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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C. 20460 

 

OFFICE OF THE ADMINISTRATOR 

SCIENCE ADVISORY BOARD 

June 25, 2008 

EPA-CASAC-08-015 

The Honorable Stephen L. Johnson 

Administrator 

U.S. Environmental Protection Agency 

1200 Pennsylvania Avenue, N.W.

Washington, D.C. 20460 

Subject: Clean Air Scientific Advisory Committee’s (CASAC) Peer Review 

of EPA’s Integrated Science Assessment (ISA) for Oxides of 

Nitrogen – Health Criteria (Second External Review Draft) 

Dear Administrator Johnson: 

The Clean Air Scientific Advisory Committee (CASAC), augmented by subjectmatter-experts to form the CASAC Oxides of Nitrogen Primary National Ambient Air 

Quality Standards (NAAQS) Review Panel (hereafter referred to as the panel, roster 

contained in Enclosure A) held a public meeting on May 1-2, 2008 to review EPA’s 

Integrated Science Assessment for Oxides of Nitrogen – Health Criteria (Second External 

Review Draft) (EPA/600/R-07/093aB, March 2008). The Chartered CASAC held a 

public teleconference on June 11, 2008 to review and approve this report.

 The Integrated Science Assessment (ISA) states (Page 1-1) that its purpose is to 

present a “concise review, synthesis, and evaluation of the most policy-relevant science” 

and to communicate the “critical science judgments relevant to the review of national 

ambient air quality standards for review of the primary standard for oxides of nitrogen 

(NOx).” Although the CASAC finds that the second draft ISA was much improved 

compared to the first draft reviewed in November 2007, the document in its current state 

does not provide adequate guidance as to what would be expected at current ambient 

concentrations. CASAC finds that scientific data exist with which to answer this 

question, albeit with some level of uncertainty, so that the document can provide an 

adequate scientific basis for the exposure and policy assessments during the next stage of 

the NAAQS review. Perhaps the most important consideration in improving the 

document is a much better discussion of the significance of the epidemiology data for a 

potential risk assessment, despite the uncertainties associated with those data. 

Incorporating an analysis of the available epidemiology data will allow estimation of the 

potential uncertainties that need to be fully described and quantified in the risk and 

exposure assessment. The ISA discussion should consider the effect of co-exposures to 
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other pollutants, the relationship between ambient and personal exposures, and how the 

problems associated with the available epidemiology studies limit their use for risk 

assessment. Because of EPA’s accelerated NAAQS schedule for NOx, CASAC may not 

have an opportunity to provide additional input for revising the ISA and so underscores 

its advice that the document be further strengthened to support the NAAQS review. 

Panel consensus comments on how the ISA might be further strengthened are 

given below in the form of responses to the Agency’s charge questions. Individual 

comments from CASAC panel members are enclosed in Enclosure B. 

Charge Question 1. What are the views of the Panel on the characterization of the 

search strategy for identifying literature, criteria for study selection, the framework 

for scientific evaluation of studies and causality determination? 

Substantial improvements have been made based on prior comments. The process 

for review of recent literature is reasonable and the results appear to be accurately 

reported. In regard to the Agency’s approach to synthesis of the evidence and causal 

inference, an extensive Annex has been prepared that reviews a number of relevant 

frameworks. The background is a useful foundation for informing the selected approach 

for assessing available evidence and should be extended to justify the adopted 

framework. Based on this Annex, the Agency has made changes in Chapter 1 that are 

responsive to prior critiques. In particular, there is a description of literature selection; an 

approach to evaluating evidence for inferring causality is provided; and a reasonable set 

of descriptors of strength of evidence for causation is offered. 

EPA has improved the second draft ISA by having a better prepared first chapter 

that includes the framework for the document. However, the sections that synthesize the 

evidence are still somewhat loosely written, and do not systematically apply the 

guidelines offered by Bradford Hill and adopted by the Agency. (Note, these should not 

be renamed as “decisive factors,” a misnomer). Too often, sections that are offering 

judgments as to the strength of evidence use such language as “taken together” or 

“integrating” without a more specific application of the criteria offered by Hill. 

Nonetheless, the revised Chapter 1 and the approach set out represents an advance over 

the earlier draft. 

Additional issues that are not considered are publication and model selection 

biases, a concern given that many studies address the health effects of air pollution and 

employ multivariable models to attempt to isolate the effects of particular pollutants at 

specific temporal or spatial scales. There may have been some tendency on the part of 

investigators to report positive associations or not to reflect the full health effect from 

such factors as multiple lags. 

