ and NO~z~, whereas NO~z~ is defined as the difference between
NO~y~ and NO~x~, which is an internally consistent but circular set of
definitions. I recommend listing the chemical species that constitute
NO~y~ for clarity (as done in the Annex). Also, NO~z~ does not include
all oxides of nitrogen (NO and NO~2~ are not included). These
definitions could be brought in the third paragraph of Section 2.2 (p.
2-2) as well.

*Charge questions 1 and 2:* It is stated in the second paragraph of
Section 2.2 (third and fourth lines) that "NO~2~ typically \[is\] in the
range of 5 to 10% of NO" for combustion sources. First, it would be
better to refer to % of NO~x~ rather than % of NO. Second, this range is
misleading because it is incorrect for several sources. For example,
some coal-fired power plants have emissions of NO~2~ that are less than
5% of NO. Also, diesel vehicles equipped with particulate emission
control now have NO~2~ emissions that are significantly above 10% of
NO~x~. This is an issue that will also affect the estimates of future
population exposure and a discussion of the evolution of the NO/NO~2~
speciation in mobile sources appears warranted.

*Charge question 1:* Figure 2.2.1 and third paragraph of Section 2.2:
The figure is too complicated in some ways and incomplete in other ways.
To the extent possible, eliminate minor reaction pathways for simplicity
(for example, delete the formation of NO~2~ from HNO~3~). The arrow
leading to NO~3~^-^ from NH~4~^+^ is incorrect; I assume that the author
meant PM formation from those two chemical species. Then, show an arrow
originating from these two species and leading to inorganic PM nitrate;
add also sea salt and alkaline dust along with NH~4~^+^. On the other
side of the figure, add the formation of organic PM nitrates. On line 20
of p. 2-2, add ozone as an oxidant of NO~2~. Delete "As shown in Figure
2.2.1" from the first text line below the figure (p. 2-3). Add a
sentence that mentions natural emissions of NO~x~ from soil, biomass
fires and lightning.

*Charge question 1:* On lines 10-13 of p. 2-4, the sentence needs to be
rewritten: the uptake of HNO~3~ by aqueous particles (rather than
aerosols) will not remove HNO~3~ from the atmosphere very rapidly unless
it rains; similarly, uptake by cloud droplets will not remove HNO~3~ if
the cloud evaporates.

Line 16 of p. 2-4: list the precursors of ozone (NO~x~ and VOC).

*Charge question 2:* First full paragraph of p. 2-7 (Section 2.3 on
measurements): There is a need for a conclusion. Is EPA recommending
replacement of the current chemiluminescent measurement technique? Is
the luminol reaction technique (used in many atmospheric research
programs and discussed in the Annex) a possibility? Also, one should
note that NO~2~ is not the only criteria pollutant which is poorly
measured: ozone and PM measurements also suffer from measurement
artifacts. Furthermore, if epidemiological studies have been based on
the chemiluminescent technique, would it be wise to change the
measurement technique at this time, as consistency between the NAAQS and
the measurement technique used to determine attainment should be
important?

*Charge question 2:* Section 2.5.2.2.1: This section discusses the
spatial variability of ambient NO~2~ concentrations. A major issue with
NO~2~ concentrations is their strong gradient near roadways (as
discussed in Section 4.1.3) but this section only discusses spatial
variability at larger scales. It would be useful to bring up the
near-roadway spatial variability in this section to set the stage for
further discussions pertaining to exposure (such as in Section 4.1.3 and
in the Methods document).

**Chapter 3. Integrated health effects of NO~2~ exposure**

*Charge question 4:* This chapter discusses the results of clinical,
toxicological and epidemiological studies related to NO~2~ exposure. In
the case of epidemiological studies, the uncertainty in the NO~2~
ambient concentration measurement is of interest (I assume that the use
of higher NO~2~ concentrations in clinical studies minimizes the
measurement uncertainty). It is likely that the NO~2~ concentrations
were obtained from routine measurement networks (this is explicitly
mentioned for some studies, e.g., Lin et al., 2004, but not for all of
them) and that the chemiluminescent method was used. Given the
discussion of the uncertainties of this monitoring method in Chapter 2,
it seems desirable to explicitly state which measurement method was used
for the epidemiological studies reported in Chapter 3. If all those
epidemiological studies used routine monitoring network data, this could
be stated upfront in the chapter, with a reference to Section 2.3.

**Chapter 4. Susceptible and vulnerable populations**

*Charge question 7:* Section 4.1.3 addresses high-exposure groups with a
discussion that focuses first on occupational exposure (bus and taxi
drivers, highway patrol officers, etc.) and second on geographical
exposure (e.g., residences and schools located near roadways). It may
help to make the distinction more explicit (e.g., two sub-sections) as
those two types of high-exposure groups may be fairly distinct. For
example, residences and schools located near major freeways may relate
to an environmental justice concern whereas occupational exposure may
fall under occupational health.

**Chapter 5. Findings and conclusions.**

*Charge question 2:* Section 5.2, p. 5-2: I do not understand the
rationale for having measurements of NO~y~. It seems that the NO~y~
measurement is driven by the fact that there is less artifact than for
the NO~2~ measurement. However, the health effects discussion of Chapter
3 addresses predominantly NO~2~. How would EPA use a NO~y~ monitoring
network to determine the attainment status of a NO~2~ standard?

*Charge question 2:* Section 5.3, pp 5-3 and 5-4: The strong NO~2~
spatial gradients near roadways need to be discussed.

**Annex 2.7.1. Chemical transport models**

This Annex section needs to be rewritten.

A general comment concerns the fact that only the regional Community
Multiscale Air Quality model (CMAQ) is discussed here. NO~2~ exposure is
to a large extent a near-source issue and CMAQ is not designed to
address ambient air pollutant concentrations near their source of
emission. Other models such as AERMOD for point sources (e.g., stacks)
and CALINE4 for line sources (e.g., roadways) are then more appropriate
than CMAQ. Therefore, such local-scale models should be discussed to an
extent similar to that of CMAQ in this section.

Furthermore, this section of the Annex looks tailored for an O~3~ ISA
rather than for a NO~x~ ISA. For example, the discussion of CMAQ model
performance evaluation focuses on ozone (rather than NO~2~) and does not
reflect in any case the most recent performance evaluation studies.

