![](media/image1.wmf){width="1.0833333333333333in"
height="1.0291666666666666in"}

**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON D.C. 20460**

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

June 25, 2008

EPA-CASAC-08-015

The Honorable Stephen L. Johnson

Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, N.W.

Washington, D.C. 20460

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

Dear Administrator Johnson:

The Clean Air Scientific Advisory Committee (CASAC), augmented by
subject-matter-experts to form the CASAC Oxides of Nitrogen Primary
National Ambient Air Quality Standards (NAAQS) Review Panel (hereafter
referred to as the panel, roster contained in Enclosure A) held a public
meeting on May 1-2, 2008 to review EPA's *Integrated Science Assessment
for Oxides of Nitrogen -- Health Criteria (Second External Review Draft)
(EPA/600/R-07/093aB, March 2008)*. The Chartered CASAC held a public
teleconference on June 11, 2008 to review and approve this report.

The *Integrated Science Assessment* (ISA) states (Page 1-1) that its
purpose is to present a "concise review, synthesis, and evaluation of
the most policy-relevant science" and to communicate the "critical
science judgments relevant to the review of national ambient air quality
standards for review of the primary standard for oxides of nitrogen
(NO~x~)." Although the CASAC finds that the second draft ISA was much
improved compared to the first draft reviewed in November 2007, the
document in its current state does not provide adequate guidance as to
what would be expected at current ambient concentrations. CASAC finds
that scientific data exist with which to answer this question, albeit
with some level of uncertainty, so that the document can provide an
adequate scientific basis for the exposure and policy assessments during
the next stage of the NAAQS review. Perhaps the most important
consideration in improving the document is a much better discussion of
the significance of the epidemiology data for a potential risk
assessment, despite the uncertainties associated with those data.
Incorporating an analysis of the available epidemiology data will allow
estimation of the potential uncertainties that need to be fully
described and quantified in the risk and exposure assessment. The ISA
discussion should consider the effect of co-exposures to other
pollutants, the relationship between ambient and personal exposures, and
how the problems associated with the available epidemiology studies
limit their use for risk assessment. Because of EPA's accelerated NAAQS
schedule for NO~x~, CASAC may not have an opportunity to provide
additional input for revising the ISA and so underscores its advice that
the document be further strengthened to support the NAAQS review.

Panel consensus comments on how the ISA might be further strengthened
are given below in the form of responses to the Agency's charge
questions. Individual comments from CASAC panel members are enclosed in
Enclosure B.

**Charge Question 1. What are the views of the Panel on the
characterization of the search strategy for identifying literature,
criteria for study selection, the framework for scientific evaluation of
studies and causality determination?**

Substantial improvements have been made based on prior comments. The
process for review of recent literature is reasonable and the results
appear to be accurately reported. In regard to the Agency's approach to
synthesis of the evidence and causal inference, an extensive Annex has
been prepared that reviews a number of relevant frameworks. The
background is a useful foundation for informing the selected approach
for assessing available evidence and should be extended to justify the
adopted framework. Based on this Annex, the Agency has made changes in
Chapter 1 that are responsive to prior critiques. In particular, there
is a description of literature selection; an approach to evaluating
evidence for inferring causality is provided; and a reasonable set of
descriptors of strength of evidence for causation is offered.

EPA has improved the second draft ISA by having a better prepared first
chapter that includes the framework for the document. However, the
sections that synthesize the evidence are still somewhat loosely
written, and do not systematically apply the guidelines offered by
Bradford Hill and adopted by the Agency. (Note, these should not be
renamed as "decisive factors," a misnomer). Too often, sections that are
offering judgments as to the strength of evidence use such language as
"taken together" or "integrating" without a more specific application of
the criteria offered by Hill. Nonetheless, the revised Chapter 1 and the
approach set out represents an advance over the earlier draft.

Additional issues that are not considered are publication and model
selection biases, a concern given that many studies address the health
effects of air pollution and employ multivariable models to attempt to
isolate the effects of particular pollutants at specific temporal or
spatial scales. There may have been some tendency on the part of
investigators to report positive associations or not to reflect the full
health effect from such factors as multiple lags.

A further issue in integrating the evidence is the substantial
difference in the doses and mixtures of pollutants and their
interactions given to animals or human volunteers in toxicology and
clinical studies versus those experienced by the populations in
epidemiology studies. Specific consideration needs to be given to the
relevance of mechanisms identified in toxicology studies to effects
observed in the epidemiology studies.

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

Overall, the description of the atmospheric dynamics, measurement
techniques and ambient concentrations is adequate, though aspects are
still wanting. The document would benefit greatly by having summaries at
the end of each section with the points most key to providing
information that will be used in technical documents supporting the
rulemaking for NO~2~, in particular those that inform the rest of the
ISA and the risk/exposure assessment (REA) and delineate what matters.
The Panel still views that a quantitative summary of sources would be
beneficial. The REA relies heavily on the application of various
modeling techniques, including AERMOD and an empirical approach for
estimating on-road NO~2~ concentrations. Consequently, the needed
background information on their scientific fundamentals, and their
ability to reproduce observed concentrations, should be covered in the
ISA. Along those lines, given the importance of on-road concentrations,
that section of the ISA should be enhanced, with additional attention
given to street canyon concentrations. Siting characteristics of
monitors should be incorporated into all analyses of monitoring data.

The Panel found that the section on measurement interferences continues
to give a somewhat distorted picture of the importance of interferences.
The implications of the interferences should be made explicit (i.e., by
quantifying how much the interferences impact the peak NO~2~ levels and
annual averages and identifying whether the interferences pose an
important issue for exposure and epidemiology studies). Given the
potential that the REA may depend more heavily on the epidemiology
results, the ISA should more comprehensively assess how NO~2~ levels
correlate with air quality variables besides particulate matter (PM)
mass (either PM~10~ or PM~2.5~), ozone and sulfur dioxide, e.g.,
addressing the correlations with elemental carbon, organic carbon and
other combustion products. It is known that carbon particles will adsorb
NO~2~when they are exposed to high concentrations of the gas in the lab.
EPA should consider the extent to which this may occur in the
atmosphere*.*.

In the last section on dosimetry, there is little progress to report on
extrapolation modeling since the 1993 Criteria Document. Nevertheless,
the established dosimetry models could be applied to the many of the key
studies in the ISA, particularly to put response data collected from
animals and humans on a comparative footing with each other and with the
exposure conditions in the epidemiological studies.

**Charge Question 3. 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? 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?**

The second draft ISA is substantially improved in organization and
content compared to the first draft. The revised document has addressed
a number of the concerns expressed by CASAC. New publications from the
scientific literature since 1993 have been appropriately incorporated
into this ISA draft. Substantial new findings have occurred since 1993
that are relevant to the issue of health risks related to oxides of
nitrogen. These include animal toxicology studies, human clinical
studies and epidemiology studies. Although the exposure concentrations
in animal toxicology studies are typically well above ambient
conditions, they do provide biological plausibility for adverse health
effects that can be attributed to NO~2~.

Panel members concur with the primary conclusions reached in the ISA
with regard to health risks that are associated with NO~2~ exposure. In
particular, the Panel agrees with the conclusion that the current
scientific evidence is "sufficient to infer a likely causal relationship
between short term NO~2~ exposure and adverse effects on the respiratory
system." The strongest evidence in support of this conclusion comes from
epidemiology studies that show generally positive associations between
NO~2~ and respiratory symptoms, hospitalizations or emergency department
visits, as summarized in Figure 5.3.1. Furthermore, we would conclude
that the epidemiology studies show significant effects related to NO~2~
exposure that are robust in some cases, even when adjusted for
co-pollutants. One limitation of the available epidemiology studies,
however, is an inability to establish a definitive NO~2~ exposure level
that can be specifically associated with the observed adverse health
effects. Consequently dose-response relationships are difficult to
establish for NO~2~, however best estimates and their uncertainties
should be discussed. Separately and for future consideration, there is a
recognized need to consider regulatory approaches to complex mixtures of
air pollutants rather than considering each pollutant individually.

The human clinical studies reviewed in the ISA need to be interpreted
with caution. The lowest reported effect of NO~2~ exposure was found in
three Swedish studies of airway responses to antigen challenge in
allergic asthmatics. However, other human clinical studies have shown
mixed results with some studies failing to find biologically significant
health effects at similar or higher levels of NO~2~ exposure alone. In
addition, although airway responses to antigen challenge can be
considered an adverse health effect, admission to a hospital or a visit
to an emergency department for an exacerbation of asthma can be
considered a clearer adverse effect. Epidemiology studies more directly
address these adverse health effects and provide evidence identifying
health risks related to ambient NO~2~ exposures. In summary, the new
scientific literature reviewed in the second draft of this ISA document
provides a number of strong indications of possible NO~2~ health
effects, but confounding or exacerbating co-pollutants and variable
findings in human clinical studies remain problematic. Of special
concern are potential interactions with particulate matter, potentially
increasing lung NO~2~ dosages above what would occur with NO~2~ alone.
These aspects should be addressed in considering a revised criteria
standard for NO~2~.

**Charge Question 4. What are the views of the Panel on the
characterization of groups likely to be susceptible or vulnerable to
NO~2~ and the potential public health impact of NO~2~ exposure?**

Overall, the draft ISA does an adequate job of discussing the public
health significance of exposure to ambient NO~2~. The chapter 4 summary
indicates that persons with preexisting respiratory disease (especially
asthma), children, and older adults may be more susceptible to the
effects of NO~2~ exposure. While the panel agrees with this assessment,
other subpopulations may also be at increased risk of adverse health
effects from exposure to ambient NO~2~. Specifically, there is evidence
in the ozone and PM health effects literature that individuals who have
poor dietary intake of antioxidants, are obese, or have certain genetic
variants, as well as premature or low-birth-weight infants, may be more
susceptible to these pollutants. Since NO~2~ is thought to cause health
effects by a similar oxidant injury pathway to ozone and fine PM, these
subpopulations should be considered in this chapter. We suggest that a
table or figure be included in the document to more clearly identify
subpopulations that are likely susceptible to adverse effects of
exposure to NO~2~ and to identify the research that indicates that
susceptibility.

The panel recommends that the draft ISA more clearly communicate the
distinction between "susceptibility" and "vulnerability." Susceptibility
as used in the latest draft ISA appears to describe those factors that
may be considered "host" or "intrinsic" while vulnerability appears to
be related to an interaction between susceptibility (risk-based on
intrinsic risk factor) and increased risk of exposure. As currently used
in the document, these terms have overlapping meanings that could lead
to unnecessary confusion.

**Charge Question 5. What are the Panel's views on the adequacy of this
second external review draft ISA to provide support for future exposure
and policy assessments?**

The Panel has several comments on the adequacy of the draft ISA as a
basis for exposure and policy assessments. First, Chapter 5
satisfactorily summarizes the information and judgments from earlier
chapters that are relevant to exposure and policy assessments. The
authors of the draft have both accurately reflected that earlier
material and chosen the material most relevant for further assessments.

The charge question, however, asks not only about the fidelity of
Chapter 5 in presenting results from earlier chapters, but also whether
the draft provides an adequate basis for exposure and policy
assessments. The CASAC Panel is not convinced that the chapter, as
currently written, has met this goal, but the Panel believes that the
chapter and the draft can be improved to that point through the
improvements we have suggested in our review. Chapter 5 does indicate
directions that are important for exposure and policy assessments:
towards sensitive subpopulations that should be considered; towards
specific health effects that should be considered; and towards the
difficulties in estimating exposure due to uncertainties in the
relationship between ambient monitoring results and personal exposures.
In each of these categories more details need to be

provided so that a risk assessor can find useful summary information to
inform how an exposure/risk assessment should be structured and how the
residual uncertainties should be characterized.

At present, the draft provides an inadequate basis for performing
exposure and policy assessments quantitatively, or even summarizing the
information that will be used in such assessments. The draft is
uninformative as to what the levels of exposure are for any specific
population in any specific geographic location. The authors should have
summarized at least the ambient exposure information available (alluded
to in the previous chapters) and then drawn judgments as to the validity
of using that information in specific kinds of exposure assessments
(e.g., the spatial scale on which variability can be determined and how
to correct for indoor exposures). This summary and its interpretation
can be offered without moving into the policy domain or even unduly
specifying the tasks of further exposure assessors. There also should be
a succinct statement as to whether an exposure-response curve can be
developed, so that the risk assessor is not left solely with the option
of using methods akin to hazard quotients.

