![](media/image1.wmf){width="1.0833333333333333in"
height="1.0291666666666666in"} **UNITED STATES ENVIRONMENTAL PROTECTION
AGENCY**

**WASHINGTON, D.C. 20460**

OFFICE OF THE ADMINISTRATOR

SCIENCE ADVISORY BOARD

August 8, 2008

EPA-CASAC-08-017

The Honorable Stephen L. Johnson

Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW

Washington, DC 20460

> Subject: Clean Air Scientific Advisory Committee's (CASAC) Peer Review
> of EPA's *Integrated Science Assessment (ISA) for Sulfur Oxides --
> Health Criteria* (Second External Review Draft, May 2008)

Dear Administrator Johnson:

The Clean Air Scientific Advisory Committee (CASAC), augmented by
subject-matter-experts to form the CASAC Sulfur Oxides Primary NAAQS
Review Panel conducted its review of EPA's *Integrated Science
Assessment (ISA) for Sulfur Oxides -- Health Criteria* (Second External
Review Draft, May 2008) on July 30-31, 2008. The first draft ISA was
reviewed by CASAC in December of 2007 and subsequently revised in
response to CASAC advice transmitted in January 2008. This letter
presents CASAC's advice on the second draft ISA issued in May 2008.

The CASAC finds that the second draft ISA is greatly improved and that
the Agency has been responsive to the CASAC\'s earlier review. There are
some remaining concerns as described in our answers to the Agency\'s
charge questions in the main body of this letter. Our major concern is
the conclusions in the ISA regarding the weight of the evidence for
health effects for short-term exposure to low levels of SO~2~. Although
the ISA presents evidence from both clinical and epidemiological studies
that indicate health effects occur at 0.2 ppm or lower, the final
chapter emphasizes health effects at 0.4 ppm and above. As discussed in
our responses to Charge Questions 3 and 5, CASAC believes the clinical
and epidemiological evidence warrants stronger conclusions in the ISA
regarding the available evidence of health effects at 0.2 ppm or lower
concentrations of SO~2~. The selection of a lower bound concentration
for health effects is very important because the ISA sets the stage for
EPA's risk assessment decisions. In its draft *Risk and Exposure
Assessment (REA) to Support the Review of the SO~2~ Primary National
Ambient Air Quality Standards* (July 2008), EPA chose a range of 0.4 ppm
-- 0.6 ppm SO~2~ concentrations for its benchmark analysis. As CASAC
will emphasize in a forthcoming letter on the REA, we recommend that a
lower bound be set at least as low as 0.2 ppm. With this and other
modifications as recommended below, CASAC finds the scientific quality
of the ISA acceptable for rulemaking.

CASAC's response to EPA's charge questions are summarized below.
Individual recommendations from Panel members to strengthen the final
ISA are appended in Enclosure B.

**Charge Question 1: The framework for causal determination and judging
the overall weight of evidence is presented in Chapter 1. Is this the
appropriate approach? Is it appropriately applied in the case of SOx?
How could the framework or its application be refined?**

Chapter 1 has been improved, particularly by drawing on recent reports
that offer models of approaches for causal inference and classification
schemes for the weight of evidence for inferring causation. The ISA
utilizes a five-level hierarchy for causal determination to be
consistent with the *Guidelines for Carcinogen Risk Assessment* (EPA,
2005). We concur with using the five levels but recommend that the
descriptions be changed to better reflect the level of certainty or
confidence in the classification of the level of evidence. The phrasing
of the second level is particularly problematic in its addition of the
wording "likely causal relationship." The approach to evidence
interpretation should avoid using statistical significance as a
criterion for evidence interpretation. CASAC recommends that EPA
reconsider the language used to describe the weight of evidence,
particularly for the first three categories which cover a range of
certainty or confidence in causal inference that extends from full
certainty to lesser degrees. The language used should be consistent with
other such schemes used by EPA.

For the criteria pollutants, the ISA needs to acknowledge that the
pollutants exist in complex mixtures and to broadly consider the
implications for interpreting the evidence in the ISA. We also
specifically recommend improvement in the presentation of the
epidemiological concepts of effect modification and confounding that are
particularly challenging in the face of multi-pollutant mixtures. Other
aspects of the chapter also need greater development including the
treatment of uncertainty. The concept of "margin of safety" also needs
elaboration. Figure 1 is not effective and unless the text is expanded
to explain many of the relationships depicted, it needs to be abandoned
or replaced.

Finally, we applaud the specification of questions at the beginning of
the first chapter that outline specifically the intent of the ISA, and
the integration of the answers to these questions, as obtained from the
evidence in the ISA, in the concluding chapter. This structure will
provide a clear scientific foundation for the development of the Risk
and Exposure Assessment document.

**Charge Question 2: Have these revisions to Chapter 2 improved its
assessment of the currently available scientific knowledge on
atmospheric sciences and exposure and its relevance to the evaluation of
human health effects presented in later chapters?**

Chapter 2 is significantly improved from its earlier version and
previous

comments from the Panel have been taken into account. There are,
however, some points that need to be addressed in greater detail and
other points require some clarification. Since the REA will focus on
5-minute averages of SO~2~ concentrations, a more comprehensive
discussion of the available 5-minute SO~2~ concentration data is
warranted. For example, a table presenting information similar to that
in Table 2-4 would be useful. A better discussion of the discussion of
the distributions and time-trends of 5-minute average concentrations is
needed as is greater consideration of which distribution best represents
ambient data (normal or log-normal). Further, the analyses should
address correlation between the 5-minute and one-hour average
concentration distributions. Figure 2-11 needs to be redrafted to
provide a better depiction of diurnal SO~2~ ambient concentrations. The
fact that the trend in SO~2~ concentrations is due to changes in SO~2~
emissions rather than to changes in measurement technique should be
stated more definitively.

The rationale behind the selection of the six states selected for
analysis should be better described; some consideration may need to be
given to areas where the potential effect of ship emissions on SO~2~
could be significant (i.e., major U.S. ports). Analyses (e.g.
stratification for source proximity and strength and use of maps) of
selected urban areas should be presented to characterize the
representativeness of ambient monitors for characterizing population
exposure. Since AERMOD is used in the REA, there is a need to describe
it in the Annex.

Adsorption of SO~2~ onto particles which is discussed in more detail in
Chapter 3 needs to be further discussed in Chapter 2. However, this will
need to be placed in perspective because concentrations of particulate
matter (PM) and SO~2~ used in the animal toxicological studies discussed
in Section 3.1.5 were several orders of magnitude above typical ambient
concentrations. In addition, it should also be noted that atmospheric
chemistry studies do not indicate significant amounts of sulfite on
atmospheric PM

Chapter 2 correctly points out the difficulties associated with
characterizing exposure (e.g., limited information on indoor
concentrations, and vertical and horizontal SO~2~ concentration
gradients). However, the implications for the characterization of health
effects could be better described and discussion on the implied
uncertainties expanded. More discussion of the effect of exercise on
health effects in exposure studies is warranted. In particular, the ISA
points out that whether SO~2~ is inhaled via nasal vs. oral breathing
makes a difference for SO~2~ uptake, however, the implications for the
analysis of the health effects studies need to be discussed in greater
detail.

**Charge Question 3: In the revision, we reduced redundancy, added
summary sections and reorganized Chapter 3. In addition, discussions on
potential confounding by, and interactions with, co-pollutants have been
added. The 2nd draft ISA also includes additional analyses of
individual-level data from human clinical studies (Sections 3.1.3. and
4.1.1) that builds upon the analysis included in the 1994 Supplement to
the Second Addendum. The toxicology sections were reorganized to focus
on studies using more relevant concentrations of SO~2~ and sections were
added to better discuss mode of action and potential particle-SO~2~
interactions. We are requesting CASAC review specifically on these
analyses as well as on the integration of the overall evidence from the
human clinical, animal toxicological, and epidemiological studies.**

Chapter 3 is vastly improved from the previous draft of the ISA. The new
analyses of human clinical studies are helpful. CASAC believes, however,
that more emphasis should be placed on effects seen at concentrations
lower than 0.4 ppm. The Panel is concerned about the potential
underestimation of the proportion of asthmatic persons affected by
short-term exposure to SO~2~ because only mild and moderate asthmatic
adults were recruited to participate in the clinical studies. People
with more severe asthma or poor control of their symptoms may be more
susceptible and may respond more adversely to SO~2~ and discussion of
this point should be expanded in the chapter. The potential influence of
medication use on asthmatic responses to SO~2~ should also be discussed.
In general, the evidence from the animal toxicological, controlled human
exposure, and epidemiological studies has been satisfactorily
integrated. However, the gap between the greater level of SO~2~ used in
the clinical studies and the relatively lower ambient concentrations
associated with respiratory morbidity in the epidemiological studies
needs to be clearly acknowledged. The relevance of the higher dose
animal studies also needs to better developed. The results of the
studies involving extremely high levels of metal oxide or carbon-SO~2~
mixtures suggest that SO~2~ effects may be potentiated by co-exposure to
particles, but the relevance of these results to ambient exposures is
unclear. Section 3.1.5 should be greatly condensed to give a more
focused discussion of the mechanistic implications of the mixture
studies without presentation of experimental details. While the new
summary sections are a welcome addition to the chapter, their quality is
uneven. It would be helpful if these sections were written in a style
that applied the causal inference approach outlined in Chapter 1 in a
consistent manner.

**Charge Question 4: The section on concentration-response relationships
in Chapter 4 was reorganized and revised to include analysis of
individual-level data from the human clinical studies and some
additional discussion of the difficulties of discerning a threshold in
population-level data. In addition, revisions were made to better
characterize groups likely to be susceptible or vulnerable to SOx and
the potential size of the population at risk for SOx-related health
effects. Finally, revisions were made to reduce redundancy with material
presented in Chapter 3. Have the revisions made to Chapter 4 improved
the characterization of the potential public health impact of SOx
exposure?**

Revisions to Chapter 4 have improved the characterization of potential
health impacts of SOx exposure, but additional clarification,
evaluation, and amplification is needed. The Panel recommends that EPA
revisit the definitions of susceptibility and vulnerability. The
definition of susceptibility should consider the form of the
dose-response relationship and the magnitude of response at a given
dose. Greater clarity and specificity is needed in the definition of
this concept if it is to be used without ambiguity. The current
definition is limited in concept and inconsistent with toxicological and
epidemiological usage. EPA should harmonize the definitions of
susceptibility and vulnerability across documents for intra-Agency and
inter-pollutant consistency.

Additional analyses of the cited clinical chamber data could be
performed to gain insights regarding the population distribution of
effects at exposures lower than 0.4 ppm SO~2~; there appears to be an
indication of effects below this level when the pooled data are
considered. Specific details are provided in individual comments. See
comments from Drs. Avol, Hattis, Kinney, Pinkerton, Samet and Sheppard
In addition, the discussion should do a better job of acknowledging that
epidemiology studies generally lack power to distinguish between linear
and non-linear response forms.

A more complete discussion of potentially at-risk (i.e. susceptible
and/or vulnerable) sub-populations is needed. The discussion should
emphasize the importance of linking populations at potential risk due to
age and disease status with considerations related to exposure and
activity distributions in these groups. The joint distribution of all
these factors defines the population at risk of adverse health impacts
from SO~2~ exposures. In addition, discussion of the geographical
location of at-risk populations with respect to pollution sources needs
to be included and related environmental justice concerns addressed, if
appropriate. EPA needs to provide additional justification for its
decision to focus on children and older adults with respect to short
term respiratory health effects of SO~2~.

**Charge Question 5: Revisions were made to better integrate findings
from atmospheric sciences, ambient air data analyses, exposure
assessment, dosimetry, and health evidence in Chapter 5. To what extent
do these findings support conclusions regarding causality of SOx related
health effects at relevant exposures?**

The Panel concurs with the conclusion that short term exposures to SOx
are causally related to changes in respiratory responses, however we do
not accept the levels on which the ISA focuses. The clinical and
epidemiological studies warrant a stronger conclusion about health
effects at lower levels. The range of exposures emphasized in the ISA
(0.4 - 0.6 ppm) has clearly carried over to the thinking used in the
REA. Adoption of this range might leave substantial numbers of
exercising mild asthmatics at considerable risk. Table 5-1 of the ISA
presents studies showing that 5 -- 20% of mild to moderate asthmatics
experience moderate or greater decrements in lung function at SO~2~
concentrations as low as 0.2 -- 0.3 ppm. For ethical reasons severe
asthmatics were not part of these clinical studies, but it is not
unreasonable to presume that they would have responded to even a greater
degree. In addition, the epidemiological evidence shows emergency room
visits and hospitalizations for respiratory illnesses associated with
24-hour SO~2~ levels below the current standard (0.14 ppm averaged over
at 24-hour period). Collectively, this evidence should lead to a
conclusion that 0.2 ppm or even a lower level of short-term exposure is
an appropriate lower bound value for EPA's benchmark analysis.

The Panel was impressed by the way the preceding chapters' information
was summarized in a series of tables that effectively collated the
textual materials, tables, and figures from the preceding chapters as
well as the wealth of data contained in the appendices. The conclusions
regarding causality with regard to short-term exposures are reasonable.
A better discussion is needed on the range of exposures at which effects
are observed in the clinical studies and the much lower range at which
effects are observed in the epidemiological studies. In addition, the
importance of identifying susceptible subgroups of subjects, and
estimating the contribution of these groups to population shifts in
response characteristics may be a task for the REA, but that document
should be informed by a discussion of this issue in the ISA.

The larger question is whether the additional research carried out in
the last 10 years has led to a substantial change in the scientific
basis for making decisions regarding the basis for setting standards for
SO~2~. Although the ISA answers this question affirmatively, the final
chapter should be organized to answer all of the policy-relevant framing
questions introduced in Chapter 1. The answers to these questions would
greatly improve the usefulness of this document as a scientific prelude
to the *Risk and Exposure Assessment*.

With respect to the entire ISA, there remains the longstanding issue
associated with the Clean Air Act\'s single pollutant approach to
analysis and rulemaking. In the real world, we breathe complex mixtures
of multiple pollutants, thus isolating the effects of a single pollutant
requires simplifying assumptions that depart from real world phenomena.
With SO~2~ in particular, the reality of having to adjust for the
possible confounding contributions of other pollutants makes definitive
determinations of assigned causality a challenge.

In closing, the CASAC is pleased to provide the Agency with advice and
recommendations in the development of this ISA for Sulfur Oxides, which
is a fundamental part of the new NAAQS review process. We look forward
to providing additional advice as the Agency completes the NAAQS review
process for sulfur oxides.