[]{#__RefHeading___Toc184090841 .anchor}[Comments from Dr. 'Lianne'
Elizabeth Sheppard]{.underline}

Comments on the ISA

Overall: I commend the contributors for a good first effort at creating
a new integrated document for this new process. The overall organization
of the ISA is moving towards the goal of providing a shorter document
with a more integrated perspective. There should be thorough
cross-referencing with the annexes to keep the ISA short and streamlined
yet well supported. Chapter 2 has many good organizational features, but
certain topics need to be added and I had difficulty with many details.
Chapter 3 ideally will be simplified and shortened, with the goal of
less literature review and more integrated assessment. However, there
are so many subtle differences between studies and effect estimates that
I am concerned that the effort to condense will make important
distinctions even more opaque. The integrated synthesis of Chapter 5
gives about the right level of detail. Criteria for judgments need to be
stated clearly so the integration is as transparent as possible. For
outcomes judged to be "likely causal" I suggest summarizing the set of
quantitative estimates that will be brought forward into the risk
assessment.

Chapter 2: Generally I think this chapter needs to be reworked to make
the discussion clearer, use consistent definitions throughout, give
specific definitions for quantities and use the same terminology for
them throughout the document (needed for the many correlations in
particular), and align the review of exposure with the next chapter's
health analysis. Consider adding a glossary or definitions table to this
section giving specific formulas for each specific quantity that is
referred to so the reader can easily distinguish all the different
correlations that are discussed. Consider reorganizing the chapter to
review exposure features in the context of specific epidemiological
study designs. Add discussions about whether NO~2~ is a surrogate for
the actual exposure, the role of monitor siting in air quality data, and
the relationship of NO2 with other ambient concentration measurements
(other oxides of nitrogen measures as well as other pollutants).

2-15 l 16: Section 2.5.2: Different features of exposure are important
for different epidemiological study designs. Review of exposure must be
done within the context of an epidemiological study design.
Epidemiological study design must be integrated into this review. Acute
studies with time-varying exposure and cohort studies with long-term
average exposure target different aspects of exposure and thus different
measurement features will dominate.

2-15 l 21-24: For (3), how does temporal scale of the data contribute to
this comparison?

2-17 l 27: Fix the table (2.5-1 p. 2-52) so the time scale of all the
measurements is clear.

2-17 l 30: Insert annual? "mean annual concentration"?

2-17 l 31: Modify to "between daily measurements at individual site
pairs".

2-18 l 1: Insert "daily average" before concentrations. How is COD
calculated? Note: This definition appears in the Annex, so
cross-referencing between the ISA and the Annex is needed.

2-18 l 9-10: Where does the proximity information come from? The
discussion on this page suggests to me there are features of the
monitoring sites that may be as important as the spatial location and
that the analysis should be expanded to better describe other important
features. How do monitoring siting criteria influence the results of the
Table 2.5-1 analyses?

2-19 l 26-28: Why would sheer number of monitors be a reason for
representativeness of community or personal exposures?

2-25 l 13-24: In all the tables and figures mentioned (plus others), it
is not clear what each correlation measure is and whether the different
correlations should even be compared. In a later part of this chapter
(p2-27) definitions of three types of correlations are given (though
sadly without formulas to make it even clearer), but these definitions
aren't used here or in other parts of the chapter. Before discussing any
correlations, define each one clearly and then qualify every use to
indicate which is being discussed. Note annex section AX3.5.1 also
addresses issues with correlations and clearly states two important
points: that different correlations have different meanings for
different study designs and that the type of correlation can have a big
impact on the resultant estimate.

2-29 l 17: *F~inf~*

2-31 l 3: "differences in study results" with respect to what?

2-31 l 12: Insert "time series" before epidemiological. This is a place
where the statement depends upon the study design of interest.

2-31 l 17-29: Refer to the definitions on p 2-27 l 17: Insert "daily
average correlation" to clarify *r~s~*. l 18: Insert "(longitudinal
correlation)", etc.

2-32 l 14: Replace "do" with "may". While it is correct that this paper
made the argument that community average non-ambient exposures don't
vary across communities, this was not supported by data and it is easy
to hypothesize scenarios where the statement would not be true (e.g.
because of different prevalence of gas stoves across communities).

2-32 l 22: Insert "in time series studies". The Sheppard paper made
statements *in the context of the time series study design*. They do not
apply in general to all epidemiological study designs.

2-33 l 8-9: While the statement that indoor sources could affect ambient
levels is certainly true, how often would this influence be a large
enough contribution to matter practically?

2-35 section 2.5.3.1: Again, need to factor in study design in this
assessment.

2-35 l 19: Now here's a new term for a correlation. A glossary or table
of terms is certainly needed.

2-35 l 23: Clarify the phrase "in moving away from the urban core".

2-36 l 2: Certainly the suggested analysis can easily be done from
existing AQS data?

2-36 l 13-17: I question whether the description and supporting table
are anything close to a good incisive summary of the St Louis data.

2-37 Figure: Also evaluate by distance between sites to determine if a
different pattern becomes apparent.

2-37 l 7: Add a qualifier for the correlation. Also lines 12, 15.

2-37-38: I question whether any of the comparisons of correlations on
these pages represent any kind of reasonable comparison. There are
different periods, seasons, site characteristics, etc., in each of the
different estimates, all of which could have an important impact on a
measure of correlation. For example, correlation estimates can be
dramatically affected by the inherent variability in the data (which
will be lower for analyses restricted to a single season than analyses
that look at all seasons combined).

2-38 l 18: Why is statistical significance important to mention here?

2-39: I'm not convinced it makes sense to combine the data as is done on
this page (including the figure) to present composite diurnal
variability. I suspect that with so many other sources of variability at
play (e.g. site, city, season), the diurnal patterns get washed out in
this composite figure.

2-44 l 29-30: If it is worth mentioning the other analysis, please focus
on the estimates and 95% CIs, *not* on the statistical significance of
the estimates. The significance statement implies this is a different
result, but the estimate and CI may or may not support that conclusion.

2-45 l 4: Can't the figure also show the wheeze results?

2-48 l 28: Figure needs uncertainty estimates (e.g. 95% CI) added.

2-49 caption: Note SD

2-50 l 11: Give the reader more context. For instance, begin the
sentence with "Among the \_\_\_\_ outcomes evaluated, ..."

2-51 l 11-14: Is it possible to make this sentence clearer, particularly
statements on line 12? Add "ambient source" before co-pollutants? Other
combustion byproducts are still an issue for indoor exposures.

2-52: Rework this figure to be more informative. Add time period to the
title.