On the summarization of health effects, this chapter is greatly improved
from the previous draft. t identifies health effects associated with
exposure to nitrogen oxides and the strength of evidence supporting
causality of associations. On the issue of whether effects would be
expected at current ambient concentrations, however, the chapter does
not provide adequate guidance. This is one of the weakest aspects of the
current draft, even though this is one of the most important conclusions
to be drawn from the document. Some statement with regard to the degree
of certainty in the occurrence of effects at ambient levels is needed,
no matter how difficult it may be to characterize uncertainty. The
chapter also should summarize evidence on, and draw summary conclusions
for, the issue of whether associations between NO~2~ and health
responses in epidemiology studies result from NO~2~ exposures per se or
whether NO~2~ is a surrogate for other exposures associated with
common-cause sources. The information to support such a conclusion is
scattered throughout the document, but an explicit and articulate
consideration of this issue would greatly improve the draft.

Finally, to meet that goal, the draft ISA should be improved through a
better discussion of the significance of the epidemiology data for a
potential risk assessment despite the uncertainties associated with
those data. Incorporating an analysis of the available epidemiology data
into the risk assessment will allow estimation of the potential
uncertainties that need to be fully described and quantified in the risk
and exposure assessment. The ISA discussion should consider the effect
of co-exposures to other pollutants, the relationship between ambient
and personal exposures, and how the limitations of the epidemiology
studies impact their use for risk assessment.

In closing, the CASAC was pleased to review this second draft of the ISA
for the primary NO~x~ standard and looks forward to continued
interactions with the Agency in this important task.

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

**Enclosures**

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

Enclosure B: Compilation of Individual Panel Member Comments on EPA's
Integrated Science Assessment (ISA) for Integrated Science Assessment
for Oxides of Nitrogen -- Health Criteria (Second External Review Draft)

**Enclosure A**

**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

\*Unable to participate in the May 1-2, 2008 CASAC Panel Meeting

**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

**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: Compilation of Individual Panel Member Comments on EPA's
Integrated Science Assessment (ISA) for Integrated Science Assessment
for Oxides of Nitrogen -- Health Criteria (Second External Review
Draft**

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

[Comments from Professor Ed Avol 11](#__RefHeading___Toc201991112)

[Comments from Dr. John Balmes 14](#__RefHeading___Toc201991113)

[Comments from Dr. Douglas Crawford-Brown
18](#__RefHeading___Toc201991114)

[Comments from Dr. Terry Gordon 23](#__RefHeading___Toc201991115)

[Comments from Dr. Dale Hattis 25](#__RefHeading___Toc201991116)

[Comments from Dr. Donna Kenski 26](#__RefHeading___Toc201991117)

[Comments from Dr. Steven Kleeberger 28](#__RefHeading___Toc201991118)

[Comments from Dr. Timothy Larson 29](#__RefHeading___Toc201991119)

[Comments from Dr. Kent Pinkerton 30](#__RefHeading___Toc201991120)

[Comments from Dr. Edward Postlethwait 32](#__RefHeading___Toc201991121)

[Comments from Dr. Armistead Russell 33](#__RefHeading___Toc201991122)

[Comments from Dr. Jonathan Samet 35](#__RefHeading___Toc201991123)

[Comments from Dr. Richard Schlesinger 38](#__RefHeading___Toc201991124)

[Comments from Dr. Christian Seigneur 39](#__RefHeading___Toc201991125)

[Comments from Dr. Elizabeth "Lianne" Sheppard
42](#__RefHeading___Toc201991126)

[Comments from Dr. Frank Speizer 47](#__RefHeading___Toc201991127)

[Comments from Dr. George Thurston 49](#__RefHeading___Toc201991128)

[Comments from Dr. James Ultman 51](#__RefHeading___Toc201991129)

[Comments from Dr. Ronald Wyzga 53](#__RefHeading___Toc201991130)

[]{#__RefHeading___Toc201991112 .anchor}[Comments from Professor Ed
Avol]{.underline}

**General Document Comments**

This is an impressive compilation of a great deal of work that reflects
the large amount of effort put into it. It is generally well-written and
with sufficient detail and reference to provide readers with useful
guidance and documentation, as needed. There is a great deal of
important and useful information in each of the several chapters,
although the respective chapters have a slightly different architecture
to them. Several important points are made in some chapters (such as
Chapter 2), but not always emphasized at a section or chapter conclusion
(as they are, for example, in Chapter 3). Although an excellent summary
of the chapters appears as Chapter 5, is it worth considering having a
conclusion, summary, or results section at the close of each chapter to
re-emphasize or focus on the critical points raised?

Agency ISA Charge Questions

1\. What are the views of the Panel on the characterization of the
search strategy for identifying literature, criteria for study
selection, the framework for scientific evaluation of studies and
causality determination?

Everything seems appropriate and well --described, except for the
operational assignments for causality (P1-16, lines 22-23). I agree with
the utility of a gradation of confidence in conclusive statements, but
it's a bit confusing as to the clear distinction between "sufficient to
infer a causal relationship" and "sufficient to infer a likely causal
relationship". Isn't the clarification currently present ("more likely
than not") the definition for the next lower level of confidence
("suggestive but not sufficient to infer a causal relationship")?

2\. To what extent are the atmospheric chemistry and air quality
characterizations clearly communicated, appropriately characterized, and
relevant to the review of the primaryNO2 NAAQS? Are the properties of
ambient oxides of nitrogen appropriately characterized, including
spatial and temporal patterns and relationships between ambient oxides
of nitrogen and human exposure? 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?

In general, yes...However, P2-7 through P2-10, Section 2.3 provides
useful (and much appreciated) information regarding the various
approaches to measurement of ambient levels of nitrogen-containing
species, but does not provide any succinct conclusions or directed
message for the reader. Perhaps a closing paragraph or bullet to provide
a "take-home" message would be valuable? What discrete message(s) are
you are trying to convey in this section?

3\. 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? What are the views of the Panel on the conclusions
drawn in the draft ISA regarding the strength, consistency, coherence
and plausibility of NO2-related health effects?

This portion is generally excellent - well-written, thoughtfully
presented, and meticulously designed. The summary figures, visually
presenting the results of numerous studies to gauge consistency of
response for a given outcome, is a noteworthy accomplishment that adds
to the accessibility of the document. The summary of evidence sections
at the close of each section are invaluable and much-appreciated.

(P3-4, line 24) -- A comment made here that "Relatively few new clinical
and animal (NO2) toxicologic studies have been published since 1993..."
seems inconsistent with a review of the literature. A PubMed search
reveals over 200 publications reporting on NO2 health outcomes, animal
studies, etc...? Please clarify or correct this sentence.

4\. What are the views of the Panel on the characterization of groups
likely to be susceptible or vulnerable to NO2 and the potential public
health impact of NO2 exposure?

(P4-9, Section 4.3 and elsewhere) A brief but clear delineation of the
operational differences between susceptibility and vulnerability in this
document would be useful; this is likely to otherwise create some
confusion. Is vulnerable being used to describe "a lack of defenses
against" or something more? Is susceptible being used to describe being
"prone to a certain response" or something more? This section discusses
children and older adults as being "...particularly susceptible to air
pollution...", but aren't they more vulnerable? If they were missing a
specific gene (in the oxidant stress pathway) or had pre-existing
disease (such as emphysema, asthma, or possibly diabetes), then they
would be susceptible.

5\. What are the Panel's views on the adequacy of this second external
review draft ISA to provide support for future exposure and policy
assessments?

Overall, this document provides sufficient support for future exposure
and policy assessments.

**Specific Comments**

Chapter I - IntroductionP1-13, Fig 1.6-2 -- shouldn't "Mediated Effect"
arrows from PM to NOx to O3 go in both directions? NOX can affect PM
formation which can then have an effect on observed outcomes, and O3 can
affect NOx levels which will affect the entire chain of events.
Similarly, shouldn't there be a "Surrogate" arrow from NOx to Other
Pollutants?

Chapter 2 -- Source to Tissue Dose

P2-18, line 1 -- (spelling error in San Bernardino, and I don't think I
have ever heard this region referred to as the San Bernardino
"Valley"...??)

P2-21, Figure 2.5-1 (spelling error, "In a residence"(68.7%)

Chapter 3 - Integrated Health Effects of NO2 Exposure

(No additional specific comments other than those above)

Chapter 4 -- Public Health Significance

(No additional specific comments other than those above)

Chapter 5 -- Integrative Summary and Conclusions

This chapter is an excellent compilation of the assembled data.

[]{#__RefHeading___Toc201991113 .anchor}[Comments from Dr. John
Balmes]{.underline}

[Agency Charge Question 3]{.underline}. 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? What are the views of
the Panel on the conclusions drawn in the draft ISA regarding the
strength, consistency, coherence and plausibility of NO2-related health
effects?

GENERAL COMMENTS

The second external review draft of the NOx ISA is much improved. In
particular, the discussion in Chapter 1 on the "EPA Framework for Causal
Determinations" provides an integrative approach to how the agency will
assess the evidence presented in the subsequent chapters. Given that
this is the first ISA to be produced under the agency's new process for
reviewing a "criteria" pollutant NAAQS, it is important to provide such
an integrative approach as a precedent. My major concern about this
draft of the NOx ISA is that in certain summaries of sections of Chapter
3, the framework described in Chapter 1 is insufficiently applied. I
will provide specific examples below.

In my opinion, the discussion of healthy effects of short-term exposure
to NO2 in Chapter 3 is appropriate and fairly well integrated. My major
concern with this discussion involves a statement is made on p. 3-14 and
repeated on p. 3-15, 3-61, and p. 5-12 that "the onset of inflammatory
responses in healthy subjects appears to be between 100 and 200 ppm-min,
i.e., 1 ppm for 2 to 3 h." Figure 3.1-1 is presented to demonstrate this
threshold graphically, but appears to be the wrong figure, perhaps an
alternative version of Figure 3.1-2. In any event, Figure 3.1-1 presents
studies of the effect of NO2 on allergen-induced lung function and
inflammatory responses not the studies of the airway inflammatory effect
of NO2 alone that are described on pp. 3-12 to 3-14. This figure needs
to be replaced with one that actually supports this important statement.

The discussion of respiratory effects associated with long-term exposure
to NO2 is important since several prospective cohort epidemiological
studies have been published since the 1993 NOx NAAQS review that
reported adverse effects on growth of lung function. There is a
subsection on "Toxicological Studies" on p. 3-89 and 3-90 that is
apparently intended to provide mechanistic support for the results of
the epidemiological studies. However, the discussion on pp. 3-95 and
3-96 of "Animal Studies of Long-Term Morphological Effects to the
Respiratory System" is both more comprehensive and concise. I would
delete the subsection on p.3-89.

On p. 3-90, the concluding paragraph for section 3.4.1 on "Lung Function
Growth" provides no assessment of the strength of the association
between long-term exposure to NO2 and decreased rate of growth of lung
function among children. This paragraph merely states that the
epidemiological studies og long-term exposure to NO2 aqre likely
confounded by other ambient pollutants. Unfortunately, section 3.4.5,
which is supposed to be the summary and integration of evidence on
"Long-Term NO2 Exposure and Respiratory Illness and Lung Function
Decrements" also does not provide an assessment of the strength of the
association. This is a critical deficiency given the relative importance
of the issue of potential respiratory effects of long-term NO2 exposure.
The section also does not directly assess the strength of the
association for either "Asthma Prevalence and Incidence" or "Respiratory
Symptoms". It is not until Chapter 5 that the strength of the
association for long-term exposure to NO2 and respiratory morbidity is
assessed.

Another concern that I have regarding section 3.4.5 is the long
discussion on animal toxicological studies that have found effects of
NO2 on host defense against respiratory infections on pp. 3-98 to 3-100.
While I believe that this discussion is technically accurate, I find
that it is unnecessary and distracting given the relative lack of
discussion of the strength of the epidemiological evidence on long-term
exposure to NO2 and asthma and the total absence of such discussion
regarding respiratory symptoms.

[Agency Charge Question 4]{.underline}. What are the views of the Panel
on the characterization of groups likely to be susceptible or vulnerable
to NO2 and the potential public health impact of NO2 exposure?

Chapter 4 does an adequate job of discussing the public health
significance of exposure to ambient NO2. The chapter Summary (4.5)
indicates that persons with preexisting respiratory disease (especially
asthma), children, and older adults may be more susceptible to the
effects of NO2 exposure. I agree with this assessment of the evidence.
There is one statement in section 4.5, however, with which I am
uncomfortable. The final sentence on p. 4-16 states that "evidence,
albeit inconsistent, exists for a gender-age-based difference in
susceptibility" regarding the effects of NO2 on children with asthma. I
find this statement to be too strong. While I agree that there is
evidence that the incidence of asthma differs between boys and girls
with age, the evidence for a gender-age-based difference in
susceptibility to effects of NO2 exposure in asthmatic children is too
limited to draw any conclusions. I would delete this sentence.