A further issue in integrating the evidence is the substantial difference in the 

doses and mixtures of pollutants and their interactions given to animals or human 

volunteers in toxicology and clinical studies versus those experienced by the populations 

in epidemiology studies. Specific consideration needs to be given to the relevance of 

mechanisms identified in toxicology studies to effects observed in the epidemiology 

studies. 
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Charge Question 2. To what extent are the atmospheric chemistry and air quality 

characterizations clearly communicated, appropriately characterized, and relevant 

to the review of the primary NO2 NAAQS? Are the properties of ambient oxides of 

nitrogen appropriately characterized, including spatial and temporal patterns and 

relationships between ambient oxides of nitrogen and human exposure? Does the 

information in Chapter 2 provide a sufficient atmospheric science and exposure 

basis for the evaluation of human health effects presented in later chapters? 

Overall, the description of the atmospheric dynamics, measurement techniques 

and ambient concentrations is adequate, though aspects are still wanting. The document 

would benefit greatly by having summaries at the end of each section with the points 

most key to providing information that will be used in technical documents supporting 

the rulemaking for NO2, in particular those that inform the rest of the ISA and the 

risk/exposure assessment (REA) and delineate what matters. The Panel still views that a 

quantitative summary of sources would be beneficial. The REA relies heavily on the 

application of various modeling techniques, including AERMOD and an empirical 

approach for estimating on-road NO2 concentrations. Consequently, the needed 

background information on their scientific fundamentals, and their ability to reproduce 

observed concentrations, should be covered in the ISA. Along those lines, given the 

importance of on-road concentrations, that section of the ISA should be enhanced, with 

additional attention given to street canyon concentrations. Siting characteristics of 

monitors should be incorporated into all analyses of monitoring data. 

The Panel found that the section on measurement interferences continues to give a 

somewhat distorted picture of the importance of interferences. The implications of the 

interferences should be made explicit (i.e., by quantifying how much the interferences 

impact the peak NO2 levels and annual averages and identifying whether the interferences 

pose an important issue for exposure and epidemiology studies). Given the potential that 

the REA may depend more heavily on the epidemiology results, the ISA should more 

comprehensively assess how NO2 levels correlate with air quality variables besides 

particulate matter (PM) mass (either PM10 or PM2.5), ozone and sulfur dioxide, e.g., 

addressing the correlations with elemental carbon, organic carbon and other combustion 

products. It is known that carbon particles will adsorb NO2when they are exposed to high 

concentrations of the gas in the lab. EPA should consider the extent to which this may 

occur in the atmosphere.. 

In the last section on dosimetry, there is little progress to report on extrapolation 

modeling since the 1993 Criteria Document. Nevertheless, the established dosimetry 

models could be applied to the many of the key studies in the ISA, particularly to put 

response data collected from animals and humans on a comparative footing with each 

other and with the exposure conditions in the epidemiological studies. 

Charge Question 3. To what extent is the discussion and integration of evidence 

from the animal toxicology and controlled human exposure studies and 

epidemiologic studies technically sound, appropriately balanced, and clearly 

communicated? What are the views of the Panel on the conclusions drawn in the 
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draft ISA regarding the strength, consistency, coherence and plausibility of NO2-

related health effects? 

The second draft ISA is substantially improved in organization and content 

compared to the first draft. The revised document has addressed a number of the 

concerns expressed by CASAC. New publications from the scientific literature since 

1993 have been appropriately incorporated into this ISA draft. Substantial new findings 

have occurred since 1993 that are relevant to the issue of health risks related to oxides of 

nitrogen. These include animal toxicology studies, human clinical studies and 

epidemiology studies. Although the exposure concentrations in animal toxicology 

studies are typically well above ambient conditions, they do provide biological 

plausibility for adverse health effects that can be attributed to NO2. 