Sincerely,

***/Signed/***

Dr. Rogene Henderson

Chair

Clean Air Scientific Advisory Committee

Enclosures

**U.S. Environmental Protection Agency**

**Clean Air Scientific Advisory Committee (CASAC)**

**Sulfur Oxides Primary NAAQS Review Panel**

**CASAC MEMBERS**

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

**Dr. Ellis B. Cowling**,[^1] Emeritus Professor, , Colleges of Natural
Resources and Agriculture and Life Sciences, North Carolina State
University, Raleigh, NC

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

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

**Dr. Donna Kenski**, Director of Data Analysis, Lake Michigan Air
Directors Consortium, Des Plaines, IL

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

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

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

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

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

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

Research Triangle Park, NC

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

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

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

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

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

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

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

**Dr. George Thurston**, 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, Palo Alto, CA

**SCIENCE ADVISORY BOARD STAFF**

**Dr. Holly Stallworth**, Designated Federal Officer, Science Advisory
Board Staff Office, Washington, D.C.

**Individual Comments on the *Integrated Science Assessment for Sulfur
Oxides -- Health Criteria (*Second External Review Draft, May 2008) from
Clean Air Scientific Advisory Committee (CASAC) Sulfur Oxides Primary
National Ambient Air Quality Standards (NAAQS) Review Panel**

[**Mr. Ed Avol** 2](#__RefHeading___Toc205963115)

[**Dr. John Balmes** 5](#__RefHeading___Toc205963116)

[**Dr. Doug Crawford-Brown** 9](#__RefHeading___Toc205963117)

[**Dr.** **Terry Gordon** 13](#__RefHeading___Toc205963118)

[**Dr.** **Dale Hattis** 15](#__RefHeading___Toc205963119)

[**Dr. Donna Kenski** 18](#__RefHeading___Toc205963120)

[**Dr.** **Patrick Kinney** 21](#__RefHeading___Toc205963121)

[**Dr. Steven Kleeberger** 24](#__RefHeading___Toc205963122)

[**Dr. Timothy Larson** 26](#__RefHeading___Toc205963123)

[**Dr. Kent Pinkerton** 32](#__RefHeading___Toc205963124)

[**Dr. Edward M. Postlethwait** 35](#__RefHeading___Toc205963125)

[**Dr. Jonathan M. Samet** 37](#__RefHeading___Toc205963126)

[**Dr.** **Richard Schlesinger** 40](#__RefHeading___Toc205963127)

[**Dr.** **Christian Seigneur** 42](#__RefHeading___Toc205963128)

[**Dr.** **Lianne Sheppard** 47](#__RefHeading___Toc205963129)

[**Dr.** **George Thurston** 48](#__RefHeading___Toc205963130)

[**Dr.** **James Ultman** 51](#__RefHeading___Toc205963131)

[**Dr. Ronald E. Wyzga** 53](#__RefHeading___Toc205963132)

[]{#__RefHeading___Toc205963115 .anchor}**Mr. Ed Avol**

Comments on SOx ISA 2^nd^ Draft

[Question 1 (a modified Chapter 1 on the framework for causal
determination)]{.underline}

The continuing EPA-and-Clean-Air-Act self-imposed restriction to
consider individual pollutant effects (in this case, SO~2~ from
particulate SOx) makes the framework for evaluation of the overall
weight of evidence a challenging one, due to the common sources of
pollutant generation (and virtually no difference in the potential
targets of source emission reductions). The reality of having to adjust
for the possible confounding contributions of other pollutants makes
definitive determinations of assigned causality a messier proposition,
since the likely presence of other ambient co-pollutants provides a
"smoke-screen" of sorts for the true stimulator (or
stimulator[s]{.underline}) of response and effect.

The framework described in Chapter One, aside from the recurring general
concern for an archaic approach that attempts to evaluate health effects
on a discrete pollutant-by-pollutant basis in the face of ever-growing
information about additive and synergistic physical, chemical, and
physiological interactions, seems a reasonable way to proceed.

[Question 2 (an expanded Chapter 2 on atmospheric chemistry of
SO~2~)]{.underline}

The additional sections about monitoring information are useful in
developing an overall appreciation for the historical monitoring network
and nationally downward trend in SO~2~ exposure. My personal opinion
regarding the inclusion of design criteria for station placement is that
there is more detail than necessary presented here, and most of it is
generic (to any acceptable monitoring site's placement).

The improved information presented does improve the overall assessment
of the currently available knowledge and is relevant to subsequent
discussions of human health effects.

[Question 3 (a revised Chapter 3 on Integrated Health
Effects)]{.underline}

The chapter is still a long compendium of information (over 100 pages),
but the summary figures are very helpful in providing a "meta-view" of
numerous studies. So much information on such a range of health outcomes
is presented that, at chapter's end, some sort of distillation of what
the chapter conclusions were would have been helpful. This might be in
the form of a table, listing category (morbidity, mortality, etc), SO~2~
exposure (long-term or short-term), health outcome (lung function,
symptoms, ED visits, hospitalizations, etc), and judgment (causal,
insufficient, etc), which would assist the reader in interpreting the
weight of evidence from the 100+ pages of data...which is precisely what
appears as Table 5.3 in Chapter 5! Accordingly, it might be worth
referring the reader to or providing some linkage to the Chapter 5
summary discussion.

[Question 4 (Revisions to Chapter Four, Public Health
Impacts)]{.underline}

This revised description of the public health impacts of SO~2~ exposure
is substantively improved, but could still profit from further
clarification, focus, and specificity. The over-arching questions to be
addressed include the following: (1) what insights do current data
provide regarding the shape of the concentration-response function for
SO~2~? (2) Is there evidence of a threshold of response? (3) Are there
populations at risk? (4) If there are populations at risk, who are they?
To the credit of the ISA staff, these issues are discussed, but they are
not always clearly/succinctly summarized or brought to some final
resting point in the document.

For example, the presentation of concentration-response functions and
the topic of thresholds of response are understandably linked, but the
presentation in the document is inter-twined (in sections 4.1.1 to
4.1.3) and thus more difficult to follow than need be. With regard to
the question of concentration-response functions, the presented data
from clinical and epidemiological studies suggest there is support for a
linear concentration--response function claim (more supportive from the
clinical chamber studies, less convincing but somewhat supportive from
the epi studies). With regard to a threshold of response, the data are
inconclusive. This discussion, particularly in Section 4.1.3, should be
separated into two sections (one on the concentration-response function,
and the other on threshold response).

The discussion of susceptible and vulnerable populations (Section 4.2)
is also in need of some improved specificity (but is admittedly improved
over the previous version). Much of the appropriate information is
contained in the discussions, but structurally, the respective sections
do not always follow the specified title or deliver on the promised
topic. There remains some confusion about definitions of
"susceptibility" and "vulnerability". Reasonable working definitions are
provided in the text (at the bottom of p4-9 and top of p4-10), but then
these are lumped together into a discussion of "somewhat sensitive
subgroups" a few lines later (lines 8-14, p4-10).

A discussion about the potential importance of genetic factors is
presented in Section 4.2.2, but much of the two-page discussion is
generically about air pollution and not specifically about SO~2~.

Section 4.3 (which needs to be re-titled to "Populations at Adverse
Risk" or something, since the current title is the chapter title) is a
valuable perspective on how to think about the multiple health outcomes
being presented.

Section 4.3.2 (Estimation of Potential Numbers of Persons in At-Risk
Susceptible Population Groups in the US) doesn't quite deliver on its
title promise, in that numbers are estimated for only a few of the
several susceptible sub-groups identified. Still, the point is made that
many people are potential at increased risk for exposure and possible
response. The concluding paragraph in the chapter (lines 10 through 18
on p4-23) provides a declarative overview on the issue (in essence, that
there are could be a considerable public health impact, because there
are large numbers of susceptible sub-groups), but seems to fall short by
not saying something about the likelihood of exposure to levels likely
to trigger the range of health outcomes identified.

(One final note -- is the comment regarding Figure 4.6 "...demonstrating
that the SO2-related excess risk for asthma is, on average, 50% higher
among children when compared to risk estimates that include all ages..."
(lines 7-9, p4-23) over-reaching, given the error bars, available data,
and risk range \[\~RR 1.05-1.1\]?)

[Question 5 (revised Chapter 5 on Integrated Findings of
Causality)]{.underline}

This chapter has a significant task and a large body of multiple outcome
data from over 20 years to summarize. The summary Table 5.3 is
especially useful, in distilling the current judgments to brief
paragraphs of conclusions for endpoints of potential health interest.

The document provides an interesting series of comments regarding
"previous conclusions" and "current conclusions" in Table 5.3, but it is
not clear to what "previous" review these comments refer. (Presumably,
these "previous" comments refer to the 1996 NAAQS SO~2~ review, but one
could also interpret this as a reference to an earlier version of the
ISA). This should be explicitly specified in the document.

The larger question here is the following: have the additional years of
data, research, and observations changed our judgment regarding the
health effects of SO~2~? The comments in Table 5.3 regarding previous
and current conclusions make it difficult to determine, and should be
simplified to reflect a clearer conclusion of where we are today.

[]{#__RefHeading___Toc205963116 .anchor}**Dr. John Balmes**

Comments on SOx ISA \-- 2^nd^ Draft

Charge Question 3: In the revision, we reduced redundancy, added summary
sections and reorganized Chapter 3. In addition, discussions on
potential confounding by and interactions with copollutants have been
added. The 2nd draft ISA also includes additional analyses of
individual-level data from human clinical studies (Sections 3.1.3. and
4.1.1) that builds upon the analysis included in the 1994 Supplement to
the Second Addendum. The toxicology sections were reorganized to focus
on studies using more relevant concentrations of SO2 and sections were
added to better discuss mode of action and potential particle-SO2
interactions. We are requesting CASAC review specifically on these
analyses as well as on the integration of the overall evidence from the
human clinical, animal toxicological, and epidemiological studies. To
what extent is the discussion and integration of evidence from the
animal toxicology and controlled human exposure studies and
epidemiologic studies technically sound, appropriately balanced, and
clearly communicated?

GENERAL COMMENTS

The revised Chapter 3 is much improved by virtue of the reduced
redundancy, added summary sections, reorganization, and additional
discussions involving co-pollutants. The new analyses of human clinical
studies in Sections 3.1.3 and 4.1.1 are helpful. In general, the
discussion of the results of the animal toxicological, controlled human
exposure, and epidemiological studies that have been reviewed is
technically sound. The major exception to this comment is the discussion
of the effect of SO2 on lung function responses to inhaled house dust
mite allergen in asthmatic adults with pre-existing sensitization to
this allergen on page 3-31. As written, the draft indicates that SO2
"enhanced sensitization to house dust mite". This is incorrect. In fact,
it would be unethical to induce or enhance sensitization to a common
aeroallergen in human subjects.

The integration of the animal toxicological, controlled human exposure,
and epidemiological studies that have been reviewed is also technically
sound, balanced, and clearly communicated with several exceptions on
page 3-91. The summary statements about the evidence in Sections 3.4.2.2
and 3.4.2.3 are too strong as worded. I have suggested revised wording
(see below in Specific Comments).

Perhaps my biggest concern about the current draft of Chapter 3 involves
the references. Many papers cited in the text are simply not listed in
the References, and some citations are obviously wrong (see some
examples below in Specific Comments).

SPECIFIC COMMENTS

p\. 3-13, line 28 The word "allergic" should be deleted from this
sentence. SO2 is too small of a molecule to elicit an allergic response
on its own. The presence of eosinophils in bronchoalveolar lavage fluid
does not mean that SO2 induced an allergic response. In addition, the
Gong et al. (2001) study is not listed in the References.

p\. 3-30, line 11 The Gong et al. (2001) study is both not listed in the
References and is not a sheep study.

p\. 3-31, lines 8-14 The two studies cited in this paragraph did not
show that SO2 "enhanced sensitization to the allergen in asthmatic
individuals." Rather, these two studies showed [enhanced airway
responses to inhaled allergen in asthmatic individual with preexisting
sensitization to house dust mite]{.underline}.

p\. 3-31 , line 7 The word "preexisting" should be deleted from this
sentence. Increased morbidity with infection does not necessarily mean
that there was preexisting disease.

p\. 3-32, lines 24-25 For clarity, the sentence should read "...and was
[also]{.underline} higher in the winter months (mean 25.7 ppb \[SD
15.8\]) [than]{.underline} in the summer months (mean 10.6 ppb \[SD
15.1\]."

p\. 3-39, line 11 The Ito et al. (2003) study is not listed in the
References.

p\. 3-39, line 13 This sentence should be revised as follows: "A study
conducted in New York City..." In addition, this study is not listed in
the References.

p\. 3-42, line 25 For clarity, this sentence should be revised as
follows: "In summary, [only a]{.underline} few studies provide results
[for]{.underline} respiratory health outcomes other than asthma and
COPD[, and these results are mixed]{.underline}."

p\. 3-45, lines 14-15 I would delete "and to a more limited extent the
human clinical studies" from this sentence.

p\. 3-46, lines 24-26 This sentence should be revised as follows: "These
findings of increased [airway]{.underline} resistance are in concordance
with the limited epidemiological study [results of Taggart et al. (1996)
that showed]{.underline} SO2-induced [increases in]{.underline} AHR
[among asthmatic adults]{.underline}.

p\. 3-46, line 31 I would add "non-elderly" before adults in this
sentence.

p\. 3-48, line 4 "bronchial responsiveness" should be changed to [lung
function responses]{.underline}. A decrease in FEV1 is not necessarily a
bronchial response.

p\. 3-49, lines 1-3 The dog study discussed in the 1982 AQCD should be
cited.

p\. 3-51, line 25 and p. 3-52, line 1 For clarity, this statement should
be split into two sentence as follows: "...of sulfite[.
D]{.underline}ose-dependent decreases... and above [were also
observed]{.underline}."

p\. 3-53, line 8 The Peters et al. (1996) paper cited appears to be the
wrong reference for the Hong Kong study.

p\. 3-58, line 4 The Routledge et al. (2006) study cited is not listed
in the References

p\. 3-59, line 3 The Gold et al. studies cited are not listed in the
References.

p\. 3-61, line 4 The Peters et al. (2000) study cited is not listed in
the References.

p\. 3-61, line 15 The Dockery et al. (2005) study cited is not listed in
the References.

p\. 3-64, line 1 The Liao et al. (2005) study cited is not listed in the
References.

p\. 3-67, line 1 The Ballester et al. 2001 study cited is not listed in
the References.

p\. 3-75, line 4 "...the association between air pollutants and
mortality [was]{.underline} examined..."

p\. 3-76, line 2 The Le Tertre et al (2002) and Ballester et al. (2002)
studies cited are not listed in the References.

p\. 3-77, line 26 and p. 3-78, line 1 For clarity, I would revise these
two sentences into one as follows: "..health effects studies [in Asia
that]{.underline} summarized the results from mortality and hospital
admission studies published in the peer-reviewed scientific literature
from 1980 through 2003."

p\. 3-91, line 2 I would revise this statement as follows: "...studies
do not [provide sufficient evidence to infer that]{.underline} long-term
exposure to ambient SO2 [has]{.underline} a detrimental effect on lung
function."

p\. 3-91, lines 18-19 Similarly, I would revise this statement as
follows: "...studies do not [provide sufficient evidence to infer
that]{.underline} long-term exposure to ambient SO2 causes prolonged
effects on lung morphology.

p\. 3-94, line 11 I would add "ambient" before SO2 in this sentence.

p\. 3-97, line 28 "Furthermore, the epidemiological studies
[do]{.underline} not provide..."

p\. 3-102, line 19 The Liu et al. (2003) study cited is not listed in
the References.

p\. 3-102, lines26-27 For clarity, I would revise this sentence as
follows: "The most robust association [with intrauterine
mortality]{.underline} was observed for an index of three gaseous
pollutants NO2, SO2, CO)."

p\. 3-105, line 2 The Japanese study discussed in the 1986 Secondary
Addendum should be cited.