The major problem I have with Chapter 5 is that the relatively strong
evidence for an effect of long-term exposure to NO2 on growth of lung
function in children reported by both the Sothern California Children's
Health Study and the Mexico City study (Rojas-Martinez et al.) is
diluted by combining discussion of these studies with those on asthma
and respiratory symptoms. In my opinion, the issue of the strength of
evidence for a long-term effect of NO2 on growth of lung function needs
to be dealt with more directly in the document, in both Chapters 3 and
5.

SPECIFIC COMMENTS

3-11, line 5 "...increases inflammation in children [with
asthma]{.underline}."

3-14, line 8 This statement would better reflect the studies discussed
on the previous pages if it were worded "...NO2 concentrations ≤2.0 ppm
in healthy adults."

Figure 3.1-1 wrong figure

3-16, line 3 "Challenge with "specific allergens" [can be performed in
allergic]{.underline} asthmatics."

3-20, line 28 delete second "of" in this line

3-22, line 7 "By 72 h, bronchopulmonary hyperreactivity
[was]{.underline} comparable."

3-37, line 19 delete "from a meta-analysis" in this line

3-61, lines 7-10 This statement would better reflect the data summarized
if worded as follows: "Controlled human exposure studies provide
consistent evidence for airways inflammation at [a NO2 concentration of
2.0 ppm (one study found airway inflammation at a concentration of 1.5
ppm)]{.underline}; the onset of the inflammatory response..."

3-75, line 12 "...mortality in [28 of]{.underline} the same cities..."

Figure 3.4-1 The x axis in the lower graph should be labeled "FEV1".

Figure 3.4-4 Use decimals rather than commas for the y axes. Explain
"study phase" in the legend.

3-88, line 4 "[The association between long-term exposure to NO2 and
decreased PEF was comparable to that found in the CHS, but associations
with forced volumes]{.underline} were considerably weaker."

3-89 and 3-90, Toxicological Studies I would eliminate these three
paragraphs. The summary of the toxicological literature on 3-95 and 3-96
is better.

3-90, lines 8-16 There is a lack of assessment of the strength of
association in this summary.

3-95, line 1 "The association of NO2 with dry cough at night [observed
in the German study]{.underline}..."

3-98, line 25 "...major cohort [studies]{.underline}, the CHS in
southern California and [a]{.underline} birth cohort [study]{.underline}
in the Netherlands,..."

3-98, line 29 to 3-100, line 2 I would eliminate this discussion on
potential mechanisms of NO2 effects respiratory illness because the
first sentence on p. 3-98 (lines 29-30) is at odds with the summary of
the epidemiological evidence for respiratory symptoms on p. 3-95 (lines
23-26). The information discussed here also does not relate to long-term
NO2 exposure and asthma prevalence which was the subject of the
preceding paragraph on p. 3-98.

3-100, line 23 "...an OR of 1.10 [for lung cancer]{.underline}..."

3-100, lines 28-31 "[Exposure to]{.underline} 10 μg/m^3^ (5.2 ppb) of
NO2 was associated with an OR of 1.08 [for lung cancer]{.underline} (95%
CI: 1.02, 1.15)[;]{.underline} exposure to ≥30 μg/m^3^ (15.7 ppb) was
associated with an OR of 1.36 (95% CI: 1.01, 1.83)[.
However]{.underline},..."

3-104, line 13 "...with other *NO~2~^-^* sources..."

3-106, line 29 "...exposed to 2.0 [and]{.underline} 1.0 ppm..."

3-112, line 8 "...examined association[s]{.underline} between..."

3-113, line 18 "are suggestive of [a]{.underline} traffic-related air
pollution [effect on mortality]{.underline}, but..."

4-7, line26 "limitation of this [experimental animal]{.underline}
work..."

4-11, line 8 "Several glutathione S-transferase (GST)
[genes]{.underline} have common..."

4-13, line17 delete "biologically" from this sentence

4-16, lines 30-32 This statement is a bit of a stretch based on the
evidence presented.

[]{#__RefHeading___Toc201991114 .anchor}[Comments from Dr. Douglas
Crawford-Brown]{.underline}

The primary question addressed in this review is in reference to Chapter
5, Integrative Summary and Conclusions, and focuses on the adequacy of
the ISA (especially Chapter 5) to provide support for future exposure
and policy assessments. I begin by noting that this second draft is a
significant improvement on the first. The authors have dealt with the
majority of my comments on the first draft, and have responded to the
majority of comments made by the committee as a whole in our earlier
review. There is beginning to emerge a vision for what the ISAs in
general are intended to accomplish, so this is a positive step forward
for the EPA staff.

On the primary issue of adequacy as a basis for exposure and policy
assessments, my comments are of two kinds. First, Chapter 5 does indeed
summarize the information from earlier chapters that would be relevant
to exposure and policy assessments. The authors have done a good job of
both accurately reflecting that earlier material and choosing the
material that is most relevant. They have drawn appropriate conclusions
from that earlier material, including assessments of the strengths and
limitations of the conclusions. While I might still have some quibbles
over the lack of formal assessment of the epistemic strength of
conclusions, I fully agree with the judgments they have made as to
whether the evidence for each category of effect is conclusive,
supportive, inconclusive, etc. I don't think I could trace the judgments
of the authors back to any specific reasoning they have done, because
the only reference to that reasoning is a vague citation of the Hill
criteria (criteria that seem to me woefully inadequate as a
philosophical basis for rigorous assessments of epistemic status). But
the judgments of the authors nonetheless appear to be the correct ones
based on the available evidence.

The second issue is whether Chapter 5 not only summarizes accurately the
information in earlier chapters (which it does) but also provides an
adequate basis for exposure and policy assessments. Here I am less
comfortable the chapter, or even the entire document, has met the
target. It is certainly the case that both the document and the chapter
point the reader in directions that will be important for exposure and
policy assessments. The reader is guided to judgments on the appropriate
sensitive subpopulations that should be considered; on the specific
effects that should be considered; on issues related to the relationship
between ambient monitoring results and personal exposures; and on the
issue of whether epidemiological studies are confounded by exposures to
the mix of air pollutants that normally accompany exposure to oxides of
nitrogen. An assessor will, therefore, find much useful information in
the document and in Chapter 5.

However, neither the chapter nor the document provides an adequate basis
for performing exposure and policy assessments quantitatively. It is not
possible from the document alone to see what the levels of exposure will
actually be to any specific population in any specific geographic
location. I realize this level of detail may not be what is intended by
an ISA, but then I am left wondering what could be meant by asking
whether the document provides an adequate basis for exposure assessment.
The only way it could do that, in my mind, is to summarize the actual
exposure information available, guiding the reader to understanding how
well that information will allow accurate estimates of exposure to
specific subpopulations in specific geographic areas. The ISA does not
summarize exposure information, or even monitoring information, but
instead summarizes the strengths and limitations of that information.
The latter is an important goal, as it will place caveats on the use of
more detailed information in later exposure assessments. But it leaves
the task of assembling the information on concentrations, and converting
these to estimates of exposure, to a later step in the assessment
process. ***As a result, I am not comfortable that the ISA provides an
adequate basis for subsequent exposure and policy assessments, but
rather provides an adequate basis for these subsequent steps to
understand the strengths and limitations of the available data. Having
said that, this may be all that the ISAs are intended to accomplish, in
which case the current document would be judged adequate.***

I also was looking for some sort of scientific statement as to how the
information available ought to be used in conducting an exposure or
policy assessment. This can be done without wandering into policy
decisions. Are the authors suggesting that no exposure-response curve
can be developed, and hence the assessments must be conducted in ways
similar to non-cancer risk assessments (with a presumed threshold of
effect)? Should an uncertainty factor be applied? Would the goal of an
assessment be to estimate the number of people in the U.S. population
exposed at levels above the threshold (or with a hazard quotient above
1)? Should there exposure be averaged over an hour, or 4 hours or a day
or year? These are questions that will crucial in a future assessment
and can be answered scientifically without getting into the policy
realm, so I expected to see them here if the document is to provide an
adequate basis for exposure and policy assessments.

I then have a series of specific issues to raise.

1\. I continue to be less than convinced by the epistemic assessments
performed, or at least the formal descriptions of the assessments. The
reference on page 5-1 is to the Hill criteria (which are completely
inadequate philosophically in my view) and to "other pertinent
frameworks". No reference is provided to these other frameworks, so I
have no idea what they are. I realize the ISA is not a philosophical
document, but some better guidance as to how the specific judgments of
the quality of conclusions are developed is needed. There is no problem
in stating that they are informed judgments based on some set of
criteria (and then stating these criteria). Having said that, I do agree
with the conclusions drawn and so will not push this point too strongly.

2\. The fourth bullet on Page 5-1 asks whether new data affect the
plausibility of judgments about oxides of nitrogen causing adverse
health effects. I had expected to see some further qualification such as
"adverse health effects at levels of exposure of at levels found in the
environment".

3\. On Page 5-3, the bullets don't seem to follow at all from the
opening sentences of the paragraphs. I agree with what is contained in
the bullets, but they seem to me unconnected to the sentences that
presumably introduce them. I have read this paragraph several times and
just don't see the link.

4\. In that same list of bullets, 6^th^ bullet, the authors talk about
artefacts. There is no explanation as to what an artefact means, how it
affects exposure or policy assessments, what a positive artefact would
be (presumably in contrast to a negative one), etc.

5\. The listing of issues in section 5.2.2 is a good one, and is
certainly useful to anyone conducting an exposure assessment. But I
point back to my earlier comment that even if the issues raised here are
the correct ones, it is not possible to take this and form a basis for
an exposure assessment because specific data are not provided and
summarized. I also expected a bullet suggesting how exposures SHOULD be
estimated, rather than simply listing the limitations in any exposure
measures. I would expect a recommendation as to the ratio of personal to
ambient levels in specific settings, the time period over which exposure
should be averaged, etc. I also expected some conclusion as to whether
it is even valid to use ambient monitoring results, from the network set
up for regulatory monitoring, as a starting point for estimating
exposures.

6\. The last paragraph in section 5.2.2 cautions against strict
conclusions being drawn based on the epidemiological studies due to a
lack of conclusive evidence that ambient and personal exposures are
completely correlated. The implications of a lack of complete
correlation depend on the differences in exposure levels between the
different exposure categories in the study. The implications become more
significant as the exposure groupings are closer together in exposure,
in which case there can be significant misclassification and therefore
bias towards the null (generally at least). I think a more nuanced
conclusion here is needed.

7\. I found the summary tables quite useful, so the authors are to be
applauded for developing them in this coherent fashion.

8\. In the sections on effects, it would be useful if the authors were
to provide information as to whether an increase in exposure changes the
fraction of people with effect, the frequency with which a subset of
people develop the effect, the severity of the effect, etc. I realize
that this distinction may not be so important in a regulatory decision
(where one person getting the effect N times counts the same as N people
getting the effect once), and that the available exposure-response
information may not allow development of exposure-response curves, but
some comment on this issue would be useful.

9\. In the last paragraph (Page 5-22), the authors correctly conclude
that it is plausible to believe that effects are occurring at levels of
exposure below the current NAAQS. But the question here is "how far
below?". I should think that the science assessment (this document)
would be the place where the EPA states clearly the answer to this
crucial scientific issue -- an issue that will greatly affect the policy
assessment.

[]{#__RefHeading___Toc201991115 .anchor}[Comments from Dr. Terry
Gordon]{.underline}

Charge Question 3. 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?

The ISA document is a tremendous improvement over the first draft. There
are appropriate-length discussions of key studies and the overall
message of the ISA is clearly communicated. There are, perhaps, sections
of the animal toxicology data that have too much detail given the
high(er) concentrations of NO2 used in some studies. As mentioned in
past discussions by the Panel, animal toxicology studies should be
included in the ISA only when they are of relevant concentrations.

What are the views of the Panel on the conclusions drawn in the draft
ISA regarding the strength, consistency, coherence and plausibility of
NO-related health effects?

The development of the guidelines to evaluate the strength, consistency,
coherence, and plausibility of NOx-related health effects is critically
important to the ISA. In a similar fashion, the use of structured
language to describe relationships between exposure to NOx and adverse
health effects is an important improvement to the ISA. The 5 descriptor
categories appear well thought out and appropriate, but discourse on
these categories may bring modifications to future ISAs if not this one.

Minor Comments:

Disclaimer page

Page ii -- first line -- First or second external draft?

Page ii, para 2 -- typo for (4) before "to set...."?

Page 1-17, para 2 -- Why would tox and cancer have a linear response?
Many researchers say otherwise. What does dose-transitional mean?

Page 2-4, last line -- 'at low temperature' is imprecise; does this mean
ambient temperatures?

Page 2-21, figure 2.5-1 -- Label for largest part of pie chart should be
'In a residence'.