Panel members concur with the primary conclusions reached in the ISA with 

regard to health risks that are associated with NO2 exposure. In particular, the Panel 

agrees with the conclusion that the current scientific evidence is “sufficient to infer a 

likely causal relationship between short term NO2 exposure and adverse effects on the 

respiratory system.” The strongest evidence in support of this conclusion comes from 

epidemiology studies that show generally positive associations between NO2 and 

respiratory symptoms, hospitalizations or emergency department visits, as summarized in 

Figure 5.3.1. Furthermore, we would conclude that the epidemiology studies show 

significant effects related to NO2 exposure that are robust in some cases, even when 

adjusted for co-pollutants. One limitation of the available epidemiology studies, 

however, is an inability to establish a definitive NO2 exposure level that can be 

specifically associated with the observed adverse health effects. Consequently doseresponse relationships are difficult to establish for NO2, however best estimates and their 

uncertainties should be discussed. Separately and for future consideration, there is a 

recognized need to consider regulatory approaches to complex mixtures of air pollutants 

rather than considering each pollutant individually. 

The human clinical studies reviewed in the ISA need to be interpreted with 

caution. The lowest reported effect of NO2 exposure was found in three Swedish studies 

of airway responses to antigen challenge in allergic asthmatics. However, other human 

clinical studies have shown mixed results with some studies failing to find biologically 

significant health effects at similar or higher levels of NO2 exposure alone. In addition, 

although airway responses to antigen challenge can be considered an adverse health 

effect, admission to a hospital or a visit to an emergency department for an exacerbation 

of asthma can be considered a clearer adverse effect. Epidemiology studies more directly 

address these adverse health effects and provide evidence identifying health risks related 

to ambient NO2 exposures. In summary, the new scientific literature reviewed in the 

second draft of this ISA document provides a number of strong indications of possible 

NO2 health effects, but confounding or exacerbating co-pollutants and variable findings 

in human clinical studies remain problematic. Of special concern are potential 

interactions with particulate matter, potentially increasing lung NO2 dosages above what 

would occur with NO2 alone. These aspects should be addressed in considering a revised 

criteria standard for NO2. 
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Charge Question 4. What are the views of the Panel on the characterization of 

groups likely to be susceptible or vulnerable to NO2 and the potential public health 

impact of NO2 exposure? 

Overall, the draft ISA does an adequate job of discussing the public health 

significance of exposure to ambient NO2. The chapter 4 summary indicates that persons 

with preexisting respiratory disease (especially asthma), children, and older adults may 

be more susceptible to the effects of NO2 exposure. While the panel agrees with this 

assessment, other subpopulations may also be at increased risk of adverse health effects 

from exposure to ambient NO2. Specifically, there is evidence in the ozone and PM 

health effects literature that individuals who have poor dietary intake of antioxidants, are 

obese, or have certain genetic variants, as well as premature or low-birth-weight infants, 

may be more susceptible to these pollutants. Since NO2 is thought to cause health effects 

by a similar oxidant injury pathway to ozone and fine PM, these subpopulations should 

be considered in this chapter. We suggest that a table or figure be included in the 

document to more clearly identify subpopulations that are likely susceptible to adverse 

effects of exposure to NO2 and to identify the research that indicates that susceptibility. 

The panel recommends that the draft ISA more clearly communicate the 

distinction between “susceptibility” and “vulnerability.” Susceptibility as used in the 

latest draft ISA appears to describe those factors that may be considered “host” or 

“intrinsic” while vulnerability appears to be related to an interaction between 

susceptibility (risk-based on intrinsic risk factor) and increased risk of exposure. As 

currently used in the document, these terms have overlapping meanings that could lead to 

unnecessary confusion. 

Charge Question 5. What are the Panel’s views on the adequacy of this second 

external review draft ISA to provide support for future exposure and policy 

assessments? 

The Panel has several comments on the adequacy of the draft ISA as a basis for 

exposure and policy assessments. First, Chapter 5 satisfactorily summarizes the 

information and judgments from earlier chapters that are relevant to exposure and policy 

assessments. The authors of the draft have both accurately reflected that earlier material 

and chosen the material most relevant for further assessments. 

The charge question, however, asks not only about the fidelity of Chapter 5 in 

presenting results from earlier chapters, but also whether the draft provides an adequate 

basis for exposure and policy assessments. The CASAC Panel is not convinced that the 

chapter, as currently written, has met this goal, but the Panel believes that the chapter and 

the draft can be improved to that point through the improvements we have suggested in 

our review. Chapter 5 does indicate directions that are important for exposure and policy 

assessments: towards sensitive subpopulations that should be considered; towards 

specific health effects that should be considered; and towards the difficulties in 

estimating exposure due to uncertainties in the relationship between ambient monitoring 

results and personal exposures. In each of these categories more details need to be 
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provided so that a risk assessor can find useful summary information to inform how an 

exposure/risk assessment should be structured and how the residual uncertainties should 

be characterized. 