[]{#__RefHeading___Toc205963117 .anchor}**Dr. Doug Crawford-Brown**

Comments on SOx ISA -- 2^nd^ Draft

My comments here focus largely on Chapters 4 and 5, although it was
necessary to review the earlier chapters as well because Chapter 5
especially draws on materials from those earlier chapters. It is clear
to me that the EPA is getting better at this process of creating an ISA.
The document is well organized; it is easy to follow the reasoning used
by the authors; and they appear to me to have reached the appropriate
summary conclusions on the ability of SOx to produce effects even at
levels below the current NAAQS, at least for short-term exposures. The
document overall provides an adequate basis "to provide support for
future risk, exposure and policy assessments", in the sense that it
establishes the existence of effects in policy-relevant ranges of
exposure, identifies issues associated with exposure, and identifies
sensitive subpopulations. It would not be possible to use the document
alone as the basis for performing an actual risk assessment because
there is inadequate assessment of exposures nationally or in specific
subpopulations. But I presume such a formal, quantitative risk
assessment would be the task of the Exposure and Risk Assessment
document. Still, I continue to have trouble understanding the role of
the ISAs in meeting the needs of risk assessment. This document
continues the pattern of being an inadequate basis for such a
quantitative approach, even if it does systematically review the
evidence on which such a quantitative assessment might ultimately be
based.

My specific comments are:

1\. I like the formulation of the questions on page 1-2. They seem to be
a refinement of these questions in previous ISA documents, recognizing
the need not to just consider new information but to integrate new
information into past assessments.

2\. On page 1-5, the authors note that associations are not sufficient
for proof of a causal relationship. Later they mention that
epidemiological studies provide evidence of an association. Still later
in the document, they use the epidemiological evidence as a basis for
concluding that there is a causal relationship. This is not consistent,
although I think the inconsistency begins with the first claim: that
associations do not prove causality sufficiently. This needs some
nuance, as associations ARE an important component of causal reasoning,
even if not fully compelling. I disagree with views that associations
are not relevant in claims of causality -- they can in fact be
compelling, rational evidence if sufficiently well established and
reliable.

3\. In the figure on page 1-6, I note that some aspects of the bottom
half of the figure, such as lifestyle, CAN be influenced by community
norms, and so are not strictly individual-level factors.

4\. The topic of multifactorial causation on page 1-9 is interesting.
But there are real questions as to whether policy can deal with such
complex mixtures, leading perhaps to different standards in different
regions where the mix differs. The common basis could be overall risk,
not the allowed concentration of any one contaminant, but there will
still be significant issues of equitable treatment of the class of
emitters in different regions if the mix differs between those regions
(which in turn would require different levels of control on the same
class of emitters in different regions).

5\. On page 2-39, the authors state that exposure misclassification may
result if total human exposure is not disaggregated. I am not sure WHICH
exposure is then misclassified. Is it the exposure to ambient levels? If
one is using total exposure to SOx, perhaps through personal monitors,
in epidemiological studies, there is no exposure misclassification due
to a lack of disaggregation. There WOULD be misclassification if one is
trying to get at the effect of ambient, policy-relevant exposures alone.
I assume they don't mean misclassification of total exposure.

6\. Table 2-9 presents a number of studies, and then the authors appear
to settle on 0.13 as the slope. This value is the highest one in the
table by a factor of 2 to 3, and I don't feel the authors have explained
adequately why they chose this particular result from amongst those in
the table. I'm sure there is a rationale, but it doesn't come across in
the writing and so there will be suspicion that the choice was based on
conservatism rather than this being the best study.

7\. The discussion of Berkson type errors on page 2-53 is correct,
although I don't see where the authors eventually conclude whether the
errors in the specific studies used here are or are not Berkson type. I
presume they assume the errors will lead to misclassification and bias
towards the null, but I can't see this stated clearly. If there IS bias
towards the null, they should state this as a final conclusion, which
then has implications for application of any slope factors and the
degree to which a standard is health protective with a margin of safety.

8\. On page 2-54, the authors have not noted that the slope factor can
be incorrectly increased if location near a source is correlated with
sensitivity. For example, if poverty causes sensitivity due to poor
nutrition, and land prices decline the closer one gets to a major
source, then exposure and sensitivity are correlated and beta will be
increased above that found when this correlation is not present.

9\. In the section on Dosimetry, the authors have summarized the studies
adequately. However, there remains the problem of how SOx gets into the
deep lung given the rapid absorption in the nasal passages, or how its
movement into the surface of hygroscopic particles might affect this
penetration. I came away from the chapter not quite clear whether the
authors were saying penetration to the deep lung is insignificant,
significant only for mouth breathing, or unknown quantitatively.

10\. On page 2-61, the middle paragraph seems inconsistent. How can
uptake in a 3 year old be slightly higher than for an adult but uptake
per unit surface area be the same, given the smaller surface area in a 3
year old? It seems to me a higher uptake in a 3 year old would produce
an even larger difference in uptake per unit surface area. Or could the
authors be in some sense conflating uptake fraction and total uptake?

11\. The figures in Chapter 3 are good and useful. It is especially good
that they are in a consistent format. The authors could improve the text
by describing how the studies could be combined quantitatively or at
least qualitatively. Otherwise, the reader is left with just
"eye-balling" the graphs for a mean value - or choosing a single study -
IF quantitative analysis is needed. Is meta-analysis not appropriate,
and if not, why not? But perhaps the figures are there only to suggest a
robust claim of an association. Still, the authors should state that if
it is the case. The reader also needs to be told whether the studies in
the figures represent a full sampling of such studies, or have been
selected from a larger set to form a subset -- this subset would then
need to be defined.

The following questions are related to Charge Question 4:

12\. In Chapter 4, I continue to have a problem with the ISAs separating
exposure levels and sensitivity in determining the public health impact.
The authors do a good job of describing the sensitive subpopulation, and
then of estimating the size. It is evident that there are a significant
number of people who fall into this category. But having sensitive
people present does not equate to a public health impact unless
exposures are sufficient, and this chapter makes no attempt to quantify
the exposures to these people. So I am not convinced that tables such as
4-2 provide a quantitative measure of public health impact.

13\. On page 4-1, there is mention of a population-response threshold. I
don't know what this term means. Populations don't have thresholds,
individuals do and these thresholds are distributed. There are several
places in this chapter where the authors make it sound as if there are
population characteristics such as thresholds that can be found in
studies, and I don't believe there are. The belief in population
thresholds also is inconsistent with earlier claims in the chapter that
intersubject variability is one of the causes of linearity of population
response at low exposures.

14\. I don't understand why the exposure-response section is not placed
into Chapter 3. Surely this is both important information for that
chapter, and is in fact the MOST important information for understanding
the effect of any lowering of the NAAQS.

15\. It is unfortunate that the clinical E-R curves do not extend down
into the region of policy interest. Figures 4-2 and 4-3 suggest there
may be some leveling of the curves in the lower region of exposure,
which has significant implications for the incremental or marginal
effectiveness of policies that push exposures below these levels.

16\. It would be useful to show the existing NAAQS level on these E-R
curves, so the reader can see where extrapolation is needed. This is
particularly important because the units of the X axis change between
several of the figures.

17\. The complexity of the curve in Figure 4-5 is intriguing, as we find
the same thing in radiation dose-response curves. It usually occurs when
there are competing beneficial and detrimental effects at low exposures,
due to compensatory mechanisms kicking in.

18\. On pages 4-9 and 4-10, a susceptible subpopulation is defined as
one that might show effects below concentrations needed in the general
population. This is much too vague of a statement, as it applies to any
individual whose individual threshold is below the population median
(50% of the population therefore being susceptible). And again, there IS
no general population response, only the aggregate response of
individuals with a distribution of thresholds. Better definitions of
susceptible and sensitive are needed, ones related in some way to
percentiles of the intersubject variability distributions and some
notion of biomodality of these distributions.

Based on Comments 12-18, I judge that Chapter 4 is better overall than
the previous draft, and is nicely organized for the kinds of information
presented. But I continue to have problems with the way in which public
health impact is quantified. I don't believe this chapter provides
quantitative information on actual impacts, but rather the POTENTIAL for
impacts if exposures are sufficient.

19\. Figure 4-6 suffers from having a wide range of ages in the young
group (0-14 years). Is there no way to narrow in on the much younger
ages where sensitivity seems especially pronounced?

The following comments apply to Charge Question 5:

20\. Chapter 5 continues the pattern of having little formal framework
for integrating information. The EPA seems to cite a different source
for frameworks in each ISA (here it is the NAS Institute of Medicine
Report). I don't have an alternative to offer, so just believe it would
be best if the authors just state the principles they are using directly
and not rely on a particular source (requiring the reader to go back to
those sources for clarification).

21\. On page 5-2, line 20, a causal relationship is inferred
(reasonably), but needs to be accompanied by a statement of the levels
of exposure at which the relationship applies. The existing statement is
too broad. There are causal relationships between exposure and adverse
effect for all things in the world, at some level of exposure.

22\. The discussion of uncertainty throughout is inadequate. It could
lifted out of here and placed down into any of NAAQS ISAs, it is so
generic. There needs to be a better summary of the uncertainty and its
implications for specific judgments that might be required in exposure
and risk assessments.

Overall, Chapter 5 provides a good compendium of information that should
prove useful for the exposure and risk assessment stages. It adequately
summarizes causal claims, although I don't believe it properly places
caveats with respect to the exposure levels at which these causal claims
are strong.

[]{#__RefHeading___Toc205963118 .anchor}**Dr.** **Terry Gordon**

Comments on SOx 2^nd^ Draft ISA

General Comments:

This is an excellent draft ISA and for the most part is clear and
logical. The authors have made logical connections between the
epidemiology, clinical, and animal studies and arrived at fair
conclusions regarding the adverse health effects associated with ambient
exposure to SO~2~. Also, the order of the sections in each Chapter is
very good. Perhaps, NCEA should formalize the order and format of
sections so that future ISA's follow this order (to avoid everyone's
suggestion to change the order to their individual preferences).

Charge Question 3: "In the revision, we reduced redundancy, added
summary sections and reorganized Chapter 3. In addition, discussions on
potential confounding by and interactions with copollutants have been
added. The 2nd draft ISA also includes additional analyses of
individual-level data from human clinical studies (Sections 3.1.3. and
4.1.1) that builds upon the analysis included in the 1994 Supplement to
the Second Addendum. The toxicology sections were reorganized to focus
on studies using more relevant concentrations of SO2 and sections were
added to better discuss mode of action and potential particle-SO2
interactions. We are requesting CASAC review specifically on these
analyses as well as on the integration of the overall evidence from the
human clinical, animal toxicological, and epidemiological studies."

The reduction in redundancy and the addition of summary sections has
aided in making this Chapter clear and concise. The authors have reduced
the animal studies so that a true picture (of their contribution to
understanding the biologic plausibility of the adverse effects of SO2)
is now presented. The addition of the toxicology section that discusses
potential particle-gas interactions and enhanced responses in exposed
animals is very appropriate in the level of detail and its relevance to
the ISA.

Charge Questions 4 & 5: The revisions are excellent and made the
chapters very readable with minimal overlap with Chapter 3 and each
other. The dose-response evaluations are appropriate, but the final
conclusions in Chapter 5 might be worded more strongly so that the REA
working group has more guidance as to which health endpoints and data
sets (epidemiology and/or clinical) are appropriate for risk
evaluations.

Detailed Comments:

Page 1-1, line 13 -- While this statement is probably true for sulfite,
given the added section(s) on particle-sulfur dioxide interactions, it
seems premature to conclude on the first page of the ISA that sulfuric
acid (potentially layered on particles) are present in insignificant
concentrations in the ambient environment.

Page 1-5, line 11 -- typo: data complement

Page 2-44, line 11 -- Chao ref is missing here (2001 ref?).

Page 2-52, lines 5-16 -- This section is a bit redundant with similar
discussions on page 2-47 lines 7 & 8, page 2-48 lines 1-5, and page 2-42
lines 19-28. Possibly combine in one place?

Page 3-6, lines 3 and on -- Should a brief discussion of sulfuric acid
be added to the discussion of sulfite chemistry/interactions/metabolism?

Page 3-7, line 9 -- Because line 5 mentions 'cholinergic' pathways,
saying that acetylcholine is '[also]{.underline} thought to be
involved....' is incorrect.

Page 3-12, figure 3-1 -- Add 'provocative' to the definition of PC(SO2).

Page 3-14, lines 19-30 (and onto the next page) -- This section should
be condensed to a couple sentences or cut because of the questionable
relevance of 100-2000 ppm sulfur dioxide even if the dosing was brief or
in vitro.

Page 3-27, line 8 -- Please add refs for the 'several other
studies....'.

Page 3-31, line 5 -- Insert 'pseudo-' before 'measure of airway
obstruction'

Page 3-37, Figures 3-6 & 3-7 -- Would a meta-analysis be appropriate for
these studies? Also, The visual separation of the ED visits and the
Admissions studies should be more distinctly labeled.

Page 3-39, line 13 -- 'study conducted in ??' Where?

Page 3-40, line 13 -- A positive association for the Lee, 2002 study is
not presented in Figure 3-7. The only Lee study in the figure has a
negative association (2006). Typos?

Page 3-50, line 15 -- Chen, 1992?

Page 3-55, line 22 -- Is this statement true regarding adults? Page 3-25
says inconclusive evidence. Should the text read 'older adults'?

Page 3-57, line 1 -- Should the word 'peak' be inserted before
'ambient'?

Page 3-57, line 18 -- What are 'consequent cardiac deaths'?

Page 3-83, line 13 -- 'and/or' is unclear

Page 3-85, lines 4-10 - µg/m^3^ should be converted to ppm for ease of
reading.

Page 3-92, line 10 -- This statement about 3 other recent studies should
be deleted or expanded/referenced.

Page 3-99 -- This section is nicely written and clearly hits the right
level of discussion of high dose studies and their quasi-relevance.

Page 4-3, figure 4-1 -- Inclusion of 0.10 and 0.50 in the bar graph
implies that zero percentage changes occurred vs. the actual absence of
data at those exposure concentrations.

