\ UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
o WASHINGTON D.C. 20460
OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD
June 18, 2013
EPA-CASAC-13-006
The Honorable Bob Perciasepe
Acting Administrator
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, N.W.
Washington, D.C. 20460
Subj ect: Consultation on the EPA's Draft Plan for the Development of the Integrated Science
Assessment for Nitrogen Oxides - Health Criteria (May 2013 Draft)
Dear Acting Administrator Perciasepe:
EPA's Clean Air Scientific Advisory Committee (CASAC) Oxides of Nitrogen (NOx) Primary National
Ambient Air Quality Standards (NAAQS) Review Panel held a public meeting on June 5, 2013 to
conduct a consultation with EPA staff on the EPA's Draft Plan for the Development of the Integrated
Science Assessment for Nitrogen Oxides - Health Criteria (May 2013 Draft). The Panel generally found
the Draft ISA Plan to be a useful roadmap for the development of the ISA.
The Science Advisory Board Staff Office has developed the consultation as a mechanism to provide
individual expert comments for the EPA's consideration early in the implementation of a project or
action. A consultation is conducted under the normal requirements of the Federal Advisory Committee
Act (FACA), as amended (5 U.S.C., App.), which include advance notice of the public meeting in the
Federal Register.
No consensus report is provided to the EPA because no consensus advice is given. The individual
CASAC NOx Review Panel members' written comments are provided in Enclosure A.
We thank the EPA for the opportunity to provide advice early in the NAAQS review process. The
Committee does not expect a formal response from the EPA.
Sincerely,
Dr. H. Christopher Frey, Chair
Clean Air Scientific Advisory Committee
Enclosure
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NOTICE
This report has been written as part of the activities of the EPA's Clean Air Scientific Advisory
Committee (CASAC), a federal advisory committee independently chartered to provide extramural
scientific information and advice to the Administrator and other officials of the EPA. The CASAC
provides balanced, expert assessment of scientific matters related to issues and problems facing the
agency. This report has not been reviewed for approval by the agency and, hence, the contents of this
report do not necessarily represent the views and policies of the EPA, nor of other agencies within the
Executive Branch of the federal government. In addition, any mention of trade names or commercial
products does not constitute a recommendation for use. The CASAC reports are posted on the EPA
website at: http://www.epa.gov/casac.
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U.S. Environmental Protection Agency
Clean Air Scientific Advisory Committee
CASAC Oxides of Nitrogen Primary NAAQS Review Panel (2013-2016)
CHAIR
Dr. H. Christopher Frey, Distinguished University Professor, Department of Civil, Construction and
Environmental Engineering, College of Engineering, North Carolina State University, Raleigh, NC
CASAC MEMBERS
Mr. George A. Allen, Senior Scientist, Northeast States for Coordinated Air Use Management
(NESCAUM), Boston, MA
Dr. Jack Harkema, Professor, Department of Pathobiology, College of Veterinary Medicine, Michigan
State University, East Lansing, MI
Dr. Helen Suh, Associate Professor, Bouve School of Health Sciences, Northeastern University,
Boston, MA
Dr. Ronald Wyzga, Technical Executive, Air Quality Health and Risk, Electric Power Research
Institute, Palo Alto, CA
CONSULTANTS
Dr. Matthew Campen, Associate Professor, College of Pharmacy, University of New Mexico,
Albuquerque, NM
Dr. Ronald Cohen, Professor, Chemistry, College of Chemistry, University of California, Berkeley,
Berkeley, CA
Dr. Douglas Dockery, Professor and Chair, Department of Environmental Health, School of Public
Health, Harvard University, Boston, MA
Dr. Philip Fine, Atmospheric Measurements Manager, South Coast Air Quality Management District,
Diamond Bar, CA
Dr. Panos Georgopoulos, Professor, Environmental and Occupational Medicine , UMDNJ-Robert
Wood Johnson Medical School, Piscataway, NJ
Dr. Michael Jerrett, Professor and Chair, Division of Environmental Health Sciences, School of Public
Health , University of California, Berkeley, Berkeley, CA