At present, the draft provides an inadequate basis for performing exposure and 

policy assessments quantitatively, or even summarizing the information that will be used 

in such assessments. The draft is uninformative as to what the levels of exposure are for 

any specific population in any specific geographic location. The authors should have 

summarized at least the ambient exposure information available (alluded to in the 

previous chapters) and then drawn judgments as to the validity of using that information 

in specific kinds of exposure assessments (e.g., the spatial scale on which variability can 

be determined and how to correct for indoor exposures). This summary and its 

interpretation can be offered without moving into the policy domain or even unduly 

specifying the tasks of further exposure assessors. There also should be a succinct 

statement as to whether an exposure-response curve can be developed, so that the risk 

assessor is not left solely with the option of using methods akin to hazard quotients. 

On the summarization of health effects, this chapter is greatly improved from the 

previous draft. t identifies health effects associated with exposure to nitrogen oxides and 

the strength of evidence supporting causality of associations. On the issue of whether 

effects would be expected at current ambient concentrations, however, the chapter does 

not provide adequate guidance. This is one of the weakest aspects of the current draft, 

even though this is one of the most important conclusions to be drawn from the 

document. Some statement with regard to the degree of certainty in the occurrence of 

effects at ambient levels is needed, no matter how difficult it may be to characterize 

uncertainty. The chapter also should summarize evidence on, and draw summary 

conclusions for, the issue of whether associations between NO2 and health responses in 

epidemiology studies result from NO2 exposures per se or whether NO2 is a surrogate for 

other exposures associated with common-cause sources. The information to support such 

a conclusion is scattered throughout the document, but an explicit and articulate 

consideration of this issue would greatly improve the draft. 

Finally, to meet that goal, the draft ISA should be improved through a better 

discussion of the significance of the epidemiology data for a potential risk assessment 

despite the uncertainties associated with those data. Incorporating an analysis of the 

available epidemiology data into the risk assessment will allow estimation of the potential 

uncertainties that need to be fully described and quantified in the risk and exposure 

assessment. The ISA discussion should consider the effect of co-exposures to other 

pollutants, the relationship between ambient and personal exposures, and how the 

limitations of the epidemiology studies impact their use for risk assessment. 
In closing, the CASAC was pleased to review this second draft of the ISA for the 

primary NOx standard and looks forward to continued interactions with the Agency in this 

important task.

 

Sincerely, 

/Signed/ 

Dr. Rogene Henderson, Chair 

Clean Air Scientific Advisory Committee 

Enclosures

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

Enclosure B: Compilation of Individual Panel Member Comments on EPA’s Integrated 

Science Assessment (ISA) for Integrated Science Assessment for Oxides of Nitrogen – 

Health Criteria (Second External Review Draft)

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Enclosure A 

U.S. Environmental Protection Agency 

Clean Air Scientific Advisory Committee 

Oxides of Nitrogen Primary NAAQS Review Panel 

CHAIR 

Dr. Rogene Henderson, Scientist Emeritus, Lovelace Respiratory Research Institute, 

Albuquerque, NM 

CASAC MEMBERS 

Dr. Ellis B. Cowling, * University Distinguished Professor At-Large, Emeritus, Colleges of 

Natural Resources and Agriculture and Life Sciences, North Carolina State University, Raleigh, 

NC 

Dr. James Crapo, Professor of Medicine, Department of Medicine, National Jewish Medical 

and Research Center, Denver, CO 

Dr. Douglas Crawford-Brown, Professor and Director, Department of Environmental Sciences 

and Engineering, Carolina Environmental Program, University of North Carolina at Chapel Hill, 

Chapel Hill, NC 

Dr. Donna Kenski, Data Analyst, Lake Michigan Air Directors Consortium, Des Plaines, IL 

Dr. Armistead (Ted) Russell, Professor, Department of Civil and Environmental Engineering , 

Georgia Institute of Technology, Atlanta, GA 

Dr. Jonathan M. Samet, Professor and Chair of the Department of Epidemiology, Bloomberg 

School of Public Health, Johns Hopkins University, Baltimore, MD 

CONSULTANTS 

Mr. Ed Avol, Professor, Preventive Medicine, Keck School of Medicine, University of Southern 

California, Los Angeles, CA 

Dr. John R. Balmes, Professor, Department of Medicine, Division of Occupational and 