Page 3-6, table 3.1-1 -- Under peripheral blood, 'Total macrophages'
should be (re)moved as they are in the lower airways.

Page 3-8, para 3 -- The 3 to 9 ppm 2 week study has little relevance to
the toxicity of exposure to peak ambient levels of 0.05 or 0.1 ppm NO2.
Also, it is unbalanced to give the details and results of this high dose
study and then say that alveolar macrophages are a sensitive target for
NOx's effects and give no refs on macrophages and just refer the reader
to the Annex.

Page 3-12, figure 3.1-1 -- The figure legend needs more details (e.g.,
what are the + and -- on the Y-axis for; what does the \* mean?; what do
the 3h and 6h mean? Some of this is explained later in the legend of
figure 3.1-2.

Page 3-22, first and second line -- Needs a ref.

Page 3-22 -- There is a lot of detail here for high dose (5 ppm and 20
ppm NO2) animal studies. Please consider cutting the long paragraph and
summarizing in a couple of sentences.

Page 3-24 -- Add 'Nonspecific' before 'Airways' in the title for
consistency with the last 2 subtitles.

Page 3-25, para 2 -- Delete 'of' before 'as low as....'. Having stated
that effects can occur at 0.26 ppm, why include the 1-sentence results
of a 5 ppm study?

Page 3-44, para 4 -- Elsewhere the Gong study had 18 subjects.

Page 3-47 -- I may be reading this all wrong but some of the bars on the
figure make no sense: on the preceding page, it says the Tolbert study
had a 2% increase with a 95% CI of 0.5, 3.3. The figure shows a
significant box with error bars totally dissimilar the reported 95% CI.
The same goes for the Barnett (2005) study which says something
different in the text (page 3-47) than is in the figure. Should all data
be re-checked?

Page 3-59, second line -- insert 'for asthma' after '.... or ED visits'.

Page 3-59, line 7 -- Adding 'other' before 'diseases' would make this
sentence clearer.

Page 3-62, lines 4, 5 -- I'm not sure what is meant by '....NO2 effects
to be mediated by other pollutants or exposures;'

Pages 3-62, 63 -- Although the physiology descriptions are good, the
text has 15 lines describing HRV and then 5 lines to say there have been
mixed results. The same goes for the repolarization section -- 5 lines
to describe what it is and then 1 line to say there was no effect.
Condense?

Page 3-79, 2nd para -- The statement regarding animal studies and
mortality as an endpoint in acute studies is not correct. Several
studies have looked at LC50 values for NO2 in different species.

Page 3-90, para 3 -- This paragraph on epidemiology appears to be
misplaced in this tox section.

Page 3-96, para 1 -- A mention of the higher doses used in animal tox
studies could be added to qualify the last sentence.

Page 3-111, para 3 -- Add 'a' before 'sensitivity'.

Page 3-118, para 2 -- Should the last line of this para read, 1.0 to
2.8, or 0 to 1.28?

Page 4-4, first line -- Has this really been recapitulated in preceding
sections of this chapter?

Page 4-8, para 1 -- Adding a conclusion sentence for this section on
asthma would be appropriate. The same goes for the other susceptibility
sections.

Page 4-12, para 1 -- The sentence states that in-vehicle concentrations
are 2 to 3 times 'ambient'. Does this mean that it's higher in the
vehicle than just outside the car? Or does it mean compared to
non-traffic ambient levels?

Page 4-13, first line -- Ponce 2003 or 2005?

Page 4-16, para 2 -- This is a strange intro sentence for the Summary
section.

Page 5-26 -- The title for the table is unclear -- Legend of Figure
5.3-1??

[]{#__RefHeading___Toc201991116 .anchor}[Comments from Dr. Dale
Hattis]{.underline}

1\. What are the views of the Panel on the characterization of the
search strategy for

identifying literature, criteria for study selection, the framework for
scientific

evaluation of studies and causality determination?

I used a few different methods to evaluate the results of the literature
search. First I read through all of the references cited at the end,
noting the frequency of 2006-2008 references, and selecting in
particular titles that appeared highly relevant to the analysis of
health hazards. From the large numbers of 2007 references and the
occasional 2008 citation, it is clear that the authors have brought
their literature searches up to date as of the present. I then retrieved
the abstracts for about a dozen interesting recent references and
checked how the revised ISA reported on them in the main text or tables.
In every case I found that the description in the text or tables
corresponded reasonably to the abstract.

[]{#__RefHeading___Toc201991117 .anchor}[Comments from Dr. Donna
Kenski]{.underline}

*Charge Question 2: To what extent are the air quality characterizations
and analyses clearly communicated, appropriately characterized, and
relevant to the review of the primary NO2 NAAQS? Are the properties of
ambient oxides of nitrogen appropriately characterized, including
spatial and temporal patterns and relationships between ambient oxides
of nitrogen and human exposure? 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?*

This second draft ISA is much improved from the first draft ISA and it
was gratifying to see the panel's suggestions from the last review
incorporated to a large extent. The discussions of measurement
interference and its spatial and temporal variability were much better,
as was the discussion of ambient concentrations of NO2. The paragraph on
NO2 increases in other countries was somewhat irrelevant (p. 2-13, lines
25-30) and could be deleted or moved to the section on policy-relevant
background concentrations. Sec. 2.4.5 on concentrations of NOz species
is still quite limited and I think more information on these various
species and their interrelationships would be helpful. Data are
admittedly sparse but there are more papers that could be usefully
summarized. Two that I know of are:

[*Continuous wet denuder measurements of atmospheric nitric and nitrous
acids during the 1999 Atlanta
Supersite*](http://www.sciencedirect.com.proxy.cc.uic.edu/science?_ob=ArticleURL&_udi=B6VH3-47X1PMP-7&_user=186797&_coverDate=03%2F31%2F2003&_alid=731327087&_rdoc=6&_fmt=high&_orig=search&_cdi=6055&_sort=d&_docanchor=&view=c&_ct=9&_acct=C000013678&_version=1&_urlVersion=0&_userid=186797&md5=95d495b2e43dc68a7956e2cf86f08d8a),
Atmospheric Environment, Volume 37, Issues 9-10, March 2003, Pages
1351-1364\
Zhang Genfa, Sjaak Slanina, C. Brad Boring, Piet A. C. Jongejan,
Purnendu K. Dasgupta

[*Measurements of gaseous HONO, HNO3, SO2, HCl, NH3, particulate sulfate
and PM2.5 in New York,
NY*](http://www.sciencedirect.com.proxy.cc.uic.edu/science?_ob=ArticleURL&_udi=B6VH3-48KMCYN-1&_user=186797&_coverDate=06%2F30%2F2003&_alid=731442368&_rdoc=2&_fmt=high&_orig=search&_cdi=6055&_sort=d&_docanchor=&view=c&_ct=35&_acct=C000013678&_version=1&_urlVersion=0&_userid=186797&md5=8331325280032b1381b2f54153fd80bb),
Atmospheric Environment, Volume 37, Issue 20, June 2003, Pages
2825-2835,\
Abdul Bari, Vincent Ferraro, Lloyd R. Wilson, Dan Luttinger, Liaquat
Husain

Section 2.2.1 on sources of NOx still needs to be augmented with a
*shortened* version of Annex Table AX2.6-1 (the old AX2-3) giving
quantitative data on emissions contributions from major source
categories. Fig. 2.2.1 is nice but just doesn't convey any quantitative
sense of emissions.

The reorganized Sec. 2.5 on exposure is a much better integration of the
relevant information.

In the previous CASAC review, we requested that chapter 2 in particular
include section summaries, as was done so effectively in later chapters.
It doesn't seem like this has been accomplished, but it would help tie
up this chapter and make the conclusions drawn from it in Chapter 5 more
obviously connected to the relevant sections.

Aside from these fairly minor tweaks, I found this section of the ISA
satisfactory and I think (together with the supporting documentation in
the annexes) that it provides a suitable basis for the Risk and Exposure
Assessment.

Other comments:

Chapter 5 is great; it gave a fair and balanced presentation of the
studies reviewed and the conclusions drawn. Very helpful.

In our review of the first draft ISA, we requested that EPA consider
multipollutant approaches to managing air quality. While acknowledging
that changing the traditional one-pollutant-at-a-time approach is likely
to take considerable time and effort to implement, I'd like to encourage
EPA to move in that direction with the ISA process. The inclusion of
data for multiple N species as well as some sulfate and oxidant
chemistry was a step forward.

p\. 2-17, Fig. 2.4-6d, title of figure should be Weekend, rather than
Weekday

[]{#__RefHeading___Toc201991118 .anchor}[Comments from Dr. Steven
Kleeberger]{.underline}

The document reads very well. I have very few comments that would not be
considered only editorial- or style-related. However, I found the
Figures 3.1-1 and 3.1-2 to be somewhat confusing. While the information
presented is very useful, I would suggest that the data would be better
presented in tabular form rather than figures. At first glance, the +/-
on the y-axis suggests a degree or quantitation of positive or negative
finding. It would be simpler simply to list the studies in a table with
negative and positive categories.

[]{#__RefHeading___Toc201991119 .anchor}[Comments from Dr. Timothy
Larson]{.underline}

General Comments:

I am limiting my comments to the exposure issues covered in Chapter 2
and parts of Chapter 6. In general, this document is much improved on
the first draft and the authors should be commended. The issues raised
by the committee upon review of the first draft have been addressed for
the most part. I think the Chapter 6 summary of the topics in Chapter 2
is reasonable and consistent. The discussion of NO2 infiltration seems a
little long.

However, I disagree with the statement beginning on page 2-31 about
street canyons being complicated and modeling their effects to be
"highly problematic". In fact, recent work has shown that both CFD and
much simpler integral models provide reasonable predictions (c.f. Di
Sabatino S, Buccolieri R, Pulvirenti B, et al. (2008) *Atmos.
Environ.*** ** 41 **(**37) **,** 8316-8329). In addition, there are a
number of recent studies showing good prediction skill with these
simpler models (c.f. Mensink C, Cosemans G (2008) *Env. Modeling &
Software.*** ** 23 **(**3) **,** 288-295; Berkowicz R, Ketzel M, Jensen
SS, et al. (2008) *Env. Modeling & Software.*** ** 23 **(**3)**,**
296-303; Ghenu A, Rosant JM, Sini JF (2008) *Env. Modeling &
Software.*** ** 23 **(**3)**,** 314-321). This seemingly minor point is
in fact rather important to the interpretation of the spatial
heterogeneity of NO2 in built up urban areas. These studies and others
(e.g. Vardoulakis S, Gonzalez-Flesca N, Fisher BEA, et al. (2005)
*Atmos. Environ.*** ** 39 **(**15) **,** 2725-2736) indicate that street
canyons are similar in NO2 concentrations to on-road values in otherwise
open areas, i.e., enriched by about a factor of 2 above measurements
taken away from the road in more open areas. Including a discussion of
the skill level of these models in similar applications and a multiscale
approach that includes street canyons seems appropriate (c.f. the Danish
forecast system at
[[http://www2.dmu.dk/1_viden/2_Miljoe-tilstand/3_luft/4_spredningsmodeller/5_Thor/default_en.asp]{.underline}](http://www2.dmu.dk/1_viden/2_Miljoe-tilstand/3_luft/4_spredningsmodeller/5_Thor/default_en.asp)).

This adds another dimension to the exposure assessment, namely the fact
that pedestrians spend time walking in these canyons and having windows
opening onto these canyons and can therefore experience exposures for
equal or greater times than they do on roads in transit (they may not
even own cars in dense urban areas).

Specific comments:

Page 2-25 line 26 and page 2-26 line 6: Text seems to arrive at
different conclusions about passive samplers without comment.

Page 2-35 line 13: This sentence needs a reference that indoor pollution
affects outdoor levels.

Page 2-49 line 6: Reference to Table 2.5-5, but table does not exist nor
does Table 2.5-6.

Page 2-51 line 16: The NO2 east-west spatial variation in greater Los
Angeles varies broadly with distance from the coast due to well known
meteorological and chemical phenomena. NO2 levels in Riverside are
determined in large part by pollution transported from upwind urban
areas to the west.

Page 2-55 Table 2.5-9 is presented without comment.

[]{#__RefHeading___Toc201991120 .anchor}[Comments from Dr. Kent
Pinkerton]{.underline}

[Agency Charge Question 3]{.underline}. 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? What are the views of
the Panel on the conclusions drawn in the draft ISA regarding the
strength, consistency, coherence and plausibility of NO2-related health
effects?