2-55-56: In addition to various suggestions about correlations that
affect this table, explain what all the numbers in the table mean. What
is meant by sample size? What is n? Often there is more information
about the "sizes" than is implied, e.g. one can infer there are 12 days
for 55 adults in the Laird et al results. Omit p-values. What does
"pooled" mean? Justify using R^2^ in the same table as the correlation.
(Has the square root been taken? Is a simple linear regression model
used?) Same comments apply to 2-57-59.

2-65: Add "daily average measures" to the title. Add seasonal
representation to all studies or a clarifying footnote. Include the
number of days in the estimate. Note the distance between sites, site
features and any other important site characteristics. Include the
summary statistics such as the number of sites in the mean, the range
and SD.

2-66 Table 2.5-8: Add "daily average" in the title. Plot vs. distance
and add n's.

2-66 Tables 2.5-9 2.5-10: Add Daily average at a single site" before
"ambient" and "subject-specific daily average" before personal. Add n's,
days, seasons and type of correlation as relevant.

Chapter 3 summary comments: As I note in my discussion of the
Schildcrout et al paper below and other CASAC members pointed out, the
reporting of study results is not always correct and thus I suggest
statements of study results should be checked throughout this chapter.
Some CASAC members suggested some studies have been omitted. The term
"significant" or "statistically significant" appears to be used as
synonymous with scientifically important. If a specific result is worth
mentioning I think the estimate and 95% CI should also be given,
regardless of the statistical significance. (e.g. 3-15 l 10)

3-23 l 13: There were no NO~2~ data in Seattle, so this city should be
dropped from the list.

3-23 l 14: Each subject had an (approximate) average of 2 months of data

3-24 l 6, 7: Given the prevalence of asthma symptoms, the rare disease
assumption does not hold and the word "risk" should not be used in place
of "odds". The analysis was for asthma symptoms, not specifically cough.

3-27 l 5-22: More information is needed about the universe of studies
being compared before these conclusions can be drawn.

3-102 l 6: Another example where the more informative comment would
focus on point estimates and CIs, not statistical significance.

Chapter 5:

5-3 l 30: The statement "potentially leading to exposure error..."
depends upon the study design. It appears that the time series study
design is being assumed here.

5-4 l 1-2: Use forthcoming analyses incorporating geographic covariates
and monitor siting information to inform and modify this statement.

5-4 l 21: I think the important scientific criterion should be magnitude
of the correlation rather than its statistical significance.

5-5 l 3-4: I think this is an overstatement and depends both on the
purpose of the proxy (i.e. the epi study design to which it will be
applied) and the definition of "reasonable".

5-10 l 10: Perhaps this statement should not have a bullet?

[]{#__RefHeading___Toc184090842 .anchor}[Comments from Dr. Frank
Speizer]{.underline}

**INTEGRATED SCIENCE ASSESSMENT FOR OXIDES OF NITROGEN---HEALTH CRITERIA
(first external review draft, dated August 2007)**

Answers to Charge Questions (paraphrased)

Submitted by Frank E. Speizer, MD

Date: October 18, 2007

Chapter 2. Are atmospheric chemistry and air quality characterized
clearly, appropriate, and relevant to the review of NO2 primary NAAQS?

Section 2.2 [Atmospheric Chemistry]{.underline}: Quite frankly, I do not
find either the Figure 2.2-1 or its description very helpful. What does
"different sources emit NOx at different altitudes" mean? The figure
suggests that automobiles and smoke stacks are emitting NO into some
atmospheric level; not clear where as dashed box doesn't tell me how
high up. The text says this is better described in Annex AX2.2 (but
should be some indication here). The figure itself is complex and
certainly as describe doesn't stand alone. It is also not clear what the
relevance of the remaining details of section 2.2 do for consideration
of the NAAQS.

Section 2.3-4, Pages 2-6-2-11: [Ambient Measurements]{.underline}: This
section summarizes well the nature of the data base. It might be worth
indicating, since the text suggests a limitation of the number of
measurements, something about the distribution of measures across the
US. Figure 2.4-2 may have the data (or at least it may be in AX2.9).

Section 2.5 [Exposure Issues]{.underline}: Generally well handled. Minor
fixes necessary. Bottom of page 2-30 it would be good to define "...poor
to good."

Page 2.31, end of first paragraph. What are the biases introduced by
this misclassification? Can they be considered random? This needs
further discussion, particularly as it is this measurement that is used
in the time-series epi studies. The next page sounds as though it was
written by a different person. These two sections need to be tied
together better.

Section 2.6 [Dosimetry]{.underline}: Probably true but disappointing
that there appears to be no new work since 1993 AQCD. The important
statement of this section is in lines 10-15 on page 2-41. If this is all
there is so be it.

Section 2.7 [Indoor and personal exposures:]{.underline} Good summary.

Chapter 3: Integrated Health Effects

My primary concern is the length of this chapter, at something over 150
pages. The chapter starts out by telling us there is not much new and
then goes on...and on...and on. The saving grace is the excellent number
of figures that clearly are almost self describing of the state of the
science and how it has been gathered since 1993, and the excellent
summaries at the end of each section. I believe far too much detail of
each study is give in the text, and to be truly integrated I would have
expect more of the detail in the Appendix rather than here. For example
(and I could have picked several) the section 3.3.1.6.1 is well
characterized by the figure and the details with CI for each study is
simply not necessary in this document. Would have much rather read an
integrating summary on page 3.57 that provided a quantitative statement
summarizing the impact across studies. In fact that is what pages
3/57-3.62 does. The authors then do the same thing for cardiovascular
diseases and the results seem to be predictable. Another example of this
reading more like a CD is found on page 3-144 with details of old work
at very high(\>5-50ppm) exposures.

What is missing is a truly integrated interpretation of all of the
results. What do we now know we did not know in 1993 and how can it
inform our judgment in the setting of the components of the standard?
The chapter still reads more like a CD than an Integrated Summary, and I
am left without the ability to think about "form", "level," "average",
and in this case chemical form (at lease to the end of this chapter)..

Section 3.4.4 Cancer incidence and long term exposure: The obvious
contrast between the two positive and concordant epidemiological studies
described on page 3-127; and the lack of evidence of a positive effect
in animals and in vitro for NO2 with positive evidence in same for
mixtures of NO2 with other pollutants points to the fact that NO2 as an
ambient exposure for human does not occur in isolation. Section 3.4.4.1
that is supposed to be the Integration and biological plausibility
simply summarizes the findings and does not discuss this issue. This
needs to be expanded, since the conclusion in the summary paragraph in
section 3.4.5 essentially dismisses the possibility of cancer, and I
would argue this is wrong.