Page 4-6, line 8 -- This sentence is not consistent with figure 4-5
which shows no real change at 10 ppb.

Page 5-2, line 1 -- Is this sentence accurate? 'west to east' implies a
gradient from the west coast to the east coast.

Page 5-10, 5-11 -- A nicely written evaluation.

Page R-24 -- Zeger ref has a typo on the pages.

[]{#__RefHeading___Toc205963119 .anchor}**Dr.** **Dale Hattis**

Comments on SOx ISA -- 2^nd^ Draft

[Response to question 4 and to some extent question 3 on the analysis of
individual-level clinical concentration-response data for the short term
bronchoconstriction response to SO2]{.underline}.

I was encouraged that the ISA authors included empirical information
from three papers by Linn et al. (1987, 1988, and 1990) that are similar
to the Horstman et al. individual data for these responses that I
analyzed in my comments to the earlier draft of the ISA. Unfortunately
there does not seem to have been any effort to compare the risk
assessment implications of the Linn et al. data with those of the
Horstman data, let alone put them in to a combined analysis for
derivation of an overall estimate of the concentration-response function
for asthmatics. The concentration-response section of the REA also lists
several other sources of individual data on similar responses that have
not been summarized or analyzed as of yet.

Three types of information can readily be extracted from the existing
body of clinical observations: The ED50 for particular responses, the
breadth of the population distriubiton of thresholds, and the form of
the distribution (i.e. does it appear to be lognormal, or some more
complex shape?)

For reference, the Horstman et al. paper gave individual SO2 threshold
concentrations for 27 asthmatics for a doubling of specific airway
resistance. These data are reasonably, but not perfectly compatible with
a lognormal distribution (Figure 1). (In this figure, the straight line
represents a fitted lognormal distribution for the data. The slight
departures of the data above the line on both the low and
higher-concentration ends of the distribution may suggest some tendency
toward bimodality in the underlying distribution of individual
thresholds, but these data are not sufficient to make a firm conclusion
on that point). By averaging the logarithms of the individual thresholds
for this effect we find an ED50 (geometric mean dose expected to produce
the response in 50% of an exposed asthmatic concentration) of 1,040 ppb,
with 90% confidence limits of 739-1475 ppb. From the standard deviation
of the logarithms of the individual values we find a geometric standard
deviation for interindividual variability in the thresholds of
2.38---meaning that based on these data, 90% of the individual
thresholds in a similar population of asthmatics should be expected to
be between 250 and 4340 ppb.

The newly presented information from the Linn et al papers for the same
response are unfortunately not given as individual values, but
essentially in histogram form---the number of asthmatics studied who
respond at a few discreet dose levels. I have analyzed these assuming a
lognormal distribution of individual thresholds using an Excel program
adapted from Haas (1994) and used extensively in my prior work on human
interindividual variability in susceptibility (Hattis et al. 2001). The
data provided from the Linn et al. papers suggest an ED50 for the
doubling of specific airway resistance in exercising asthmatics of about
580 ppb---a little lower, but probably not significantly lower than the
range indicated by the Horstman et al. data. (I did not assess the
confidence limits for the ED50 in this case) The Linn et al. data also
indicate a slightly greater amount of interindividual variability than
those of Horstman---a geometric standard deviation of 2.85 with 90%
confidence limits of 2.10-5.75. Together, if we assume a lognormal
distribution of individual thresholds as before, the central estimate of
interindividual variability and the central estimate of the ED50 from
the Linn et al data would indicate that 95% of exercising asthmatics
should have this response at between 104 and 3250 ppb. Unfortunately,
there is reason to doubt that the distribution is perfectly
lognormal---a goodness of fit test indicates a barely statistically
significant departure of the data from expectations from a lognormal
model at P \< .05.

There are a couple of ways to combine these data for an aggregate
analysis. One simple way that I did was to add the Horstman observations
where they would fall in the histogram-like data from the Linn et al.
papers. When this is done, the ED50 indicated by the combined data is
just under 700 ppb and the geometric standard deviation for
interindividual variability is 2.52 with 90% confidence limits of
2.01-3.83. The revised central estimate ED50, combined with the central
estimate of the geometric standard deviation would indicate that 90% of
exercising asthmatics should respond between 150 and 320 ppb. Again,
however, the combined data depart from expectations of a lognormal
distribution model at a P level of slightly less than 0.02. In further
exploration of the combined data (including experiments of other
research groups) I would recommend an attempt to fit a mixture of two
lognormal distributions. I could not attempt this in this analysis,
however because a mixture of two lognormals involves estimation of 5
parameters (two means, two standard deviations and a parameter to
measure the fraction of the population that belongs to each component
distribution) and the Linn et al. data are aggregated only into 4
ranges. There is likely to be an infinite number of perfect-fit
solutions when one uses only 4 data points to estimate 5 parameters.

If it is of interest to EPA staff, I will provide the Excel spreadsheet
showing these calculations.

**References**

Haas, C. N. \"Dose Response Analysis Using Spreadsheets\" Risk Analysis
14:1097-1100 (1994).

Hattis, D., Russ, A., Goble, R., Banati, P., and Chu, M. "Human
Interindividual Variability in Susceptibility to Airborne Particles,"
[Risk Analysis]{.underline}, Vol. 21(4), pp. 585-599 (2001).

**Figure 1**

![](media/image2.wmf){width="6.665972222222222in"
height="5.791666666666667in"}

[]{#__RefHeading___Toc205963120 .anchor}**Dr. Donna Kenski**

Comments on SOx ISA -- 2nd Draft

General comments: The revisions to Chapter 2 have improved it
substantially. In particular, Sections 2.5.3 and 2.5.4 on exposure
measurement errors were improved and clarified. The added tables and
discussion were helpful. The added information on 5-minute averages was
a good start, but lacked enough detail to form adequate basis for
decision-making. The dismissal of these data because of the voluntary
nature of the reporting and their variability over time and space is
troubling. In light of the number of health studies showing effects at
5- to 15-minute exposure times, the importance of the information for
the Risk and Exposure Assessment, and given EPA's request that the
states collect this data, it seems unreasonable to dismiss it in this
document without even a rudimentary summary of the data. The REA goes on
to glean important information from the relationship of the 5-minute
peaks to hourly means, so the very limited discussion in this document
is surprising. This particular shortcoming was not apparent in the
previous version of the ISA, before the REA had been drafted. The
removal of the NOx information from Annex B was a good decision; it
makes it much easier to find the relevant data for SO2. Some specific
comments follow:

2-1 line 13 The initial phrase, "Industrial emissions..." is somewhat
mischaracterized; perhaps the authors meant anthropogenic emissions?
Utility emissions are usually regarded separately from industrial
emissions.

2.  1^st^ paragraph. This section still needs a simple sentence
    quantifying biogenic or natural sources. It is unacceptable to spend
    2 paragraphs describing natural sources and still not quantify them
    except as 'small', which could be 10% or 1% or 0.01%. Even Table B-3
    doesn't do so; the reader is left to infer that such emissions are
    less than 0.00 Tg/yr.

2.2. Line 12 Refers to Table B-6, which does not exist. It doesn't look
like this data is available in the revised Annex.

2.3 line 14 Reference to Annex B.5 should be B.6

2.8 Sec. 2.4.1 The addition of the monitor siting criteria was helpful.
The open-path information is probably unnecessary, however. The sampling
and analysis discussion didn't describe any open path instruments for
SO2 and since these are a tiny fraction of the reporting network, if
there are any at all, it could be deleted without harm to the rest of
the discussion.

2.11 The new figures 2.1-2.6 are a useful addition. However, the
rationale for choosing these 6 areas for focus needs to be clearly
stated. Was it because they have the most monitors, or the highest
concentrations, or the most spatial heterogeneity or homogeneity?

2-11 line 16 ...as well as the subset of *monitors* in Cuyahoga County.

2-19 line 9 'Overrepresentation' sounds judgmental. 'Predominance' might
be a better word choice

2-23 Fig. 2-11 At the risk of sounding like a broken record, I will
point out again that this figure is a poor depiction of diurnal cycles.
If the point is to show diel variation, as the text says, then the
variation in the median (or some higher percentile, if all the medians
are zero) is of much more interest than the outliers, which is all one
can see on this plot. Plot the medians on a scale that can be read, as
in Figs. 2-12 -- 2-15, rather than emphasizing the meaningless noise in
the outliers. Maybe a log scale would work better. The plot is not
useful as currently configured. Also, it's not clear what the caption
means by 'all cities *in focus.*' It seems to imply that these are the
cities included in the Figs. 2.1-2.6, but the text says it summarizes
all the data in AQS, so that should be clarified.

26. The description of the 5-minute sample data is still lacking. The
    text and Tables 2-6 and 2-7 don't agree. For example, Table 2-6 has
    80 monitors reporting 5-min averages and Table 2-7 lists 16 monitors
    reporting all 12 5-minute values. The text reports that 108 monitors
    reported 5-min averages and 15 monitors reported all 12 values.
    These need to be reconciled.

2-34 line 6 Annex Section B-6 should be B-3

2-46 line 27 A monitoring site at an elevation of *250 m* above street
level? Is this correct?

47. line 1 ...should 'outdoor' be 'personal' instead? Ambient
    concentrations *are* outdoor concentrations.

2-56 line 19 or -\> for

2-63 line 5 delete 'of'

5-2 lines 5-6 Transport of SO2 plumes from Asia and Europe really wasn't
discussed in the previous sections, so this statement doesn't belong in
the conclusions unless it is supported by the earlier text.

5-2 lines 15-18 Here's another dismissal of the 5-min data as
unimportant for determining concentrations and exposures at short time
durations. This just doesn't make sense. Perhaps the data are
insufficient to make sweeping generalizations about national exposure,
but they certainly are useful and valid, and their temporal variability
is exactly what makes them valuable and why we collected them in the
first place. A more reasonable statement here would be that the existing
5-minute data are not adequate to assess exposure on a national scale --
but then, neither are the hourly data.

5-2 line 24 remove the 7 after exposures

5-3 lines 8-11 This statement is correct, but would be much stronger if
the 5- minute SO2 concentrations had actually been summarized in this
document.

[]{#__RefHeading___Toc205963121 .anchor}**Dr.** **Patrick Kinney**

Comments on SOx ISA -- 2nd Draft

One general concern I have relates to the way the ISA interprets the
public health relevance of concentrations below those studied in the
human clinical studies, i.e., 0.2-0.4 ppm. As noted in the ISA, these
studies look at effects in groups of people who do not represent the
full range of susceptibilities present in the general population. In
addition, clinical studies study very small numbers of subjects as
compared with the population exposed to ambient concentrations. These
two issues limit the power of clinical studies to quantify
exposure-response relationships at ambient-relevant concentrations.
Given this, it is incorrect to assume, as EPA seems to do in the current
ISA, that the lowest-observed effect concentration represents a
threshold below which no effects occur. After all, we are concerned with
protecting the US population, which contains over six orders of
magnitude more people than have been studied in a typical clinical
study. A better way to interpret the exposure-response results from
clinical studies is that they provide points on a exposure-response
function that extends down to zero ppb. This concept should be discussed
in the ISA, providing a better foundation for its application in the
health risk assessment in the REA. It also would help to bridge the
large gap that currently exists between the exposure levels at which
responses/associations are observed in clinical/epidemiologic studies.

p\. 1-7, line 12: change "occur" to "exist"

p\. 1-7, line 24: change "with" to "with respect to"

p\. 1-8, line 2: it should be noted as well that control for
confounders, whether by adjustment or stratification, is only successful
when the confounder is well measured. This point is often overlooked.

p\. 1-8, first full paragraph: Needs to be reworked. It\'s not clear
whether you\'re talking about confounders, the exposure of interest, or
both. It seems to change from one sentence to the next.

p\. 1-8, second full paragraph: To the lay reader, it may be unclear
what you mean by covariates as opposed to confounders here. Also, this
section on confounders would benefit from a clear definition of
confounding at the outset.

p\. 1-13, line 13, insert "controlled human exposure studies," before
"epidemiological"

p\. 1-14, box on causality categories, in the row labeled "inadequate to
infer the presence...", insert "quantity," before "quality"

p\. 2-8, section 2.4. This section should start off with an intro
paragraph stating purpose and approach of the section. The very
technical minutia of the initial text is off-putting as written.

p\. 2-8, line 17: need to insert definitions of the three geographic
scales in terms of kilometer ranges or such.

p\. 2-9 through 2-11, line 2: this whole section reads like a guidance
manual for setting up a monitoring station. I don\'t think we need that
here. Can\'t we assume that existing monitors satisfy these criteria,
and move on? Once sentence would be enough to say that.

p\. 2-9, line 3: define "monitoring path", or better yet, delete this
whole discussion.

p\. 2-10, line 6: I don't think the "open path" analyzer was defined or
described earlier. Please add that. How relevant is this? Is this an EPA
equivalent method? If not, why discuss?

p\. 2-11, section 2.4.2: It would be better to start off by presenting
descriptive information and summary statistics on the national data
(e.g., table 2-4) rather than focusing on six particular states.
Rationale for these six states is not sufficiently clear. Please expand.

p\. 2-21, Figure 2-10: a similar map showing emissions at US ports would
be a very useful addition.

p\. 2-21, line 10: what is "diel"?

p\. 2-22, Table 2-4: This table should be referred to repeatedly
throughout subsequent sections, especially chapter 4.

p\. 2-23, figure 2-11: not clear what is meant by "cities in focus"

p\. 2-32 and vicinity: I was surprised not to see any data from the
5-min so2 results. Why mention it here if no data are to be shown? Must
explain why data are not shown.

p\. 2-38 and later in Section 2.5: The uncertainties are discussed
extensively, but are never summarized quantitatively in any way.

p\. 2-57, line 9 and elsewhere: should be beta hat, not beta.

p\. 2-57, line 19: add text on effect of measurement error on SE(beta
hat)

p\. 2-58, line 5: spelling of physicochemical

p\. 3-25, line 15: please provide a quantitative measure of how
prevalent these observations are. e.g., what fraction of 10 min avgs are
above 0.4? the term \"sometimes\" could be mis-interpreted as something
like 10-20%. Reality is probably many orders of magnitude lower than
that.

p\. 3-39, line 13, sentence starting "a study conducted" needs grammar
fix.

p\. 3-43, line 4: state range of ppb for which excess risk is calculated
here, and put this range into the context of SD of ambient 24-hour
averages.

p\. 3-44, figure 3-8 and following text: I'm troubled that there are no
studies reported here that included PM2.5 as a co-pollutant. This
omission is an important caveat that should constrain any conclusions
regarding robustness. Especially so given the dismissal of the long-term
mortality results for SO2 on the basis of concerns over sulfate PM2.5
confounding.

p\. 3-45, lines 13-18: This seems too glib. I don't agree that coherence
and biological plausibility are satisfied when comparing chamber results
at 200-600 ppb and epi results are for ambient levels two orders of
magnitude lower. Need to include this caveat.

