UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                                   WASHINGTON D.C. 20460
                                                               OFFICE OF THE ADMINISTRATOR
                                                                SCIENCE ADVISORY BOARD

                                     June 8, 2007

EPA-CASAC-07-005

Honorable Stephen L. Johnson
Administrator
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460

       Subject: Clean Air Scientific Advisory Committee's (CASAC) Consultation on the
               Draft Integrated Plans for Review of the Primary NAAQS for NO2 and SO2

Dear Administrator Johnson:

       The Clean Air Scientific Advisory Committee (CASAC or Committee) Oxides of
Nitrogen (NOx) and Sulfur Oxides (SOx) Primary National Ambient Air Quality Standards
(NAAQS) Review Panel (Panel) met on May 11, 2007, via a public teleconference to conduct a
consultation onEPA's Draft Plan for Review of the Primary National Ambient Air Quality
Standard for Nitrogen Dioxide (Draft Integrated Plan for Review of the Primary NAAQS for
NO2, February 2007) and Draft Integrated Plan for Review of the Primary National Ambient Air
Quality Standards for Sulfur Dioxide (Draft Integrated Plan for Review of the Primary NAAQS
for SO2, April 2007).  The CASAC roster is attached as Appendix A of this letter, the NOX &
SOx Primary NAAQS Review Panel roster is contained in Appendix B, and Panel members'
individual written comments are provided in Appendix C.

       The SAB Staff Office has developed the consultation as a mechanism to advise EPA on
technical issues that should be considered in the development of regulations, guidelines, or
technical guidance before the Agency has taken a position. 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. Although
there per our customary practice will be no consensus report from the CASAC as a result of this
consultation, the Committee would nonetheless like to underscore several key points that arose in
the conduct of its consultation on the draft integrated plans for review of the primary NAAQS for
NO2 and SO2.  These are provided as follows, along with the names of those Panel members
whose individual written comments expand on these  points or issues:

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   •   The existing NC>2 and 862 primary (and secondary) standards as well as the current draft
       integrated plans for review of primary NC>2 and SC>2 standards are narrowly focused on
       considerations of direct exposure effects from these gaseous pollutants alone.  The plans
       appear to specifically exclude any consideration of the combined influences of the many
       secondary transformation products (gaseous, aerosol and deposition) which inevitably
       result from, and coexist with, these precursor pollutants. EPA may eventually conclude
       in the associated Policy Assessments for primary NOX and SOX (to be published in the
       form of ANPRs) that there are more efficient alternative mechanisms (such as through
       PM2.5 standards or the Clean Air Interstate Rule) for mitigating adverse health or welfare
       impacts of SOx and NOx transformation products.  However, it would seem useful to
       include some consideration of the health and welfare effects of S and N transformation
       products (or other pollutant mixtures) in the ISAs and the risk/exposure assessments for
       both the primary and secondary NAAQS for NC>2 and SC>2. (Mr.  Poirot and Dr. Cowling)

   •   It is not clear how the Agency will select the most relevant literature to include in its
       Integrated Science Assessments (ISAs) for primary NOx and SOx, nor how any new
       information would be managed that might come available between the  CASAC's review
       of the 2nd Draft ISAs for primary NOX and SOX in April and July 2008, respectively, and
       the release of the corresponding Advance Notices of Proposed Rulemaking (ANPRs) in
       April and June  2009. (Dr. Larson and Dr. Speizer)

   •   There is apparent confusion over the use of SO2 versus  SOx and  NO2 versus NOx in the
       documents. These terms should be carefully and consistently employed. Also, the  SOx
       plan states in one place that particulate sulfates will not be considered, yet the ambient
       level of SO2 is of concern because it contributes to  sulfate formation. In addition, the
       NOx document does not say whether nitrate particles will be considered. Furthermore,
       multi-pollutants and their influence on the toxicity of NOx and SOx should be considered
       in the integrated plans. This is particularly true for particles and  ozone. (Mr. Avol, Dr.
       Gong, Dr. Hattis, Dr. Kleeberger, Dr. Russell, Dr. Sheppard, Dr.  Speizer, Dr. Thurston
       and Dr. Ultman)

   •   Risk assessment cannot be excluded from the risk/exposure document.  Both quantitative
       and qualitative  evidence are necessary for the integrated assessment of risk leading to
       NAAQS policy recommendations. Semi-quantitative risk assessment information, such
       as estimates of risk bounds, should be incorporated where quantitative assessment is not
       possible. It is also not clear how the information on uncertainty  and variability (i.e., the
       results of the uncertainty analysis) will be used. Additionally, rural as well as urban areas
       should be evaluated for potential NOx and SOx exposures. (Dr. Henderson, Mr. Avol, Dr.
       Crawford-Brown, Dr. Hattis, Dr. Kinney, Dr. Russell, Dr. Seigneur and Dr. Sheppard)

       Finally, several members remarked on how the review of the primary NAAQS for NOx
and SOx will be conducted, noting in particular that the process by which EPA's positions are
developed and presented in the ANPRs needs to be clear and transparent. (See, in particular, the
individual written comments from Mr. Avol, Dr. Gong, Dr. Sheppard and myself.)

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       The CASAC was pleased to consult with the Agency on these draft integrated plans for
review of the primary NAAQS for NC>2 and SC>2 and would appreciate a formal response from
EPA indicating how Agency staff intents to incorporate these comments into the final planning
documents. In addition, the Committee looks forward to conducting a peer review of EPA's first
draft ISAs and risk/exposure methodologies for the review of the primary NAAQS for NOx and
SOx later this calendar year.  As always, we wish EPA staff well in this important task.

                                              Sincerely,

                                             /Signed/

                                              Dr. Rogene Henderson, Chair
                                              Clean Air Scientific Advisory Committee
cc:    Marcus Peacock, Deputy Administrator
      George Gray, Assistant Administrator, ORD
      Robert Meyers, Acting Assistant Administrator, OAR
Appendix A - Roster of the Clean Air Scientific Advisory Committee
Appendix B - Roster of the CASAC NOX & SOX Primary NAAQS Review Panel
Appendix C - Comments from Individual Panel Members

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                                 NOTICE

       This report has been written as part of the activities of the U.S. Environmental
Protection Agency's (EPA) Clean Air Scientific Advisory Committee (CASAC), a
Federal advisory committee administratively located under the EPA Science
Advisory Board (SAB) Staff Office that is chartered to provide extramural scientific
information and advice to the Administrator and other officials of the EPA. The
CASAC is structured to provide balanced, expert assessment of scientific matters
related to issue 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 in the Executive
Branch of the Federal government, nor does mention of trade names or commercial
products constitute a recommendation for use. CASAC reports are posted on the SAB
Web site at: http://www.epa.gov/sab.

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     Appendix A - Roster of the Clean Air Scientific Advisory Committee
                     U.S. Environmental Protection Agency
                   Science Advisory Board (SAB) Staff Office
              Clean Air Scientific Advisory Committee (CASAC)


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

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

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

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

Mr. Richard L. Poirot, Environmental Analyst, Air Pollution Control Division, Department of
Environmental Conservation, Vermont Agency of Natural Resources, Waterbury, VT

Dr. Armistead (Ted) Russell, Georgia Power Distinguished Professor of Environmental
Engineering, Environmental Engineering Group, School of Civil and Environmental
Engineering, Georgia Institute of Technology, Atlanta, GA

Dr. Frank Speizer, Edward Kass Professor of Medicine, Channing Laboratory, Harvard
Medical School, Boston, MA
SCIENCE ADVISORY BOARD STAFF
Mr. Fred Butterfield, CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W.,
Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@epa.gov)
(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff
Office (Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington,
DC 20004, Telephone: 202-343-9994)
                                        A-l

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Appendix B - Roster of the CASAC NOX & SOX Primary NAAQS Review Panel
                       U.S. Environmental Protection Agency
                     Science Advisory Board (SAB) Staff Office
                Clean Air Scientific Advisory Committee (CASAC)
                CASAC NOX & SOX Primary NAAQS Review Panel


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

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

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

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

 Dr. Henry Gong, Professor of Medicine and Preventive Medicine, Medicine and Preventive Medicine,
 Keck School of Medicine, University of Southern California, Environmental Health Service, Downey,
 CA

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

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

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

 Dr. Steven Kleeberger, Professor, Lab Chief, Laboratory of Respiratory Biology, NIH/NIEHS, Research
 Triangle Park, NC

 Dr Timothy Larson, Professor, Department of Civil and Environmental Engineering, University of
 Washington,  Seattle, WA
                                           B-l

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

Mr. Richard L. Poirot*, Environmental Analyst, Air Pollution Control Division, Department of
Environmental Conservation, Vermont Agency of Natural Resources, Waterbury, VT

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

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

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 [M.D.]*, Edward Kass Professor of Medicine, Channing Laboratory, Harvard
Medical School, Boston, MA

Dr. George Thurston, Associate 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,
P.O. Box 10412, Palo Alto, CA
SCIENCE ADVISORY BOARD STAFF
Mr. Fred Butterfield, CASAC Designated Federal Officer, 1200 Pennsylvania Avenue, N.W.,
Washington, DC, 20460, Phone: 202-343-9994, Fax: 202-233-0643 (butterfield.fred@,epa.gov)
(Physical/Courier/FedEx Address: Fred A. Butterfield, III, EPA Science Advisory Board Staff Office
(Mail Code 1400F), Woodies Building, 1025 F Street, N.W., Room 3604, Washington, DC 20004,
Telephone: 202-343-9994)
* Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the EPA
  Administrator
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       Appendix C - Comments from Individual Panel Members
       This appendix contains the preliminary and/or final written comments of the
individual members of the Clean Air Scientific Advisory Committee (CAS AC) Oxides
of Nitrogen (NOx) and Sulfur Oxides (SOx) Primary National Ambient Air Quality
Standards (NAAQS) Review Panel who submitted such comments electronically.  The
comments are included here to provide both a full perspective and a range of individual
views expressed by Panel members during the review process. These comments do not
represent the views of the CAS AC, the EPA Science Advisory Board, or the EPA itself.
Panelists providing review comments are listed on the next page, and their individual
comments follow.
                                     C-l

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Panelist                                                                      Page#




Mr. Ed Avol	C-3




Dr. Ellis Cowling	C-5




Dr. Douglas Crawford-Brown	C-7




Dr. Henry Gong	C-12




Dr. Terry Gordon	C-13




Dr. Dale Hattis	C-14




Dr. Rogene Henderson	C-16




Dr. Patrick Kinney	C-17




Dr. Steven Kleeberger	C-18




Dr. Timothy Larson	C-19




Dr. Kent Pinkerton	C-21




Mr. Rich Poirot	C-24




Dr. Armistead (Ted) Russell	C-27




Dr. Richard Schlesinger	C-30




Dr. Christian Seigneur	C-33




Dr. Elizabeth A. (Lianne) Sheppard	C-34




Dr. Frank Speizer	C-37




Dr. George Thurston	C-39




Dr. James Ultman	C-42




Dr. Ron Wyzga	C-44
                                        C-2

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                                      Mr. Ed Avol


                       Comments on the Draft Plan for Review of the
             Primary National Ambient Air Quality Standard for Nitrogen Dioxide


                     Ed Avol, NOx-SOx Primary Review Panel Member
Pl-2, line 5 - Ambient NOx chemistry is intimately bound between gaseous NOx emissions and
particle NO3 formation. How will this be addressed, considered, and weighted in the "Integrated
Science Assessment" or "Science Assessment Support Document"? Comments in the Plan (P4-
3, line 12, for example) suggest that particulate nitrate information is relevant to the proposed
discussion. If the plan is to only  consider gas-phase processes, how can this be scientifically
justified in terms of air quality and public health?