Section 3.5 Mortality and Long-term exposure. Data base well summarized
however, there does not really appear to be an integrated section.
Section 3.5.4 and figure 3.4-5 summarizes data but what does it mean?
The section ends with a sentence on page 3.143 that is really not
helpful. Authors should be able to provide a more integrated statement.

Section 3.6 This whole section could be considerably shorter. The
details of the experimental data are really not necessary. If one wanted
to produce a cartoon that summarized all these finding on mechanisms it
might be interesting if there were any human data to back up the
potential health effects at reasonable exposure levels.

Chapter 4 Susceptible and Vulnerable populations:

Section 4.1 pages 4.-1 to 4-11 presents an excellent summary of the
issues related to vulnerability. This seems to me to be a model of what
an ISA chapter should contain. However, table 4.1 is most disappointing
in that it is simply a summary of what is in the text. The authors need
to take the material in the Appendix 6 tables and summarize one table
that breaks out the susceptible and vulnerable population and present
that in the main text. This should be relatively easy as the references
are in the text and the detail that might be included in each category
of risk is in the appendix tables.

Page 4-10, line 5, 6: The suggestion that stronger evidence is based on
p values seems inappropriate.

Section 4.2 and concept of Adverse Health Effects. I do not find this
section useful at all. Tables 4.1.2 and 4.1.3 are standard reference
material and don't seem belong here.

Section 4.2.2 reads like a good beginning to a section on population
estimates but is quite incomplete. Additional material is needed on COPD
and other respiratory diseases. If one considers Age alone we need a
paragraph of the age trends in the population. Ditto high exposure
groups (occupational work forces data exist and need to be summarized).
Other potentially susceptible groups, Urban poor? Newborns? Not clear
that oxidative stress polymorphisms exist but if not a statement about
this should be made.

Chapter 5

Section 5.2. I would have thought that given a bullet on motor vehicles
as a large source of urban NO2 that there should be a similar bullet to
put in context the degree to which stationary sources emit NO2. In
addition, for completeness sake should there be a bullet for indoor
sources (gas stoves)? Rest of the chapter seems to be a reasonable
summary.

ISA NOXAug2007chargequestions

[]{#__RefHeading___Toc184090843 .anchor}[Comments from Dr. George
Thurston]{.underline}

General comments on Chapters 3 and 4 of the ISA

As discussed at our last meeting, this document should comprehensively
consider the NOX-PM interaction, given the importance of PM to the many
of the same endpoints and studies considered here. This factor is
mentioned here and there, but nowhere is this aspect of NOX associations
with health separately discussed across all the document aspects (e.g.,
in Toxicology: is NOx affecting macrophage ability to handle particles?,
or in Epidemiology: is NOX a acting as a marker of traffic PM?). These
concerns are touched upon here and there, but need to be organized and
brought together, and thereby considered in a "holistic" way. Indeed,
these issues need to be handled comprehensively in both the SOX and NOX
documents Overall, while there are smatterings of references (here and
there) to PM-NOX interactions as an possible confounder in various
passages, I see PM as the insufficiently addressed \"elephant in the
room\" of each of these two new gaseous pollutant assessment documents.
I recommend that the NO~x~ and SOx documents both address this issue
more directly and comprehensively.

The criteria for the evaluation of the health effects considered are not
sufficiently laid out at the start of the health chapter (Chapter 3)
and, as a result, the various sections are primarily litanies of studies
without consistent evaluations across endpoints. On Pg. 3-1, lines 7-8,
it is stated that the experimental evidence is evaluated in the document
for strength, consistency, coherence and plausibility. Presumably this
is based upon Sir A.B. Hill's treatise, but it should be referenced, and
the rationale for the selection of these specific criteria from Hill's
longer list, and how they will be applied, needs discussion here. In
addition, these criteria not consistently considered across the chapter,
which would be a helpful step for each summary discussion in the
chapter. (For example, on page 3-6, robustness is instead noted as an
evaluation criteria instead, but how it is being defined and applied is
not explained). I feel that such a consistent application of the A.B.
Hill criteria across the various sections, especially as a function of
pollutant averaging time and concentration when possible, would enhance
the value and usefulness of the document.

Specific Comments

[Chapter 3.]{.underline}

Section 2.7 (Indoor and personal Exposure Health Studies) seems like it
is more appropriate for integration in Chapter 3, which deals with
health effects. Perhaps the exposure aspects/trends from the studies
should be introduced here, but the health effects belongs in Chapter 3.

Pg. 3-1, lines 7-8, It is stated here that the experimental evidence is
evaluated in the document for strength, consistency, coherence and
plausibility. Such choices in evaluation criteria need to be justified,
and then applied across all sections consistently (see above general
comment in this regard).

Pg 3-1, lines 27-29. Good point made here, but not clearly enough. Needs
sentence restructuring. Also, perhaps this sentence belongs in a
separate section on the potential/evidence for PM-NO~x~ interactions
that might account in part or whole for associations found between NO~x~
and health effects.

Pg. 3-4, lines 29-30. I think "Over all" should be "Overall," I also
think a comma after the work "equivocal" would help clarify the
sentence's meaning.

Pg 3-5, lines 28-29. Define how the consistency and robustness are being
evaluated, and support this statement further.

Pg 3-6, line 14. No comma needed after "in part"

Pg 3-8, ,line 14. This seems an appropriate place to discuss NO~x~-PM
interactions with respect to mucociliary clearance of PM.

Pg 3-9, ,line 13. This seems an appropriate place to discuss NO~x~-PM
interactions with respect to NO~x~ effects on macrophage activities in
coping with PM.

Pg 3-12, ,line 20. This seems an appropriate place to discuss NO~x~-PM
interactions with respect to infectious microorganisms.

Pg. 3-17, line 8. Sentence structure unclear: inverse relationship
between increases in NO~x~ and decreases in FVC? Needs rephrasing, as
seems to be a double negative.

Page 3-19, line 14. Add reference back to discussion of Wendley and
Silverman, 2001 on Pg. 3-16, lines 8,9.

Page 3-22, lines 2-22. Refer back more explicitly to the assessment
criteria set out at the start of the chapter.

Page 3-31, lines 5-9. Refer back more explicitly to the assessment
criteria set out at the start of the chapter.

Page 3-33, lines 5,6. Sentence too long and convoluted. Needs to be
broken into two sentences, something like: "In a study completed by
Gavres et al. (1994), the same protocol was applied in a separate group,
but assessed immediately after exposure. In this case, no effects were
found in...".

Page3-36, lines 10-20. Do the studies meet the criteria set out at the
start of the chapter? For what averaging times and concentration levels?