p\. 3-55, lines 16 to 25: This section needs to acknowledge the exposure
levels observed on average in epi studies, in metrics equivalent to
those used in ch amber studies, e.g., 1-hr averages -- noting means,
sds, 95th percentiles etc. This is done for the chamber results but for
some reason is ignored when describing the epi findings. Table 2-4 is
the relevant reference.

p\. 4-1, sentence on lines 20-23. This sentence is false. It is not true
that most epi studies evaluate whether there is a threshold. Few if any
epi studies evaluate that question directly. Please edit.

p\. 4-3, Figure 4-1: indicate in footnote which of these results are
statistically significant.

p\. 4-4, section 4.1.2: in linking the chamber findings with the epi
findings, it is important to compare the dosimetry in at least a
semi-quantitative way, taking into account the differences in exposure
concentrations and activity levels.

p\. 4-4, line 10: change "was" to "could not be distinguished from" The
key point is that there is very limited power to formally test whether
something is linear or not. Failure to reject linearity isn't equivalent
to "observing that the relationship was linear"

p\. 4-5, lines 8-10: this is a good example of the kind of concentration
cross-referencing that I was looking for earlier.

p\. 4-6, Figure 4-4: tell us which of these results are statistically
significant, or better yet, provide confidence intervals at each point
on the curve. OK to limit to one lag to simplify display since they all
say roughly same thing.

p\. 4-9, line 4: insert quantitative LOD (e.g., 3 ppb) in parenthesis
after "detection"

p\. 4-9, lines 13-14: again the issue of "observing that the
relationship was linear"

p\. 4-17, Figure 4-6: throughout the document, EPA concludes that ED
visits and hospitalizations are associated with SO2 for children and
older adults. This doesn't come through very clearly from this figure.
Can the results for younger adults be added? Can histograms be created
of the RRs within each age range? This would provide stronger backup for
EPA's conclusions about age-related effect modification.

p\. 4-19, line 19: Edit grammar. As stated, it suggests that most
studies examine effect modification by SES, which is clearly untrue.

p\. 4-22, lines 19-27: need to include the fact that these findings are
observed only with heavy exercise. Then later you need to estimate
fraction of asthmatics who spend time at those exertion levels, and also
the fraction of time that people are exposed to these ambient levels.
Both are needed for risk assessment discussions that follow.

p\. 4-23, line 9: this is obvious place to insert 1-2 paragraphs
discussing the fraction of relevant exposure levels and exertion levels
experienced by sensitive subgroups.

p\. 4-23, line 16: risk only occurs with exposure, so need to discuss
exposures here too.

[]{#__RefHeading___Toc205963122 .anchor}**Dr. Steven Kleeberger**

Comments on SOx 2^nd^ Draft ISA

3\. In the revision, we reduced redundancy, added summary sections and
reorganized Chapter 3. In addition, discussions on potential confounding
by and interactions with copollutants have been added. The 2nd draft ISA
also includes additional analyses of individual-level data from human
clinical studies (Sections 3.1.3. and 4.1.1) that builds upon the
analysis included in the 1994 Supplement to the Second Addendum. The
toxicology sections were reorganized to focus on studies using more
relevant concentrations of SO2 and sections were added to better discuss
mode of action and potential particle-SO2 interactions. We are
requesting CASAC review specifically on these analyses as well as on the
integration of the overall evidence from the human clinical, animal
toxicological, and epidemiological studies.

Overall, the reorganized Chapter 3 is greatly improved over the previous
version. In particular, the following aspects of the Chapter were
useful:

-   Summary of findings from the previous review -- these provide much
    needed and useful reference points to enable evaluation of the more
    current investigations.

-   Redundancy was largely eliminated, though some repetition remains
    that could be edited or removed.

-   Additional individual-level data (i.e. specific numbers of
    individuals in response groups) enabled better evaluation of
    between-individual variation and the impact on interpretation of
    results.

-   Removal of animal studies that used SO2 concentrations that had
    questionable environmental relevance was appropriate, though some
    remain that likely could also be removed.

-   The end-section summaries were very useful and largely presented a
    reasonable evaluation of the literature with respect to weight of
    evidence for causal determination.

-   Incorporation of the effects of SOx intervention and subsequent
    change in health outcomes into evaluation of causality was
    appropriate and useful.

Additional Comments:

While it may be argued that SO2/particle interactions should be included
in the ISA document, the case was made in the REA that the current
review of the SO2 NAAQS would focus on gaseous species of sulfur oxides
and not consider health effects directly associated with particulate
sulfur oxide species. These species and their health effects instead
will be reviewed in the PM document. However, one of the sections in the
SO2 document (3.1.5) includes effects of SO2 layered on particles and
sulfite aerosols. I did not find the section fit particularly well with
the rest of the document and raised additional questions that could not
be answered, or may have been answered in the PM document. My
recommendation would be to eliminate this section.

The REA clearly differentiates between long-term exposure (months to
years), short-term exposures (hours to days), and short-term peak
exposures (5-10 minutes) throughout the document, especially beginning
with the Health Effects chapter (part 4). The ISA differentiates
primarily between long-term exposure and short-term exposures, with the
short-term peak exposures embedded in the latter (e.g. section 3.1.3).
An introductory statement or small paragraph placed at the beginning of
the major sections of Chapter 3 (e.g. 3.1) which define the distinction
may help the reader to place the studies in the intended perspective.

Minor

P 3-4, line 5: delete "a" from "presenting a more details"?

P 3-13, lines 26 and 28: is it correct to suggest that SO2 may elicit an
allergic inflammatory response? SO2 is not an allergen.

P 3-17, lines 9-21. I am not sure that this section really provides
"biological plausibility for the effects of SO2 on respiratory symptoms
in humans". The relevance of MUC5AC expression induced by SO2 using in
vitro models and in rats exposed repeatedly to 2 ppm SO2 to respiratory
symptoms in humans is questionable, and presenting these preliminary
studies is not necessary.

P 3-103, line 10. "is" should be "are"?

[]{#__RefHeading___Toc205963123 .anchor}**Dr. Timothy Larson**

Comments on SOx ISA 2^nd^ Draft

*Chapter 2:*

Section 2.4 is reorganized and shortened with a more appropriate focus
on interurban variability. Tables 2-4 and 2-5 are particularly useful in
this regard. The information on correlations with other pollutants is
obviously limited by the lack of co-located monitors. The discussion of
the available 5-minute data is an important addition to the chapter, but
it is very brief, given the importance of this data in the REA. We are
left with a statement that these data are "very difficult to use
precisely", without knowing exactly what that means. Do the authors mean
the measurements are difficult to use because they are inaccurate or
that they are accurate but are highly variable across time and space?

Based on my prior review comments, I note that on page 2-52 the
statement is still made that "when personal exposure concentrations are
above detection limits, a reasonably strong association is observed
between personal exposures and ambient concentrations". This statement
is based primarily on the results of one study done in one city over two
seasons. In addition, there are no studies that have assessed the
relationship between community exposures and central site concentrations
of SO2. Appropriately, the summary chapter has been changed to place the
significance of these results (or lack thereof) in the context of
epidemiological study design and now avoids repeating the statement on
page 2-52.

*Other comments:*

On page 3-52 the statement is made that "aerosol particles act as
carriers and deliver SO2 to the lower respiratory tract". The evidence
supporting this is based primarily on studies done on rats exposed to
relatively high levels (1 to 10 milligrams per cubic meter) of freshly
generated zinc, copper or carbon black particles in combination with
SO2. These studies report a synergistic effect of SO2 in combination
with the particles and measure sulfate and/or sulfuric acid coatings on
the particles exposed to SO2 as a possible explanation for the
interaction. There is one study listed on page E-17 by Clarke et al
(2000- it is not in the reference list but I assume it is the one in
Inhalation Toxicology v12, pp169-186) that is summarized as seeing
synergistic effects at more realistic levels of sulfate particles (\~20
micrograms per cubic meter). However, to produce these particles in the
lab required 1 milligram per cubic meter of carbon black particles and 1
ppm SO2 at 85% RH. In summary, the studies listed in support of the
statement on page 3-52 were done at very high levels relative to
contemporary atmospheric SO2 levels (effects in the Clark et al study
were seen after 5 to 6 days of exposure to 1 to 10 ppm whereas the ISA
summary of typical SO2 levels over this averaging period are typically
below 0.01 ppm; similarly, the PM levels were 1 -10 mg/m3 whereas
typical PM levels of fine carbon are 1-10 ug/m3). Although these studies
do support the notion of an increased response to sulfate-coated
particles, they do not support the summary statement on page 5-11 that
"the synergism observed with combined exposure to SO2 and PM in the
animal toxicological studies provides supportive evidence for the
SO2-related respiratory effects observed under ambient conditions in the
epidemiological studies". In fairness, this is presented in the document
as an interpretation rather than a conclusion. Given the unrealistically
high SO2 and PM levels used in the animal studies (factor of 100 to 1000
relative to realistic ambient levels) , its hard to claim that these
studies provide supportive evidence for the relevant epidemiological
studies.

**Dr. Ted Russell**

Comments on SOx ISA \-- 2^nd^ Draft

The 2^nd^ Draft ISA is an improvement over the first, though could still
benefit from some pointed analyses, particularly in light of the
direction of the associated RWA. In particular, the REA deals
predominately with assessing the exposure and risks associated with
5-minute average SO2 concentrations, and how such concentrations are
associated with 1-hr average levels. Thus, this section of the ISA could
be improved. In particular, added analysis of the structures of 5-minute
and 1-hr average concentrations, and how the two correlate. In
particular, the concentrations that lead to the 5-minute maximum and
1-hr levels are from the same distributions, and thus are strongly
linked. Having the correlation structure would be useful to the staff
developing the REA. Indeed, such information could help streamline their
chapter on air quality data. At present, the ISA has little analysis of
the five-minute results. It is interesting to note that the current ISA
says that it is "very difficult to use (these data) precisely", yet the
REA does significant analysis of the data (and I am not sure what they
mean by "precisely").

I would think that SO2 concentrations being observed at a monitor will
tend to follow a log-normal distribution, whether one considers
five-minute or one-hour average values, and that the two distributions
would have a similar mean, but that the GSD would differ. (The geometric
means of the two would not necessarily be the same, given that the
one-hour average is an arithmetic average). Thus, this section should
consider presenting concentration statistics in terms of the geometric
averages and standard deviations (GSD) (they will need to address how
the below detection limit values are treated). From this, one could
assess how the GSD's of the five-minute and one-hour levels correlate,
as well as how the five-minute and one-hour maximums correlate. One
might think that the five-minute maximum can be well approximated as a
function of the one-hour maximum and associated GSD.

Page 1-1, line 12: monomeric, [gaseous,]{.underline} sulfur species.

Page 1-9, line 18: The science is not uncertain... the results contain
uncertainty.

Page 2-3, line 13: The sulfuric acid will move to a condensed, not
necessarily aqueous, phase. Further, it is not removed.

Page 2-3, line 18: What about sulfate?

Page 2-4, lines 20 on. This section is a abit confusing. They state that
most of the oxidation is via aqueous phase chemistry, then use the
gas-phase lifetime to calculate an overall lifetime. Again, it would be
best if they used results from a US-based set of simulations to address
the formation, fate and lifetime.

Section 2-3: Again, provide a straightforward answer to the question as
to whether sampler issues impact the issues under consideration here,
and I suspect the answer is no.

Table 2-4: Define units, make the caption more complete.

Page 2-25, line 9: I still think you mean three summer months, not
seasons.

Figure 2-11: This figure is still of limited utility. It is impossible
to see the frequency of observations at the low end. Provide a plot that
actually provides such information. All this figure does, really, is
indicate an average (which is too low to discern) and the maximums. Use
a log scale. Better yet, give a table of arithmetic mean, geometric
mean, maximum, minimum and geometric standard deviation. If you want,
you can add a traditional SD, though I would state this is less helpful.

I was pleased to see Sections 3.1.5.2.1-3.1.5.2.5 dealing with
SO2-particle interactions, though none of these dealt with the dynamics
of SO~2~ uptake, and evaded the question of how likely such mechanisms
may be in the atmosphere. Uptake of SO2 on atmospheric particles is
likely very slow, as is seen by the ability for SO2 and particles to
coexist in the atmosphere for long amounts of time. Further, the
studies' use rather artificial surfaces that would be considered much
more reactive and potentially absorbing than atmospheric aerosols. A
further limitation to how the results in these sections may be applied
in this assessment is that the products of the interaction between SO2
and the particles would be monitored as part of the PM matrix, and be
regulated as PM. While there is a significant amount of sulfate in PM,
which can be explained by gas and aqueous phase oxidation of SO2, there
is rather little sulfite, suggesting that particles would provide little
avenue as a mechanism to transport significant quantities of SO2 deeper
in to the lung. SO2 has a low Henry's law constant, so little will be
stored as sulfite in the aqueous phase in a naturally occurring aerosol.
This section should be more critical in its assessment of the importance
of such processes. At present, there is no indication from observation
of atmospheric aerosols that the studies discussed are relevant, and,
conversely, there is ample evidence to suggest what is found is limited
to laboratory generated aerosols that are then exposed to extremely high
levels of SO2.

Summary and Conclusions:

Page 5-1, line 25: I would add "... facilities, though emissions from
tall stacks may have a lesser impact on high concentrations at ground
level due to diffusion."

5-11, line 2: Here, it says that effect estimates were found to be
robust when using 2-pollutant models, but in Chapter 3, Fig 3-8, suggest
that the significance of the SO2 effect decreases when including PM10,
sometimes leading to its being insignificantly different from zero? I
probably also take exception to the conclusions in Chapter 3 dealing
with their interpretation of the multi-pollutant assessment.

In response to the Charge Questions:

*1. The framework for causal determination and judging the overall
weight of evidence,*

*is presented in Chapter 1. Is this the appropriate approach? Is it
appropriately*

*applied in the case of SOx? How could the framework or its application
be refined?*

The current version is improved. I will leave the adequacy issue to
those with a more appropriate expertise.

*2. The discussion of the atmospheric chemistry of SOx has been expanded
to provide a*

*better characterization of the spatial heterogeneity of urban SO2
concentrations and*

*correlations of SO2 with other pollutants. We also included new
sections describing*

*the regulatory network and siting criteria with maps of SO2 and other
monitors. A*

*brief section describing the available 5-minute SO2 data was also
included. In*

*addition, the relationships between outdoor, indoor, and personal
exposure to SO2*

*were clarified with additional details on sources of exposure error.
Have these*

*revisions to Chapter 2 improved its assessment of the currently
available scientific*

*knowledge on atmospheric sciences and exposure and its relevance to the
evaluation*

*of human health effects presented in later chapters?*

While the new chapter is, indeed, improved, as discussed above there are
still some further needs. In particular, the section on 5-minute
averages is inadequate given the reliance of the REA on 5 minute data.
This chapter should have CDFs for 1-hour and associated 5-minute SO2
data, as well as a characterization of the correlations. The chapter
would still benefit from a table of sources and their amounts. Given the
discussion in Sections 3.1.5.2.1-3.1.5.2.5, this chapter should provide
a scientific foundation for the relevance of the proposed mechanisms and
how they are supported by observational evidence in the atmosphere.