Dr. Joel Kaufman, Professor, Department of Environmental Health, University of Washington , Seattle,
WA
ii
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Dr. Patrick Kinney, Professor, Department of Environmental Health Sciences, Mailman School of
Public Health, Columbia University, New York, NY
Dr. Michael T. Kleinman, Professor, Department of Medicine, Division of Occupational and
Environmental Medicine, University of California, Irvine, Irvine, C A
Dr. Timothy V. Larson, Professor, Department of Civil and Environmental Engineering, University of
Washington, Seattle, WA
Dr. Jeremy Sarnat, Associate Professor of Environmental Health , Rollins School of Public Health ,
Emory University, Atlanta, GA
Dr. Richard Schlesinger, Associate Dean, Department of Biology, Dyson College of Arts and
Sciences, Pace University, New York, NY
Dr. Elizabeth A. (Lianne) Sheppard, Professor, Biostatistics and Environmental & Occupational
Health Sciences, School of Public Health, University of Washington, Seattle, WA
Dr. Junfeng (Jim) Zhang, Professor, Department of Preventive Medicine, Keck School of Medicine,
University of Southern California, Los Angeles, CA
SCIENCE ADVISORY BOARD STAFF
Mr. Aaron Yeow, Designated Federal Officer, U.S. Environmental Protection Agency, Science
Advisory Board (1400R), 1200 Pennsylvania Avenue, NW, Washington, DC, Phone: 202-564-2050,
Fax: 202-565-2098, (yeow.aaron@epa.gov)
in
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A
of by CASAC NOx on
EPA's Draft Plan for the Development of the Integrated Science Assessment
for Nitrogen Oxides -Health Criteria (May 2013 Draft)
Mr. George A. Allen A-2
Dr. Matthew Campen A-3
Dr. Ronald C. Cohen A-4
Dr. Douglas Dockery A-5
Dr. Philip Fine A-6
Dr. Panos Georgopoulos A-7
Dr. Jack Harkema A-ll
Dr. Michael Jerrett A-12
Dr. Patrick Kinney A-13
Dr. Michael T. Kleinman A-14
Dr. Timothy V. Larson A-15
Dr. Jeremy Sarnat A-16
Dr. Richard Schlesinger A-17
Dr. Elizabeth A. (Lianne) Sheppard A-18
Dr. Helen Suh A-19
Dr. Ronald Wyzga A-20
Dr. Junfeng (Jim) Zhang A-21
A-l
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Mr. George A. Allen
Chapters 1 and 2 - The process overview and the history of reviews for the primary NAAQS for NO2
are useful and well written. It is helpful to have the target dates for major milestones of the ISA
development.
Chapter 3, development of the ISA, is well organized and provides appropriate information on the
process, including the literature search and study quality evaluations - two key early steps in the ISA
development. Page 9 lines 25-27 and page 10 lines 3-6 note the issue of confounding co-pollutant
interactions, an important issue for health effect studies since NO2 often serves as a surrogate indicator
of a wide range of mobile-source pollutants that to a large degree co-vary with NO2 or NOx. This theme
is carried forward in subsequent sections of this draft, which is appropriate. It is discussed very clearly
and in more detail on page 16, part F (Uncertainties),
Page 12, lines 5-6 note measurement method issues with the existing Federal Reference Method (FRM)
for NO2. New methods are now available that use a photolytic (UV) NO2 to NO converter (instead of
the classic moly-based converter) that is specific to NO2. One instrument manufacturer sells a photolytic
NO2 instrument that is an EPA Federal Equivalent Method. Presumably the photolytic converter method
will be considered as a replacement for the current NO2 FRM in this review cycle.
Page 12, Lines 10-13 and elsewhere on this page note the issue of near-road exposures. At present, there
are limited long-term data for the near-road environment, especially in a multi-pollutant context. The
new EPA near-road monitoring network that is just now [and over the rest of 2013] becoming
operational should provide very useful data, including other relevant near-road pollutants, but data will
not be available in time for the August 2013 first draft. By the time the second draft is expected (April
2014), there should be one-half to one year of data available from at least 25 near-road sites to inform
these exposures.
Appendix A is a helpful summary of the legislative requirements behind the NO2 NAAQS, including
references to actions since the 1990 Clean Air Act that clarify the Act's intent, including the 2001 ruling
that EPA can not consider the cost of implementing the standard.