Page 3-44, lines 5-24. Do the studies support/challenge any of the
chapter's evaluation critieria? For what NO~x~ levels and averaging
period ranges?

Page 3-49, lines 18-19. Lin or Linn?

Page 3-51, line 20. add "potential" before the word "effect"

Page 3-54, Figure 3.2-11. Are there confidence intervals available that
could be plotted around each point? This would enhance the
interpretability of the data as to whether the relationship differs
significantly from linear, or not.

Page 3-57, lines 6-7. Extreme caution must be taken in interpreting
multi-pollutant models, given the potential for inter-correlations of
the effect estimates and large uncertainties. This caveat needs to be
made here. That said, these results have implications regarding the
interaction of PM and NO~x~, which also bears discussion here.

Page 3-57, lines 15-16. Need to expand the discussion of NO2 as a
possible surrogate for traffic PM here. The evaluation criteria set out
at the start of the chapter should be considered here, as well.

Page 3-68, lines 2-3. Add discussion of NO2 as a possible surrogate for
traffic pollution.

Page 3-72, line 1. Add "Multi-City" to the section title.

Page 3-79, line 32. How is the term "robust" applied here? That the
estimates are unstable when correlated variables are added? This result
is not surprising, and may be a reflection of that fact, and not that
the effect is real or not. Perhaps this term (robustness of NO~x~
results to consideration of covariables) should be explicitly defined
and added to the list of evaluation criteria at the start of the
chapter.

Page 3-80, lines 23-24. Expand discussion of the various evaluation
criteria and whether they are met, as a function of concentration and
averaging period, where relevant and possible.

Page 3-83, lines 12-13. Note the difference of effect as a function of
averaging time in the overall discussion of this section.

Page 3-84, line 8. Add comma after "sources" for clarity.

Page 3-84, lines 21-25. What are the implications of these conclusions
with respect to the previously stated evaluation criteria?

Page 3-90, line 10. Add "in Multi-City Studies" to the section title.

Page 3-91, lines 4-7. Note these considerations in an overall discussion
of the potential role of PM-NO~x~ interactions in the reported results.

Page 3-94, lines 26-30 and Page 3-95, lines1,2. Note how these
conclusions do or do not satisfy the evaluation criteria set out at the
start of the chapter.

Page 3-95, lines 10-13. I don't agree with this statement. Lags could
easily vary from cause to cause (and city to city for that matter), and
assigning "one-lag-fits-all" is not necessarily optimal. A distributed
lag model would be best when daily data are available. Providing a range
of effect estimates between: 1) forcing one chosen lag on all outcomes
or cities; and, 2) choosing the best fit for each outcome/city, is
probably the best way to provide the range of possible results when
distributed lag models are not possible.

Page 3-97, Section 3.3.3. Need to expand discussion of the NO~x~-PM
interaction at line15-16. Also, need to discuss the implications of this
discussion to the evaluation criteria noted at the start of the chapter.

Page 3-98, section 3.3.4. This section speaks to the coherence of
effects, and the implications to causality should be discussed.

Page 3-111. Lines 18-19. Expand consideration of the traffic hypothesis
in this section, considering all endpoints.

Page 3-119, lines 4-10. Discuss implication of these NO~x~ effects on AM
to PM health effects in the lung.

Page 3-128, lines 27-28. Include consideration of these results in
separate PM-NO~x~ interaction discussions.

Page 3-131, lines 6-20. Consider implications of these findings to the
evaluation criteria provided at the start of the chapter (consistency,
coherence, etc.).

Page 3-136, lines 7,8. Include these conclusions in a separate PM-NO~x~
interactions discussion.

Page 3-141, Section 3.5.4. Consider implications of these findings to
the evaluation criteria provided at the start of the chapter
(consistency, coherence, etc.).

Page 3-149. Consider the potential implications, if any, of gaseous
acidity on the bio-availability of transition metals in particles in the
same aerosol.

Page 4-4, lines 1-26. These comparisons would be more meaningful and
interpretable if they were also presented in terms of their absolute
attributable risks (e.g., effects/ppb/1000,000 persons) for each
sub-population. The same percent increases in risk can have very
different absolute impacts in different sub-populations, given that
their baseline rates of incidence (that the percents are applied to) can
be quite different. This needs to be addressed throughout this chapter.

Page 4-13, line 20. "southern states"?

[]{#__RefHeading___Toc184090844 .anchor}[Comments from Dr. James
Ultman]{.underline}

**Integrated Science Assessment for Oxides of Nitrogen -- Heath
Criteria**

**Comments on First External Review Draft \-- James Ultman**

To my knowledge, this is the first ISA produced in the revised process
for revising the NAAQS for a criterion air pollutant. The ISA is
intended to be a streamlined version of the Air Quality Criteria
document that provides the basis for a subsequent risk assessment.
Compared to the Criteria document, the ISA is intended to place more
emphasis on integration and assessment of research published since the
previous review rather than on a detailed presentation of these new
studies.

The authors had and have much to contend with in developing the ISA for
NO~2~. There is considerable new information to assimilate in animal,
human and particularly epidemiological studies. Unambiguous
interpretation and evaluation of these studies is clouded by
uncertainties in measurement, exposure pattern and confounding by
copollutants. Nevertheless, the document has been successful in
summarizing the new studies in a succinct fashion and providing a
qualitative argument that NO~2~-related respiratory health effects are
occurring in spite of the current NAAQS, particularly in children and
asthmatics.

[General Comments]{.underline}

As in any document of this complexity, there are shortcomings in the
draft ISA. I have a few general comments of the document as a whole.

1)  First and foremost, if the ISA is the precursor to a risk
    assessment, it must use the current standard to provide a context
    for the relevance of the new studies. This is particularly important
    because of the wide range of exposure concentrations that were
    imposed in laboratory studies or observed in epidemiological
    studies. Yet, the current standard was mentioned only in the preface
    of the document, as far as I can see, never explicitly compared to
    the conditions in the key scientific studies used to support the
    conclusions in chapter 5.

2)  Related to my first point is the question of the perceived impact of
    new science on the

adequacy of the level, indicator, form and averaging time in the current
standard.

> The document does not explicitly discuss this issue. Naturally, final
> numbers and conclusions will be better described in the risk
> assessment that follows the ISA. Still, I believe that the authors can
> discuss how the new findings regarding exposure pattern, different
> exposure mixtures and levels of exposure might impact the NAAQS.