*3. In the revision, we reduced redundancy, added summary sections and
reorganized*

*Chapter 3. In addition, discussions on potential confounding by and
interactions with*

*copollutants have been added. The 2nd draft ISA also includes
additional analyses of*

*individual-level data from human clinical studies (Sections 3.1.3. and
4.1.1) that*

*builds upon the analysis included in the 1994 Supplement to the Second
Addendum.*

*The toxicology sections were reorganized to focus on studies using more
relevant*

*concentrations of SO2 and sections were added to better discuss mode of
action and*

*potential particle-SO2 interactions. We are requesting CASAC review
specifically on*

*these analyses as well as on the integration of the overall evidence
from the human*

*clinical, animal toxicological, and epidemiological studies.*

As discussed above, Sections 3.1.5.2.1-3.1.5.2.5 should be assessed for
their likely importance in the atmosphere and to resulting exposures.
Such sections should not be added without appropriate foundation and
discussion of how likely they are to be of actual importance.

*4. The section on concentration-response relationships in Chapter 4 was
reorganized and revised to include analysis of individual-level data
from the human clinical studies*

*and some additional discussion of the difficulties of discerning a
threshold in*

*population-level data. In addition, revisions were made to better
characterize groups*

*likely to be susceptible or vulnerable to SOx and the potential size of
the population at*

*risk for SOx-related health effects. Finally, revisions were made to
reduce*

*redundancy with material presented in Chapter 3. Have the revisions
made to*

*Chapter 4 improved the characterization of the potential public health
impact of SOx*

*exposure?*

*5. Revisions were made to better integrate findings from atmospheric
sciences, ambient*

*air data analyses, exposure assessment, dosimetry, and health evidence
in Chapter 5.*

*To what extent do these findings support conclusions regarding
causality of SOxrelated*

*health effects at relevant exposures?*

The greatly streamlined Chapter 5 is an improvement. I will take issue
with the use of the studies cited suggesting that the particles act as
ways to deliver SO2 significantly more efficiently to the deeper lung,
and that the sulfur associated with the particles is predominantly
sulfate formed from chemical reactions in the atmosphere, and very
little is from SO2 interacting directly with dry particles. The
molecular kinetics and atmospheric observations both argue against this.

[]{#__RefHeading___Toc205963124 .anchor}**Dr. Kent Pinkerton**

Comments on Sox ISA -- 2^nd^ Draft

**General Comments:** The second external review draft of the integrated
science assessment document for Sulfur Oxides/Health Criteria is much
improved over the 1^st^ draft. The chapters are well organized and
logical. The regulatory history for sulfur oxides is interesting to
observe with no changes since 1969, although comments were solicited for
a 1 hour standard of 0.4 ppm as well as a 5 minute standard of 0.60 ppm
SO~2~ in 1988. The current standard for sulfur oxides remains at 0.14
ppm averaged over a 24 hour period, not to be exceeded more than once
per year and 0.030 ppm annual arithmetic mean with SO~2~ as the
indicator.

The authors of the document have focused each chapter to address the
most relevant issues and have presented a rather thorough and updated
review of the literature since the most salient features of past
reports. New publications presented in the 2^nd^ draft ISA are highly
appropriate, well-presented with a balanced interpretation. The
presentation of positive and negative studies is well balanced with
possible interpretations provided based on a solid scientific basis.

**Question 4:** The section on concentration-response relationships in
Chapter 4 was reorganized and revised to include analysis of
individual-level data from the human clinical studies and some
additional discussion of the difficulties of discerning a threshold in
population-level data. In addition, revisions were made to better
characterize groups likely to be susceptible or vulnerable to Sox and
the potential size of the population at risk for Sox-related health
effects. Finally, revisions were made to reduce redundancy with material
presented in Chapter 3. Have the revisions made to Chapter 4 improved
the characterization of the potential public health impact of Sox
exposure?

**Response:**

The concentration-response relationships are clearly presented in
Chapter 4. Human clinical studies provide compelling data to demonstrate
SO~2~-induced decrements in lung function (FEV~1~) and specific airway
resistance (sRaw) in asthmatics following limited (10 minute) exposure
to SO~2~. An increasing proportion of asthmatic responders to increasing
levels of SO~2~ further confirm a strong concentration-response.

Epidemiological studies, although less definitive than human clinical
studies, also provide strong evidence of increasing asthma
hospitalizations with increasing 1-hour maximum SO~2~ levels ranging
from 0.20 to 0.60 ppm. An important point to emphasize in both the human
clinical and epidemiological studies is the observation that significant
effects were noted at SO~2~ levels beginning slightly above 0.20 ppm.

Based on the human clinical and epidemiological study findings reported
in Chapter 4, it appears the approach to be implemented in the REA by
the EPA of these findings is to use 0.4 to 0.6 ppm as the beginning
level for consideration to derive an appropriate level of safety to
public health. Although data (especially the human clinical study) shows
an increased response as SO~2~ levels are increased in a classical a
concentration-response profile, a strong rationale needs to be made for
not beginning at a maximal SO~2~ concentration of 0.20 ppm.

Once again, similarities between human clinical and epidemiological
studies should be emphasized, although I would agree that the human
clinical studies provide the most compelling evidence in considerations
for setting the standard for SO~2~.

The difficulty in establishing a threshold in population-level data is
well presented in Chapter 4. Human clinical studies are likely to be the
best source for setting risk levels, but epidemiological studies
continue to provide strong supportive evidence as well. It is
questionable whether one should consider non-linear
concentration-response relationships to SO~2~ levels, based on
epidemiological studies, especially those studies illustrated in figures
4-4 and 4-5. These studies demonstrate effects beginning in the 0.2 to
0.3 ppm level. I would suggest (as somewhat already stated in the text
of Chapter 4) it is important to not over-interpret these
epidemiological findings as being non-linear. To do so, would also
require an explanation in the Schwartz et al study (1994) (Figure 4-5)
for a negative odds ratio at a low level (0.10 ppm) of SO~2~ and a
non-linear increase in the odds ratio as levels of SO~2~ increase to 0.4
ppm.

Chapter 3 contains a comprehensive overview the scientific literature
along with a complete and thorough review of new studies published since
the previous review. The presentation and stated interpretation and
conclusions of this data in general are logical and balanced. The
summaries found at the end of each section in Chapter 3 are helpful
reminders and a reasonable and rational reflection of the section
conclusions.

Chapter 4 is written to address critical issues of public health impact
as discussed above. The chapter contents are presented in such a fashion
to utilize critical data presented in Chapter 3 without being redundant.
The definition and significance of susceptible and vulnerable
populations is discussed. These are important factors that require a
clear explanation in order to identify the appropriate populations at
risk. Should these two populations identified as "susceptible" and
"vulnerable" have overlap, is this also a critical component in
estimating the appropriate size of the population at risk.

Excellent examples of epidemiological studies are presented to further
confirm sensitivity of children with asthma to SO~2~. Similar
sensitivity in adults has not been found. Genetic factors related to
health outcomes were also considered with regard to air pollutants as an
important factor to consider in future studies. A study by Winterton and
colleagues (2001) has found a significant association between SO~2~ and
the homozygous wild-type allele for TNF-alpha.

Within chapter 4 is also presented a number of studies to examine
age-related susceptibility with a good balance of studies and outcomes.
The tables and figures throughout the chapter are highly complimentary
to the text. To estimate the size of the population at risk is an
important determinant, but will need to incorporate the appropriate
parameters.

In summary, this is an excellent chapter. Since the standard has not
changed since its original inception in 1969-71, if the potential
decision by EPA in the REA is to suggest changes in the standard to
promulgate a 5-10 minute peak or 1-hour maximal level of SO~2~, this
potential to recommend a very different standard from the current
standard needs to be clearly justified in this chapter or in the REA.

Specific comments:

Page 4-2, line 26: please state the meaning of sRaw in the text

[]{#__RefHeading___Toc205963125 .anchor}**Dr. Edward M. Postlethwait**

Comments on SOx ISA -- 2^nd^ Draft

The second draft of the SO~x~ ISA is clearly improved. Suggested points
for consideration include:

1\. Much of the document focuses on the potential impacts of short term,
relatively higher concentration exposures. In this regard, it is
important to describe and/or illustrate the characteristics of short
term spikes. This may be important for exposure/risk predictions since
it is assumed that 5-10 minute exposures will be modeled as steady state
exposure conditions but in the real world such spikes may, for example,
be very sharp rather than the square wave exposure patterns that are
generally employed in most human clinical investigations.

2\. Do the tables which include compilations of relative risks computed
from population studies include points which are not statistically
significant? If so, then there may be an unintentional bias in
representing potential health impacts. If none significant results are
to be presented, they should be identified as such to appropriately
inform the reader.

3\. While the human clinical studies of asthmatics show apparent
thresholds at SO~2~ levels between 0.4 and 0.6 ppm, other data may
suggest that some individuals may respond at lower concentrations. Thus
it is recommended that predictive estimates utilize concentrations below
the proposed benchmark 0.4 ppm level.

4\. The above highlights an appreciable challenge for conducting risk
estimates in that some population studies suggest effects occur at
levels well below those observed during clinical studies. The ISA would
clearly be strengthened by an improved integration/synthesis regarding
the potential genesis of effects threshold differences, especially since
the chapter on dosimetry clearly describes that \> 90% of inhaled SO~2~
is scrubbed in the upper airways so that during environmentally relevant
exposures only very small amounts of SO~2~ would penetrate to anatomic
regions involved in bronchoconstrictive events. Thus at least an attempt
to clarify the apparent discrepancies is warranted.

5\. The concluding language in the various health effects sections
relating exposures to the various biological endpoints of interest would
be strengthened by more internal consistency. For example, it is stated
that there is sufficient evidence "to infer a causal relationship
between respiratory morbidity and short-term exposure to SO~2~", which
is unequivocal based on clinical studies. However, in other sections
statements regarding causality have the caveat "at current ambient
levels." Thus, while asthmatics, and likely most individuals, will
respond at some threshold exposure level, whether this occurs at
[ambient]{.underline} levels is not consistently addressed. Because of
the dearth of more current data and the confounding associated with
multipollutant exposures in population studies, the ISA would benefit by
more thorough discussion of the potential for SO~2~ to induce biological
effects versus those effects that are/can be detected under ambient
conditions.

[]{#__RefHeading___Toc205963126 .anchor}**Dr. Jonathan M. Samet**

Comments on SOx 2nd Draft ISA

[General Comments]{.underline}:

[Overview]{.underline}:

This second draft Integrated Science Assessment (ISA) has been redrafted
following the initial review by CASAC. Along with the draft ISA for
Nitrogen Oxides, it represents the second use of the new evidence review
approach by the Environmental Protection Agency. As such, it remains
critical that a useful model be established for future reviews.

In this regard, I still find the second draft ISA to be deficient. While
changes have been made, the approach to evidence identification, review,
and synthesis remains inadequately specified. In the revised Chapter 1,
while the Agency has begun to more formally set out criteria for
evidence evaluation and standard approaches for classifying the strength
of evidence for causation, the overall approach still needs development
and its application in the subsequent chapters of the ISA is not
sufficiently thoughtful. My responses to the charge questions follow:

[Question 1]{.underline}:

This question asks whether the framework set out in Chapter 1 is
appropriate and adequately applied, and whether the Agency's approach
for causal inference needs to be strengthened. The Agency, in developing
its approach, has relied on a number of recent reports that offer
models, including the approach taken in the Surgeon General's Reports
and the conceptual framework set out in the recent Institute of Medicine
document, *Improving the Presumptive Disability Decision-Making Process
for Veterans*. These documents along with the others that are cited do
provide useful approaches. The Agency's adoption of a five-level set of
descriptors of strength of evidence is appropriate and should prove
useful for decision-making based on the degree of certainty provided by
scientific evidence considered. Through its application, the Agency will
be able to refine the review and synthesis process and, in particular,
set precedents for responding to evidence reaching different levels of
certainty for causation. For example, would evidence reaching the
"suggestive" level be a sufficient foundation for altering a NAAQS?

There are still limitations of Chapter 1, however. The discussion of
association versus causation is not well formulated and the authors are
not clear in discussing key concepts that affect interpretation of
epidemiological data. For example, confounding and effect modification
are addressed rather superficially, as is measurement error. I urge the
staff to continue to refine this material, because it will become a
model for future ISAs. The authors comment on the complexity of
determinants of health and of response to an environmental agent, such
as sulfur dioxide. However, their approach to doing so is limited and
Figure 1-1 is presented with little explanation.

The discussion of uncertainty is brief and needs expansion. A more
systematic approach to describing uncertainty would be useful, both
around determination of causation and with regard to the quantification
of effect. This important issue is handled in only one page.

I was concerned by the application of the approach for causal inference
in subsequent chapters. The discussion is limited around evidence
synthesis, particularly in Chapter 3. There needs to be a better
template for assuring standardization of discussion of the strength of
evidence.

[Charge Question 4]{.underline}:

The revised Chapter 4 adequately sets out the quantitative information
from the human clinical studies. The plots are clear in showing the
observed concentration-response relationships. The epidemiological data
are also described, although the findings cannot be so readily
summarized.

The chapter offers definitions of "susceptible" and "vulnerable" that
need some strengthening. Is a susceptible population as defined or one
that has a steeper exposure-response relationship than a non-susceptible
population? The definition given here emphasizes response at a lower
concentration than in the general population. The distinction between
susceptibility and vulnerability lies in a greater biological response
for susceptible individuals and a greater risk for exposure (higher
exposure?) in a vulnerable population. Later in the chapter this
distinction becomes blurred.

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

  --------------------------------------------------------------------------
  **Page   **Line   **Comment**
  \#**     \#**     
  -------- -------- --------------------------------------------------------
  1-5      1        Need introduction here that a hierarchy of evidence may
                    be identified and that for some pollutants human
                    clinical studies may provide the most compelling
                    evidence, e.g., CO, but not for all, e.g., PM.

  1-5      6        Delete "can"

  1-5      8        A panel study is a cohort study

  1-5      9        "...occasionally in epidemiology:" and offer the
                    opportunity to investigate a change in exposure.

  1-5      15       "species" and the model used

  1-6      5        "The results are" delete and substitute "observed risk
                    represents"

  1-6      8        The alternatives are chance and bias

  1-6      8        "subjects in a population" usually volunteers

  1-7      3        Randomization needs better description: of exposure
                    (pollutant [vs]{.underline} sham or of people (pollutant
                    or sham).

  1-7      6        Delete randomness, substitute "the role of chance"

  1-7      16       "Nutritional deficits" Such as?