A-2
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Dr. Matthew Campen
It would be good to provide a review of known reactions of NO2 in the airway surfactant / epitheilail
lining fluid. In the ISA Development document the following question was raised:
What NOx reaction products can be found in the respiratory tract cells, tissues, or fluids that may
serve as markers of NOx exposure and effect?
This question is appropriate but possibly underemphasized, as emerging science suggests that the initial
pollutant-lung microenvironment interactions may be essential to driving systemic effects, and some
consideration to per-2008 studies on this topic (William Pryor, Ed Postlethwaite, others) may be
valuable for NOx immediately, but also for the next round of reviews of O3 and PM. There is a new
paradigm emerging that degradation by-products, rather than circulating cytokines or neurally-mediated
events, may be central to the systemic effects of inhaled pollutants, and recent studies with NO2 in
humans is consistent with this idea. Thus, review of the NOx reactions with surfactant proteins and
phospholipids in the airways will be very important.
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Dr. Ronald C. Cohen
Suggested revision pg 12, 3rd bullet: Changes in itlaics.
What spatial and temporal patterns can be seen in air quality data for NOx? In particular, what patterns
can be seen on a micro-scale near sources including major roadways, power plants and wood-burning
stoves? What patterns can be seen on urban, regional and national scales based on satellite data?
For item B on the same page, I suggest adding a question that would require discussion of the interaction
of meteorology with concentration and exposures. For example:
What are the relationships between diurnal variations in the boundary layer height, NOx concentrations
and exposures. What new information is available to characterize the influence of meteorological
parameters and exposures?
A-4
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Dr. Douglas Dockery
There have been a substantial number of epidemiologic studies since 2008 reporting health effects
associated with proximity to roads. Most of these lack any NOx or other air pollution exposure data.
What is their role in the NOx ISA?
Especially strong associations are reported with acute cardiovascular events. In this case, given other
observational and experimental evidence for CVD associations, roadway proximity studies would
appear to provide supporting evidence for causality.
Roadway proximity studies are also reporting associations with other unexpected health outcomes. In
these cases, the evidence is suggesting new areas for investigating rather than suggesting causality.
These roadway proximity and traffic studies are consistent with associations with NOx exposures, but
also could be explained by other traffic air pollutant emissions, or factors associated with traffic such as
noise. Noise has recently remarkably little attention as a potential alternative exposure in this country,
although there are a substantial number of observational studies from Europe.
The Draft NOx ISA Development plan highlights many of the issues with NOx exposure
misclassification related to personal versus ambient fixed site, relative errors compared to co-pollutants,
and indoor versus ambient outdoor exposures. There is suggestion that remote satellite sensing may
provide usable data in the future. More attention needs to be given to exposure modeling based on land-
use regression and neighborhood modeling.
The health effects of NOx have received much more attention in Europe and other countries than in the
United States. The statement that more weight will be given to US or Canadian studies than European
studies because of more comparable sociodemographic characteristics is narrow-minded and
undervalues potentially superior observational science.
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Dr. Philip Fine
There is a focus on near-road NO2 exposures, commensurate with recent monitoring regulations. First,
any recently collected near-road NO2 data should be part of the air quality and exposure analysis.
Second, other near-source NO2 exposures should also be considered. Point source modeling has
suggested that large non-road or stationary sources, such as rail yards, may lead to localized NO2 levels
at least as high as near road locations.
Newer engine control technology has effectively lowered tailpipe NOx emission overall. But the ratio of
emitted NO2 to NO may be increasing. While this has little impact on regional NO2, ozone, and PM,
local NO2 exposure may not necessarily be decreasing at the same rate as overall tailpipe NOx
emissions.
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Dr. Panos Georgopoulos
The "Draft Plan for the Development of the Integrated Science Assessment for Nitrogen Oxides -
Health Criteria" (Draft - May 2013) is a thoughtful and well-prepared document that builds upon the
experience accumulated through developing the series of Integrated Science Assessments, that USEPA
has completed in recent years. These assessments have been of great value in the field of air quality,
representing substantial contributions to the effort of transforming and synthesizing large amounts of
information from disparate sources into issue-related knowledge. The proposed plan provides a solid
foundation for updating and even improving the 2008 Integrated Science Assessment (ISA) for Oxides of
Nitrogen - Health Criteria (EPA/600/R-08/071), that been an excellent resource for scientists and
regulators.
