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 subjectmatter-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 SO2. 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

SO2. 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 SO2 Primary National Ambient 

Air Quality Standards (July 2008), EPA chose a range of 0.4 ppm – 0.6 ppm SO2

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? 

ii
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 SO2 concentrations, a more 

comprehensive discussion of the available 5-minute SO2 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 SO2 ambient 

concentrations. The fact that the trend in SO2 concentrations is due to changes in SO2

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 SO2 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 SO2 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 SO2 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 

SO2 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 SO2 is inhaled via nasal vs. 

oral breathing makes a difference for SO2 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 

iii
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. 

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 SO2 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 SO2 and discussion of this point should be expanded in the 

chapter. The potential influence of medication use on asthmatic responses to SO2 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 SO2 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-SO2 mixtures suggest that SO2 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 doseresponse 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. 

iv
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 

SO2; 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 SO2 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 

SO2. 

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 SO2

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 SO2 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. 

v
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 SO2. 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 SO2 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 

vi
Enclosure A

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,

*

 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 

 

*

 Did not participate in the July 30-31, 2008 review of the second draft ISA. 

i 
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. 

ii
Enclosure B

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 

Dr. John Balmes................................................................................................................ 5 

Dr. Doug Crawford-Brown.............................................................................................. 9 

Dr. Terry Gordon............................................................................................................ 13 

Dr. Dale Hattis................................................................................................................. 15 

Dr. Donna Kenski............................................................................................................ 18 

Dr. Patrick Kinney.......................................................................................................... 21 

Dr. Steven Kleeberger .................................................................................................... 24 

Dr. Timothy Larson........................................................................................................ 26 

Dr. Kent Pinkerton ......................................................................................................... 32 

Dr. Edward M. Postlethwait .......................................................................................... 35 

Dr. Jonathan M. Samet .................................................................................................. 37 

Dr. Richard Schlesinger ................................................................................................. 40 

Dr. Christian Seigneur.................................................................................................... 42 

Dr. Lianne Sheppard ...................................................................................................... 47 

Dr. George Thurston ...................................................................................................... 48 

Dr. James Ultman ........................................................................................................... 51 

Dr. Ronald E. Wyzga...................................................................................................... 53 
 Mr. Ed Avol 

Comments on SOx ISA 2nd Draft 

Question 1 (a modified Chapter 1 on the framework for causal determination)

The continuing EPA-and-Clean-Air-Act self-imposed restriction to consider individual 

pollutant effects (in this case, SO2 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 stimulators) 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-bypollutant 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 SO2)

The additional sections about monitoring information are useful in developing an overall 

appreciation for the historical monitoring network and nationally downward trend in SO2

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)

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), SO2 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)

This revised description of the public health impacts of SO2 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 SO2? (2) Is 

2
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 SO2. 

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 subgroups), 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 

3
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)

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 SO2 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 SO2? 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. 

4
Dr. John Balmes 

Comments on SOx ISA -- 2nd 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 

5
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. 

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 higher in the 

winter months (mean 25.7 ppb [SD 15.8]) than 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 few studies provide results for respiratory health outcomes other than 

asthma and COPD, and these results are mixed.” 

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 resistance are in concordance with the limited epidemiological study 

results of Taggart et al. (1996) that showed SO2-induced increases in AHR among 

asthmatic adults. 

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. 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. Dose-dependent decreases... and above were also 

observed.” 

6
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

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 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 long-term exposure to ambient SO2 has 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 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 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 was observed for an index of three gaseous 

pollutants NO2, SO2, CO).” 

7
p. 3-105, line 2 The Japanese study discussed in the 1986 Secondary Addendum

should be cited. 

8
Dr. Doug Crawford-Brown 

Comments on SOx ISA – 2nd 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 

9
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 

10
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. 

11
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. 

12
Dr. Terry Gordon 

Comments on SOx 2nd 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 SO2. 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?). 

13
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 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/m3

 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. 

14
Dr. Dale Hattis 

Comments on SOx ISA – 2nd 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. 

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 

15
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, Vol. 21(4), pp. 585-

599 (2001). 

16
Figure 1 

-2 -1 0 1 2

-1

0

1

2

Lognormal Plot of the Distribution of Individual Sensititivities 

(SO2 Concentrations Needed to Double Specific Airway

Resistance) For 27 Exercising Asthmatics (Horstman et al. 1986)

Z-Score

Log(ppm SO2)

y = 0.0189 + 0.374x R^2 = 0.934

 

17
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. 

2-2 1st 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 openpath 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? 

18
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. 

2-26 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? 

 

2-47 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 

19
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. 

20
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 lowestobserved 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. 

21
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. 

22
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. 