Pl-2, line 19 - Who will prepare the policy assessment, and how can the public be assured that
the best science, and not political policy, has a substantive role in the process?

P4-6, lines 21 and 22 - why is this question limited specifically to traffic, and not to any
combustion source (home fireplaces, industrial stationary sources, etc.) affecting ambient NC>2?

P4-6, line 25 - add ".. .or indoor  space/water heating sources..." after ".. .gas stoves.

P4-7, line 7 - why are other health effects related to NOx exposure relegated to the status of
"may be evaluated"? Isn't the purpose do the ISA to identify and compile the recent science and
observed health outcomes, without a priori censure or determination of which health outcomes
might be of interest?

P4-7, line 16 - ".. .add ".. .or pre-existing susceptibility  (i.e., genetic, biochemical)..."; the
identified group of "pre-existing  disease state" is arbitrary and limiting, and the current literature
should at least be reviewed for susceptible groups.

P4-7, line 25 - As in the previous comment, other susceptible groups (i.e., genetically
susceptible) may be relevant here as well, and the available literature should be canvassed with
the widest possible initial filter.

P4-8, line 29 - add ".. .or other identified susceptibility (i.e., genetic)..."

P4-10, line 15 - replace "animal-to-man" with "animal-to-human"

P4-10, line 20 - add "genetic susceptibility" to the list for consideration

P4-10, lines 25 and 26 - the issue is not whether children and asthmatics are more sensitive than
the general population to NOx exposure, but rather, whether there is supporting evidence that
                                           C-2

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there are (a) susceptible sub-groups of the population with increased sensitivity to NOx, and if
there are, (b) what we know or can surmise about the characteristics of that sub-population.

P5-2, line 24 - It would seem potentially more useful to review ambient data made available
since the previous NAAQS review, so the window of reviewable data should be the last decade,
not the last three or four years.

P5-3, lines  1 and 2 - Major locations to be evaluated should include both urban areas impacted
by traffic (Los Angeles, Houston, New York, Phoenix) and rural areas. Metropolitan areas in
rapid growth, as well as those with a long history of minimal change, should be considered.

P5-3, lines  7 and 8 - Isn't this potentially going to be related to location (urban vs. rural, or
roadside vs. regional)?  If this is potentially going to be an important
confounder/adjustment/covariate, should this be modified to include the notion of location?

P5-4, line 7 - Why is this necessarily  limited to urban areas across the US?

P6-1, lines  2 and 3 - Which section/department of the EPA will be charged with development of
the ANPR?

P6-1, line 12 - why  is it assumed there is ".. .a gap between the Agency's scientific assessments
and the judgments required of the Administrator..."?
                                          C-4

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                                   Dr. Ellis Cowling


                                                                        Dr. Ellis Cowling
                                                           North Carolina State University
                                                                           May 17, 2007

                     Individual Post-Consultation Comments on the
 Draft Plan for Review of the Primary National Ambient Air Quality Standards for Sulfur
                                    Dioxide and the
 Draft Plan for Review of the Primary National Ambient Air Quality Standard for Nitrogen
                                        Dioxide

My colleagues on CAS AC have offered a number of very constructive comments on specific
details of these two very similar draft plans. My preference instead is to focus attention on the
most general rather than more specific aspects of these two plans - that is, the fundamental
reason for conducting these periodic reviews of NAAQS for all six criteria pollutants, and, of
course, also, these two specific criteria pollutants - sulfur dioxide and nitrogen dioxide.

I am well aware that these two "Draft Plans for Review" refer only to reviews of the primary
(public-health based) standards for SO2 and the single primary standard for NO2j and thus do not
deal directly with reviews of the secondary (public-welfare based) standards for these two
criteria pollutants. I am also aware that a second set of "Draft Plans for Review" probably will
be developed for the secondary (public-welfare based) standards for these two pollutants.
Especially  since the decision has been made to conduct separate reviews for the primary and
secondary standards for each of these two criteria pollutants, it is desirable that an appropriate
relationship be maintained between these two review processes.

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

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

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

 "What scientific evidence and/or scientific insights have been developed since the last review to
indicate if the current public-health based and/or the current public-welfare based NAAQS need
to be revised or if alternative levels, indicators, statistical forms, or averaging times of these
                                          C-5

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standards are needed to protect public health with an adequate margin of safety and to protect
public welfare?"
With regard to the important distinction in purpose of the primary (public health) and secondary
(public welfare) NAAQS standards, it is noteworthy that in all five cases in which a secondary
NAAQS standard has been established, the secondary standard has been set "Same as Primary."

In this connection it is also important to recognize that "public welfare effects" are defined in the
Clean Air Act to include, but are not limited to: "effects on soils, water, crops, vegetation, man-
made materials, animals, wildlife, weather, visibility, climate, damage to and deterioration of
property, and hazards to transportation, as well as effects on economic values and on personal
comfort and well-being, whether caused by transformation, conversion, or combination with
other air pollutants."

The Clean Air Act also specifies that "Any national secondary ambient air quality standard ...
shall specify a level of air quality the attainment and maintenance of which in the judgment of
the Administrator ... is requisite to protect the public welfare from any known or anticipated
adverse effects associated with the presence of such air pollutant in the ambient air."

Thus, a second very critical question that needs to be answered with regard to all six criteria air
pollutants is:

 "What scientific evidence and/or scientific insights have been developed since the last review to
indicate whether, and if so, what particular ecosystem components or other air-quality-related
public welfare values, are more or less sensitive than the populations of humans for which
primary standards are established and for this reason may require a different level, indicator,
statistical form, or averaging time of a secondary standard in order to protect public welfare. "

I hope these two "critical scientific questions" will be borne in mind carefully as CASAC
joins with the various relevant parts of the Environmental Protection Agency in completing
the upcoming reviews of both the primary and secondary National Ambient Air Quality
Standards for  these two criteria pollutants and the four other criteria pollutants that will
follow under the guidance of the new NAAQS review processes.
                                           C-6

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                            Dr. Douglas Crawford-Brown


                         Review of Draft IP for Nitrogen Dioxide

                                  Doug Crawford-Brown

Given that this is a draft IP, there is not a lot that can be said at this stage since the real issues
will revolve around how these plans are implemented in the actual assessments. Still, there are a
few initial issues I want to raise. The issues raised here are largely identical with those raised in
my review of the Nitrogen Dioxide IP, as the two documents are almost identical.

1. On page 3-2, the question is raised as to whether there is evidence of effects at exposure levels
lower than those found in the previous studies. I believe this should refer to lower levels and/or
shorter periods of time (i.e. exposure duration), although the latter issue is hinted at later in the
questions.

2. On page 4-1, the issue is raised of the new studies being integrated into the older ones. I would
like to have  seen a sentence or two as to how that will be done. There are always two approaches
to this: either treat the older conclusions as a form of prior and then ask whether the new data
cause you to change these prior conclusions, or re-do the older assessment entirely with the new
data folded into the pool of data to be considered. The authors are not clear which is to be done
here, but the results can differ between the two approaches since the former sets up a kind of
epistemic barrier the new data must possess to move the assessor off previously established
positions. The latter approach is, of course, also more time intensive.

3. The approach for locating new data, starting on page 4-2, is well developed, so I have no
suggestions  there. While I appreciate the desire to use only peer reviewed literature, this
requirement is getting less germane as internet publishing expands, and at some point the EPA
will need to confront this issue.

4. The material  on Exposure beginning with page 4-6 is a bit sketchy, and I understand the need
to be so at this stage. However, I have some  significant issues to raise as to how activity patterns
of individuals, including movement through geographically inhomogeneous fields of
concentration, will be treated. The most fundamental issue is whether the assessment is intended
to reflect, in the greatest detail possible, the actual exposures to actual individuals in the
population, or the exposures that would occur if an individual were to adopt some activity pattern
that puts them at greatest risk. There certainly is merit in the argument that one wants the former,
as it best reflects the actual risks being experienced by the population given their current
distribution  of activity patterns. But there is equal merit in the argument that the job of the EPA
is to create environments within which individuals could move in whatever activity patterns they
choose without  sacrificing their rights to protection against significant health risks. In the latter
case, one would model scenarios that are designed to be reasonable expectations of what people
might choose to do in  the environment, rather than trying to model these activities
probabilistically. This will be an issue we can discuss more when in session.
                                           C-7

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5. On page 4-7, second bullet, the authors raise the issue of whether there are effects on lung
functions changes or development. It is important here to also consider whether these effects are
to be determined adverse. I realize this is in part the intention of the phrase "potential clinical
relevance" in the next bullet, but the effects in that third bullet are not identical with those in the
second.

6. On pages 4-7 and 4-8, the authors begin to confront the idea that past exposures at low but
chronic levels might affect an individual's sensitivity to shorter term but higher concentration
exposures, and to infection. This issue seems to me important, since the chronic exposures could
either sensitize or de-sensitize people.

7. On page 4-9, third bullet under Biological Mechanisms of Action, the authors might consider
adding something like ".. .and what are the implications..." to the end of the bullet.

8. On page 4-10, second bullet under Susceptible Populations, the presumption is that children
and asthmatics are more sensitive. I realize this is the predominant case, but I would be inclined
at this stage to not stack the deck in the question, but rather to ask the extent to which these
groups are more or less sensitive.

9. On page 5-1, the authors state that they anticipate an inability to produce a quantitative health
risk assessment. Do they really mean no quantitative health risk assessment can be conducted, or
do they mean it will need to be an assessment that ends with something like a hazard quotient
rather than a probability and/or severity of effect? And will it be driven by the HQ in the most
sensitive subpopulation? This sentence just leaves me wondering what the assessment WILL end
up producing that is useful in setting a NAAQS if there is  insufficient exposure-response
information to estimate risks. Perhaps the problem here is that I consider an HQ value to be a
legitimate result of a risk estimation procedure while perhaps the authors do  not? I am
particularly unclear as to how the screening assessment results will be used to determine whether
a more refined assessment is warranted. There should be at least some rudimentary decision
criterion, pre-specified, to guide this process. I suppose the bullets on page 5-5 are intended to in
some way specify criteria for this decision, but they are too generic to play that role.

10. In section 5, the authors are beginning to consider the  issue of the spatial resolution that will
be needed to estimate exposures. I agree that greater spatial resolution might be good to have, but
there are two caveats to this. First, I am not convinced that the quality of predictions of exposure
at fine spatial resolution are accurate below some level of resolution. Second, the spatial
resolution should not be any better than the spatial resolution of the activity patterns for
individuals. There comes a point at which increased spatial resolution in ambient air
concentration or microenvironment concentration is more than washed out by uncertainties in
activity patterns.