  1-7      17       "from epidemiological studies" Not inferred from epi
                    studies alone.

  1-7      19       Delete statistical

  1-7      24       Delete "with", substitute of

  1-7      25       Effect modification can also be examined with models

  1-8      1        "possible mechanisms" and the distributions of these
                    factors in the population under study.

  1-8      4        "In multivariate analyses..." true? On what basis?
                    References?

  1-8      10       But not necessary

  1-12     10       Delete "the absence of", Substitute not meeting

  1-13     1        "recent publications" All relevant?

  1-14     19       "The complex molecular and..." What does this mean?

  3-1      7        Delete "nature", substitute role

  3-1      21       May provide evidence

  3-2      9        And to precisely characterize exposure/response

  3-2      23       Delete "test", not a test-an application

  3-3      2        "thus, ~~attempts~~ results of models that attempt to
                    distinguish

  3-3      11       Delete errors, substitute problems

  3-3      14       Why?

  3-3      22       "reliability" or validity?

  3-8      25       How were studies selected?

  5-2      20       "led to the conclusion that ~~it~~" Substitute the
                    evidence.

  5-2      26       ~~The,~~ substitute An immediate response

  5-2      27       "bronchoconstruction, ~~this response is mediated"~~

  5-3      1        Depending on concentration

  5-3      8        "human clinical studies (finding reporting of
                    ~~reporting~~ respiratory symptoms)"

  5-3      12       "5-20%" Of asthmatics

  5-4      24       "internal coherence" What is this?

  5-6      6        How do they provide plausibility?

  5-9      12       "much uncertainty remains" What does this mean? What
                    kind of uncertainty?

  5-11     17       "Individuals in, substitute having a chronic"

  5-12     4        "data support the finding..." Not the proposed language
  --------------------------------------------------------------------------

[]{#__RefHeading___Toc205963127 .anchor}**Dr.** **Richard Schlesinger**

Comments on SOx ISA -- 2^nd^ Draft

Overall, the 2^nd^ draft improves on the 1^st^ in integrating the
various disciplines. However, there is still room for improvement in
some of the sections as noted below. In many cases, the various
disciplines are not really integrated but rather separate discussions of
each are just placed in the same section. A true integration would
interweave the epi with mechanistic support from the controlled studies.

 The inclusion of a section on mixtures, i.e., 3.1.5, is an improvement,
but it is not clear why that section was placed where it was. I think
that a section on mixtures and the potential for interaction related to
all health outcomes from SO2 for all exposure scenarios should be
developed and placed at the end of the chapter prior to the Conclusions.

Table 5-3 is excellent and provides a very nice summary overview of the
conclusions of the ISA and comparison to the previous Criteria Document.

Specific Issues

> 1\. Section 3.1.3 is titled, Respiratory Effects Associated with Peak
> Exposure. In reality, this is a discussion of studies that involve
> exposures for 1 hr or less to single levels of SO2 without any
> baseline in animal and human clinical evaluations. Thus, the use of
> the term peak may be misleading since this may imply some higher level
> relative to some lower baseline. This section should also be
> renumbered as follows:
>
> 3.1.3.1    Clinical Studies
>
> 3.1.3.2  Animal Studies

 

> 2\. Section 3.1.4 discusses Epi studies and this should be reflected
> in the section heading. Furthermore, lines 7-21 on page 3-17 should be
> moved to section 3.1.2.

 

> 3\. Section 3.1.4.3 is an attempt to integrate animal, human clinical
> and epi studies.

 

> 4\. Page 3-48, lines 15-17. The inconsistency may be due to the fact
> that the specific nature of the interaction may depend upon the
> specific co-pollutant.

 

> 5\. Section 3.1.6 seems to be out of place here. Perhaps the material
> could be integrated into other sections.

 

> 6\. Section 3.2. title should perhaps read "systemic" rather than
> "other."

 

> 7\. The conclusions in section 3.2.2.are not totally consistent with
> the statements made on page 3-59, lines 24-27. In one case, the
> evidence is noted as inconsistent while in the other it is noted to be
> inadequate.

 

> 8\. On page 4-1, add "and vulnerable" following susceptible on line
> 10.

 

> 9\. The comment on page 4-12, lines 1-2, that epi studies suggest that
> people with preexisting respiratory diseases are more susceptible to
> effects from SO2 contradicts the comment on page 4-11, lines 12-13.
>
> 10.      The sentence on lines 17-19 on page 4-20 is not clear. 

[]{#__RefHeading___Toc205963128 .anchor}**Dr.** **Christian Seigneur**

Comments on SOx ISA -- 2^nd^ Draft

**Charge Question 2. *Have these revisions to Chapter 2 improved its
assessment of the currently available scientific knowledge on
atmospheric sciences and exposure and its relevance to the evaluation of
human health effects presented in later chapters?***

The second version of the ISA for the health criteria of sulfur oxides
shows significant improvements compared to the first draft version.
Comments made last year on the discussion of the physico-chemical
processes that govern the evolution of sulfur oxides in the atmosphere
have been addressed in this revised version. Therefore, the following
comments on the second version tend to address points of detail or
clarification rather than fundamental issues.

**Chapter 2. Source to tissue dose**

Section 2.2, p. 2-3: "Because the saturation vapor pressure of H~2~SO~4~
is extremely low, it will be removed rapidly by transfer to the aqueous
phase of aerosol particles and cloud drops". This is true only if
aqueous particles or cloud drops (or fog droplets) are present. For
example, under dry conditions, gaseous sulfuric acid may be transferred
to particles to form dry particulate ammonium sulfate.

p\. 2-20: The SO~2~ and sulfate concentration maps shown in Figures 2-8
and 2-9 originate from the CASTNET data using some spatial interpolation
methodology. Note that EPA's Clean Air Market Division (CAMD) has
developed some data fusion approach that combines the CASTNET data with
a CMAQ simulation to produced concentration maps that are improved
compared to the simple CASTNET interpolation maps (CAMD contact: Melissa
Rury).

Annex B

CTMs are sometimes referred to as chemistry-transport models (e.g., p.
B-15, line 1), sometimes as chemical-transport models (e.g., Title of
Section B-5). It may be preferable to use a single term throughout the
document.

p\. B-7, lines 12-13: The statement that transportation related sources
only have a minor contribution to SO~2~ ambient levels suggests a strong
east-coast bias. In California, where point sources have low SO~2~
emissions compared to the eastern U.S., ships can be a major
contributing source to SO~2~ concentrations. As a matter of fact, it
would be appropriate to highlight the recent State of California
regulation on sulfur content authorized for diesel fuel of ships that
are within the proximity of the Californian coast.

p\. B-17, line 6: The Weather Research & Forecast (WRF) model is now the
preferred meteorological model; add it in the parentheses before RAMS.

p\. B-22, line 14: The discussion points out that a plume-in-grid
treatment affects the simulation results for ozone concentrations. This
effect is due to the improved treatment of the NO~x~ emissions when
using a subgrid-scale representation of major point sources. In reality,
the plume-in-grid treatment redistributes the ozone concentrations with
little effect on the overall ozone budget (e.g., Karamchandani et al.,
Development and application of a state-of-the-science plume-in-grid
model, *J. Geophys. Res*., **107**, 4403-4415, 2002). Since the document
focuses on SO~x~, it should be noted that a plume-in-grid treatment of
SO~x~ (and NO~x~) emissions has a significant effect on secondary
sulfate (and nitrate) formation that may lead to up to 15% less sulfate
(or nitrate) formation from those major point sources treated with a
subgrid scale representation within the 3-D grid-based model
(Karamchandani et al., Plume-in-grid modeling for particulate matter,
*Atmos. Environ*., **40**, 7280-7297, 2006).

p\. B-25: It is true that compensation of errors may lead to good model
performance for the wrong reasons and that the performance evaluation of
individual model components is desirable. Therefore, it would be
appropriate at this point to mention the effort made to evaluate the
aqueous chemistry component of SO~x~ models either in the laboratory
(Waltrop et al., *J. Atmos. Chem*., **12**, 1-17, 1991) or in the
atmosphere (Daum et al., *Atmos. Environ*., **18**, 2671-2684, 1984).
Also, the evaluation of reactive plume models against aircraft data
should be addressed.

p\. B-25: This section only discusses regional and global CTM for SO~x~
and does not present any information on plume dispersion models that are
used to estimate local (e.g., within 50 km) impacts of major SO~x~
emission sources. Since a plume dispersion model (AERMOD) will be used
to conduct the Risk and Exposure Assessment, it is desirable to have a
section in the Annex that presents this type of models, their
limitations and available performance evaluation results.

**Dr. Frank E. Speizer**

Comments on SOx ISA -- 2^nd^ Draft

Chapter 1 :

Page 1.6, Figure 1-1. I do not find this particular figure that useful.
Perhaps Gee & Payne-Sturges, 2004 have sufficient text that accompanies
the figure to make it useful, but simply putting it out without adequate
descriptors do not help. I could imagine many of the arrows going in
both directions if not in opposite directions. My suggestion would be
either to expand the text of abandon the figure.

Page 1-6, section 1.3.3 the first sentence I this section needs to be
modified. There is another alternative way of stating what is being
said. After all there are no clinical studies of tobacco smoke and lung
cancer. The studies are all epidemiological "association" studies. But
the consistency and reproducibility and the magnitude of the
associations are so overwhelming that there are no alternative tenable
explanations (there were early on but these have all but gone away).

Page 1-14, last box in table from previous page. I think it would be
worth putting a limit on "any level of exposure" Perhaps something like
reasonable level or at least in human non-toxicological levels.

Page 1-15 end of section 1.3.8. Two issues that are not discussed here,
(will need to be addressed somewhere) but I thought should be part of
this overall assessment of causality are "uncertainty" and "margin of
safety". There are a various interpretations of each and laying out some
definitions, even if they might be different definitions used by
different people, would be useful. What constitutes a level of
uncertainty that is acceptable to all, 90% of regulators, 50% of
regulators etc? Similarly, are there percents of uncertainly that are
judged by advocacy groups that are different? With regard to margin of
safety ditto. Is it 20% margin, 50%, 100%, 500%. A discussion up front
in the document might be a useful exercise and might put CASAC, Staff,
and administrative policy makers all on same page.

Focus Question 1.

I think the cataloging of the descriptions of how causation might be
determined is reasonable. The issue really isn't how we generally
understand how epidemiology, clinical studies and animal toxicology data
are used. More important issues are the ones raised in my last point
above. I know there have been focus group discussions on the topic and
there may even be some published research on the subject. The more I
think about it the more important is seems to me that it be part of this
chapter. Adding this material would substantially change the discussion
and perhaps aid in what will be a difficult discussion is subsequent
chapters when causation gets interpreted in making recommendations for
standards.

Additional Comments related to other Chapters.

Figure 3-1, Page 3-12: This is an important figure that should be more
thoroughly discussed. The figure indicates, from one of the larger early
studies that there are marked discrepancies in the responsiveness of
individual subjects. About 25% of the subjects were essentially
unresponsive in terms of airway sensitivity below 2 ppm and another 25%
were responsive below 0.5 ppm. Thus, in assessing group data it is
obviously the case that within any group the responders and the
non-responders need to be considered separately if at all possible. In
this study of asthmatics, in which the presumption would be that the
response pattern would be random across the group, this clearly was not
the case. I am sure that I and others argued in the past that this
raises concern that in attempting to justify a short term standard the
fact that which 25% of the asthmatic population would be affected cannot
be determined prior to exposure argues for consideration in the setting
of a standard with an adequate margin of safety. I would contend that
25% of the population of asthmatics is a larger fraction of the most
sensitive population than one should be comfortable to ignore in setting
a short term standard. This argument did not win the day in 1994. The
data since that time has further established the issue that there are
what might be called "super sensitive" groups of people and the whole
issue of both what proportion of the population should be protected and
what the margin of safety should be will need to be revisited. In this
case margin of safety is not a surrogate for uncertainty of effect but a
measure of the size of the population to be protected.

In reaching a conclusion on page 3-46 the general impression is that the
evidenced is suggestive. However, not taken into account in reaching
these conclusions is the evidence that not all subjects within any given
population are equally sensitive to the impact of SO2. In my mind this
phenomena tips the balance that regulation of short term exposure is
necessary.

This point is made even more effectively in Section 4.1.1 on page 4.2-3
along with figure 4-1. Given that sRaw is measured as doubling and FEV1
change is measured as 15% decrease the range of changes from 0.2ppm to
0.6 is quite substantial and is consistent with a significant adverse
effect that will need to be modeled in the risk assessment.

A better job needs to be done in indicating that subgroups of subjects
appear to be more sensitive and may be driving the overall assessments
in any specific study. These subgroups appear to exceed 5% to 13% for
sRaw and FEV respectively, at the lowest levels of exposure tested (0.2
ppm). The lack of a threshold at these (relatively) high levels of
exposure as compared to "background of less than 15ppb makes
straightforward extrapolation uncertain. I am sure there are people who
are sensitive at these lower levels but finding an appropriate level and
population at risk will be difficult.

With regard to long term exposure and mortality the larger (and better)
conducted US studies are consistent but when assessed in the context of
all studies that might be interpreted as negative leave the impression
that the results are inconsistent and therefore no prudent declaration
of causal association can be made. This seems slightly off base as there
is adequate reasoning given as to why some studies might be positive and
some negative and one simply cannot sum the total of studies.

Summary and Conclusions Chapter

The conclusion about the "very few monitors" Page 5-2, line 16 suggests
that one strong recommendation in this chapter is that an expanded
network of monitors are needed. This may or may not be true depending
upon the distribution seen at existing monitors in that with a 1 hour
mean of 13ppb and a 99^th^ percentile value of 120-700ppb little
information is supplied other than the conclusion given that the max is
not contributing to the mean. Some full distributions might help lead to
the conclusion as to how much additional monitoring is necessary outside
potential known hotspots.

Having the key finding summarized and reproducing the summarizing tables
from the appendices is useful.

[]{#__RefHeading___Toc205963129 .anchor}**Dr.** **Lianne Sheppard**

Comments on SOx 2nd Draft ISA

*Overall assessment*: This document is much improved from the previous
version. Generally it flows better and more closely attains its goal of
presenting an integrated science assessment of SO2 and its effect on
health.

*Charge question 1*: The Chapter 1 framework is reasonable.

*Charge question 2*: Chapter 2 is better.

-   There is better characterization of the spatial distribution of SO2
    monitors, but the discussion is still lacking in the sense that
    there is no stratification of analyses by micro vs. neighborhood
    scale monitors. This is an important feature to take into account in
    the interpretation of epidemiological studies. What fraction of
    monitors in each area falls in these categories? How many areas with
    SO2 monitors lack any neighborhood scale monitors?

-   Section 2.5 is a good addition and a good effort was made in 2.5.4
    to discuss important features of exposure assessment for
    epidemiological studies. The availability of neighborhood scale
    monitors should be brought into this discussion, as well as the
    reactivity of SO2.