General Comments:

The organization and improvement of the second draft ISA document for
Oxides of Nitrogen -- Health Criteria, compared to the original draft
are excellent. The revised document has addressed a number of concerns
expressed by CASAC for the original draft document. In my opinion, the
content, flow, presentation and logic of materials are well done. New
publications from the scientific literature since 1993 incorporated into
this ISA draft are extensive and impressive. The majority of these
papers cited in the document are highly relevant from an environmental
perspective. A number of the new toxicology documents provide biologic
plausibility, however, exposure concentrations in these studies are
typically well above ambient conditions (greater than or equal to 5
ppm). The addition of new epidemiologic and human clinical studies to
this second draft of the ISA is highly impressive and far exceeds new
animal toxicology studies. However, those new toxicology studies
included demonstrate effects as low as 0.4 ppm (in a lung vitamin
deficit model in the guinea pig). Airway hyperresponsiveness following
repeated NO2 exposure at 1 and 2 ppm for up to 12 weeks in guinea pigs
has also been demonstrated. Each of these studies adds further validity
for the biologic plausibility of NO2 health effects. Human studies also
provide strong evidence for health effects at NO2 levels in the
0.04-0.08 ppm range as 1 hour peaks. New data to demonstrate greater
sensitivity to NO2 in the form of increased airway responsiveness
(approximately 10-fold) for asthmatics vs. healthy individuals further
emphasizes the importance for consideration of susceptible populations
and children in consideration of setting the NO2 standard
recommendation. In summary, the second draft of the ISA document
represents an excellent compilation and reasonable interpretation of new
research findings that should greatly aid in formulating decisions for
setting the next criteria standard for oxides of nitrogen. Summary
statements made for many of the sections under Chapter 3 were very
helpful. I feel the conclusions made in the ISA document using
integrative analysis of epidemiologic, human clinical and animal
toxicological evidence provide strength, consistency, coherence and
plausibility for NO2-related health effects.

Minor Comments:

1)  P 2-35, line 15 Will increased use of biomass fuels lead to an
    increase in NO2 concentration in the future?

2)  P2-40: this section provides an excellent detailed description on
    the relationship of personal exposures to ambient concentrations.

3)  P 2-50 Is there a reason for no section labeled as 2.5.7?

4)  P 3-6: Excellent table to summarize the proposed mechanisms whereby
    NO2 exacerbates airway symptoms.

5)  P3-12: Figure 3.1.1: It would be helpful to more completely label
    the y axis. Perhaps "observed response" could be added. At first
    examination, the meaning of the symbols + and -- is not clear.
    Does + mean increased or adverse response; does -- mean no change
    from control or a reduction of response from control?

6)  P3-18: Figure 3.1.2: Same comments as for Figure 3.1.1., although
    the text referring to this figure clarifies the meaning of + and --
    for the y-axis.

7)  P3-25: Excellent comparison of NO2 concentrations leading to
    increased airway responsiveness in healthy and asthmatic humans and
    animals.

8)  The intervention study of Pilotto et al (2004) provides striking
    evidence for health effects among asthmatic children for NO2
    concentrations at extremely low levels. The only concern for the
    interpretation of this study remains the possibility that ultrafine
    particles, rather than NO2 may be driving this effect.

9)  There appears to be strong evidence of NO2 effects on
    physician-diagnosed asthmatic children (Pilotto et al., 2004).
    Although it may be difficult to completely rule out the effects of
    ultrafine particles, multi-pollutant models continue to demonstrate
    robust NO2 health effects when adjusting for other pollutants such
    as CO, O3 and PM.

10) P 3-50, line 29: the term "not sensitive" in this sentence is
    unclear. Does this mean co-pollutant regression analysis does not
    work or that other co-pollutants do not confound NO2 effects?

11) Excellent studies are included throughout the document to
    demonstrate positive associations between ambient NO2 concentrations
    and health effects among young children and older adults (65+
    years).

12) There continues to be a concern relative to confounding of
    co-pollutants, as well as NO2 being a surrogate for other
    pollutants. However, there appears to be consistent data throughout
    more recent publications to suggest NO2 can elicit health effects at
    current ambient levels.

13) Susceptible populations are clearly an important group to consider
    for NO2 health effects. The Southern California Children's Health
    Study clearly points to NO2-related changes with reduction in lung
    growth function in children.

14) Excellent summary and integration of scientific evidence for all
    aspects of health effects of NO2 throughout the document.

    []{#__RefHeading___Toc201991121 .anchor}[Comments from Dr. Edward
    Postlethwait]{.underline}

1\. In general the document shows considerable improvement over the
initial draft and thus the EPA staff should be commended.

2\. The issue of endogenous NO2 generation appears not to have been
addressed as a potential contributor to uncertainties with regard to
data interpretation, thresholds, and assessing posited mechanisms of
action. This is especially important for three of the posed question in
section 5.1 regarding has new information altered support for occurrence
of health effects, at what levels of NOx do health effects of concern
occur, and plausibility of adverse health effects.

3\. On page 2-61, the section dealing with modeling NO2 dose should be
clarified with regard to NO2 flux. The term "NO2 flux to air-liquid
interface" does not accurately describe the net movement of NO2 from the
intrapulmonary gas phase into the surface lining layer, or potentially
epithelial cells. If NO2 flux occurs as written, there is a disconnect
between the sites of focal injury and mass transfer from the
intrapulmonary gas phase.

4\. To this reader, there is a consistent ambiguity in the way NO2
thresholds are presented. As written, it is not especially clear in the
document whether the lack of documented thresholds means that NO2
related effects can be extrapolated to zero \[NO2\] in a linear fashion
or that threshold concentrations have not been identified due to the
numerous confounding factors. The document would be strengthened if this
issue was revised throughout to unequivocally present a consistent
interpretation.

5\. It is somewhat curious that the document supports causal
relationships between NO2 exposure and acute but not chronic health
effects. If NO2 is able to induce short term effects at the denoted
concentrations, one would anticipate that individuals residing in the
same geographic locale would also experience long term impacts. Thus, it
may be useful to consider whether this represents an inconsistency or is
due to any number of mitigating factors.

6.  Per discussions from the initial review meeting, the document does
    not extensively link the potential occurrence of short term NO2
    spikes and health outcomes. A more thorough discussion in the
    summary chapter (Chapter 5) of the possible occurrence rates, NO2
    spike concentrations and thus exposures relative to the current long
    term average values, and observed effects would strengthen the
    document and provide the impetus to help support a shorter term
    standard if warranted.

    []{#__RefHeading___Toc201991122 .anchor}[Comments from Dr. Armistead
    Russell]{.underline}

**Post-Meeting Amendment**

Given the redirection of the REA, I think it is particularly needed that
the ISA highlight (further stress and discuss) epidemiologic studies
that have included multi-pollutant models with NO~2~, particularly those
that have included other combustion byproducts like EC, Total Carbon
(TC) and CO. In doing so, they need to provide caveats on the
interpretation of such studies, but also recognize their importance.
They should note that PM2.5 and O3 are poor indicators for exposure to
combustion emissions. If there are studies demonstrating how PM might
act as a carrier for NO~2~ that should also be assessed.

**Original**

Again, like the first draft, the 2^nd^ Draft ISA is an effective
document for providing the information needed to conduct the risk and
exposure assessments. It is substantially improved from the last draft.
However, I was a bit disappointed that some pieces did not get changed
between the 1^st^ and 2^nd^ drafts.

1.  I still think there should be a table of sources in Section 2.2.1.
    There is no Table 2-3 in the Annex: it is Table 2.6-1. Having a
    table in the ISA might help OAQPS note that their commercial air
    craft estimate for Philadelphia does not look right. They should
    also note that being an elevated source also leads to the emissions
    being more dispersed. Indeed, the highest NO2 levels found in cities
    are not from EGUs.

2.  In the chemistry section, a bit more should be said about NO to NO2
    transformation as NO2 is the apparent indicator species.

3.  The measurement section is still a bit biased when highlighting the
    Mexico studies. Mexico City is a unique place, so I tend to downplay
    those results. Switzerland is more appropriate. There really should
    be some US-based studies.

4.  The section on ambient concentrations presents an appropriate level
    of information on NO2 levels in the US at the country/urban scales,
    but should provide more information on NO at the same time. I would
    treat them together, with much of the transport discussed as
    transport and decay of NOx. If one looks at the REA, an important
    issue is roadway levels. This is hardly treated here. This section
    should discuss roadway levels of NO2 and NO, as opposed to covering
    it later in 2.5.4. A major missing component of ambient
    characterization is that of other pollutants. It is important to
    show the correlation between NO2 and some other species (e.g., EC)
    and I think it belongs here as opposed to later in 2.5.8. It would
    seem to fit more naturally here.

5.  2-31. It is not apparent that a 15 m monitor will lead to an
    underestimate of what people are breathing given that in cities
    (e.g., NY) air inlets in to homes may be that high. Also, as noted
    in the REA, very few of the monitors are at 15m. Give a balanced
    presentation.

6.  2.5.4: This section is fine, but could go deeper to provide the
    detail that is ultimately needed in the REA. It should discuss the
    conversion of NO to NO2 with information as to conversion rate and
    how quickly NO falls off and NO2 rises. The current REA uses little
    from this section, instead deriving its own fit to the decay. It is
    also not apparent how the REA used the information about intrusion
    of the vehicles own exhaust in to the cabin.

7.  2.5.8. This is a very important section, and I think it does a
    reasonable job of providing the type of information needed to see
    how NO2 correlates with other important species, including EC. One
    of the problems with having this section much later in the document
    is that they then go over points discussed earlier (e.g., diurnal
    variation).

8.  Conclusions:

    a.  P5-3, L19. In the body of the ISA, they never use 25%\... even
        though I think the 50% value given earlier is extreme, whatever
        number chosen here should be supported in the ISA.

    b.  P5-3, L21-23. I would not add "are difficult to predict". CMAQ
        can do so.

    c.  5-3, L30: Precise is not the correct word here. Possibly
        accurate, but I would say that it may be accurate enough for the
        job at hand, so I would back off on this statement altogether.

    d.  P5-5, L7: While true, we find out in the ISA this is not a real
        problem since most monitors are not at 15m.

Something to think about for future ISA's: you should have a section
discussing the models that might be appropriate for estimating ambient
levels and, possibly, exposure. In this case, it would be AERMOD and
APEX. This section should provide the model formulation, inputs and an
evaluation of its capabilities. Modeling is discussed to some degree in
the NOx-SOx SNAAQS ISA, which is good (though the committee wanted more
evaluation).

[]{#__RefHeading___Toc201991123 .anchor}[Comments from Dr. Jonathan
Samet]{.underline}

[General Comments:]{.underline}

The second draft ISA for oxides of nitrogen (NO~x~) is improved and
responsive in many respects to concerns raised by CASAC members,
including myself, at the review of the first external review draft. The
Agency's staff has attempted to be responsive in setting out a better
framework for evidence identification, evaluation, and synthesis. I am
hopeful that continued progress will be made to sharpen this process, in
order to address issues that are still unsolved. Additionally, I think
that the peer review process would be enhanced generally by the
preparation of a note to CASAC that sets out the Agency's responses to
major concerns raised by the CASAC reviewers. Such responses would be
consistent with usual practice of peer review, and would provide a
trail, documenting how comments made by CASAC were taken into account.

My responses to the charge questions from the Agency follow, and the
attached table lists specific comments.

[Charge Question 1:]{.underline}

In response to comments with regard to the Agency's approach to
literature identification, study selection, and synthesis of the
evidence, as well as causal inference, an extensive annex has been
prepared that reviews a number of relevant frameworks. The background is
a useful foundation for justifying the selected approach. The Agency has
made a number of changes in Chapter 1 that are responsive to prior
critiques. In particular, there is a description of literature
selection, an approach to evaluating evidence for inferring causality is
provided, and a reasonable set of descriptors of the strength of
evidence for causation is offered.

On reading the draft ISA, there has been some impact throughout the
document of having a better prepared first chapter and this framework.
However, the sections that synthesize the evidence are still somewhat
loosely written, and do not systematically apply the guidelines offered
by Bradford Hill, and adopted by the Agency. (Note, that these should
not be renamed as "decisive factors", a misnomer). Too often, sections
that are offering judgments as to the strength of evidence use such
language as "taken together or "integrating" without a more specific
application of the criteria offered by Hill. Nonetheless, the new
Chapter 1 and the approach set out represents an advance over the
earlier draft. Discussion is needed as to whether the list developed by
Hill should be replaced with the shorter set used in the Surgeon
General's Report. Perhaps, a comparison could be made with a test case.

One issue that is left unaddressed is publication bias, a reasonable
concern given that many studies address the health effects of air
pollution and employed multivariable models to attempt to isolate the
effects of particular pollutants. There must have been some tendency on
the part of investigators to report positive associations. This topic
needs to be mentioned, as the existence of publication bias would be
difficult to set aside for some of the epidemiological studies.