The following comprise a brief series of suggestions that could enhance certain aspects of the plan for
the new ISA; in some cases they may essentially be requests for explicitly identifying in the plan issues
that could in fact be implicitly addressed in the new ISA, however they are of sufficient significance to
justify explicit consideration.
1. ASSESSMENT OF DATA PATTERNS AND TRENDS FOR NOx EMISSIONS AND
CONCENTRATIONS
a. Advancements (including significant methodological) in developing emission inventories
for NOx, that have taken place since the 2008 ISA, should be identified and assessed
explicitly. Quantifying emission levels and patterns in time and space for urban and rural
regions as well as for specific, both outdoor and indoor, microenvironments, under a
variety of conditions, is critical not only for exposure and risk characterization but also
for rational management and mitigation. Therefore the identification of progress - as well
as of remaining uncertainties and challenges - in this area is important.
b. NOx-related issues are inherently multiscale and appropriate consideration of this fact
should be explicit in the ISA plan. Identifying attributes of both short- and long-term
emission and concentration patterns and trends (and, subsequently, of associated
exposures) requires systematic consideration of temporal variability across multiple time
scales. Also, different physical processes dominate different spatial scales, whether the
scales are defined from the perspective of emission sources or from the perspective of
(human) receptors. These scales vary from local and near-field (from the source
perspective) and from personal and residential (from the receptor perspective), to
neighborhood, urban, inter-urban, regional, national, continental, and global scales. The
draft plan explicitly identifies consideration of near-road and national scales (page 12,
lines 12-13), but the consideration should be expanded to other scales as well.
c. Spatiotemporal patterns and trends in both emissions (anthropogenic and biogenic) and
ambient concentrations should be developed for the new ISA through synthesis of
A-7
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available data. The plan of analysis should expand upon that of the 2008 NOx ISA and
should consider multiple temporal and spatial scales not only for NOx but for co-
occurring air pollutants as well.
d. Assessment of the potential impacts of climatic change patterns, and of potential future
changes in energy production and usage, on the levels and patterns of NOx emissions
should be explicitly considered in the ISA. Changes in regional, anthropogenic and non-
anthropogenic, emissions may affect base/background concentrations in relation to
human population exposures.
2. ASSESSMENT OF MODELING CAPABILITIES FOR NOx TRANSPORT AND
CHEMISTRY ACROSS MULTIPLE SCALES IN BOTH OUTDOOR AND INDOOR
SETTINGS
a. Advancements (and remaining challenges and limitations) in modeling the multiscale
ambient transport and chemistry of NOx should be explicitly assessed in the ISA and
included in the plan. In fact, transport and dispersive/diffusive mixing of emitted NOx
species with ambient air is intricately coupled with atmospheric chemistry, as steep
gradients as well as random (turbulent) fluctuations in NOx concentrations (associated
with "localized" - point and line - emission sources) will impact the effective rates of
nonlinear reactions involving these species and other atmospheric constituents. Advances
in modeling these gradients and their effects, such as "plume-in-grid" (PiG) models,
adaptive grid models, higher order chemical closure models, etc., should be identified and
evaluated as part of the new ISA.
b. Evaluation of advancements in modeling NOx emissions, transport/mixing, and
chemistry in indoor environments is also very important from the perspective of exposure
characterization.
3. ASSESSMENT OF MODELING CAPABILITIES WITH RESPECT TO CHARACTERIZING
ESSENTIAL ATTRIBUTES OF POPULATION EXPOSURES
a. The status of population exposure characterization should be evaluated in the context of
metrics that account explicitly for different population-relevant attributes of short and
long-term exposures, such as pervasiveness, persistence, severity, and efficacy of
exposures. The current ability of available data and models to quantify the relative
contribution of "far-field" emissions (e.g., from power plants) versus "nearby" emissions
(e.g., from a gas stove indoors) to human exposures, should be evaluated and assessed for
a wide range of conditions. Advancements (as well as remaining "data gaps") in
databases that link human activities to time and location (microenvironment), employing
relational and spatiotemporal data management systems, are critical for the improvement
A-8
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and reliability of modeled exposure estimates and should be assessed as part of the new
ISA.