*Charge question 3*: Chapter 3 is much more readable and well organized.

*Charge question 4*: The revision to the concentration-response modeling
discussion is reasonable. Discussion of vulnerable and susceptible
groups is reasonable, but could possibly still benefit from a catalogue
(e.g. in a table) of all potential vulnerabilities and susceptibilities
that warrant consideration. The public health impacts section appears to
be incomplete. While the gradation of responses and the prevalence of
respiratory disorders tables are useful, these are not linked to provide
any inference about degree of public health importance of SO2 exposure
in the population.

*Charge question 5*: There is good integration in Chapter 5.

*Specific comments*: To be added.

[]{#__RefHeading___Toc205963130 .anchor}**Dr.** **George Thurston**

Comments on SOx 2nd Draft ISA

*1. The framework for causal determination and judging the overall
weight of evidence, is presented in Chapter 1. Is this the appropriate
approach? Is it appropriately applied in the case of SOx? How could the
framework or its application be refined?*

RESPONSE: Yes, I feel the staff has done an excellent job of properly
incorporating and explaining both the weigh of evidence criteria and the
causality inference framework.

*2. The discussion of the atmospheric chemistry of SOx has been expanded
to provide a*

*better characterization of the spatial heterogeneity of urban SO2
concentrations and*

*correlations of SO2 with other pollutants. We also included new
sections describing*

*the regulatory network and siting criteria with maps of SO2 and other
monitors. A*

*brief section describing the available 5-minute SO2 data was also
included. In*

*addition, the relationships between outdoor, indoor, and personal
exposure to SO2*

*were clarified with additional details on sources of exposure error.
Have these*

*revisions to Chapter 2 improved its assessment of the currently
available scientific*

*knowledge on atmospheric sciences and exposure and its relevance to the
evaluation*

*of human health effects presented in later chapters?*

RESPONSE: Yes, this is much improved, but I would like to see a better
representation of the trends in short-term SO~2~ concentrations (i.e.,
1-hr maximum). While there has clearly been improvement in annual
average SO~2~ concentrations, as would be expected given the advent of
the acid rain control program, these efforts have focused on lowering
overall tons of SO~2~ emissions, and not on lowering maximum impacts. So
the question remains, have we seen a reduction in peak SO~2~ exposures
near major sources? As such, I would ask that plots of the distribution
of 1-hour maximum values (for which many more sites are available than
for 5-minute peaks) over time to better elucidate how much improvement
we are making in lowering peak SO~2~ exposures.

Another issue I have with Chapter 2 is the inadequate coverage of the
PM-SO~2~ interaction, and the potential for the co-presence of PM to
increase lung dosage and health effects of SO~2~ over and above that
indicated by controlled animal and human populations using pure SO~2~
gas, without associated PM (which would be the case in the real world).
While the document includes research by Amdur on page 2-60, it does not
include her work very clearly showing the way that co-presence of PM
along with SO~2~ increases the impact of acute SO~2~ exposure. While
these studies are discussed in Chapter 3, they are probable even more
important to mention here as well, as they are important to our
understanding of SO~2~ doses in the real world. Now, while SO~2~ has a
relatively low Henry's law constant, and it might therefore be expected
that little will be stored as sulfite in the aqueous phase in a
naturally occurring aerosol, but the Amdur studies conversely imply that
this SO~2~-PM interaction is a strong one, so the document needs to more
thoroughly investigate this mechanism, and better sort out its possible
role in enhancing the effects of ambient SO~2~. This might very well be
an important consideration in trying to extrapolate from controlled
studies to effects in populations, as, if ignored, it may well mean that
the human health effects of elevated SO~2~ exposures will be
underestimated, and the SO~2~ concentrations required for a response
would be underestimated, as well. This consideration also points to the
greater relevance of using epidemiology for risk assessment, rather than
controlled exposures to subjects, since epidemiology will have already
incorporated such PM-SO~2~ interactions that happen in the real world,
but not in controlled exposure environments lacking PM.

3\. *In the revision, we reduced redundancy, added summary sections and
reorganized*

*Chapter 3. In addition, discussions on potential confounding by and
interactions with*

*copollutants have been added. The 2nd draft ISA also includes
additional analyses of*

*individual-level data from human clinical studies (Sections 3.1.3. and
4.1.1) that*

*builds upon the analysis included in the 1994 Supplement to the Second
Addendum.*

*The toxicology sections were reorganized to focus on studies using more
relevant*

*concentrations of SO2 and sections were added to better discuss mode of
action and*

*potential particle-SO2 interactions. We are requesting CASAC review
specifically on*

*these analyses as well as on the integration of the overall evidence
from the human*

*clinical, animal toxicological, and epidemiological studies.*

RESPONSE: While this section makes advances, Section 3.1.5.2.5 is wholly
inadequate. It ignores the major implication of these interactions: that
exposure studies that do not include the potentiating effects of PM on
SO~2~ exposures will very likely have both underestimated the size of
SO~2~ effects and the overestimated the SO~2~ levels at which such
effects may be experienced in the co-presence of particles (i.e. in the
real world).

4\. *The section on concentration-response relationships in Chapter 4
was reorganized and revised to include analysis of individual-level data
from the human clinical studies*

*and some additional discussion of the difficulties of discerning a
threshold in*

*population-level data. In addition, revisions were made to better
characterize groups*

*likely to be susceptible or vulnerable to SOx and the potential size of
the population at*

*risk for SOx-related health effects. Finally, revisions were made to
reduce*

*redundancy with material presented in Chapter 3. Have the revisions
made to*

*Chapter 4 improved the characterization of the potential public health
impact of SOx*

*exposure?*

RESPONSE: Again, in this chapter, there is little acknowledgement of the
fact that many of the clinical and animal studies were done using pure
SO~2~, without co-PM exposures, as would occur in the real world. This
is especially critical in section 4.3.2, where the clinical studies are
used to indicate benchmarks of effects. Such a choice of levels at which
various effects would occur must take into account the documented
effects that PM would have on the size and threshold of effects by
SO~2~. For example, based on the work of Amdur and others, a
conservative factor to adjust for the copresence of PM might well be
applied to estimate the levels at which such clinical symptoms might
occur in the real world.

5*. Revisions were made to better integrate findings from atmospheric
sciences, ambient*

*air data analyses, exposure assessment, dosimetry, and health evidence
in Chapter 5.*

*To what extent do these findings support conclusions regarding
causality of SOxrelated*

*health effects at relevant exposures?*

RESPONSE: The big issue that needs more discussion is why the
epidemiology shows health effects associations at much lower
concentrations than do the clinical studies. The paragraph at the top of
page 5-11 does discuss one likely explanation of this apparent paradox:
the effects of the fact that "aerosol particles act as carriers and
deliver sulfur-containing compounds more effectively to the lower
respiratory tract". However, more discussion is needed here of the fact
that this may well account for why epidemiological associations are
found at SO~2~ concentrations well below where effects are documented by
clinical studies using pure SO~2~ exposures.

[]{#__RefHeading___Toc205963131 .anchor}**Dr.** **James Ultman**

Comments on SOx ISA -- 2^nd^ Draft

**General Comments**

This second draft of the ISA provides a significant improvement over the
first draft, both with respect to content and chapter organization.

Apparently, the framing questions that originally appeared on page 1-2
in the first draft of the ISA have been deleted from the second draft.
The answers to several (but not all) of these questions can be culled
from the final "Conclusions" section on page 5-12 of the revised
document. Given the importance of these questions in informing the REA
as well as the final rulemaking, EPA staff should consider reinserting
the questions into Chapter 1 and then explicitly answering them in
Chapter 5.

**Comments on Chapter 2 and Charge Question #1**

[General]{.underline}

A major improvement in this chapter is the new material on monitor
locations, particularly those 108 sites where 5-minute averages have
been recorded.

I am, however, puzzled by the statement on lines 1-2 of page 2-32 that:
"Although these 5-minute data meet AQS minimum quality assurance
requirements...these data (are) very difficult to use precisely." This
appears to be the rationale for not including any actual data from these
sites in the document.

In fact, this very set of data, is used in the first draft REA to model
the relationship between peak and short-term ambient SO2 concentrations.
I suggest that disconnect between the ISA and REA be remedied by
including some data, in either a tabular or graphical form, regarding
the peak and 1-hour short-term concentration data obtained from the
monitors listed in tables 2-6 and 2-7. Is it possible, for example, to
examine and compare the relationships between the two concentration
averages over time at various sites?

The text indicates that ambient monitors are allowed to be sited at any
vertical location between 2 and 15 meters above the ground (pg. 2-9
lines 3-4). Yet, there is vitually no discussion of vertical SO2
gradients nor the errors such gradients introduce when using ambient
concentration as a surrogate for ground-level concentration. For
example, ground-level concentrations near point sources will be much
lower than concentrations recorded from monitors high off the ground. It
would be beneficial for the ISA to provide a better qualitative and
quantitative appreciation of this.

[Specific Comments]{.underline}

**Page; lines**

**2-3; 10 &12** Define terminology (OH for hydroxyl free radical and
HO~2~ for hydroperoxyl radical) immediately after the equation in which
they first appear.

**2-9; 3-4** How large a difference between monitored concentrations is
a variation of 2-15 m difference in monitor height likely to introduce?
How does this difference depend on distance to the point source?

**2-14; 1** Make sure that SLAMS and NAMS acronyms have been previously
defined.

**2-23; 9** I assume that you mean "the Pearson correlation coefficients
(r) for [concentration data from multiple monitors taken as
pairs]{.underline} in these CMSA's..."

**2-26; 9-11** 104 sites +15 sites is greater than the total of 108
sites mentioned in the previous sentence.

**2-41; 5** Given the importance of exercise in promoting health effects
in asthmatics, it is important that this be included as a personal
activity in this list.

**2-41;17-21** Incomplete, run-on, sentence.

**2-58; 14** For clarification, it would be helpful to add a phase
indicating that the Henry's Law constant is inversely proportional to
solubility.

**One-way flow versus cyclic flow\-\--**

**2-59; 4-5** What the text refers to as "total respiratory tract
absorption" is presumably the retained dose of SO2 over a complete
respiratory cycle.

**2-59;** **18-20** In these experiments, the upper airways were
isolated from the lower respiratory tract, and absorption was measured
during one-way flow (as opposed to the bidirection flow that occurs
during a complete respiratory cycle). This was also the case for other
investigations that are cited later on pages 2-59 and 2-60.

**2-63; 6-8** It is precisely because of desorption during exhalation
that cyclic flow experiments report smaller absorption efficiencies than
one-way flow experiments. This explanation should be worked into the
discussion.

[]{#__RefHeading___Toc205963132 .anchor}**Dr. Ronald E. Wyzga**

Comments on SOx ISA -- 2^nd^ Draft

**Charge question 3**: In the revision, we reduced redundancy, added
summary sections and reorganized Chapter 3. In addition, discussions on
potential confounding by and interactions with copollutants have been
added. The 2^nd^ draft ISA also included additional analyses of
individual-level data from human clinical studies (Sections 3.1.3 and
4.1.1) that builds upon the analysis included in the 1994 Supplement to
the Second Addendum. The toxicology sections were reorganized to focus
on studies using more relevant concentrations of SO2 and sections were
added to better discuss mode of action and potential particle-SO2
interactions. We are requesting CASAC review specifically on these
analyses as well as on the integration of the overall evidence from the
human clinical, animal toxicological and epidemiological studies.

**Response to charge question**: By and large I applaud the efforts
undertaken in the revision. It increases the presentation and discussion
of the human clinical studies, which I believe are extremely informative
about the health effects of SO2. The focus is clearly upon respiratory
responses, especially among asthmatics. I previously had sent the Agency
staff several papers of human clinical studies, which have hopefully
aided in this effort. They provide comprehensive input to aid our
understanding of responses of asthmatics exposed to SO2 in the chamber.
To some extent the results presented in the ISA could have been extended
to indicate the importance of other factors, such as the influence of
routine asthma medication and weather upon response.

I believe the document was largely successful in integrating results
across scientific disciplines although I note that several highlighted
toxicological studies do utilize exposures orders of magnitude higher
than those which occur in the ambient environment. (e.g., 0.8-6mg/m3 and
1-2ppm SO2). Special note should be made of the fact that these
concentrations are extremely high and not representative of those that
occur in the real world. The copollutant issue in epidemiological
studies is a difficult one to address largely because few studies
address this issue systematically, making it difficult to resolve this
issue definitively. I would urge the document to ask for more systematic
investigation of this issue within individual studies.

**Overall comments**: This document is substantially improved over the
previous draft; it considers the informative human clinical studies in
more detail and correctly focuses upon respiratory health, especially
asthma issues. I believe that relatively small changes in the document
are needed. I give my specific comments below, which generally ask for
further clarification or greater articulation of the presented material.

**Specific comments**:

p\. 2-23, ll. 9-20: perhaps some discussion about the dependence of
exposure to SO2 on whether an individual (monitor) is in the plume from
a point source is warranted.

p\. 3-11; ll. 7-18: Another reason for the similarity in response
between mild and moderate/severe asthmatics is that the latter were not
able to exercise as intensely as the mild asthmatics. It should also be
noted that studies (e.g., Gong et al., 1996; Gong et al/. 2001; Linn et
al. 1988) have shown that medicated asthmatics were not sensitive to SO2
exposure.

p\. 3-15, ll. 11: insert "exercising, non-medicated" before asthmatics.

P. 3-16, l. 3: Linn et al., 1983 reported a significantly increased
response among asthmatic subjects utilizing a mouthpiece for exposure as
opposed to those with unencumbered breathing. This reference can be
cited here.

p\. 3-35, l. 10: "statistically"

p\. 3-43, ll. 10-19: Systematic examinations of the potential influence
of co-pollutants on study results are rare. Studies often consider a
limited set of co-pollutant with no discussion about why other
co-pollutants are not considered. It would be useful to indicate the
need for more systematic review of this issue within a study.

p\. 3-45, ll. 1-7: It should be noted that the panel studies found
responses at ambient levels only when asthmatics were exercising.

p\. 3-46, l. 31: reference should be given.

p\. 3-47, ll. 14-20: It should be noted that exposure was by mouthpiece.
See comments for p. 3-16.

p\. 3-49, ll. 16 and following: It should be noted that the exposure
levels in the studies cited in this section were extraordinarily high.
This comment applies to section 3.15.2.5.

p.  3.55, ll. 21-22: It should be noted that controlled human studies
    did not find responses in adult atopics. (Linn et al., 1987).

p\. 4-2, l. 1: Measurement error can also serve to linearize
dose-response estimates.

p\. 4.4, ll. 10-11. See comment for page 4-2.

p\. 4-11, ll. 4-13: It might also be noteworthy to indicate that
asthmatics on routine medication do not appear to respond to SO2 while
exercising.

[^1]: ^\*^ Did not participate in the July 30-31, 2008 review of the
    second draft ISA.