3)  As it now stands, the ISA summarizes current state of the science
    but does not consistently assess the soundness and the relevance of
    the individual studies. In other words, most of the document comes
    across more as an "Integrated Science Summary than an "Integrated
    Science Assessment." For example, the final chapter, Chapter 5,
    appears to isolate the critical studies on which the conclusions are
    based, but no rationale as why these studies have been chosen is
    explicitly stated.

4)  Some major editorial work needs to be done to improve the
    organization within and among the chapters. At a minimum,
    redundancies within and among different chapters should be
    identified and removed, and misplacement of material between
    chapters should be corrected. Also, as pointed out in 1-3, much of
    the discussion relating to the relative value of the new studies and
    their impact on the NAAQS should be made more explicit.

[Chapter Comments]{.underline}

[Chapter 1]{.underline}

It would be useful if the 5 points in lines 21 to 30 reemerged at the
end of chapter 5 with explicit answers given there.

[Chapter 2]{.underline}

Pg 2-10. Line 1. Add "to" after "Contributions"

Figure 2.4-2. This must have originally been a color-coded graph whose
scale has been rendered ambiguous by direct copying. Please transform
the figure to true gray-scale.

Eqs. 2-1 to 2-5. Given the fact that these equations are rarely referred
to, I am not convinced that they are needed. A schematic figure that
illustrates the effects of people moving between different
microenvironments (i.e., indoor and outdoor), engaged in different
activities, etc. would be more useful. Such a figure would also be
helpful in clarifying the writing in sections 2.5.2.3.2 and 2.5.2.3.3 on
the relationship between personal exposure and ambient concentration.

Pg. 2-19. Line 16. I don't understand what is meant by "mixing ratios."
How is this different from concentration gradients, or does it mean the
same thing?

Pg. 2-21. Line 1. Nitric oxide is a mediator that plays many important
roles in human physiology. It is relevant that the author's estimated
how expiration of endogenous NO would affect environmental levels. But
it does raise another, probably more important question. That is, how
does inhaled NO originating from combustion sources and reduction of
atmospheric NO2 affect the physiological functions that endogeneous NO
usually provides. It would be worthwhile to add (either here or in
chapter 3) a short discussion on the biology of NO, particularly its
effect on the cardiovascular system.

Pg. 2-25. Line 18. The "ambient" concentration and "outdoor"
concentration should be defined. The difference between the two terms is
not readily apparent, and yet they are important elements of this
chapter.

Pp. 2-32 Lines 29-31 & Pg 2-33 Lines 1-23. This material is redundant
with the immediately preceeding subsection.

Figure 2.5-5. In the caption, change "Asterisks" to "X's"

Section 2.6 on Pp 2-20 & 2-41. The dosimetry section occupying half the
title of this chapter, occupies only two pages of text. I agree that
there has not been much new research in NOy dosimetry research since the
last review, so I suggest changing the chapter title. The dosimetry
section itself could benefit from some discussion of animal-to-human
extrapolation modeling. In the rest of the document, animal experiments
are treated purely as a means of informing the toxicological mechanisms
and plausibility of human health effects. In fact, it may be possible to
extrapolate the animal exposures to equivalent human exposures to
provide a more meaningful context for the observed exposure-response
effects.

Section 2.7 beginning on Pg. 2-41. This section includes a combination
of personal exposures and resulting health effects. It might be better
to move this material to chapter 3 where health effects are discussed.

[Chapter 3]{.underline}

General: Much if not most of the new information on the health effects
of NOy comes from epidemiological studies. Since the results of the
epi-studies are generally presented in terms of relative risk and odds
ratio, the document should include an explicit definition of these
terms. More importantly, it is hard for the nonstatistician (i.e., me)
to appreciate what constitutes an important value for either of these
parameters. In other words, is it possible to state when an OR or RR
reach a value that we should worry about 1.01, 1.1, 1.5, 2.0....?

Pg. 3-1 Lines 10-11. The authors appear to be saying that \<5ppm is
"environmentally relevant." Figure 2.5-5 contradicts this point of view.

Pg. 3-2 Line 26 NO and HNO3 are not vapors.

Pg. 3-3 Lines 27-28. change "range of proposed mechanisms" to "factors"

Figure 3.2-2 In the ordinate, change "oob" to "ppb"

Figure 3.4-1 Two of the ordinates are labeled "PM10." One of them needs
to be corrected.

[Chapter 4]{.underline}

The lung growth studies from the California Children\'s Health study are
particularly important in identifying children as a unique (and probably
susceptible) population with respect to NO2 exposure. Since most
laboratory studies have been done on adults, some discussion of how
exposure conditions that produced health effects on adults would
extrapolate to children. This could best be done within the context of
extrapolation modeling. There is at least two peer-reviewed papers
related to this subject (Sarangapani et al., Inhalation Toxicology,
15:987-1016, 2003; Ginsberg et al., J. Toxicology Environ Health-Part
A). 68:573-615, 2005)

[]{#__RefHeading___Toc184090845 .anchor}[Comments from Dr. Ronald
Wyzga]{.underline}

**Comments on "Integrated Science Assessment for Oxides of Nitrogen:**

**Health Criteria**

Ronald E. Wyzga, Sc. D.

**Questions 1-3**: I combined my comments for these questions because
the dividing line among these three questions is not always clear.

I have 3 general comments:

-   The document could give a much clearer discussion about the spatial
    and temporal heterogeneity of NOx levels. My understanding is that
    there are two distinct contributions to ambient NOx levels: a
    general contribution tied to more distant sources; and peaks near
    specific sources, e.g., roadways. This can lead to considerable
    spatial and temporal heterogeneity that is not clearly conveyed in
    the document. One reason for this is that monitors are often sited
    away from point sources, and therefore do not capture this lack of
    homogeneity. The document needs to discuss this in more detail in
    conjunction with the siting characteristics of monitors.
    Consideration of measurements from monitors far from specific
    sources could distort the analyses/discussion in this section.

-   There is some confusion about the distribution of species within the
    NOx definition. In particular, I would like to see more about the
    relative importance of NO and NO~2~ at different sites: near
    sources, away from sources, winter measurements, summer
    measurements, indoor measurements, outdoor measurements. Some
    indication of the relative conversion rates to and lifetimes of
    different species should also be discussed in more detail. It is
    also my understanding that most extant monitors also capture NO
    measures, but that these are not reported by the states. Efforts to
    publish these data could aid future health analyses as NO can be a
    vaso-dilator could influence health outcomes, and some toxicological
    studies suggest that NO can elicit adverse responses directly.