4. ASSESSMENT OF (MECHANISTIC) MODELING CAPABILITIES WITH RESPECT TO
CHARACTERIZING DOSIMETRY AND MODES OF ACTION FOR NOx, INCLUDING
INTER-SPECIES EXTRAPOLATIONS
a. The status of interspecies extrapolation for inhalation dosimetry should be evaluated and
assessed in a quantitative rather than in a qualitative context; in particular, existing data
gaps that currently limit the ability of dosimetric models for NOx to incorporate
quantitatively effects of reactivity etc. should be characterized, and research needs for
filling these data gaps should be identified. This evaluation should then be extended from
respiratory to whole body toxicokinetics.
b. The draft plan includes consideration of qualitative comparison of NOx (toxicity or in
general biological response) mechanisms across species (page 13, line 18). It is
recommended that the comparison is in fact extended to any relevant biological
pathways/networks for which information may be available at different biological scales
(from molecular signaling to histological response). Consideration of such information
may provide components for the development of quantitative mechanistic toxicodynamic
models for NOx.
c. Availability of information for adding considerations of intraindividual variability (in
biological response) to those of interindividual variability (p. A-6), should be evaluated.
5. CLARIFICATION OF SYSTEMATIC CONSIDERATIONS OF VARIABILITY WITH
RESPECT TO CHARACTERIZING NOx EFFECTS AND RISKS FOR INDIVIDUALS AND
POPULATIONS
a. Though the draft plan demonstrates a substantial focus on identifying uncertainty and
variability issues relevant to risk characterization, the discussion of "intrinsic" and
"extrinsic" factors affecting risk, "and/or factors affecting dose or exposure" on page 17
(lines 3-27) under "G. At-risk Lifestages and Populations," can be further improved.
Though it is noted that "some factors (e.g., age) may influence risk through multiple
mechanisms," it does not fully recognize the relevance of multiscale networks that link
"exposure biology" and "behavioral biology" with health effects. As an example,
socioeconomic status, activities, diet, and biology (physiology and biochemistry) for an
individual are dynamically interdependent, with the dependencies forming "influence
networks," that potentially include both negative and positive feedback loops of various
"strengths". Explicit considerations of age and gender in conjunction with genetic
A-9
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variability, physiological variability, behavioral variability, etc. within populations of
concern present substantial challenges in relevant information analyses (especially since
both the above listed attributes and their variabilities are not independent), but will
eventually be required for more thorough characterizations of environmental health risk
issues.
A-10
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Dr. Jack Harkema
I have read over the documents you have provided. I have no preliminary written comments at this time,
other than to say that the current draft plan for the development of the ISA for Nitrogen Oxides - Health
Criteria is adequately developed and includes a process that appropriately resembles that recently
adopted for the most recent Ozone ISA.
A-ll
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Dr. Michael Jerrett
The section dealing with exposure appears underdeveloped compared to other central parts of the report.
I recommend that the EPA examine the conceptual model put forward by the National Academy of
Science in the report entitled, "Exposure Science in the 21st Century: A Vision and a Strategy." The
report carefully documents the elements of exposure science that are important for understanding all
aspects of exposure, and the CAS AC would benefit from such a systematic approach to the ISA.
The section on how to establish causality is not clearly laid out and needs to be articulated in a way that
gives readers an understanding of how, for example, the review will weight potentially conflicting
evidence supporting different aspects of causality (e.g., coherence between epidemiology and toxicology
vs. consistency among epidemiological findings).
Reviews of the evidence should give similar weight to studies from Europe as those from the US or
Canada. Similarly there should be a thorough review of studies from Latin American and Asia. In all
instances, the differences in underlying population characteristics, health behaviors, co-exposures, levels
of economic development, and pollution mixtures as sources of heterogeneity in the findings, which may
limit applicability to the U.S. population.
A-12
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Dr. Patrick Kinney
The Draft ISA Plan is in very good shape. I have just a few very minor comments.
Page 9, top: this section would be more appropriately titled "Evaluation of Individual Study Quality and
Relevance". Much of the section focuses on relevance rather that quality.
Page 9, lines 1-3: move this sentence to the previous section.