[Charge Question 3:]{.underline}

This charge question relates to the integration of evidence from the
various lines of investigation. Of particular concern is the
plausibility of effects observed in epidemiological studies in the
context of animal and human toxicology. There is no doubt that high
levels of NO~x~ can injure the lung and other organs. For setting the
NAAQS, the plausibility of effects at ambient concentrations is
particularly relevant. I am concerned that the draft ISA has only
partially addressed the plausibility of effects at current ambient
concentrations and at those investigated in a number of the
epidemiological studies. The ISA appropriately notes that both clinical
and animal studies are carried out at doses well above those that are
typical for population exposures. The document would be improved if more
attention could be given to considering the relevance of mechanisms
observed at higher levels to effects at ambient levels.

[Charge Question 4:]{.underline}

Chapter 4, "Public Health Significance", provides as overview of
populations potentially at increased risk from exposure to NO~x~.

The listing of susceptible subgroups covers those of both particular
relevance and of general relevance. The various groups identified are
appropriate, although I have concern that EPA will follow the same
template for all pollutants without giving sufficient consideration to
the relevance of particular subgroups for particular pollutants.

[Charge Question 5:]{.underline}

The revised document is greatly improved. It identifies health effects
associated with exposure to nitrogen oxides and the strength of evidence
supporting causality of associations. It makes an attempt to assess
whether effects would be expected at current ambient concentrations.
This is one of the weakest aspects of the current draft. Consider, for
example, the conclusory language from page 5-22: "integrating across the
epidemiologic human clinical and animal toxicological evidence presented
above, we find that it is plausible that current exposures can result in
adverse impacts to public health at ambient concentrations below for
current NAAQS for NO~2~." This sentence addresses the most critical
matter around the need to revise the NAAQS: are there effects being
observed at current ambient concentrations? The sentence addresses
plausibility. Some statement with regard to the degree of certainty is
needed, no matter how difficult it may be to characterize uncertainty.

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

  ------------------------------------------------------------------------
  **Page    **Line   **Comment**
  \#**      \#**     
  --------- -------- -----------------------------------------------------
  1-7       5        Not certain this is true!

  1-10      2        Along with considerations of plausibility

  1-10      24       That may lead to confounding.

  1-10      28       "...homogeneous groups ~~with~~ of the
                     confounding..."

  1-12      22       What does this mean?

  1-13      1        Note, the following discussion refers to statistical
                     models. The word "model" has many uses.

  1-14      23       Should not label as "decisive factors", these are
                     guidelines.

  1-18      8        Because of the experimental manipulation of exposure.

  1-18      16       There should not be uncertainty about design and
                     execution.

  3-1       24       "obscured" What does this mean?

  3-2       3        "partitioning the variance" Not the same as
                     estimating an effect.

  3-2       13       "effects observed at O-..." On what basis?

  3-2       19       "health effects (and markers of injury) that..."

  3-3       9        Could be true, but supporting references??

  3-7       5        At what concentration?

  3-10      1-2      This is a very sweeping claim. What does it mean?

  3-17      4-7      Aren't there more informative ways to show the data,
                     e.g., as a forest plot.

  3-19      29       In what way are these taken together?

  3-20      29       Not the right place for research recommendations.

  3-24      17-19    Speculation; should be deleted.

  3-26      5        Isn't this inconsistent with an NO~2~ effect?

  3-40      4        Well-recognized

  3-46      6        "pneumonia" is a LRI

  3-46      19-22    "Collectively..." a conclusion---out of place

  3-62      15-18    Where do the authors stand on this possibility?

  3-101     1        Certainly, the possibility that traffic-related
                     carcinogens are the etiologic agent needs to be
                     raised.

  3-106     11       Why confounding, implying underlying causation?

  3-107     13       "(2000..." ) and earlier

  4-5       29       Be careful not to overinterpret

  5-1       28-29    ?

  5-22      21       "Integrating across the epidemiologic" How? What does
                     this mean?

                     
  ------------------------------------------------------------------------

[]{#__RefHeading___Toc201991124 .anchor}[Comments from Dr. Richard
Schlesinger]{.underline}

Overall, this is a very good document that clearly integrates the
essential concepts required to make a judgment related to health effects
from NO2.

p\. 1-16, line 22. It may be better to change the first bullet to
"sufficient to infer a definite causal relationship" since this would
make it more consistent with the second bullet indicating a "likely"
causal relationship. The way it is written, it is not clear what the
difference is between "causal relationship" and "likely causal
relationship."

p\. 5-13, line 15. The 5 ppm exposure is quite high and its relevance to
the document is not clear.

p\. 5-16, lines 13-14. Does this sentence mean that the effects observed
could have been due to NO2 or are most likely due to confounder
pollutants?

Table 5.3-1. This is an excellent table.

[]{#__RefHeading___Toc201991125 .anchor}[Comments from Dr. Christian
Seigneur]{.underline}

*Charge question 2:*

*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 second external review draft has been considerably improved in that
regard. For example, Figure 2.2-1 is more accurate; the variability of
the NO~2~ fraction of NO~x~ emissions is now correctly discussed, and
the spatial variability of NO~2~ concentrations near sources (in
particular, roadways) is properly described.

*Are the properties of ambient oxides of nitrogen appropriately
characterized, including spatial and temporal patterns and relationships
between ambient oxides of nitrogen and human exposure?*

The spatial and temporal patterns of NO~x~ and NO~2~ are appropriately
described. As mentioned above, the strong spatial gradients observed
near roadways are discussed. The temporal variability of NO~x~ and NO~2~
concentrations is also well characterized with sufficient detail being
provided in the Annex (e.g., diurnal and seasonal variability).

*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?*

There is one aspect of the link between atmospheric science and
exposure/health effects that needs to be better discussed in the ISA.
Currently, measurement error is highlighted early on in the document
(Section 1, p-1-11) as important when adjusting for spurious
associations. The difference between true and measured ambient
concentrations is identified as one of the components of measurement
error. Such measurement errors are then discussed in detail in Section
2.3 for outdoor measurements and in Section 2.5.2 for indoor
measurements using passive samplers. Some estimates of measurement
uncertainty are provided. For outdoor measurements with the Federal
Reference Method (FRM), an average interference from NO~z~ compounds of
22% is given for Mexico City data with peak interference of 50%. A
comparative study in Switzerland is reported to have shown average
errors of 10% in winter and 50% in summer. This section concludes that
the interference is likely to be on the order of 10% or less in winter,
but much larger in summer. It is also stated that the interference from
NO~z~ compounds is less significant near the emission sources (because
there has not been enough time for NO~z~ species formation). Passive
samplers used in individual exposure studies are described in Section
2.5.2 as being within 10% of the FRM.

The epidemiological studies presented in Section 3 have used in most
cases NO~2~ measurements from FRM instruments or passive samplers.
Therefore, one may imply that there may be significant uncertainties
associated with the results of those studies because of the FRM
interference errors discussed in Section 2. However, this aspect of the
health effect uncertainty does not appear to be discussed. In reality, I
anticipate that most NO~2~ exposure occurs near emission sources where
NO~z~ concentrations are low and, therefore, interference error is
small. Also, the seasonal variability of NO~2~ concentration shows that
in most cities higher concentrations occur in winter when the
interference error is 10% or less. It may, therefore, be possible to
consider that the NO~2~ measurement error is not a major source of error
in health effects studies. However, such a point needs to be made
clearly in the ISA. One possibility is to provide a more definitive
discussion of the implication of the interference of the FRM at the end
of the introduction of Section 2.3 (p. 2-9). The fact that NO~z~ species
concentrations are low when NO~2~ concentrations are high (near emission
sources, in winter) and the reasons why (not sufficient time for
reaction, low photochemical activity) should be explicitly stated. Then,
the implications for the health effects studies need to be articulated
clearly.

**Annex 2.7.1. Chemistry-transport models**

This Annex section has been rewritten and a discussion of local-scale
dispersion models has been added. This Annex section is overall well
written and very useful. There is, however, one part, which requires
some revision. On p. AX2-67 (at the end of the discussion of
local-dispersion models), it is stated that (1) emissions from roadways
are usually not in steady state and (2) that buoyant plume rise differs
for point and line sources. The unwritten implication is that AERMOD,
the model used in the exposure and risk assessment, would not be
appropriate to simulate NO~2~ concentrations from roadways because (1)
it uses steady-state assumptions and (2) it is a point source model and
does not treat, for example, vehicle-induced turbulence. The text then
goes on to discuss CALPUFF, a non-steady-state model that can treat
dispersion from surface sources. The implication is that CALPUFF is a
better model to simulate NO~2~ concentrations downwind of line sources
such as roadways. This paragraph needs to be rewritten because (1) the
limitations mentioned for AERMOD are not entirely correct and (2) the
description of CALPUFF as a better model for line source dispersion is
incorrect.

In my earlier comments on the Methods document, I raised some concerns
regarding the use of AERMOD for line source modeling and asked why a
line source model such as CALINE would not be used. EPA replied that
CALINE was no longer supported by the developer and that AERMOD was an
acceptable model because it could be adapted for line sources. Although
further development of AERMOD to become a true roadway dispersion model
is warranted, I agreed with EPA that, given the dispersion models
currently available, AERMOD was an appropriate choice. The statement
made in the Annex regarding the non-steady-state nature of roadway
emissions is not relevant because AERMOD is used to calculate downwind
concentrations within a few hundred meters from the roadway and the
travel time will be less than one hour (i.e., the time typically used
for meteorological and emission inputs). The statement regarding the
inappropriate treatment of the initial plume dispersion characteristics
for a roadway in AERMOD is misleading as CALPUFF does not treat such
roadway initial plume dispersion either. Furthermore, one must note that
the current CALPUFF versions that are publicly available (e.g., versions
5.8 and 6) include a coding error that leads to incorrect NO~2~
concentrations near the source.

Therefore, the last two sentences of that paragraph ("In contrast, there
are models that are non-steady-state...") should be deleted and the
limitations of AERMOD when applied to line sources such as roadways
should be rewritten in a more objective light.

[]{#__RefHeading___Toc201991126 .anchor}[Comments from Dr. Elizabeth
"Lianne" Sheppard]{.underline}

*Final comments*: Generally the document is much improved and the
revisions have been responsive to previous CASAC comments.

*Charge question 1:*

Conceptually the framework outlined in Chapter 1 is on target. However
it reads very much like a preliminary incomplete draft. Section 1.6
needs to be thoroughly revised. It has many of the right concepts
mentioned, but often briefly, incompletely, or without good
justification for the proposed modifications. For instance, Annex AX1
contains a thorough compilation of previous work on evidence
classification, but details on the translation into Chapter 1 are absent
-- there is no evaluation, interpretation, or justification for the
modifications proposed on page 1-16 of the ISA. As another example Table
1.6-1 is an adaptation from two previous documents, but the details of
and reasons for the adaptation are not discussed in the Chapter or
Annex.

Detailed specific comments:

-   P 1-8 section on scientific evidence used for identifying causality:
    There is a brief discussion of features of study designs and a later
    discussion of details of study designs (p 1-10). These should be
    combined. Also key points are missing. One is that the challenge
    with experimental studies is to create conditions that reflect the
    complexity of the naturally occurring exposures. Another is that
    observational studies represent conditions experienced by the
    population but inference from them is limited because of the absence
    of experimental intervention. Another is to mention cross-species
    extrapolation.

-   P 1-9: The footnote seems out of place in this chapter since the
    notation and concepts haven't been introduced.

-   P 1-10 l 2: Is this what is meant?: "Developing evidence for going
    beyond association to causation involves integration of multiple
    sources of information into a coherent paradigm."

-   P 1-10 l 10: Revise sentence. What does "Done properly and setting
    aside randomness" mean?

-   P 1-10 l 15: But there are problems -- e.g. washout.

-   P 1-10 l 18 Experiments are stronger causally than observational
    studies tub much more limited in the realistic conditions that can
    feasibly be studied.

-   P 1-10 l 21 Confounders are only one consideration of causal
    inference from observational studies.

-   P 1-10 l 25 Study design, e.g. matching is another tool.

-   P 1-11 measurement error discussion is derived from the Zeger et al
    paper (not cited) and applies to the time series study design. It
    does not apply to all observational studies of air pollution, but
    the literature as yet does not have similar papers for other
    designs.

-   P 1-11 l 18 Replace "producing the findings" with "biasing the
    results"

-   How much should section 1.6 be a general review vs. specific
    application to the air pollution context (e.g. table 1.6-1)? It
    would be safer to directly cite the sources and then comment on
    features for this application in the text.

-   P 1-14 l 8 How about "Model averaging attempts to incorporate model
    selection uncertainty into the target parameter estimate..."

-   P 1-15 l 3-5 None of the criteria are about statistical
    significance.