-   One of the biggest issues in the interpretation of results from
    epidemiological studies is whether NO~2~ is an agent which elicits
    health response or a surrogate for another agent. For this reason it
    is important that the correlations between ambient measures of NO~2~
    and other pollutants be reported for key environments, including
    indoor environments, outdoor environments near and away from
    specific sources. These correlations should be presented for a range
    of averaging times as health studies have considered different
    averaging times. Where available correlations should not only be
    presented for currently regulated pollutants, but for other
    pollutants, which are under active investigation for potential
    health concerns. The latter include ultrafine particles and
    elemental carbon.

**More specific comments**:

-   It would be useful to prominently display the conversion rate from
    ppb NO~2~ to ug/m^3^ as studies using these measures are discussed.

-   Figure 2.4.1. needs some information about the siting
    characteristics of the monitoring sites.

-   p\. 2-18, ll. 26-29: Is this a function of the characteristics of
    monitoring site locations, etc. Clearly this is not true for
    indoor/outdoor considerations.

-   Chapter 2 presents the results of some health studies. Should these
    be moved to chapter 3?

-   Table 2.5.1 should present some description of the placement of
    monitors vis-a-vis sources and it should define the averaging times
    considered to derive the correlations.

-   Section 2.5.2.4 presents a very good discussion. One addition could
    be the possible systematic bias in exposure measurements if those
    responding were near sources and the monitors were not; hence the
    exposures of the respondents would be systematically higher than the
    exposure estimates. This would impact the estimates of
    dose-response.

**Questions 4-6**: I combined my comments for these questions because
the dividing line among these three questions is not always clear.

I have 3 major comments associated with the issues raised by the above
questions.

-   The ISA is not comprehensive in its consideration of health studies;
    in particular, several studies that report negative findings between
    NO~2~ and health are not cited. This could be because other
    pollutants (which are associated with health endpoints) are more
    prominently featured in abstracts/literature search results, etc.

The following studies are not mentioned in the text of the ISA; these
are studies with which I am familiar:

> **Metzger et al. (2007)** "Ambient Air Pollution and Ventricular
> Tachyarrhythmic Events in Patients with Implantable Cardioverter
> Defibrillators", **Epidemiology,** reports non-statistically
> significant associations between ambient NO~2~ levels and
> tachyarrhythmic events under a wide spectrum of models and analytical
> approaches. Some associations are negative and none approach
> statistical significance.
>
> **Sinclair and Tolsma (2004)** "Associations and Lags between Air
> Pollution and Acute Respiratory Visits in an Ambulatory Care Setting:
> 25-Month Results from the Aerosol Research and Inhalation
> Epidemioloigcal Study", J. Air & Waste Manage. Assoc., **54**:1212.
> This study notes that it examined the associations between NO~2~ (and
> several other pollutants) and unscheduled physician visits for asthma
> (children and adults separately), upper respiratory disease, and lower
> respiratory disease. The paper only reports the statistically
> significance results, noting that non-reported quantitative results
> are not statistically significant. NO~2~ is not significantly
> associated with any of the health endpoints studied.

I also undertook a cursory (but not comprehensive) search on Medline and
identified the following studies that are not considered; I would urge
the staff to consider these studies. I should note that my brief
interpretations need be validated as I did not have the time to
thoroughly review all of these papers:

Steinvil A, Kordova-Biezuner L, Shapira I, Berliner S, Rogowski O.
Short-term exposure to air pollution and inflammation-sensitive
biomarkers. Environ Res. 2007 Oct 1; \[Epub ahead of print\] Abstract
reports negative effects of NO~2~.

Magas OK, Gunter JT, Regens JL. Ambient air pollution and daily
pediatric hospitalizations for asthma. Environ Sci Pollut Res Int. 2007
Jan;14(1):19-23. Reports small effects of NO~2~.

Gouveia N, Bremner SA, Novaes HM. Association between ambient air
pollution and birth weight in Sao Paulo, Brazil. J Epidemiol Community
Health. 2004 Jan;58(1):11-7. Results are more robust for CO than NO~2~;
paper suggest traffic is issue.

Petroeschevsky A, Simpson RW, Thalib L, Rutherford S. Associations
between outdoor air pollution and hospital admissions in Brisbane,
Australia. Arch Environ Health. 2001 Jan-Feb;56(1):37-52. Reports no
effects of NO~2~

Stieb DM, Beveridge RC, Brook JR, Smith-Doiron M, Burnett RT, Dales RE,
Beaulieu S, Judek S, Mamedov A. Air pollution, aeroallergens and
cardiorespiratory emergency department visits in Saint John, Canada. J
Expo Anal Environ Epidemiol. 2000 Sep-Oct;10(5):461-77. Reports no
effects of NO~2~, which is negative in multi-pollutant models.

Roemer W, Clench-Aas J, Englert N, Hoek G, Katsouyanni K, Pekkanen J,
Brunekreef B. Inhomogeneity in response to air pollution in European
children (PEACE project). Occup Environ Med. 1999 56(2):86-92. Reports
no association with NO~2~.

Chen PC, Lai YM, Chan CC, Hwang JS, Yang CY, Wang JD. Short-term effect
of ozone on the pulmonary function of children in primary school.
Environ Health Perspect. 1999 Nov;107(11):921-5. Reports no effect of
NO~2~

Setiani O. Trend of air pollution and its effect on human health in
Hiroshima Prefecture\--a retrospective study in the cities of Otake,
Kure, Mihara, Takehara, Fukuyama and Kaita Town, 1977-1992. Hiroshima J
Med Sci. 1996 Jun;45(2):43-50. Reports a negative effect of NO~2~.

Hoek G, Brunekreef B. Acute effects of a winter air pollution episode on
pulmonary function and respiratory symptoms of children. Arch Environ
Health. 1993 Sep-Oct;48(5):328-35. Reports no effects for NO~2~.

Roemer W, Hoek G, Brunekreef B. Effect of ambient winter air pollution
on respiratory health of children with chronic respiratory symptoms. Am
Rev Respir Dis. 1993 Jan;147(1):118-24. Reports no effects for NO~2~.

Avol EL, Linn WS, Peng RC, Valencia G, Little D, Hackney JD. Laboratory
study of asthmatic volunteers exposed to nitrogen dioxide and to ambient
air pollution. Am Ind Hyg Assoc J. 1988 Apr;49(4):143-9. Reports effects
"not likely" due to NO~2~.

Salome CM, Brown NJ, Marks GB, Woolcock AJ, Johnson GM, Nancarrow PC,
Quigley S, Tiong J. Effect of nitrogen dioxide and other combustion
products on asthmatic subjects in a home-like environment. Eur Respir J.
1996 May;9(5):910-8. Reports no effects of NO~2~ below 600ppbv.