23
Dr. Steven Kleeberger 

Comments on SOx 2nd 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 

24
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”?

25
Dr. Timothy Larson 

Comments on SOx ISA 2nd 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 

26
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. 

27
Dr. Ted Russell 

Comments on SOx ISA -- 2nd Draft 

The 2nd 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 onehour 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 fiveminute maximum can be well approximated as a function of the one-hour maximum and 

associated GSD. 

Page 1-1, line 12: monomeric, gaseous, 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 

28
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 SO2 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 

29
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 

30
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.

31
Dr. Kent Pinkerton 

Comments on Sox ISA – 2nd Draft 

General Comments: The second external review draft of the integrated science 

assessment document for Sulfur Oxides/Health Criteria is much improved over the 1st

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 SO2

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 SO2 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 2nd 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 SO2-induced decrements in lung 

function (FEV1) and specific airway resistance (sRaw) in asthmatics following limited 

(10 minute) exposure to SO2. An increasing proportion of asthmatic responders to 

increasing levels of SO2 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 SO2 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 SO2 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 

32
of safety to public health. Although data (especially the human clinical study) shows an 

increased response as SO2 levels are increased in a classical a concentration-response 

profile, a strong rationale needs to be made for not beginning at a maximal SO2

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 SO2. 

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 SO2 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 SO2 and a non-linear increase in the 

odds ratio as levels of SO2 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 SO2. 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 SO2 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 

33
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 

SO2, 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 

34
Dr. Edward M. Postlethwait 

Comments on SOx ISA – 2nd Draft 

The second draft of the SOx 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 SO2 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 SO2

is scrubbed in the upper airways so that during environmentally relevant exposures 

only very small amounts of SO2 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 SO2”, 

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 levels is not consistently addressed. Because of

the dearth of more current data and the confounding associated with multipollutant 

35
exposures in population studies, the ISA would benefit by more thorough discussion 

of the potential for SO2 to induce biological effects versus those effects that are/can 

be detected under ambient conditions. 

36
Dr. Jonathan M. Samet 

Comments on SOx 2nd Draft ISA 

General Comments: 

Overview: 

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: 

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. 

37
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: 

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 exposureresponse 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:

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

sham or of people (pollutant or sham). 

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

38
Page # Line # Comment 

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 

39
Dr. Richard Schlesinger 

Comments on SOx ISA – 2nd Draft 

Overall, the 2nd draft improves on the 1st 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. 

40
 

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. 

41
Dr. Christian Seigneur 

Comments on SOx ISA – 2nd 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 H2SO4 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 SO2 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 SO2 ambient levels suggests a strong east-coast bias. In California, where 

point sources have low SO2 emissions compared to the eastern U.S., ships can be a major 

contributing source to SO2 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. 

42
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 NOx 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 SOx, it should be noted that a plume-in-grid 

treatment of SOx (and NOx) 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 gridbased 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 SOx 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 SOx and does not 

present any information on plume dispersion models that are used to estimate local (e.g., 

within 50 km) impacts of major SOx 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. 

43
Dr. Frank E. Speizer 

Comments on SOx ISA – 2nd 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. 

44
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. 

45
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 99th 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. 

46
 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. 

47
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 SO2 concentrations (i.e., 1-hr maximum). While there has 

clearly been improvement in annual average SO2 concentrations, as would be expected 

given the advent of the acid rain control program, these efforts have focused on lowering 

overall tons of SO2 emissions, and not on lowering maximum impacts. So the question 

remains, have we seen a reduction in peak SO2 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 SO2 exposures. 

 Another issue I have with Chapter 2 is the inadequate coverage of the PM-SO2

interaction, and the potential for the co-presence of PM to increase lung dosage and 

health effects of SO2 over and above that indicated by controlled animal and human 

populations using pure SO2 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 SO2

increases the impact of acute SO2 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 SO2 doses in the real world. Now, while SO2 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 SO2-PM interaction is a strong one, so the document 

48
needs to more thoroughly investigate this mechanism, and better sort out its possible role 

in enhancing the effects of ambient SO2. 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 SO2 exposures will 

be underestimated, and the SO2 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-SO2 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 SO2 exposures will very likely have both 

underestimated the size of SO2 effects and the overestimated the SO2 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 SO2, 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 SO2. 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. 

49
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 sulfurcontaining 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 SO2 concentrations well below where effects are documented 

by clinical studies using pure SO2 exposures. 

50
Dr. James Ultman 

Comments on SOx ISA – 2nd 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

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. 

51
Specific Comments

Page; lines 

2-3; 10 &12 Define terminology (OH for hydroxyl free radical and HO2 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 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. 

52
Dr. Ronald E. Wyzga 

Comments on SOx ISA – 2nd 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 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. 

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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. 

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