11. On page 5-6, there is also some discussion of uncertainty due to model formulation. The
description of how this will be treated is too cursory for me to feel very comfortable. There is
some hint that subjective confidence measures will be applied, but also some hint that these will
be driven solely by some sort of relative likelihood measure obtained from a fit to data. This
raises huge questions as to WHICH data will be the primary data on which the likelihoods will

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be developed, and whether model fit is the sole criterion for judging the validity and strength of a
model. I think the authors have some significant issues to consider here.

15. Finally, the assessment will be based in part on case studies in different cities. The authors
describe this choice as being rooted in an assessment of variability, giving some idea of the
upper and lower bounds of the variability. However, it is not clear how the choice of cities will
produce recognizable percentiles of the variability distribution. Is there any way in which the
EPA intends to relate specific individuals, or scenarios, in specific case studies to specific
percentiles? Absent this, it is not clear how such an assessment of variability will be related to
specific regulatory bases for setting a NAAQS.
                          Review of Draft IP for Sulfur Dioxide

                                  Doug Crawford-Brown

Given that this is a draft IP, there is not a lot that can be said at this stage since the real issues
will revolve around how these plans are implemented in the actual assessments.  Still, there are a
few initial issues I want to raise. The issues raised here are largely identical with those raised in
my review of the Nitrogen Dioxide IP, as the two documents are almost identical.

1. On page 3-2, the question is raised as to whether there is evidence of effects at exposure levels
lower than those found in the  previous studies. I believe this should refer to lower levels and/or
shorter periods of time (i.e. exposure duration), although the latter issue  is hinted at later in the
questions.

2. On page 4-1, the issue is raised of the new studies being integrated into the older ones. I would
like to have  seen a sentence or two as to how that will be done. There are always two approaches
to this: either treat the older conclusions as a form of prior and then ask whether the new data
cause you to change these prior conclusions, or re-do the older assessment entirely with the new
data folded into the  pool of data to be considered. The authors are not clear which is to be done
here, but the results can differ between the two approaches since the former sets up a kind of
epistemic barrier the new data must possess to move the assessor off previously  established
positions. The latter approach is, of course, also more time intensive.

3. The approach for locating new data, starting on page 4-2, is well developed, so I have no
suggestions  there. While I appreciate the desire to use only peer reviewed literature, this
requirement is getting less germane as internet publishing expands, and at some  point the EPA
will need to confront this issue.

4. The material  on Exposure beginning with page 4-6 is a bit sketchy, and I understand the need
to be so at this stage. However, I have some significant issues to raise as to how activity patterns
of individuals, including movement through geographically inhomogeneous fields of
concentration, will be treated. The most fundamental issue is whether the assessment is intended
to reflect, in the greatest detail possible, the actual exposures to actual individuals in the
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population, or the exposures that would occur if an individual were to adopt some activity pattern
that puts them at greatest risk. There certainly is merit in the argument that one wants the former,
as it best reflects the actual risks being experienced by the population given their current
distribution of activity patterns. But there is equal merit in the argument that the job of the EPA
is to create environments within which individuals could move in whatever activity patterns they
choose without sacrificing their rights to protection against significant health risks. In the latter
case, one would model scenarios that are designed to be reasonable expectations of what people
might choose to do in the environment, rather than trying to model these activities
probabilistically. This will be an issue we can discuss more when in session.

5. On page 4-7, second bullet, the authors raise the issue of whether there are effects on lung
functions changes or development.  It is important here to also consider whether these effects are
to be determined adverse. I realize this is in part the intention of the phrase "potential clinical
relevance" in the next bullet, but the effects in that third bullet are not identical with those in the
second.

6. On pages 4-7 and 4-8, the authors begin to confront the idea that past exposures at low but
chronic levels might affect an individual's sensitivity to shorter  term but higher concentration
exposures. This issue seems to me important, since the chronic exposures could either sensitize
or de-sensitize people.

7. On page 4-9, third bullet under Biological Mechanisms of Action, the authors might consider
adding something like ".. .and what are the implications..." to the end of the bullet.

8. On page 4-10, second bullet under Susceptible Populations, the presumption is that children
and asthmatics  are more sensitive. I realize this is the predominant case, but I would be inclined
at this stage to not stack the deck in the question, but rather to ask the extent to which these
groups are more or less sensitive.

9. On page 5-1, the authors state that they anticipate an inability to produce a quantitative health
risk assessment. I find it hard to reconcile this statement with the large amount of work that will
go into the exposure assessment. Do they really mean no quantitative health risk assessment can
be conducted, or do they mean it will need to be an assessment that ends with something like a
hazard quotient rather than a probability and/or severity of effect? And will it be driven by the
HQ in the most sensitive subpopulation? This sentence just leaves me wondering what the
assessment WILL end up producing that is useful in setting a NAAQS if there is insufficient
exposure-response information to estimate risks. Perhaps the problem here is that I consider an
HQ value  to be a legitimate result of a risk estimation procedure while perhaps the authors do
not?

10. On page 5-3, the authors approach the issue of ambient exposures and exposures in
microenvironments. From the writing, it appeared to me that they will convert ambient levels to
those in microenvironments solely through models. This seems  to me to leave out increasingly
detailed studies of the empirical relationships between these quantities, many of which have been
funded by the EPA. I may be wrong that these are being ignored, but the wording in this section
does emphasize modeling rather than data.
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11. On page 5-4, the authors are beginning to consider the issue of the spatial resolution that will
be needed to estimate exposures. I agree that greater spatial resolution might be good to have, but
there are two caveats to this. First, I am not convinced that the quality of predictions of exposure
at fine spatial resolution are accurate below some level of resolution. Second, the spatial
resolution should not be any better than the spatial resolution of the activity patterns for
individuals. There comes a point at which increased spatial resolution in ambient air
concentration or microenvironment concentration is more than washed out by uncertainties in
activity patterns.

12. On page 5-5, under Uncertainty and variability, the authors state that they will determine
".. .the relative degree of confidence in the results...". I have no idea what is meant by this.
Relative with respect to what? And what is the measure of confidence? Is  it frequentist,
subjective, Bayesian?

13. On page 5-6,1 worry about the phrase ".. .information is often not available to estimate
uncertainty separately from variability". Not only do I disagree that this is true, I can see no way
around separating these two. They are two different concepts, existing in different places in the
world (variability exists solely outside our minds, uncertainty exists solely within them - a
distinction that seems to me pretty fundamental). I have little doubt that CASAC would  have
significant concerns with the final product if uncertainty and variability are NOT separated.

14. On page 5-6, there is also some discussion  of uncertainty due to model formulation.  The
description of how this will be treated is too cursory for me to feel very comfortable. There is
some hint that subjective confidence measures  will be applied, but also some hint that these will
be driven solely by  some sort of relative likelihood measure obtained from a fit to data. This
raises huge questions  as to WHICH data will be the primary data on which the likelihoods will
be developed, and whether model fit is the sole criterion for judging the validity and strength of a
model. I think the authors have some significant issues to consider here.

15. Finally, the assessment will be based in part on case studies in different cities. The authors
describe this choice as being rooted in an assessment of variability, giving some idea of the
upper and lower bounds of the variability. However, it is not clear how the choice of cities will
produce recognizable percentiles of the variability distribution. Is there any way in which the
EPA intends to relate  specific individuals, or scenarios, in specific case studies to specific
percentiles? Absent this, it is not clear how such an assessment of variability will be related to
specific regulatory bases for setting a NAAQS.
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                                   Dr. Henry Gong

Post-Conference Comments on Draft Plan for Review of the Primary National Ambient Air
Quality Standards forNO2 (February 2007) and SO2 (April 2007)
Henry Gong
May 19, 2007

Although I was unable to participate in the teleconference on May 11,1 wish to submit some
impressions based on my review of the documents and comments by the CASAC panelists.  I
apologize if I am repeating any discussion held during the recent conference call.

I offer these general comments that pertain to both draft plans:
    1.  I appreciate (and support) the interesting and perceptive comments and perspectives
       raised by my fellow colleagues on the Panel. They raise important general and specific
       issues related to the administration and process of the review, as well as to science and
       public health.
    2.  NO2 vs. NOx?  SO2 vs. SOx?  Each plan may confuse the reader at times since it is
       unclear whether the text is actually (or should be) referring to either or both NO2 vs.
       NOx or SO2 vs. SOx, in the respective plans. Even the titles ("Draft Plans...") refer only
       to NO2 or SO2 and not to other related chemical species.  I read the NO2 Plan before the
       SO2 Plan and noted that the explanation for addressing only NO2 was missing, but an
       explanation was present for SO2 (Section 1.4. Scope of Review, page  1-6)). However,
       even the SO2 rationale is somewhat confusing in that I came away with the  perception
       that sulfuric acid, sulfates, etc., may or may not (?) be addressed.  The occurrence/
       interactions of gas-particulate mixtures is not referred to.  Thus, I recommend that careful
       consistency of terms and stronger explanations for inclusion and exclusion be used.
    3.  The series of questions about air quality, exposure, health effects, etc., to be addressed (if
       possible) in the ISA of both Plans are excellent.
    4.  Does the possible lack of a full or proper quantitative risk assessment impair a good
       estimate of the "margin of safety"?
    5.  What is the role of CASAC (if any) in the draft of the ANPR? My reading of the Plans
       suggests that the ANPR is an independently developed document published in the Federal
       Register. This presentation may, in effect, give it an "authoritative" scientific-policy
       representation and almost law-like quality. I would appreciate more information about the
       development and vetting of the ANPR.
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                                  Dr. Terry Gordon
Gordon - General Comments on NOx and SOx Draft Plans for Review

       In general, the comments I've read reflect my opinions.  Rather than repeat things, my 2
additional comments are:

1. More consistent wording should be used in directing the emphasis on the quality and inclusion
of studies in the Assessment document. At one point in the Plan, miniscule detail is given in
terms of studies must include filtered air control groups, yet Section 4-1 states that exceptions to
peer-reviewed and published studies can be made depending upon rather vague terms. This
point may be moot, however, if all relevant studies will be included in a supporting table and
only key studies discussed in the text of the documents themselves.

2. If concentration exposure levels in controlled studies must be relevant to ambient
concentrations, what will those levels be and who and when will they be decided upon? This
point may also be partially moot, as the draft chapters have already been submitted and
discussed. Also, if all studies are included in the supplemental/annex tables, then only the
studies with relevant concentrations can be discussed in the text.
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                                    Dr. Dale Hattis
 Comments on the Draft Integrated Plans for Reassessment of the SOx and NOx National
                             Ambient Air Quality Standards
                               Dale Hattis, Clark University


SO2
       I have one overarching comment/suggestion that stems from the first two bullets
representing "uncertainties" on the bottom of page 4-8. These bullets are:

          •   How do confounding by co-exposure to other pollutants and by meteorological
              factors influence the uncertainty of the evidence base for both short- and long-
              term exposures?