-   Publication bias should be addressed explicitly. Air pollution
    studies estimate small effects so some issues become relatively more
    important in this area: model selection, subgroup analyses,
    appropriate design and analysis approach (e.g. referent selection in
    case-crossover studies or panel study approach to analysis).

-   Table 1.6-1 Replace "decisive factors" and revise explanations, e.g.
    #8 drop reference to observational studies.

-   AX1-5,1-7 criteria for study selection: All studies are more or less
    successful on these criteria. Consider how to best address
    systematically evaluation and discussion of these for individual
    studies. I suggest moving towards a 1-2 page evaluation for each key
    study to be included in the annex. This evaluation will be much more
    detailed than the current appendix tables and addresses study
    features.

-   AX1-8 l 5-6 Is this regardless of analysis and reporting of results?
    For instance, an analysis that adjusts for measurement error will
    have wider confidence bands than one that doesn't. Should the study
    that goes beyond common practice by adjusting for measurement error
    be given less weight?

-   AX1-9 l 21: Stay away from statistical significance as a criterion.
    Magnitude and precision of estimates should be enough.

-   AX1-9 l 26: Do you mean natural experiments?

*Charge question 2:* Air quality and exposure

The discussion of correlations is much improved although I would like to
also see the formulas documented (e.g. in the annex) instead of just
described. However, now that the discussion is clearer, it becomes even
more questionable in my mind whether the comparisons across studies and
study designs are useful. Correlations are standardized quantities that
depend on multiple features of the data. In a correlation, not only is
the linear "relatedness" (covariance) of the two quantities important,
but so is the variability of each. Thus two estimates of correlation
could be very different just because one is restricted to a single
season (with less variability) while the other captures data from an
entire year. Since I expect this feature is extraneous to the
interpretation goal, should it be part of the comparison? More work is
needed to make the comparisons across studies, populations, pollutants,
types of correlation, etc. really useful. This is a difficult task since
the literature doesn't give clear guidance on how to summarize these
studies. That said, I was surprised to see an apparently reasonable
summary of this information in Chapter 5.

Monitor siting is an important and often hidden feature in all of the
NO2 data. It could be critically impacting the epidemiological studies
and their interpretation. This feature potentially pervades much of the
summarized literature and could be affecting conclusions. Any revisions
to the document that can be done to directly and openly address monitor
siting and its effects on results and interpretation will improve the
ISA. Unlike PM, oxides of nitrogen vary dramatically as a function of
distance from road and some monitors are sited near roads. Plus much NO2
data are being analyzed at the hourly time scale. Low correlations
between monitors could be completely driven by the local sources. For
instance, the analysis summarized in Table AX3.2-2 is focused on spatial
variability but does not identify the locations or siting features of
the monitors. Scatterplot summaries would also be revealing,
particularly appropriately included in the annex. Further analyses of
data may suggest features that should be highlighted in these
comparisons.

Specific comments:

-   Figures 2.5-4: Clarify the meaning of the sampling time (is this
    duration or averaging time?), the meaning of the information in the
    Fisher's Z-transform column, and that the reported correlations are
    shown on the native (not transformed) scale. Consider separating
    figures by study design or type of correlation reported (including
    averaging time) rather than location of study. Sorting by high vs.
    low air ventilation season may be important also.

-   Section 2.5.6: Incorporate understanding of monitor siting into this
    discussion as appropriate.

-   2-45 l 11-13: Is this a better sentence?: "The relationship between
    personal ambient NO2 exposures and ambient NO2 concentrations found
    in different types of exposure studies have distinct implications
    for different types of epidemiologic studies.

-   2-45 l 30: I wouldn't classify the relevant features of exposure to
    be the same for time series and long-term cohort studies. The cohort
    studies are mostly relying on spatial variation in a long-term
    average pollutant while the time series studies are relying on
    day-to-day variation in daily average.

*Charge question 3:* Integration of evidence about health effects and
conclusions regarding health

I found the integration and presentation of evidence in Chapter 3 to be
generally good. However there are a number of details in the
presentation I think need to be clarified to support the intent of the
chapter. It is also critical that staff continue to refine and improve
the information presented in the Annex tables. (I recognize this
represents a massive effort.) The organization of these tables has been
much improved, but I did not find that they include much more pertinent
information. In trying to discern my agreement with the interpretations
in Chapter 3 I often found I wanted to evaluate more detail on a
particular study but this wasn't available in the annex. I was trying to
answer questions such as "did this study properly adjust for
confounding", or "what is the seasonal variation in the data". There are
also some misleading features in the uniform approach to summarization
(such as the change in a 4-point symptom scale in the Chauhan et al
(2003) study that appears to be reported as an OR in the appendix and
does not include units in Chapter 3 (3-5 lines 21+)). Another important
feature of the Chauhan et al study that is discussed in Chapter 3 but
completely absent from the Annex summary is that it was conducted over a
13-month period. In looking ahead to future iterations of this ISA
process, it is important to consider how to revise the approach. One
suggestion is to prepare an annex to the annex with a much more thorough
and less constricted summary of each study. Quite likely at least a page
or more of abstracted information will be needed for each study, at
least for the studies that end up providing the greatest weight of
evidence for the inference. Finally, both for the current version and in
future versions, better indexing and cross-referencing is needed so the
supporting information can be found efficiently.

The conclusions brought forward into chapter 5 and summarized clearly in
Table 5.3-1 looked generally appropriate. I ask staff and CASAC to
consider whether it is worth also listing health outcomes that have not
been studied in this table.

Specific comments:

-   Make sure all figures and other summaries include the increment of
    NO2 (or other pollutant as appropriate) for the RR/OR estimate. This
    is not done consistently throughout the document.

-   Please downplay the apparent use of statistical significance as a
    criterion for scientific importance throughout. In that vein, change
    the y-axis for Figure 3.1-2 to not be an evaluation of statistical
    significance. The new version of Figure 3.1-1 appears to be more
    informative but I wonder if the graphic misleads in the ordering and
    scaling of the y-axis.

-   P 3-2 l 31: Add a sentence like: "Fourth only a limited number of
    conditions can be evaluated feasibly.

-   P 3-3 paragraph 1: If possible, include a comment on which of the
    limitations in toxicological studies are most important in this
    context.

-   P 3-4 l 5: This is an example of a natural experiment, not an
    intervention study. This perspective appears elsewhere in the
    document(s) as well.

-   P 3-4: Is the Shy & Love paper peer-reviewed?

-   P 3-5 l 19, 21: Make sure units are included in this reporting and
    fix AX6-30 where the effect estimate appears to be reported as an
    OR. Furthermore, the summary information in the Annex fails to
    mention that this study covers a 13-month period -- an important
    feature to consider in evaluating the results.

-   P 3-8 l 3: Why are the findings conflicting? Is this another example
    of confusing statistical significance with scientific evidence?

-   P 3-13: I couldn't find the Delfino et al (2006) paper in the Annex.

-   P 3-11 l 4: Here is an example where the increment of NO2 isn't
    cited but is important for interpretation.

-   P 3-11 l 15-16. Here is a case where the differences in correlations
    may be due to monitor siting. Any way to address that? Also define
    the correlation w.r.t. time scale, location.

*Charge question 4:*

This appears to be appropriate. Better distinguish susceptibility and
vulnerability.

I like the idea of listing all likely susceptible groups and then
determining whether there is any information in the literature about
these groups. This can be a new framework that is applied to all
pollutants and allows for a very open and transparent evaluation of our
focus on particular groups. It also clearly identifies gaps in the
literature with respect to this topic.

The concentration-response section 4.2 needs work. Much of the
discussion appears to have the time series study design in mind, and if
this is the case it should be stated (p 4-4 ll 16-24, l 25). How does
the discussion on p 4-5 l 20-29 inform our understanding of the *shape*
of the concentration-response function?

-   P 4-5 l 16-17: Does this sentence refer to a *nonlinear*
    concentration response function? Clarify.

*Charge question 5:*

Generally the integration and summarization of the evidence in Chapter 5
was quite good, even for cases where I quibble with the details in
earlier chapters. The new framework for causality supports the goals of
the ISA and provides clear-cut criteria for health endpoints to bring
forward into the Risk and Exposure assessment. More work should be done
in consistent application of the Hill criteria. The CASAC discussion
reflects my own concerns about whether this draft provides an adequate
foundation for preparation of the ERA, particularly with respect to
transparent use of the literature for policy.

Additional points from the discussion that I echo here: Has the document
clearly established what we know and what we don't know? Clearly state
the goals of chapter 5 in the beginning. Is NO2 *the* pollutant or the
index for the effects?

Detailed comments:

-   P 5-2 l 7-8: Is the evidence for conclusions only based on the Hill
    critieria? I would include consideration of the overall quality of
    the studies that are weighed.

-   P 5-3 l 7: I needed an introductory sentence for the list.

-   P 5-4 l 28-31 + 1-2 next page: Clarify the details. I want words
    inserted, e.g. "Intersite temporal correlations for hourly average
    NO2..." and "...twenty-four hour average concentration..."

-   P 5-5 bullet starting l 3: Clarify "epidemiological studies." Not
    all are the same and I presume this bullet statement refers to time
    series studies.

-   P 5-5 bullet starting l 20: This summary of the difficult to
    summarize features of personal vs ambient correlation is fairly
    reasonable. However I don't think statistical significance is the
    right criterion. Focus instead on the estimates.

-   P 5-9 figure: Insert the NO2 increment used. Add a footnote to
    caution against overinterpretation of this nice summary: "Studies
    include different lag days and adjustment variables"

-   P 5-17 l 15: Revise. Statistical significance is not the key
    feature, for instance a statistically significant effect could be in
    the "wrong" direction.

*Other general comments*:

-   There is still overuse of "statistically significant" in this
    document. This is binary summarization of the data that depends on
    multiple features including magnitude of the effect, variability,
    and sample size. It doesn't reflect scientific meaning. To the
    degree possible replace focus on statistical significance with more
    meaningful quantities (e.g. effect estimates and confidence
    intervals).

-   There continues to be a need to more thoroughly reference supporting
    information in the annex and make it easier for readers of the ISA
    to find this information.

.

[]{#__RefHeading___Toc201991127 .anchor}[Comments from Dr. Frank
Speizer]{.underline}

Chapter 2

The setting out of the conceptual model in figure 2.1 provides an
excellent overall view. The devil is in the details that follow.

Review of Atm. Chemistry and Air Quality:

Page 2.3, line 15: It is probably worth indicating that from elevated
sources the dispersion and dilution results in lower levels albeit more
widely dispersed.

Page 2.3, Line 28 and Figure 2.21: The text suggests right Side outer
box is NO~z~ but label does not appear in the figure. Needs to be added.

Page 2.6 para beginning line 10: It might be useful in the paragraph to
indicate the relative amounts of POM measured.

Spacial and Temporal pattern of ambient NOx and human exposure

Page 2.13, Para beginning line 25: Is it worth either indicating (or
speculating) that the increase in NO2 in other countries (could read
Western Europe) is related to increase diesel and other mobile source
utilization, are there canyon effects, is there a difference in fuels or
engines, etc.?

Excellent organized discussion of exposure issues pointing out some of
the uncertainty that will have to be taken into account. But certainly
providing enough evidence that subsquesnt risk assessment can be done,
at least for selective sites, albeit with less data than were available
for PM and O3.

Atm. Science and exposure provide basis for evaluation of health
effects:

Page 2.24, end of line 4: Suggest adding a table of results from McCurdy
et al 2000, giving assessment of 11 different human activity patterns.

Page 2.25, line 4 and line 9: Need to rectify the discrepancy between
the two statements although rest of paragraph provides some insight. I
do not know what to believe!

Page 2.27, Table 2.51: Needs a footnote. Table ought to be able to stand
alone rather then needing text in lines 1-7.

Page 2.28: Surely the important thing here is the paragraph beginning on
line 18. The previous paragraph beginning on line 6 is mostly
descriptive of what is in Table 2.5.1 and could have been left out.

Page 2.48, para beginning line 7: Needs editing. Discussion of P, K and
a mention of twice as not thoroughly investigated..

Page 2.50. Summary: Strengths (and weaknesses) of existing data and what
inferences can be drawn are well described.

Chapter 3

Intergrated evidence for Toxicology, human studies, and epidemiology

Table 3.1.1 Need to clarify if Chauhan et al 1998, is speculation or
summary of the literature.

Seems to me that a qualitative summary of Hill's criteria might be
created in a table for acute effects. Something like: (don't take my +s
and --s seriously).