Page 16, lines 10-16: Sentence is too long. Breakup.
A-13
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Dr. Michael T. Kleinman
1. Scope of the Current Review - The atmospheric chemistry of NOx leading to the formation of
toxic reaction products such as nitroaromatics and nitropyrenes should be part of the discussion,
especially as we begin to develop more information on multipollutant health effects even if these
are thought to have been subsumed in the discussion of PM. There has been increasing
discussion of the inhomogeneity of ambient Nox distributions. There is also increasing evidence
of increased health effects near roadways where NOx concentrations are often highest and the
potential for chemical interactions is also high. Some of these aspects are mentioned in the
discussion of Exposures (p!2) but it might be useful to express the rationale in the section on
Scope. I think that consideration of these aspects could help inform discussions of the adequacy
of current monitoring approaches as well as providing additional factors when considering the
potential benefits of NOx control beyond the direct effects of the gaseous species on health, the
role of NOx in Os formation and the formation of secondary inorganic nitrates.
2. Exposure - p!2 - It would be appropriate to include the topics of Receptor Modeling and also
Time-Activity assessments with respect to the roles these play in understanding individual
exposures.
3. The section on Dosimetry (p 13) should take notice that the level of physical activity in
individuals will influence respirations rates which will alter NOx penetration and uptake in the
respiratory tract and will also change regional deposition patterns in the lung. This can have
profound effects on potential health effects.
4. Assessment Approach - The role of NOx in cancer should be included in the questions to be
addressed (p 14 and 15). This is a 'sticky' problem but there is increasing evidence of
associations with cancer and especially metastatic disease. The interrelationship to
immunosuppression and metastatic disease may be important.
5. Although it is mentioned in passing in the Section on At Risk populations (pg 17) it would be
appropriate to discuss the role that genetic variations and polymorphisms moderate individual
susceptibility and may influence the variance of data about the concentration-response or dose-
response relationships. So-called susceptibility genes can have a regional characteristic because
of population and immigration specificities which can influence the outcomes of epidemiological
studies and increase uncertainties of exposure-related health effects.
6. Literature search selection (O3 preamble) - Figure II shows articles being screened by title. The
screening level might be expanded to Title and Abstract (which may already be the way the
review begins).
A-14
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Dr. Timothy V. Larson
My comments are directed to the exposure assessment section. The questions in this section are well
conceived and relevant. Several additional questions that could be also addressed pertain to on-road
exposures, measurement artifacts, and the siting of monitors near roads. Specifically:
1. What studies are available to examine the relationship between near-road NOx , on-road NOx,
and in-vehicle exposures to NOx? Given the concern over short term exposures at or even less
than one hour in duration, are the directly emitted NO2/NOx ratios sufficiently high such that on-
road NO2 exposure is a significant component of total NO2 exposure?
2. What are the implications to epidemiology for assessing chronic NOx exposures based upon
measurements at locations susceptible to interferences from other nitrogen compounds (e.g.
downwind sites with relatively low NOx)?
3. How well do the current and proposed near-road NO2 monitoring sites represent exposures to
populations living near major roads?
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Dr. Jeremy Sarnat
Below are several, minor comments/questions.
• To avoid confusion especially among non-CASAC readers, consider using either ppb or ppm
consistently in discussing the NOx NAAQS standards (pps. 2 and 3)
• This is a naive question, but it's not clear to me how, specifically, the Final Plan for the ISA will
inform the first draft of the NOx ISA. Both the final draft of the draft plan and the first draft of
the ISA are scheduled for August 2013. Shouldn't the Final Plan for the development of the ISA
precede the first draft? Again, sorry for my lack of understanding on the process.
• Page 10. Line 6. The suggestion that epi studies with results from copollutant analyses will be
given greater emphasis in the ISA is a bit problematic. I recognize the importance of viewing
NOx within a complex mix, but copollutant modeling is only one approach for doing this. I'd
avoid ascribing preferential language regarding mixtures characterization, or include other
approaches that are being used as well (i.e., Bayesian modeling, various factor analytical
approaches). Maybe it's just a question of including 'such as' before mention of copollutant
analyses.