          •   To what extent are the observed health effects associations attributable to SC>2
              versus the pollutant mixtures that SC>2 may be representing? For example ambient
              SO2 concentrations may be serving as a surrogate measure for long range
              transport of particles.
    I think these are both such excellent and potentially important questions that EPA should
    consider moving them from a rather peripheral discussion of uncertainties to main lines of
    analysis. As I believe was discussed in the February meeting I attended, my recollection is
    that from the earliest days of Mary Amdur's fine and extensive series of experimental
    observations in guinea pigs, mixtures of sulfur oxide gases and particles may have greater
    effects than either component administered separately.  One possible interpretation of this is
    that the particles are acting as a kind of vector for the sulfur oxide gases—facilitating the
    delivery of larger amounts of the gases in adsorbed form farther down into the respiratory
    tract than would otherwise occur.  If this turns out to be the case on full review of the older
    and newer literature, then perhaps we should be asking, "Are the concentrations/exposure
    times of 862 that are 'requisite to protect public health" different depending on typical  local
    co-exposures to particulates and/or different meteorological conditions such as humidity? If
    so, I think two kinds of policy responses could be considered:

          •   Locations with relevant monitoring data could be classified into a number of
              categories based on interacting particle and/or meteorological conditions, in order
              to provide the basis for application of a graded series of NAAQS SC>2  criteria
              taking into account the likely greater SC>2 effects in some places rather than
              others.

          •   The SC>2 NAAQS  could be modified to take the form of an index modified to take
              into account the contributions of particles and meteorological conditions on the
              862 -dependent response.  Such an index would have some technical advantages
              in that the particle and meteorological influences could be represented in
              continuous functional form,  rather than as categorical variables.
    Both of these options would respond to EPA's evident  concern that the purpose of the
    present review is to modify the 862 /SOx gas standard, not revisit the paniculate standard
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itself. An implication for the EPA work is that the plan for exposure data collection and
analysis/modeling (Section 5.3) will need to be appreciably changed to keep track of the co-
exposures of particles of various size ranges and meteorological information so that they can
be analyzed to see the effects of potential  standards reformulated in these ways.
Another comment that pertains to section  5.4, is that I would like to urge EPA to attempt a
full probabilistic risk assessment—treating both variability and uncertainty of both exposures
and health effects. This kind of high profile national-level review and analysis is just the
kind of enterprise that should be expected to utilize the most sophisticated treatment of the
very different concepts of variability and uncertainty.  This would afford the EPA an
opportunity to quantitatively define its "margin of protection" goal in setting NAAQS in
terms of assuring that there is Z% confidence that the incidence of effects of a defined level
of severity is less than some specific value. Without such definition, the policy goals of the
Clean Air Act will remain in their present vague and non-evaluatable state.
NOx
I have no specific comments on the NOx plan. However the last comment in the previous
section applies equally to both the NOx and SO2 analyses.
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                               Dr. Rogene Henderson


Comments on the draft plans for review of the primary NAAQS for NOX and SOX

Submitted by Rogene Henderson

Major general comment:
I have a comment that applies to both draft plans in regard to the third component of the review
process, i.e., the risk/exposure assessment. In both the section on Overview of the Review
Process (Section 1.1), and the section on Risk/Exposure Assessment (Section 5), the "risk" part
of the title seems to have been left out. Only the exposure assessment is discussed. In a memo
dated April 17, 2007, Marcus Peacock describes the latest version of the new review process and
states that, "I am modifying the process to enable CASAC to review and provide advice to the
Agency on the second draft risk/exposure assessment report, which will include estimated risk/
exposures associated with potential alternative standards, prior to issuance of the ANPR " Thus
the plan needs to provide for inclusion of a listing of potential  alternative standards and the
estimated risks/exposures associated with those standards in the risk/exposure assessment
documents .

Minor specific comment:
SOX document, page 4-8 lines 9-10: Should insert "SO2 -induced" before "lung inflammation"
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                                 Dr. Patrick Kinney
  Draft Plans for Review of the Primary National Ambient Air Quality Standards for NO2 and
                                         SO2
                      Comments of Patrick L. Kinney, May 18, 2007

I was very impressed by the quality of both documents. Overall, the proposed process for review
of the NAAQS looks to be reasonable.

My main substantive comment is on Section 5.1 of both documents, where the risk assessment
methodology is discussed. EPA should  provide an expanded rationale for their initial decision
not to conduct a quantitative risk assessment (QRA) for either pollutant. What is missing, and
what kind and quantity of data would EPA need in order to proceed with a QRA?

On a more philosophical level: if a) there is an insufficient health database to support risk
assessment for NO2 and SO2, and b) both NO2 and  SO2 are precursors for PM2.5 formulation,
and c) there IS a sufficient health database to support PM2.5 risk assessment, what is EPA's
rationale for continuing to regulate NO2 and SO2 as criteria pollutants? Wouldn't it be more
rational to simply set NO2 and SO2 emissions limits based on PM2.5 risk assessment?
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                                Dr. Steven Kleeberger

Steven R. Kleeberger
Laboratory of Respiratory Biology
NIEHS

Comments

NOx Document

       I have only a few comments in addition to those already raised by other reviewers.  In
particular, I wonder whether greater emphasis or detail regarding phenotypes of response to NOX
(and SOX) exposures should be written. In the Science Assessment (Section 4), pages 4-7 and 4-
8 of the NOX document, discussion of responses to short-term and long-term exposures is largely
limited to adults and, to a lesser extent, children in epidemiologic and clinical studies. I would
suggest that an unexplored, or not very well considered, aspect of air pollution relates to in utero
or epigenetic effects, and reproductive effects.  Epigenetic effects of NOX and SOX may have
important implications in development of childhood and adult diseases. Effects of pollutant on
reproductive characteristics including fecundity, prematurity, and sex ratio have not been well
studied but could be important outcomes of exposure to pregnant women.

       Susceptible populations are mentioned in many sections of the NOX and SOX documents.
However, the susceptibility factors generally considered include pre-existing disease (e.g. COPD
and asthma) or age (e.g. children).  Some mention of genetic background is made in the two
documents, but inasmuch as genetic background is increasingly recognized as an important
susceptibility factor for responsivity to pollutant exposure, I suggest that greater emphasis be
placed on this intrinsic host factor. Mention of inter-species differences in sensitivity on page 4-
10 of the NOX document could also include inter-strain differences.

       I would re-emphasize the point made by one of the reviewers that effects of mixtures
should perhaps receive greater emphasis in both documents. I recognize that mixtures are
covered by other CASAC committees, but additional emphasis in the NOX and SOX documents is
warranted.
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                                  Dr. Timothy Larson

           Comments on Draft IPs for Review of the Primary SC>2 and NC>2 NAAQS
                                     Timothy Larson
                                University of Washington

General Comments

In general, it is reasonable to have a review schedule that results in a timely assessment of the
science and a promulgation of a revised standard. However, if events as outlined do not keep on
schedule, one simple question is whether we as a committee will have a chance to review a
revised schedule that contains all the elements of the currently proposed schedule.  One would
assume so. Another question is how are 'important' late breaking studies considered?  By
'important' I mean those studies that are published between the final review of the ISA (July
2008) and the final review of the  ANPR (June 2009), and that the committee as a whole (or in
part?) deem sufficient to change the basis of a risk assessment.  This is a bit trickier and probably
deserves discussion.

Some of the questions listed in both documents in section 3.2 seem redundant. Regarding
evaluation of the newly available evidence, five of the questions are variations of the same
general question, i.e., the extent to which newly available information reinforces or calls into
question evidence for the occurrence of health effects at ambient levels. The two other questions
in this group are qualitatively different, dealing with the levels of exposure where  health effects
occur (the dose response relationship) and the aerometric relationships. I would shorten the list
and add a  specific question about our current understanding of the mechanisms of effect (the
plausibility question). Regarding the identification of alternative standards, the first question,
strictly speaking, excludes the possibility of effects at different averaging times. The effect
could occur at a higher (rather than lower) concentration than those observed previously because
of a shorter exposure time than previously considered.

I agree with Professor Speizer's suggestion that we should have access to a list of studies that
will be considered for inclusion in the SASD.

NC>2 Document:

In section 4 of the document, there are explicit criteria listed for study selection, including an
upper limit on NC>2 exposures in controlled human studies. I would suggest considering an upper
limit on NOx as well, as many of the diluted combustion exhaust studies report both NC>2 and
NO and can have fairly high levels of NO (above 1 ppm). This consideration may not be
relevant for all endpoints, but could be for some given that NO is used as a therapeutic agent.

Page 4-5 line 26: emissions of NOx?  Most NO2 is initially emitted as NO.

Page 4-5 line 28: the notion of an additive background may not hold for NO2, given the concept
of a photochemical steady state for NO2 and Os.
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Page 4-6 lines 10 and 23:  these seem like a health questions, not exposure questions

Page 4-8 line 7:  Do you mean NO2 rather than NOx?

Page 4-9 line 1: What are the criteria for there being a causal relationship?

Page 4-9 line 24: In this and the following section, are you considering only NOx or also NC>2
and NO separately?

Page 5-4 line 12:1 would also suggest that the exposure assessment take into account any
personal exposure data sets that exist and can be reliably compared with model predictions.

SO2 Document

Page 4-3 line 8: What is the rationale for down-weighting studies from other than the US or
Canada? I would think that the criteria should be the relative mix of sources of SO2 and other
pollutants, not the geography per se.

Page 4-3 line 26: what about double blinding as a requirement?

Page 5-4 line 28: Most if not all current air quality dispersion models do not predict 5-minute
average concentrations with much skill. It's not clear that this is a viable alternative.
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                                  Dr. Kent Pinkerton

                                                                           May 10, 2007

Comments on the Science Assessment of the "Draft Plan for Review of the Primary
National Ambient Air Quality Standard for Nitrogen Dioxide"

                     KentE. Pinkerton, University of California, Davis

(The comments listed below, in general, are also relevant to the Sulfur Dioxide Document)

1) The organizers and writers for the Science Assessment portion of the document are to be
   commended for their clear and logical explanation of the scope and organization of the
   science assessment to be implemented for this criteria document.

2) The approach to be taken to conduct the assessment of what is new since the last writing on
   this criteria pollutant, as well as input from the public of this scientific review are excellent
   and based on both integrated science assessment (ISA) and the creation of a science
   assessment support document (SASD). The purpose, content, and interpretation of this
   assessment approach, as well as the creation of the document are clearly outlined in the scope
   and organization of this integrated draft document.

3) The primary focus of the ISA and SASD is to present literature published since the previous
   review of the air quality criteria for NOX. Key  findings and conclusions will be briefly
   summarized from the previous document dated in 1993. More recent studies will be
   integrated into previous findings. In addition, important older studies will be specifically
   discussed and opened to reinterpretation based on more recent data.  I think this approach is
   highly logical and clearly responsive to the mandate for scientific rigor and completeness in
   reassessing the NOX criteria standard.

4) I am in complete agreement with the importance to emphasize studies conducted at or near
   NOX concentrations found in the ambient air. However, I would also emphasize the critical
   importance to also examine unique conditions in which NOX concentrations may be unusually
   high due to specific occupational conditions or conditions that may exist within certain
   dwellings or settings that may be unintentional but do occur. Such an understanding of the
   potential health effects associated with likely short-term exposures to very high levels of NOX
   is as important as those to evaluate ambient concentrations of NOX.

5) The need to include studies that may deal with NOX concentrations above  ambient levels is
   simply based on the fact that people could accidentally be exposed to NOX concentration far
   above ambient levels that may have persistent or lingering effects following such events.