  -------------- ---------- -------------- ---------- ---------- ---------- ------- -------
  Hill Criteria  Host Def & Inflammation   Short term Resp.      Lung       Hosp.   Mort.
                 Immunity                  A.R.       Symptoms   Function           

  Strength       \+         \+ (1ppm                  ++         Gen. Neg   \--     \--
                            x2-3hrs)                                                

  Consistency    \+         \+             +/-        ++         +/-        nul     \--

  Coherence      ++         +/- (in        +/- (few   ++         \-         \--     \--
                            children only) studies)                                 

  Plausibility   ++         +/-            +/-        ++         +/-        +/-     NA
  -------------- ---------- -------------- ---------- ---------- ---------- ------- -------

Ditto something for chronic effects where respiratory effects range
RR=1.1-1.3, consistent, particularly in children and adults \>65. Asthma
25% increase. No co-pollutant effect, COPD mortality no coherent
picture. Long term for other morbidity concur "inadequate evidence to
infer presence or absence of causal relation.

Sections do not contain references.

Public Health Implications

Reasonable brief summary. Potential for some confusion in the use of
terms susceptible and vulnerable. Sometimes used interchangeably when
really means different thinks. Just be careful how the terms are used.

Integrated summary and conclusions.

Table 5.3.4 might be helped in exposure levels were included.

Chapter does a good summary that will work for the risk assessment.

[]{#__RefHeading___Toc201991128 .anchor}[Comments from Dr. George
Thurston]{.underline}

In these pre-meeting comments, I will focus upon responding to my
assigned questions for the ISA.

1\. What are the views of the Panel on the characterization of the
search strategy for

identifying literature, criteria for study selection, the framework for
scientific

evaluation of studies and causality determination?

In reading the NOx ISA document, I found that the epidemiological
studies I was aware of were considered, and could see no gaps in the
epidemiological literature, which has greatly strengthened the evidence
for an association between acute NOx exposure and respiratory health
effects. With regard to the toxicological studies, I felt that,
considering the potential inter-species differences in vulnerability,
that it was very appropriate for the document to include studies that
used exposures on the order of 5 ppm (approximately 10 mg/m3) to be very
appropriate in this document, as such studies (while not useful for the
estimation of human dose-response estimation) may well provide insights
into the potential mechanisms of damage that might be caused by NOx.

One area that was lacking was a more intensive consideration of the
evidence of potential impact of the co-exposure of particles and NOx,
both in the toxicology and epidemiology. While I am not as familiar with
the toxicological literature, I note that an informative toxicological
study by H.G. Boren \["Carbon as a carrier mechanism for irritant gases"
Archives of Environmental Health, 8, 119-124\]. In this paper, a
short-term exposure to 47 mg/m3 (25ppm) of NO2 or inhalation of fine
carbon particles exhibited no gross pathological effects in the mouse
lung, but when the mice were exposed to carbon particles that had
previously been exposed to NO2, the mice developed local destructive
lesions, with loss of cells from the alveolar walls. While just one
study with high levels of NO2, this study indicates that the co-presence
of particles with NO2 can enhance the effects of NO2. Since particles
are always in co-exposure with NO2 in the real world, this may provide
an important pathway of effect, but one that is not considered by this
document, despite my raising this concern early in the process. My
question: are there more published toxicological studies considering
this particle-NOx interaction mechanism? This seems well worth another
intensive look through the entire literature with that focus in mind.

3a. 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??

?

This is where my above-noted concern really manifests itself. What we
have is a wide gap that needs to be bridged between the controlled
exposure studies and the epidemiological study results. The former show
respiratory effects of NO2 only down to about 200 ppb, while the latter
routinely and robustly document significant NO2-respiratory associations
down at ambient levels. How can that be the case? We previously
confronted a similar situation in the 1980's, when our NYU-Harvard
study's of children at summer camps documented significant lung function
decrements among children to be associated with ozone exposures below
100 ppb, while the controlled exposure studies only showed effects down
to 120 ppb. Subsequent more realistic controlled exposure studies (with
exercise) later confirmed the epidemiology, and we now have a more
protective ozone standard.

With regard to NO2, I suspect that ambient particles, always present in
epidemiological studies, but not present in controlled NOx exposure
studies, may provide the vector for the apparently enhanced effects of
NOx in epidemiology vs. controlled studies, but the evidence for this
possible avenue to justify the apparent discrepancy between the
epidemiology and the controlled-exposure studies is not sufficiently
explored in this report. In some cases it is noted in the ISA already
(e.g., the fact noted that the APHEA study found greater PM effects in
cities with higher NO2 levels), but needs to be brought together to
address this specific issue. Thus, while some of the evidence is already
present, and more may be in literature not yet brought to bear (or not
yet collected), it is important to identify in the ISA what we do and do
not know about this potential mechanism of NOx effects, and about other
possible factors that may be responsible for this apparent disparity
between the levels of effects (e.g., that the most susceptible subjects
may not be considered in controlled-exposure studies, or that exercise
may be a factor, both of which are mentioned here and there in the ISA).

The way to bring this about in the document, I suggest, is to add a
section to Chapter 5 where the questions asked at the start of the
Integrative Summary (on page 5-1) are answered to the best we can at
this time, and which identify areas of further needed investigation to
answer the question more definitively. In particular, the most important
question to be answered is:

• At what levels of nitrogen oxides exposure do health effects of
concern occur?

Answering this particular question will expedite the addressing of the
gap between the controlled-exposure results and the epidemiology
results, as well as a comprehensive consideration as to why that might
be (i.e., Particle-NOx interactions? Greater degrees of susceptibility
in the general public? Exercise? etc.).

3b. What are the views of the Panel on the conclusions drawn in the
draft ISA regarding the strength, consistency, coherence and
plausibility of NO2-related health effects

While I generally agree with judgments reached by the EPA regarding the
strength of the evidence regarding causality, there is a need to discuss
the concentrations where the various effects are applicable, as
discussed above.

[]{#__RefHeading___Toc201991129 .anchor}[Comments from Dr. James
Ultman]{.underline}

This well-organized and comprehensive document and its appendices
provides a critical analysis of the newest literature as well as
highlighting conclusions make in the 1993 Criteria Document. The EPA
staff and its consultants are to be congratulated for a job well done.

As a second draft of the ISA, the document has effectively incorporated
the most important suggestions of the NOx Review Panel including better
detailing of the criteria used to judge causality and the means by which
studies were selected for inclusion in the document.

Chapter 1.

No comment.

Chapter 2.

The description of emission sources and of the spatial variation of
ambient measurements is much improved in this chapter.

I appreciate the inclusion of figure 2-1 that provides basis for
organization of the chapter.

The sparseness of monitor sites in Figure 2.4-1 begs the question of how
compliance is uniformly enforced in all regions of the country.

Figure 2.4-2 indicates the hourly-average ambient NO2 concentration at
current monitoring sites almost never exceeds the lowest benchmark level
of 200 ppb used in the Exposure and Risk Assessment. This underscores
the importance of on-road and indoor sources that have a small influence
on the ambient air measurements but a strong influence on personal
exposure.

In figure 2.4-3 and others like it, the image should be coded in
gray-scale (rather than color) before it is printed out.

There is an error in the title of figure 2.4-6d. WeekdayWeekend.

In equation 2.5-5, C~nona~ has a subscript that is inconsistent with the
subscript on Cna used in the text.

In the dosimetry section on page 2-59, there is not much progress to
report since the 1993 Criterion Document. Because the Exposure and Risk
Assessment is based directly on observations made in clinical
experiments, the need to use such models for dose extrapolation is not
necessary for the current ISA.

Chapter 4.

No comment.

Chapter 4.

No comment.

Chapter 4.

This chapter provides an adequate summary of the research that is
anticipated to guide the risk assessment.

On page 5-3, the key finding that the NO2 concentration is overpredicted
by 25% by current monitoring methods is probably a good thing since the
overprediction is due to other NOx and NOy that may also induce a health
effect.

In the Conclusions on page 5-20, it would be appropriate to provide
direct, succinct answers to the framing questions posed on page 5-1.

**Answer to charge question 2.**

I believe that the chapter does meet all the objectives outlined in the
charge question. I do suggest, however, that material be added that
describes and supports the method of extrapolating ambient monitor
measurements to on-road concentrations. This is too important an issue
to leave for the brief discussion that currently appears in section
6.2.3 of the Exposure and Risk Assessment document.

[]{#__RefHeading___Toc201991130 .anchor}[Comments from Dr. Ronald
Wyzga]{.underline}

[Overall comments]{.underline}:

This draft is much improved over the previous version. The siting of
monitors is discussed, and there is a much better understanding of
reported ambient measurements represent. The review of the health
literature is comprehensive and makes it easier to achieve a good
overall understanding of the health consequences of NOx exposure. The
summary of the health effects discussed in Chapter 5 is an excellent
organizational tool that facilitates an understanding of the nature and
consequences of ambient exposures to oxides of nitrogen. There are a few
areas that need further clarification. These are presented below in more
detailed comments.

[Charge question 2]{.underline}: To what extent are the atmospheric
chemistry and air quality characterizations clearly communicated,
appropriately characterized, and relevant to the review of the primary
NO2 NAAQS? Are the properties of ambient oxides of nitrogen
appropriately characterized, including spatial and temporal patterns and
relationships between ambient oxides of nitrogen and human exposure?
Does the information in Chapter 2 provide a sufficient atmospheric
science and exposure basis for the evaluation of human health effects
presented in alter chapters?

I have two suggestions here. The document refers to several studies
undertaken overseas, several of which focus on distance to roadways as a
factor "affecting indoor and outdoor NO2 concentration and personal
exposure". To the extent that the overall nature of exposure could be
quite different from that in the US given differences between the US and
overseas sources in terms of fleet composition and extent of pollution
control, there should be some note made about the geographic setting of
these studies and whether the setting is typical of those found in the
contemporary US. Any information on co-pollutants and concentrations
would be particularly helpful.

Since the strength of the health argument for NO2 health effects is tied
to the observations that effects are found in studies which consider
both indoor and outdoor exposures, it would be particularly interesting
for this chapter to provide some additional information to inform this
argument. For example, given the typical sources of indoor and outdoor
NOx, how does the composition change with respect to the different
oxides of nitrogen and are the co-pollutants the same or different in
indoor and outdoor settings?

[Charge question 3]{.underline}: 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? What are the views of
the Panel on the conclusions drawn in the draft ISA regarding the
strength, consistency, coherence, and plausibility of NO2-realted health
effects?

One of the difficulties in interpreting the epidemiological study
results is that it is often unclear whether health responses are due to
traffic or to NOx per se, an ingredient of traffic-generated air
pollution. To the extent possible, the document should attempt to
indicate those studies where traffic is deemed to have a lesser
influence on NOx exposure.

I would like to see a more rigorous examination/discussion of the
co-pollutant issue; for example, which co-pollutants were discussed in
which study; which were not. Are there any differences in measurement
error, etc. I personally share some of the concerns raised by Brook et
al. (2007) cited in the document.

In several places studies were not considered because they "did not
inform"; this needs to be clarified.

[Charge question 5]{.underline}: What are the Panel's views on the
adequacy of this external review draft ISA to provide support for future
exposure and policy assessments?

The current draft is a helpful document and a great improvement over the
previous draft. With the appropriate consideration of the issues raised
elsewhere in this review, the document would be an excellent resource
for future exposure and policy assessments. I also believe that the
document needs to tackle the issue of whether associations between NO2
and health responses in epidemiological studies are a reflection of NO2
exposures per se or is NO2 an index surrogate for some other exposure
associated with NO2 sources. I believe the information is scattered
throughout the document to help address this question, but an explicit
and articulate consideration of this issue would greatly improve the
document.

Specific comments:

Page 2-21: Figure 2.5-1 "residence"

Page 2-29, ll 1-3: Does this mean that local sources and near-source
concentrations are not to be regulated? I think the wording needs to be
changed here.

Page 2-42, ll. 5-6: statistical significance per se in not as
informative as R^2^; if the sample size is large enough any non-zero
correlation will be statistically significant.

Page 2-52, Table 2.5-7: The paper by Brook et al. (2007) cited later in
the document should be mentioned here. I find it particularly noteworthy
that NO2 is highly associated with several organic compounds.

Page 3-12. Figure 3.1-1: This figure is helpful, but it should also
indicate the time and concentrations of exposure of exposure in the
subtable. See Figure 3.1-2. This would allow the reader to judge whether
the application of Haber's law is appropriate and could facilitate the
interpretation of results.

p\. 3-26, ll 28- : Are there any co-pollutants associated with these
exposures? Are they different from the outdoor studies?

pp. 3-51;3-52, Figures 3.1-10; 3.1-11: Where is Peel et al (cited
elsewhere)?

p\. 3-57, ll. 9-14: clarify what is meant by "did not inform"; if a
study is not considered, it is important to understand why. Similar
comments exist elsewhere; e.g., p. 3-58, ll 17-20.