• There's imbalance in the specificity of the questions from the Health Effects sections (p. 13)
compared to the other sections. The other sections are much broader and more conceptual than
the Health Effects section. I'm assuming different people wrote the questions for the various
sections. I understand that this is an ISA for NOx health criteria., but the differences among the
sections are fairly pronounced.
A-16
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Dr. Richard Schlesinger
I just have a few comments on the Draft Plan so far:
P. 10. The animal studies should also potentially include those in which exposure may be to NOx in
combination with other pollutants similar to what is proposed for the controlled clinical studies on lines
26-27.
P. 13. Lines 11-12. One may also indicate reaction products in systemic circulation.
P. 14. There is much redundancy in issues on this page so perhaps a more concise version can be
developed. Also, in the bullet starting on line 21, some of the changes noted are really quite overt so
what is meant by use of that term?
A-17
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Dr. Elizabeth A. (Lianne) Sheppard
Overall I found the Draft Plan for Development of the ISA for NOx - Health Criteria to be appropriate
and clearly written. I appreciated the background material that was incorporated, including the
legislative requirements summary in Appendix A, the overview of the process in the introduction, and
the references to the preamble of the Ozone ISA. I have a few specific questions and/or suggestions:
1. The draft outline for the ISA (pages A-5 to A-7) does not cover all content areas described on
pages 16-17 : E. Causality, F. Uncertainties, and H. Public Health Impacts. Based on the
discussion, I understand these are integrated into the health effects and at-risk lifestages and
populations sections.
2. P 12: Consider adding this exposure-related question, perhaps in addition to the questions
starting on line 32: To what extent is NOx a marker of the complex traffic-related pollution
mixture?
3. P 13, line 23 (section D. Health Effects): Should cognitive and aging effects be added?
4. There are several references to exposure measurement error including on line 30 of p. 14, and
line 1 of page 17. Consider rewording or expanding the questions about measurement error to
include concepts of data, study design and models. For instance, in addition to the question on
line 1 of page 17, we could add: How do features of the data, study design, and models affect the
conclusions? A similar idea could be integrated into the point on page 14.
5. P 10 line 19: Is point (3) really about power or appropriateness of study design? Consider
rewording (3) to say "appropriateness of the study design to determine responses to relevant
exposures". A similar point applies to (6) on line 28.
6. Incorporate a bullet point in B. Exposure addressing the role of exposure prediction on health
effect estimates. This topic has both methodological and practical aspects. From a
methodological perspective we now know that an essential assumption for using exposure
predictions for inference about health is that the underlying distribution of locations of monitors
used to develop predictive models is the same as the distribution of locations of subjects. From
an applied perspective, exposure data and predictions from specific studies should be evaluated
in the context of the health effect target of inference.
7. Another exposure topic brought up in our consultation call was the importance of time-activity of
people while they are in the exposure field.
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Dr. Helen Sun
General Comments
The plan for the development of the NOx ISA is well presented and does a good job of tying the ISA
framework and terminology to those used in previous ISAs. As with previous ISAs, it will be important
for the NOx ISA to include summary tables within each section that describe key studies and a chapter
that integrates findings across the different disciplines (e.g., sources to exposure to health). It was not
clear from the plan whether the public health impacts section was intended to serve as this integration
chapter.
In addition, the summary of pre-2008 findings within the individual sections should also discuss key
data gaps from the 2008 ISA. This added information will help to provide a foundation that can be used
to establish whether and how our understanding of NOx has improved since the last ISA and to justify
any changes to causality determinations.
The scope of the ISA for NOx may also need to be expanded to include consideration of other traffic
pollutant measures, such as black carbon, elemental carbon, source apportionment factors, and distance
to road. Since many post-2008 epidemiological studies have used NO2 as a marker of traffic pollution, it
is not clear how results from these studies alone will be used to draw overall conclusions, as
consideration of findings from other studies of traffic pollution is likely needed. It is possible that the
ISA will need to include some discussion of how findings for NOx relates to other commonly used
measures of traffic pollution and health.
Specific Comments
Page 8, line 22-23. The sentence beginning "Publications considered for inclusion..."] is unclear. Are all
identified studies included in the HERO database, even if they do not meet the inclusion criteria? It
makes sense for all identified studies to be included in the HERO database, with a notation added to
each of the non-included studies as to why the study was not included.