6) The authors of the current draft of the NOX document from both the EPA staff, as well as
   extramural scientists contracted to the EPA should be commended for their excellent and
   thorough evaluation of the more recent data of NOX findings. I find no serious deficiency or
   omission in the approach taken to conduct a complete and thorough literature search. Key
   words, as identified by the NCEA-RTP team, are highly appropriate.  It is assumed that
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   nitrogen-containing compounds that are based in ammonia or ammonium constituents would
   not be appropriate for this document? If not, I think it is important that the absence of other
   nitrogen-containing compounds (associated with other criteria pollutants such as particulate
   matter) be stated as not relevant (or exempt) for this criteria document.

7) The thorough review proposed of the draft document by EPA staff, as well as comments on
   draft chapters by outside reviewers are superb ways to provide a more polished and finished
   product to the members of CASAC for their review. This is very much appreciated by all of
   us serving on this Committee!

8) The criteria used for study (publication) selection for the next NOX document seems to be
   highly appropriate for epidemiological studies using both short- and long-term exposures at
   near ambient concentrations of NOX.  The selection of such studies is logical and appropriate.
   To examine the health effects of specific NOX species or indicators related to NOX sources is
   also an excellent idea. Inclusion of populations not previously involved in extensive research
   is critical. Multiple pollutant analysis is also important to undertake as part of the new
   criteria document.

9) Methodology applied in published studies is highly relevant for consideration, but it is not
   clear whether this is an area of concern that will present a serious issue in the reassessment of
   the next NOX document. Never-the-less, the evaluation of methodological issues will provide
   greater credibility for the next NOX document.

10) A continuing concern is the preferential selection of research which evaluate human
   exposures of NOxthat are limited to those studies where subjects were exposed to NO2 at
   concentrations less than Ippm.  Such criteria may be scientifically sound and logically based
   on what typically the public and/or individuals  in this country encounter.  However, do these
   selection criteria miss an important group, i.e., workers in an occupational setting where NO2
   and other species of NOX may be higher than Ippm levels or there may be transient
   conditions in which NO2 or NOX may be evident? Although I admit not being familiar with
   the literature  to be aware if such conditions exist, I would assume under specific conditions
   for space heater or gas stove use (die to faulty maintenance) that such conditions may exist in
   which NO2 levels may exceed Ippm.  This may also be true of cases in which diesel or car
   emissions through testing may lead to higher exposure levels of NO2 or NOX than this
   designated concentration of Ippm.

11) The organization and content of the SASD will focus on two goals. First, to identify
   scientific research that is relevant to informing  policy issues; second, to produce a base of
   evidence containing all of the publication relevant to the NOX review. These goals are
   appropriate and important to the preparation of this document.

12) Since the number of publications could be rather extensive, it is critical the preparation of
   this document use an approach to distill these studies into something that can easily
   understood. It is anticipated the organization of the document will categorize studies in such
   a way that will make them easy to follow.  I am confident such a plan is already in the works.
   The most obvious confirmation of this approach is the division of the draft document into
   chapters that  cover key issues, such as the chemistry of NOX, environmental concentrations  in
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   human exposure, dosimetry, toxicological studies, human clinical studies, laboratory animals,
   etc.

13)1 would recommend that some sense of the scientific rigor and relevance of each study be
   assigned with a priority score to better interpret which studies provide the most reliable and
   relevant information for setting a possible new standard for the NOX criteria.

14) The organization and content of the ISA in its current form is highly relevant, clearly
   responsive, and covers all the critical elements to be able to competently evaluate and
   interpret key issues involved in this criteria pollutant and relevant health implications.

15) The specific questions to be addressed in each  section  are well thought out. It will be critical
   that the ISA as well as the resultant document clearly identify the answer (or the lack of an
   answer!) to each of these questions in air quality, atmospheric chemistry, and short- and
   long-term health effects in both animals and humans.

16) The importance of causality is perhaps the ultimate goal such a document can provide in
   reassessing this criteria pollutant standard. To identify scientific uncertainties that continue
   to exist is also critical to help redirect efforts to better understand the potential impacts of
   NOX on human health.

17) The interaction of NOX with other atmospheric components is essential to provide the proper
   insights of how NOX under certain conditions may influence the formation or concentrations
   of other criteria pollutants.

18) Biological mechanisms of action are clearly important in better understanding health
   implications.  It is important that age, gender, and pre-existing diseases are brought into
   account to explain for some of these conditions. Such actions will help us to better
   understand susceptible populations and help exposure to NOX may impact on the quality of
   life and their well-being.

19) Plans for public and scientific review of the document prepared for NC>2 take a logical and
   clear path designed to produce the best product possible in the proper review of this criteria
   document.

20) To have the draft essay  SD undergo peer-review by external reviewers with the appropriate
   scientific expertise is fabulous. The guidelines provided to these external reviewers are clear
   and  important for them to follow.  If these actions are indeed taken and satisfied by the
   reviewers, then the work and review requested by members of CAS AC will be greatly
   facilitated to be able to identify, hopefully, any key elements that they may be missing from
   the final draft document.

21) It is our hope that CASAC's contribution to the evaluation of the NOX document will be one
   to provide the most sound and rigorous scientific review of what has been observed since the
   last publication of the NOX document. I think EPA's Draft Integrated Plan for review will
   clearly facilitate this process.  Thanks!
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                                    Mr. Rich Poirot


EPA Draft Plans for Review of Primary Sulfur Dioxide and Nitrogen Dioxide Standards:
Key Policy-Relevant Issues
R. Poirot VT DEC

Following are some general comments that apply to the draft plans for both NC>2 and SC>2.

1. What are the current functions of the primary (& secondary) NOi and SOi standards?

The current primary NC>2 and SC>2 standards were both established in 1971 and have not been
revised in the past 36 years. While there were a large number of non-attainment areas for these
pollutants in the 1970s, there are currently no areas that fail to attain the primary and secondary
standards for NC>2 and only a few (8) designated non-attainment areas for 862. From EPA's
AirData website (http://www.epa.gov/air/data/geosel.html), it appears that (with the exception of
2 monitoring sites in Hawaii Volcanoes National Park) there has been only 1 measured violation
of the 24-hour primary 862 standard and no violations of the annual primary or 3-hour secondary
862 standards over the past 5 years. Since there are no areas which attain the primary standards
but not the secondary standards, these secondary standards currently serve no useful function.
Given the absence of recent primary violations, the primary NC>2 and SC>2 standards may help
guard against future emissions increases (unlikely), but are not resulting in currently active
reductions in NOX or  862 emissions. Rather, current emissions reductions of these pollutants are
driven by other regulatory programs, including the CAA Title IV Acid Rain Control Program,
the Regional Haze Rule, and NAAQS attainment for PM2.5 and ozone - for which SC>2 and NOX
are the most important precursors.

Future SC>2 and NOX emission reductions are required under the EPA Clean Air Interstate Rule
(CAIR), which is essentially an expansion of the market-based Title IV cap and trade program.
In describing the benefits of the  CAIR rule (which will apply to only 28 Eastern states) the
Agency estimates that the future reductions in 862 and NOX emissions "will result in $85 to $100
billion in health benefits and nearly $2 billion in visibility benefits per year by 2015 and will
substantially reduce premature mortality in the eastern United States. The benefits will continue
to grow each year with further implementation." (http://www.epa.gov/interstateairquality/ ).

Conceivably, the same (or greater) degree  of these well-justified, long-overdue emissions
reductions could have been achieved (in a  shorter time period) through a tightening of the SC>2
and NC>2 NAAQS.  But the Agency has made a clear policy choice in favor of market based
controls which would essentially conflict with a NAAQS approach, since the former assumes all
emissions have  equal effects, while the latter would require reductions in specific emission
sources. For these reasons, I suspect we are basically going through the motions of symbolic
NAAQS review with a predetermined policy decision that lowering the SC>2 and NC>2 NAAQS is
not the best way to reduce the adverse health effects resulting from these pollutants.

Perhaps the NAAQS Review Plans  should clearly state this policy perspective up front. It would
also seem useful to include a detailed evaluation of future CAIR controls (and timing) in the
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risk/exposure assessment, as well as an evaluation of benefits of further tightening of C AIR
allowances and/or accelerating the time schedule. It would also seem useful to include some
specific focus on effects of SC>2 and NC>2 sources or regions (the West) which will not be subject
to future CAIR emission controls, or to consider ways in which the SO2 and NO2 primary (and/or
secondary) NAAQS might be used  in ways that are  seen as complimentary to rather than in
conflict with a market-based approach.

2. Should revisions to NOi and SOi standards include consideration of their secondary
transformation products?

Current standards are based on considerations of direct health effects from these gases only, and
do not appear to consider the combined influences of the many various secondary transformation
products which result from these precursor pollutants. In the draft 862 Review Plan, the authors
indicate (page 1-6) that the principal transformation products of SC>2 (sulfuric acid and sulfates)
will be addressed in the PM review and not considered here, except as possible confounders for
which (co-varying) SO2 may act as an indicator in epidemiological analyses. The draft NO2
Review Plan does not  specifically exclude consideration of effects of transformation products,
but it appears that the intent is to consider only health effects from gaseous NC>2, although the
draft plan frequently mixes the terms NC>2 and NOX  in an inconsistent manner, leaving the
intended meaning unclear.

In the final policy assessment, a separation of precursor and secondary pollutants and effects
may be a reasonable policy alternative, but in the beginning I think it would seem short-sighted
to intentionally exclude any consideration in the science assessment of transformation products
and pollutant mixtures. I think he Clean Air Act allows for and in several cases specifically
requires such considerations.  For example, Section  108 (c) of the 1977 (and current) CAA
Amendments specifically directed the Administrator to:

       "revise and reissue criteria relating to concentrations of NC>2 over such period (not
       more than three hours) as he deems appropriate. Such criteria shall include a discussion
       of nitric and nitrous acids, nitrites, nitrates, nitrosamines, and other carcinogenic and
       potentially carcinogenic derivatives of oxides of nitrogen."

It is noteworthy that the current NC>2 standard remains as an annual average only, and that the
draft review plan makes no mention of the above secondary transformation products. It  is also
noteworthy that the Section 302 (h) definition of welfare effects in the 1977 Amendments
originally stated that:

       "All language referring to effects on welfare includes, but is not limited to, effects  on
       soils, water, crops, vegetation, man-made materials, animals, wildlife,  weather,
       visibility, and climate, damage to and deterioration of property, and hazards to
       transportation,  as well as effects on economic values and on personal comfort and
       well-being."

This section 302 (h) was specifically revised in the 1990 CAA Amendments by adding the
phrase: "..., whether caused by transformation, conversion, or combination with other air
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pollutants" to the end of this definition (emphasis added).  So the Agency is clearly required to
consider transformation products and other pollutant mixtures in proposing and revising
secondary standards, and has been specifically directed to consider transformation products in
developing criteria for primary NO2 standards.  I think both SO2 and NO2 plans for review of the
primary NAAQS  should be revised to include assessments of combined effects of the gaseous
criteria pollutants and their various gaseous & particulate transformation products. Possibly also
some consideration should be given to evaluating mixtures of these gasses and PM which is not a
direct transformation product (i.e., NO2 + Diesel exhaust).