Pattenden S, Hoek G, Braun-Fahrlander C, Forastiere F, Kosheleva A,
Neuberger M, Fletcher T. NO2 and children\'s respiratory symptoms in the
PATY study. Occup Environ Med. 2006 Dec; 63(12):828-35. NO~2~ appears to
be an indicator for traffic-related pollutants.

de Hartog JJ, van Vliet PH, Brunekreef B, Knape MC, Janssen NA, Harssema
H. \[Relationship between air pollution due to traffic, decreased lung
function and airway symptoms in children\] Ned Tijdschr Geneeskd. 1997
Sep 20; 141(38):1814-8. Dutch. Effects are associated with truck
traffic, not NO~2~.

Brunekreef B, Houthuijs D, Dijkstra L, Boleij JS. Indoor nitrogen
dioxide exposure and children\'s pulmonary function. J Air Waste Manage
Assoc. 1990 Sep;40(9):1252-6. No relationship with NO~2~.

Penard-Morand C, Charpin D, Raherison C, Kopferschmitt C, Caillaud D,
Lavaud F, Annesi-Maesano I. Long-term exposure to background air
pollution related to respiratory and allergic health in schoolchildren.
Clin Exp Allergy. 2005 Oct; 35(10):1279-87. No consistent association
with NO~2~.

Avol EL, Linn WS, Peng RC, Whynot JD, Shamoo DA, Little DE, Smith MN,
Hackney JD. Experimental exposures of young asthmatic volunteers to
0.3ppm nitrogen dioxide and to ambient air pollution. Toxicol. Ind.
Health. 1989 Dec:5(6):1025-34. Reports no response to NO~2~ at 90ppb.

Slama R, Morgenstern V, Cyrys J, Zutavern A, Herbarth O, Wichmann HE,
Heinrich J; LISA Study Group. Traffic-related atmospheric pollutants
levels during pregnancy and offspring\'s term birth weight: a study
relying on a land-use regression exposure model. Environ Health
Perspect. 2007 Sep; 115(9):1283-92. Reports PM2.5, but no NO2 effects on
birthweight.

-   The results of other studies are not fully reported in a way that
    could be potentially misleading to the reader; in particular,
    analyses that consider the robustness of results after consider of
    other pollutants, etc. are not discussed as fully as they should be.
    I am familiar with the following studies:

Peel, JL et al. (2005) "Ambient Air Pollution and Respiratory Emergency
Department Visits", Epidemiology, 16: 164-174. The document correctly
cites the single pollutant model results from this study, but does not
mention the multi-pollutant model results in which NO~2~ significance
disappears in models with ozone (which remains statistically
significant).

Metzger, KB et al. (2004) "Ambient Air Pollution and Cardiovascular
Emergency Department Visits", Epidemiology, 15:46-56. The ISA reports
the single pollutant results, for which NO~2~ is often statistically
significant, but it does not report the multi-pollutant results. For the
earlier time period, NO~2~ is more robust than CO; for the later time
period NO~2~ is dominated by CO, total carbon-containing particles, and
oxygenated hydrocarbons.

Lipfert, FL et al. (2000a). Results are presented for single pollutant
models, but the ISA does not indicate that the associations between
mortality and NO~2~ disappear when ozone is present in a 2-pollutant
model. Later analyses (Lipfert, 2006a,b) indicate that a traffic density
variables dominates many pollution variables, including NO~2~.

Other papers where a cursory review of the paper suggests that more
elaboration of the results is warranted:

Delfino et al. (2003a) .The ISA concludes that this study was
"supportive of these \[NO~2~\] associations for asthmatics" The paper
reports associations between NO~2~ and asthma parameters, but concludes
that VOCs are particularly important; two pollutant models show no
significant associations with NO~2~.

Prescott et al. (1998): The document refers to differences in the
response of different age groups to NO~2~, without discussing the
statistical significance of these associations. According to the Annex
the resposnses are not statistically significant for either age group.

Schouten et al. (1996). The same comments made for Prescott et al.
pertain to this study.

Moseler et al. (1994). Table 4.1 should note that responses were found
only at NO~2~ concentrations above 21ppb.

-   The major difficulty in interpreting the results of epidemiological
    studies is in its attempt to ascertain whether the associations
    between health outcomes and NO~2~ are due to NO~2~ [per
    se]{.underline} or due to the possibility that NO~2~ is acting as a
    surrogate for another factor. This issue need be attacked head on
    with some discussion of these possible other factors (including
    traffic, CO, ozone, PM, EC, ultrafines, organics) and their
    relationship with NO~2~ levels. Results should be summarized from
    multi-pollutant results (with appropriate caveats for differences in
    measurement error, etc.) for each of the possible pollutant
    confounders. Results should also be summarized by environment:
    indoor, outdoor near source, outdoor away from source and by length
    of exposure (acute, chronic). I would also like some discussion of
    the likely interferences in NO~2~ measures in the above
    environments. The organization of results in this manner would help
    in interpreting the role of NO~2~ in these associations.

[^1]: Partial list of studies with negative findings that were missing
    from the ISA and merited inclusion (see Appendix B comments for
    additional references below):

    Witten A, et al. (2005) Effects of nitrogen dioxide on allergic
    airway responses in subjects with asthma. J Occup Environ Med.
    Dec;47(12):1250-9

    Aris R, et al. (1993) Effects of nitric acid gas alone or in
    combination with ozone on healthy volunteers. Am Rev Respir Dis
    Oct;148(4 Pt 1):965-73

    Metzger et al. (2007) Ambient Air Pollution and Ventricular
    Tachyarrhythmic Events in Patients with Implantable Cardioverter
    Defibrillators. Epidemiology. Sep;18(5):585-92

    Sinclair and Tolsma (2004) "Associations and Lags between Air
    Pollution and Acute Respiratory Visits in an Ambulatory Care
    Setting: 25-Month Results from the Aerosol Research and Inhalation
    Epidemiological Study", J. Air & Waste Manage. Assoc., 54:1212.

[^2]: See: Sarangapani et al. (2003) Evaluation of the potential impact
    of age- and gender-specific lung

    morphology and ventilation rate on the dosimetry of vapors. Inhal
    Toxicol. 2003 Sep; 15(10):987-1016. and Ginsberg et al. (2005)
    Review and analysis of inhalation dosimetry methods for application
    to children\'s risk assessment. J. Toxicology Environ Health-Part A.
    68:573-615.