Page 12, line 17. The discussion of NOx in a multi-pollutant context could be expanded to include
consideration of the relation of NOx to distance to roadway and traffic density and NOx as a surrogate to
traffic pollution.
Page 14 and 15. In the health effects section, the plan states that the ISA will present and evaluate data
on "studies conducted in environments near roads or other sources". While this presentation and
discussion is valuable, it should be expanded to include discussion of studies using other traffic pollutant
measures and how these studies relate to those for NO2 and health.
A-19
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Dr. Ronald Wyzga
Overall Comments: The draft plan presents a logical approach to laying out the most relevant science for
the eventual development of NAAQS standards for NOx. I would like to see more explicit discussion
about the use of human exposure patterns in the choice of indicator species and averaging time.
Specific comments:
p. 9, lines 11-12: what is meant by "sufficiently representative"? One could argue that extreme air
quality measures are of greatest concern. I don't know what a "sufficiently representative" dose metric
is.
p. 10, lines 1-6: Ideally all 3 criteria should be met, but it should be recognized that a single-city study
that satisfies criteria 2 and 3 can be more informative than a multi-city study that does not satisfy these
criteria. I would not like to see single-city studies dismissed if they satisfy the last 2 criteria. I would add
that single-city studies may be more informative than multi-city studies in the consideration of indicator
species and averaging times as I am not aware of any multi-city studies that explore these issues.
lines 7-29: Experimental studies can be particularly informative about the relative toxicity of
different NOx species and about averaging times.
p. 12, lines 1-16: It would also be important to indicate how different NOx species are related; what is
the role of atmospheric chemistry in this relationship? What are the correlations between ambient
concentrations of the various NOx species in different environments (e.g., indoor, near roadways, etc.)?
lines 17-31: I think the 3r bullet in delineating exposure patterns is particularly important. This
could be key in the consideration of averaging times for both the NAAQS and for future studies.
p. 13, line 33: Since we are considering exposures as short as one hour, we may want to change "hours"
to "minutes" in this definition.
Pages 13-15: The Uncertainty section raises a key issue in epidemiological studies: to what extent are
health effect associations with NOx due to NOx per se or due to other pollutant mixtures that NOx may
be representing? Studies of the health effects need to be exploited to help resolve this issue. Given the
discussion in the uncertainty section, the ISA clearly is concerned about this issue, but it could be made
more explicit in the Health Effects section.
Page 15, line 7: Do we want to have a clear delineation between long-term and short-term studies; e.g.,
exposures one year or greater could be defined as long-term exposures.
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Dr. Junfeng (Jim) Zhang
As a new member of the CAS AC NOx Review Panel, I found the draft plan for NOx ISA development
very well written. Reading it has given me a clear picture as to what is expected from this Committee
and what the final product will look like. I commend the EPA staff who wrote this document. Below are
my comments.
1. I understand that indoor NO2 exposure and health effects work has been reviewed and
summarized in the 2008 report. I also understand that the current review shall focus on the
literature published after 2008. However, given that there might have not been much research
done on indoor NO2 since then, it is necessary to repeat in the new ISA. Indoor NO2 research is
very helpful in assessing causality, as indoor co-pollutants may be different than outdoor co-
pollutants in the air pollution mixture.
2. To support the new 1-hour-based standard, the literature on health effects of short-term exposure
may be assessed in two categories (if publications are available): (a) the health effects resulting
from single-time or a few repeated short-term exposures most likely done in animal studies and
in human chamber studies; and (b) the health effects resulting from constant (routine) short-term
exposures such as those experienced in daily commuting or at occupational settings.
As a component of the combustion-generated air pollution mixture, NO2 may serve as a
surrogate for the mixture or for other pollutants that may be the true causal agents responsible for
observed health effects. We all realize the difficulty in sorting out whether a NO2-health
outcome association reflects the true NO2 effect or an effect of something else correlated to
NO2. To help addressing this issue, I suggest that we evaluate epidemiologic studies conducted
in different parts of the world. Because pollutant mixtures vary in different parts of the world in
terms of relative abundance of NO2 (e.g., NO2 to PM ratio), comparing the NO2 effects in
relation to different pollutant mixtures helps address the causality issue.
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