One possible approach to considering transformation products in standard setting would be to
retain the current  indicators - SO2 and NO2 - but adjust the levels or forms downward to reflect
the combined influence of secondary products.  The current SO2 plan proposes consideration of
secondary products only as they may be the actual causal factors for apparent health effects
which are statistically associated with SO2 as an indicator of correlated aerosols.  However, SO2
is not merely correlated, it is the cause of the associated aerosols, and if SO2 concentrations were
reduced by lower NAAQS, the associated secondary aerosols would also be reduced.  This was
the logic recently employed in  substantial downward revisions (to 0.008 ppm, 24-hour) of the
World Health Organization guidelines for SO2 (for which our colleagues Mort Lippmann and
Kaz Ito were principal authors). They wrote that:

       ".. .assuming that reduction in exposure to a causal and correlated substance is achieved
       by reducing sulfur dioxide concentrations, there is a basis for revising the 24-hour
       guideline for sulfur dioxide downwards, adopting a prudent precautionary approach."
       (WHO Air Quality Guidelines, Global Update 2005, Particulate matter, ozone, nitrogen
       dioxide and sulfur dioxide).

An alternative approach to considering secondary transformation products might be through
revisions to the indicator(s).  For example, a new NAAQS for "total oxidized sulfur" might be
defined the sum of S from SO2 and various sulfate compounds. The NO2 indicator might be
revised to include nitric acid, aerosol nitrate, etc. For secondary standards, deposition-based
indicators and/or critical loads  for total sulfur and nitrogen deposition might be effective
alternatives to ambient air indicators of only the individual precursor gases.
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                             Dr. Armistead (Ted) Russell
   Review of the Draft Integrated Plans for Reassessment of the NOx and SOx National
                             Ambient Air Quality Standards
                                      Ted Russell

NOx

       My first comment on the Draft Integrated Plan (IP) is that it would have been nice to
have, even at this point, a bit more of what we know about NOx and SOx (e.g., levels in the
environment, levels of possible health concern) in the IP just to get an idea of what might/might
not be important.  Something in the introductory parts would be good.

       A second thought is that the IP should lay out more of a plan to address confounders in
the health studies, and how laboratory exposures related to ambient exposures,  recognizing that
the latter exposure is more complex. In regards to the greater complexity of ambient exposures,
like ozone, one wonders if there might be other pollutants that are very closely  tied to NOx, but
would not be present in the laboratory, that have significant health effects. Given that it is an
NO2 standard, how this might be treated in a standard is unclear. However, the IP should lay out
a plan to address this case. For example, HONO is formed from NO2 heterogeneously. HONO
rapidly photolyzes, forming HO radical, a strong oxidant.  In regards to confounders, NO2  will
correlate with diesel vehicle emissions, thus, diesel particulate matter (DPM). (Though,
controlling diesel NOx will not necessarily reduce DPM or vice versa, so saying that addressing
one will work for both, as is sometimes assumed, can be wrong in this case.)

Risk/Exposure Assessment

       First, while trivial, I might invert the title of this section to say exposure/risk, as that, to
me, is the more logical order, and as noted in the first paragraph, a quantitative risk assessment
may not be in the cards.

       At first, I liked the tiered approach to figuring out how much detail and effort is required
to address this issue. If, indeed, there is little likelihood of significant concerns from exposure,
there appears to be little reason to do an APEX-level analysis. However,  there may be additional
reasons to go to that next level. One of those is that APEX-level analyses (or beyond) are quite
appropriate for other pollutants, e.g., ozone  and PM, and if the agency continues to do such for
each of the pollutants for which it is not scientifically questionable (e.g., SO2),  it will become
more routine and problems will be identified sooner.  Further, extending APEX to other
pollutants can improve its treatment of the pollutants of greatest concern.  Thus, it might  be
appropriate to commit to an APEX-level  analysis right off and gear up for it. Also, I fear that if
such a commitment is not there, it may not be done even if there might be call to do so. There is
always a crunch at the end, and such an effort could just become infeasible because of time and
resources if ample foundation is not laid earlier on. On the other hand, if there is really little
likelihood of exposures of concern, or that the information that APEX-level analysis can  provide
is of use in standard setting, it may be true that resources are better spent elsewhere.  I am not
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sure at this time, and that is where a bit more information up front in terms of likely maximum
ambient levels/exposures and levels of concern would be of use.

       The air quality analysis, alone, is insufficient as a determinant of whether the agency
should go to a screening level assessment. I say this because it is tied to ambient monitors,
which are scarce, and there is much more information out there at this time. In this case, I am
talking about the studies that are using other techniques to estimate NC>2 exposure using air
quality models and, quite importantly, techniques that use information like land-use tied to
saturation monitoring of NC>2. For example, see Henderson et al. (2007) and references therein.
Such techniques should be consulted up front to suggest if there is a high likelihood of exposures
that are significantly higher than found by analysis of ambient monitoring data.  This, possibly,
would work in to the screening level assessment, but is not explicitly mentioned there.

Criteria for Selection of Assessment Approach.

Here, I would add to the list:
    •  Analysis of more detailed exposure studies based on non-routine monitoring, including
       other hot-spot analysis (e.g., railyards, airports) and modeling.
    •  Associated pollutant exposure

Uncertainty and Variability

Their discussion of uncertainty and variability begins with and focuses on APEX, which is a bit
of a concern because they are not committed to going to that level of analysis. However,
Uncertainty and variability should be addressed no matter what level of analysis is actually
conducted. The form and extent is changed, but it is still an important piece of the exposure and
risk assessment.

Let us say that it is decided that APEX-level analysis will not happen. What then? They  should
have a plan as to how to extend the air quality analysis and screening level assessment to address
these two issues. This will, in part, be driven by the tangential information found in conducting
the  exposure analyses. They should, as part of that work, explicitly identify, and quantify,
uncertainties and variabilities (and specify which  it is).

In regards to how APEX might be applied (they are quite non-committal, which is not
necessarily wrong), things  sound fine, though the  commitment of resources should be
acknowledged.  It could  turn out that the major reason to embark along this route is to make such
practice more standard.

Risk Assessment

While the introduction to this section suggests that a quantitative risk assessment may  not be in
the  card, they really should address how a more qualitative risk assessment will be done if a
quantitative one is not.
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Henderson SB, Beckerman B, Jerrett M, et al.
Application of land use regression to estimate long-term concentrations of traffic-related nitrogen oxides
and fine particulate matter
ENVIRONMENTAL SCIENCE & TECHNOLOGY 41 (7): 2422-2428 APR 1 2007
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                               Dr. Richard Schlesinger
NITROGEN DIOXIDE DRAFT INTEGRATED PLAN

P. 1-3, L. 20-22. There is some confusion in this sentence. If the Administrator seeks to prevent
pollution levels that have been demonstrated to be harmful, then what is meant by the attempt to
prevent lower levels that may pose an unacceptable risk of harm. The levels that will be
proposed should be low enough to prevent any unacceptable risk.

P. 3-1. L. 29-30. This bullet and the two that follow are redundant. Perhaps they can be
condensed.

P. 3-2. L. 9. Is this issue referring to short or long term exposure?

P. 3-2. L. 12. What is meant by air quality issue relationships between short and long term
exposures?

P. 4-1, L. 26. After "Emphasis" add the following: ".. .in controlled exposure studies will be
placed...." The  comment does not apply to community epi studies.

P. 4-3, L. 26. Add the word "adequately" after "power to ...."

P. 4-5, L. 23. Add the word "reaction" after "Are there	"

P. 4-6, L. 16. Add the word "centralized" after "the use of..."

P. 4-6, L. 118-22.  This paragraph is not clear.

P. 4-7, L. 15. After "concern" add the following: "... including nature and time course" and
delete the fragment following "e.g.". There is no reason to provide these examples as it seems to
limit the extent  of inquiry.

P. 4-7, L. 24-25. This bullet should be incorporated into the first bullet on the page.

P. 4-8, L. 23. Add the word "other" after "asthma."

P. 4-8, L, 26-27. Doesn't this apply to short term effects as well?

P. 4-9, L. 14. Add "various other" after "including"

P. 4-10, L. 1-4.  Rewrite as  "What are the potential biological mechanisms underlying response to
NOx with a focus  on physicochemical characteristics, ...."

P. 4-10. L. 7-8.  Rewrite as  "What NOx reaction products can be found in the respiratory tract
cells, tissues or  fluids that may serve as markers of NOx exposure"
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P. 4-10, L. 9-10. This bullet is redundant with the first bullet on the page.

P. 4-10, L. 11-12. Add "host factors such as" after "effects"

P. 4-10, L. 15. Change "man" to "human"

P. 4-10, L. 27-28. Rephrase bullet as, "What is the relationship, if any, between susceptibility to
short and long term exposure to NOx"

P. 4-11, L. 11-20. What about review of experimental studies in the literature. This is not
indicated in this paragraph in terms of approach for the SASD.
SULFUR DIOXIDE DRAFT INTEGRATED PLAN
NOTE: I have indicated here specific concerns with the SOx document. Some of the
comments related to the NOx document will also apply here since the template wording in
many sections is the same. Thus, please look over some of the NOx suggestions in relation
to the SOx document.
P. 4-6, L. 3. Why is the term "ambient" needed here.

P. 4-6, L. 4. Change "of to "at."

P. 4-6, L. 10-13. This bullet is redundant with the first two bullets on the page.

P. 4-6, L. 14. Give an example of what is meant by "pattern"

P. 4-7, L. 9-10. Small airway resistance is not a good term and, in fact, small airway resistance is
not the general measure when airway resistance is used to monitor pollution effects.
Furthermore, gas-exchange surface is not a function.

P. 4-7, L. 18-19. This bullet is redundant with others above.

P. 4-8, L. 4. Add "other"  following asthma.

P. 4-8, L. 9-10. This bullet is redundant with others that preceded it.

P. 4-8, L. 22. Change "do" to "does."

P. 4-9. L. 5. What is meant by community risks in the context of this bullet.
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P. 4-9., L. 22. Add "host factors" after "of

P. 4-9, L. 26. Change "man" to "human."

P. 4-10, L. 4. Change wording to" Is preexisting respiratory or cardiovascular disease an
important factor in susceptibility to mortality associated with exposure to SOx and does age also
play a role in this relationship.
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                                Dr. Christian Seigneur

           Comments on the Draft Plans for Review of the SOX and NOX NAAQS

                                    Christian Seigneur
                        Atmospheric & Environmental Research, Inc.


I have two general comments that apply to both documents.

Data fusion:

The last bullet item of the content of the "Air Quality and Atmospheric Chemistry" section of the
ISA in the NOX document addresses the possibility of performing some data fusion to augment
the information available from monitoring sites with satellite retrievals and model outputs. This
is an excellent idea although its feasibility may be limited by the fact that one is mostly
interested in NC>2 concentrations near sources in urban areas; satellite retrievals and model
outputs may not provide sufficient spatial  resolution to be helpful here. Nevertheless, the
feasibility of this approach deserves to be  investigated.

It seems that the same data fusion approach could also apply to SC>2, but it is not mentioned in
the SOX document. I suggest including it for consistency or explaining why it would not apply to
SO2.

Uncertainty and Variability (Section 5.5 in both documents):

This section provides a good overview of the planned approach for the uncertainty analysis of
the exposure assessment. The proposed approach distinguishes very nicely between the
epistemic uncertainties (referred to as uncertainty) and aleatory uncertainties (referred to as
variability), which is the proper way to conduct an uncertainty analysis. However, it is not clear
how the results will be used. As currently written in the draft plans, the uncertainty/variability
analyses appear to be disconnected from the rest of the assessment because it is not explained
how their results will be reflected in the overall assessment. Will the uncertainty analysis results
be used in a qualitative manner when discussing the exposure assessment or will there be a
quantitative use of those results?  It would be useful to add a sentence or two at the end of these
sections to clarify that the results of the uncertainty analysis will be part of the body of technical
information used to develop the policy options.

Specific comment:

NOX document, p. 4-5, line 26: NOX instead of NC>2.
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                         Dr. Elizabeth A. (Lianne) Sheppard
           Comments on Draft IPs for Review of the Primary SC>2 and NC>2 NAAQS

Submitted by Lianne Sheppard
Final comments May 18, 2007

General Comments

I believe further clarification is needed regarding the views to be presented in the ANPR. How
will the views be selected? How much information will be given to ensure their credibility and
to document their source?  Based on the conference call of May 11, 2007 I understand the views
incorporated into the ANPR will be broader than those previously included in the Staff Paper and
include political views. I believe that any views included in the ANPR will acquire credibility
just by virtue of being included in the document. In order to ensure transparency, there needs to
be a clear and transparent process for how views are selected, a discussion of the scientific
justification of each view included in the ANPR, and full  disclosure in the ANPR of the sources
(including funding) of each view presented.

Risk/exposure assessment: It is essential that every risk and exposure assessment document have
four "assessment" sections. These are 1) the air quality analysis, 2) the exposure assessment
(screening and refined, as appropriate), 3) a qualitative risk assessment, and 4) a quantitative risk
assessment. Risk assessment cannot be excluded from the Risk/exposure assessment document.
The quantitative and qualitative risk assessment sections need to be distinct because there is a
great deal of evidence about risk that is not easily incorporated into a quantitative risk
assessment but that enters into a final  scientific judgment  of risk.  Semi-quantitative risk
assessment information, such as estimates of risk bounds, should also be incorporated where
quantitative assessment is not possible. Furthermore, it is important to recognize that both
quantitative and qualitative evidence are necessary for integrated assessment of risk leading to
policy recommendations. It is too easy for  the quantitative risk assessment to receive
disproportionate weight in the integrated assessment of risk and this is particularly likely when
the qualitative risk assessment is omitted. Finally, all "assessment" sections should be present in
the document even if not all assessments can be supported (e.g. note the anticipated plan
regarding the quantitative risk assessment, see p. 5-1 of both documents).  In that case the section
in question should state the reason(s) that the assessment is not done.

Comparison between documents: I suggest the staff compare similar sections of these two
documents to ensure both are as complete and  comprehensive as possible. For instance the
detailed questions to be addressed in the various sections  of the ISA, listed under the "Content
and Organization of the ISA" subsection of 4 differ somewhat by pollutant. To the degree that
these differences are scientifically motivated, this is appropriate, but verification is needed.
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NOx
       The whole document should discuss NOx. Some parts only discuss NC>2 and ignore other
       oxides of nitrogen.
       How will the process allow consideration of regulation of other oxides of nitrogen?
       4-6 line 1: data are spatially sparse
       4-6 Section B, particularly lines 13-17:  The question of uncertainty about the
       relationship between ambient concentration from stationary monitor measurements and
       personal exposure must be framed in the context of the epidemiological study design that
       is of interest. The issues are different for time series and cohort study designs because
       the former relies on temporal variation in exposure/concentration while the latter relies on
       spatial variability.
       4-11 lines 13-15:  how is (1) distinct from (2)?  Why is review of the epidemiologic
       literature distinguished from review of the text and tables/figures.
       5-1 -  5-7: A subsection needs to be added following section 5.3 to address the approach
       to risk assessment.
       5-2 section beginning line 18: Will this analysis be based only on data obtained from
       AQS monitoring locations? How will monitor siting criteria influence the possible
       conclusions? Where will considerations of monitor siting be considered?
       Epidemiological studies that incorporate spatially-varying exposure information are much
       more  sensitive to  siting considerations.
       5-3 lines 7-10: What is the purpose of these analyses?  How will their results affect
       understanding of exposure?
       5-4 line 1: Complexity of models relates to the bias-variance trade-off.  Simpler models
       tend to be more biased and less variable while more complex models are less biased and
       more variable.
       5-4 lines 14-17: Also it would be beneficial to determine the distribution of multiple
       exposures per person.
       5-4 lines 26-28: It is very good that now there is a plan to explicitly address individual
       longitudinal behavior patterns. This improves upon previous exposure assessment
       models.
       5-5 line 13:  This  should be restated to allow for more general relationships, e.g. replace
       "relative" with "relationship between the".
       5-6 lines 4-10. Clarify whether this plan implies separate characterization of uncertainty
       and variability.
       5-6 paragraph starting line 11: How about proposing a set of sensitivity analyses to
       compare results using different model formulations?  This would be one way to address
       model uncertainty.
       6-1 line 5: Presumably the full set of appropriate evidence- and risk-based approaches
       for reaching policy judgments have already been carefully considered in the
       risk/exposure assessment document so that the ANPR is not covering new ground at this
       point in the process.  Please clarify or replace "identify" with "review".
       6-1 line 7: Why not present risk information associated with alternate standards?
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SOx

Overall the SOx document is similar enough to the NOx document that all NOx-specific
comments should be considered for the SOx process document as well. However in several
ways the SOx document appears to be more complete. In particular section 1.4 is missing from
the NOx document, Section 6 of the SOx document has more explanation, and only the SOx
document lists the NOx and SOx panel members in Appendix A.
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                                   Dr. Frank Speizer


                Review of Draft IP for NAAQS for Sulfur Dioxide (and NOx)

Submitted by Frank E. Speizer
Pre-meeting comments 5/2/2007

       It is clear that there is considerable overlap between the 862 document and the NOx
document. The comments are likely to apply to both but will be referenced to the SC>2 document.
In addition, it is likely that these documents will be substantially revised after our first meeting,
as they read now as a tentative expression of the new approach.

Page 1-2, lines 7-11.
       It is not clear how the ISA and the SASD will really differ from the old CD and Staff
paper except that the plan appears to be that they will appear together. That said it is also not
clear how the ISA will determine how the most relevant literature pertinent to the review will be
selected. This will need to be discussed at our initial administrative conference call.
Page 3-1.
       The fact that the Court of Appeals remanded the decision for further explanation means
that this time around will need better documentation of the current state of science on the 5
minute standard and level of effects.
Page 4-1, line 10-11.
       CAS AC must at least see list of publications being assessed in the SASD, as  well as those
used in the formulation of the ISA (assuming the latter will have the  references in the document).
Page 4-2, lines 25-27
       There will need to be an agreed upon cut off date.
Page 4-3, item 3), lines 4-5
       Do not believe this is meant to exclude other studies that repeat or extend findings from
earlier years, but as presented says that they will be excluded.
Page 4-3, line 19
       Not clear that this restriction should apply. Would be worth being more specific of
purpose of study.  For mechanistic study higher doses may be ok.
Page 4-4, lines 10-14.
       How is this going to be different from the old CD?
Page 4-6, line 13-14.
       This needs to be extended to indicate which pollutants or mixtures are most implicated.
Page 4-6, line 26-29
       Need more guidance on what is meant here. (e.g. Inflammatory evidence -change in
CRP),  arrhythmias, heart rate variability, endothelial function,  or risk of MI, Stroke,
hospitalizations, other morbidity or mortality, etc).
Page 4-7, line 18-19
       Suggest handle CVD separately form reproductive and other. CVD important enough to
have separate categories to consider as is done with respiratory.
Page 4-10, section 4.3
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       I do not understand this section.  Who are the peer reviewers, how are they vetted, how
do they differ from the writers of either the SADS or the ISA? What is CAS AC's role in
evaluating this part of the process?
Page 5-2, end of section.

       It seems that the legal judgment of this was that by putting it on a national perspective
EPA violated the de jure as well as the de facto spirit of the law in being required to protect with
an adequate margin of safety a sensitive group. Therefore will need to define better than
previously what is meant by "national perspective".  Surely this must be based on expected
numbers of excess exposures.
Post-Conference Call Comments on Draft Plan for Review of the Primary National
Ambient Air Quality Standard for Nitrogen Dioxide
Submitted by Frank E. Speizer
May 15,2007

I am confining my remarks at this point to only the questions raised in the policy relevant
chapter. I found it well summarized and as discussed in the conference call was clear and
precise. I wanted to add only one point that we discussed briefly but I thought needed greater
emphasis. That is, that further discussion will be necessary with regard to the interaction of
NC>2(x) at street level with ozone. There is two-way quenching going on, and therefore
separating effects may be difficult.  Similarly, an alternative source of NOx, and maybe a major
source in some restricted areas, may be diesel mobile sources rather than gasoline mobile sources
(along with stationary sources) and in these areas may want to consider exploring alternative
approaches to utilizing the data.  This all speaks to a more modern approach of how we might
want to set standards, which may go beyond the current plan, but may need to be discussed in
setting a policy approach that is appropriate for 2009 rather than 1989.
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                                 Dr. George Thurston
Comments on Draft Integrated Plan (DIP) for Review of the Primary National Ambient Air
Quality Standards for NO? (Feb.. 2007)
       The framework of the document is satisfactory, but I had 5 issues with the document. I
will summarize them below, along with page citations to the document where they apply.

1) Section 1.4 (as found in the SOx DIP) is missing. It should appear on page 1-5.  This section
   is needed in order to make the point that the document will evaluate the health effects of all
   Nitrogen Oxides (NOx).  Thus, the document will not be limited to assessing the health
   impacts of NO2, but will also consider other forms of NOx and mechanisms by which they
   can have effects on human health.. However, for the purposes of controlling NOx, the EPA
   will use NO2 as an index of these pollutants in the setting of the NAAQS.
2) Since the document is about NOx (not NO2 alone), there are number of places in the
   document where NO2 should be changed to NOx, including: Pg. 3-1, line 30; pg. 3-2, lines 2
   and 8; pg. 4-3, linelS; pg. 4-6, lines 14 and!?; pg. 4-8, Iine20.
3) There is a need to note in this document that the interactions of the gaseous NOx with
   particles must be  assessed. Particles provide a potential vector for gaseous pollutants to
   reach deeper in the lung than they otherwise would. These gases can also change the nature
   of the particles they go into solution with (e.g. their pH), so they can also affect human health
   by  increasing the  toxicity of particles.  Thus, it is important to include these particle
   interactions in the exposure, health effects, and risk assessment components of this document
   in order to fully consider the potential toxicity of these gaseous pollutants.  This should be
   discussed in Section 1.4 when it is added. In addition, there is a need to mention the
   potential for particle-gas interactions throughout the document, including at:
   Pg. 3-2, line 14: Add bullet stating:  "What effects are a result of interactions with other
   criteria pollutants, especially PM?"
   Page 4-3, line 3: Change to read: "potential interactions, confounding, and/or modification of
   effects"
   Page 4-7, line 3:  Add a bullet stating: "How do NO2 exposures interact with other criteria
   pollutant exposures,  especially PM?
   Page 4-9, line 8:  Need a statement for long-term effects similar to that seen at lines 6 and 7
   of page 4-8 for short-term effects, such as:  "What is the nature of health effects in persons
   exposed to multi-pollutant mixtures that contain NOx, in comparison to NOx alone."
   Page 4-10, line 17:  Add a bullet stating something like: "What interactions with PM occur
   in the atmosphere that alter the toxic implications of NOx in the environment?"
   Page 4-11, line 3:  Add a bullet stating something like: "What interactions  with PM occur in
   the atmosphere that alter the susceptibility of humans to NOx in the environment?"
4)  I agree with the written comments by Kent Pinkerton regarding the need to consider
   evidence from exposure levels much higher than "near ambient" when appropriate.  In
   particular, since we know little about variations in susceptibility across humans and animals
   on the basis of genetic variability, it is unlikely that the animal and human populations
   considered in toxicological studies sufficiently represent the most  susceptible populations.
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   Thus, much higher exposure levels may be needed in those populations to elicit the same
   impacts and effects that might be seen at much lower levels in a more susceptible population.
   Therefore, the following lines need to be revised to address this fact:

   Page 4-1, line 27: edit to read" "However, in recognition of the fact that toxicological studies
   do not necessarily reflect effects in the most sensitive populations, studies at higher exposure
   levels will be included when they provide information relevant to previously unreported
   effects, evidence of the potential mechanism for an observed effect, or information on
   exposure-response relationships."
   Page 4-3, line 18: Edit to read something  like:  "In discussing the mechanisms of NOx
   toxicity,  studies conducted under atmospherically relevant conditions will be emphasized, but
   studies at higher levels will also be considered,  due to species-to-species and potential
   genetic differences between study subjects versus especially susceptible humans."
   Page 4-9, lines 2,3: Edit to read: " The ISA will place emphasis on studies conducted at
   ambient levels, except regarding evidence of biological plausibility and mechanisms, as these
   may only be observable in animal or human exposure study populations at higher levels than
   they might be observed in susceptible human populations."

5) Each section of the review document should provide a list of "Key Studies" upon which the
   section primarily relied in coming to its  major overall conclusions.
Comments on Draft Integrated Plan (DIP) for Review of the Primary National Ambient Air
Quality Standards for SO7 (April 2007)
       The framework of the document is satisfactory, but I had 5 issues with the document. I
will summarize them below, along with page citations to the document where they apply.

6) Section 1.4 needs to make the point that the document will evaluate the health effects of all
   Sulfur Oxides (SOx).  Thus, the document will not be limited to assessing the health impacts
   of SC>2, but will also consider other forms of SOx and mechanisms by which they can have
   effects on human health. However, for the purposes of controlling SOx, the EPA will use
   SO2 as an index of these pollutants in the setting of the NAAQS.  Also, on page 1-6, line 12
   of this section, the word "sulfate" should be replaced with the more general case of
   "paniculate matter (PM)"
7) Since the document is about SOx (not SO2  alone), there are number of places in the
   document where SO2 should be changed to SOx, including: Pg. 3-2, lines 8, 10, 13,15,17,
   and 21.; pg. 4-1 line 6; pg. 4-2, line 2.pg. 4-3, Iine21; pg. 4-4, lines 10-14; pg. 4-6, lines 3 to
   16 and 28; pg. 4-7, lines 6 and 9, pg. 4-8, lines 1 to 7 and 13-17, pg. 4-9, lines 10-24, pg. 4-
   10, lines 2 to 11, and page 5-1, line 19.
8) There is a need to note in this document that the interactions of the gaseous SOx with
   particles must also be assessed.  Particles provide a potential vector for gaseous pollutants to
   reach deeper in the lung than they otherwise would.  These gases  can also change the nature
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   of the particles they go into solution with (e.g. their pH), so they can also affect health by
   increasing the toxicity of particles. Thus, it is important to include these particle interactions
   in the exposure, health effects, and risk assessment components of this document in order to
   fully consider the potential toxicity of these gaseous pollutants. This should be discussed in
   Section 1.4. In addition, there is a need to mention the potential for particle-gas interactions
   throughout the document, including at:
   Pg. 3-2, line 22: Add bullet stating:  "What effects are a result of interactions by  SOx with
   other criteria pollutants, especially PM?"
   Page 4-3, line 6: Change to read: "potential interactions, confounding, and/or modification of
   effects"
   Page 4-6, line 17:  Add a bullet stating: "How do SOX exposures interact with other criteria
   pollutant exposures, especially PM?
   Page 4-8, line 19:  Need a statement for long-term effects similar to that seen at lines  20 to
   21 of page 4-7 for short-term effects, such as: "What is the nature of health effects in persons
   exposed to multi-pollutant mixtures that contain SOx, in comparison to SOx alone."
   Page 4-9, line 27:  Add a bullet stating something like:  "What interactions with PM occur in
   the atmosphere that alter the toxic implications of SOx in  the environment?"
   Page 4-10, line 12: Add a bullet stating something like: "What interactions with PM occur
   in the atmosphere that alter the susceptibility of humans to SOx in the environment?"
9)  I agree with the written comments by Kent Pinkerton regarding the need to consider
   evidence from exposure levels much higher than  "near ambient" when appropriate. In
   particular, since we know little about variations in susceptibility across humans and animals
   on the basis of genetic variability, it is unlikely that the animal and human populations
   considered in toxicological studies sufficiently represent the most susceptible populations.
   Thus, much higher exposure levels may be needed in those populations to elicit the same
   impacts and effects that might be seen at much lower levels in a more susceptible population.
   Therefore, the following lines need to be revised  to address this fact:

   Page 4-2, lines 3 to 5: edit to read" "However, in recognition of the fact that toxicological
   studies do not necessarily reflect effects in the most sensitive populations, studies at higher
   exposure levels will be included when they provide information relevant to previously
   unreported effects, evidence of the potential mechanism for an observed effect, or
   information on exposure-response relationships."
   Page 4-3, line 21 to 22:  edit to read something like:  "In discussing the mechanisms of SOx
   toxicity, studies conducted under atmospherically relevant conditions will be emphasized, but
   studies at higher levels will also be considered, due to species-to-species and potential
   genetic differences between study subjects versus especially susceptible humans."
   Page 4-8, lines 13,14: Edit to read: " The ISA will place emphasis on studies conducted at
   ambient levels, except regarding evidence of biological  plausibility and mechanisms,  as these
   may only be observable in animal or human exposure study populations at higher levels than
   they might be observed in susceptible human populations."

10) Each section of the review document should provide a list of "Key Studies" upon which the
   section primarily relied in coming to its major overall conclusions.
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                                  Dr. James Ultman

                                                                          May 20, 2007
    Comments on the Science Assessment of the "Draft Plan for Review of the Primary
                     National Ambient Air Quality Standard for SOx

                                     James Ultman
                                  Penn State University

(Although the following comments are directed at the SOX document, the same general
comments and most of the detailed comments apply to the NOX document as well).
The Integrated Review Plans (IRP) for SOx are logically organized and clearly present the
overall review process, the timetable, and the steps to be taken to develop the Risk/Exposure
assessment.

Critique

First, I want to reinforce the importance of the possible risks associated with co-pollutants,
susceptibility factors, and different exposure scenarios that affect the balance between tissue
damage and repair/adaptation processes. References to these issues do exist in the document as
now written.

Second, I feel it is important to improve the description of exposure-response and animal-to-
human extrapolation issues in the final planning document.  Based on the exposure-dose-
response paradigm used in other EPA documents, the apparent sensitivity of an animal to
inhalation exposure depends on: 1) the transformation of exposure conditions to local dose
levels; and 2) the inherent biological sensitivity at the cellular and subcellular level.  As indicated
in my detailed comments below, a more explicit recognition and description of these two
complementary factors would clarify how (given appropriate scientific studies  in the ISA)
dosimetry can inform the biological mode-of-action as well as the extrapolation of health effects
from high-to-low exposure levels and from laboratory animals to humans.

Detailed Comments:

Page   Line

1-2     19     Does not appear to be a full sentence.

1-6    10-13   This sentence appears to be inconsistent with the sentence on lines 5-7
               stating that the present review will only consider gaseous SOX.

3-2    20-21   The meaning of this  sentence is not clear.
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4-3    17-20   The criterion of exposure level and duration will be used to assess the relevance
               of animal studies.  To the extent that the toxicokinetics and biological sensitivity
               of a particular lab animal (usually a rat) and a human are the same, these criteria
               are reasonable. If scientific evidence indicates that this is not true, however,
               then some adjustment of the criteria might be appropriate.

4-6    14      I believe that this question should be placed under category C, Health Effects.

4-6    25      This section is somewhat confusing because the term "short-term" exposure
               means different things in different questions.  In some cases, the term refers to a
              "short-term peak exposure" of 5 minutes while in other questions it refers to
               exposures as long as one day. Particularly on the following lines, please make
               sure that the meaning of short-term exposure is clear: 6,9,14,18,21.

4-8   4       It would be worthwhile to generalized this question to include both exacerbation
              as well as development of asthma.

4-9  9-10     The last two questions of this section on lines 24-25 and 26-27 concern
              extrapolation issues that go beyond mechanisms of action to also include
              dosimetry issues.  Somehow the recognition that animal sensitivity is the result of
              two factors—dosimetry and intrinsic biological mode of action—should be
              explicitly recognized in the these introductory lines to section F.
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                                    Dr. Ron Wyzga

                         Comments on Draft Plan for Review of the
                     Primary National Ambient Air Quality Standard for
                                    Nitrogen Dioxide

                                 Ronald E. Wyzga, Sc. D.

By and large, the plan is reasonable; some portions of it, as noted below, are unclear to me as
indicated by my specific comments:

p.  4-3,11. 2-3:1 am unclear of what is meant by "multiple pollutant analyses"; does this mean
that methods should consider NOx in conjunction with other pollutants in an effort to understand
whether NOx is associated with health because it is possibly noxious or because it co-occurs
with other pollutants that may be noxious.

    11. 4-3: similarly I am unclear as to what is meant by point (3).   I would also urge that
multi-city analyses include and examine results for consistency across the cities.  There is value
is trying to understand differences as well as in lumping results.

   11. 22-24: depending upon the study design, there is value is having an subject serve as his/her
own control but with a different or sham level of exposure.  Comparison with age-matched
healthy controls may not be the best control for some study  designs.

   11. 26-27: what is meant by "sufficient statistical power"? Statistical power is important, but it
need be defined in terms the probability of detecting a difference of a given magnitude.

p.  4-8,11. 6-7:  is this meant to address the synergism issue or is there some other intention
behind this?
                    Comments on Draft Integrated Plan for Review of the
                    Primary National Ambient Air Quality Standards for
                                      Sulfur Dioxide

                                 Ronald E. Wyzga, Sc. D.
Overall the document provides a good roadmap.  Specific comments are given below:

p. 4-3,11. 15-16:  Please clarify; does this mean that studies should consider other pollutants as
well as SO2, jointly in models?
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      1. 24: 1 ppm is high; is it relevant for real-world exposures?

     11. 27-28:  depending upon the study design, there is value is having an subject serve as
his/her own control but with a different or sham level of exposure.  Comparison with age-
matched healthy controls may not be the best control for some study designs.

p. 4-7,11. 20-21:  is this meant to address the synergism issue or is there some other intention
behind this?
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