Environmental Medicine, University of California, San Francisco, CA 

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

Dr. Dale Hattis, Research Professor, Center for Technology, Environment, and Development, 

George Perkins Marsh Institute, Clark University, Worcester, MA 

Dr. Patrick Kinney, Associate Professor, Department of Environmental Health Sciences, 

Mailman School of Public Health , Columbia University, New York, NY 

*Unable to participate in the May 1-2, 2008 CASAC Panel Meeting 
Dr. Steven Kleeberger, Professor, Lab Chief, Laboratory of Respiratory Biology, 

National Institute of Environmental Health Sciences, National Institutes of Health, 

Research Triangle Park, NC 

Dr. Timothy V. Larson, Professor, Department of Civil and Environmental Engineering, 

University of Washington, Seattle, WA, USA 

Dr. Kent Pinkerton, Professor, Regents of the University of California, Center for 

Health and the Environment, University of California, Davis, CA 

Dr. Edward Postlethwait, Professor and Chair, Department of Environmental Health 

Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, 

AL 

Dr. Richard Schlesinger, Associate Dean, Department of Biology, Dyson College, Pace 

University, New York, NY 

Dr. Christian Seigneur, Vice President, Atmospheric & Environmental Research, Inc., 

San Ramon, CA 

Dr. Elizabeth A. (Lianne) Sheppard, Research Professor, Biostatistics and 

Environmental & Occupational Health Sciences, Public Health and Community 

Medicine, University of Washington, Seattle, WA 

Dr. Frank Speizer, Edward Kass Professor of Medicine, Channing Laboratory, Harvard 

Medical School, Boston, MA 

Dr. George Thurston, Professor, Environmental Medicine, NYU School of Medicine, 

New York University, Tuxedo, NY 

Dr. James Ultman, Professor, Chemical Engineering, Bioengineering Program, 

Pennsylvania State University, University Park, PA 

Dr. Ronald Wyzga, Technical Executive, Air Quality Health and Risk, Electric Power 

Research Institute, Palo Alto, CA 

SCIENCE ADVISORY BOARD STAFF 

Dr. Angela Nugent, Designated Federal Officer, 1200 Pennsylvania Avenue, NW

1400F, Washington, DC, Phone: 202-343-9981, Fax: 202-233-0643, 

(nugent.angela@epa.gov) 

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10

Attachment B: Compilation of Individual Panel Member Comments on EPA’s 

Integrated Science Assessment (ISA) for Integrated Science Assessment for Oxides 

of Nitrogen – Health Criteria (Second External Review Draft 

Comments Received: 

Comments from Professor Ed Avol.................................................................................. 11 

Comments from Dr. John Balmes..................................................................................... 14 

Comments from Dr. Douglas Crawford-Brown ............................................................... 18 

Comments from Dr. Terry Gordon ................................................................................... 23 

Comments from Dr. Dale Hattis....................................................................................... 25 

Comments from Dr. Donna Kenski .................................................................................. 26 

Comments from Dr. Steven Kleeberger............................................................................ 28 

Comments from Dr. Timothy Larson ............................................................................... 29 

Comments from Dr. Kent Pinkerton................................................................................. 30 

Comments from Dr. Edward Postlethwait........................................................................ 32 

Comments from Dr. Armistead Russell............................................................................ 33 

Comments from Dr. Jonathan Samet................................................................................ 35 

Comments from Dr. Richard Schlesinger......................................................................... 38 

Comments from Dr. Christian Seigneur ........................................................................... 39 

Comments from Dr. Elizabeth “Lianne” Sheppard .......................................................... 42 

Comments from Dr. Frank Speizer................................................................................... 47 

Comments from Dr. George Thurston.............................................................................. 49 

Comments from Dr. James Ultman .................................................................................. 51 

Comments from Dr. Ronald Wyzga ................................................................................. 53 
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Comments from Professor Ed Avol

General Document Comments 

This is an impressive compilation of a great deal of work that reflects the large amount of 

effort put into it. It is generally well-written and with sufficient detail and reference to 

provide readers with useful guidance and documentation, as needed. There is a great deal 

of important and useful information in each of the several chapters, although the 

respective chapters have a slightly different architecture to them. Several important points 

are made in some chapters (such as Chapter 2), but not always emphasized at a section or 

chapter conclusion (as they are, for example, in Chapter 3). Although an excellent 

summary of the chapters appears as Chapter 5, is it worth considering having a 

conclusion, summary, or results section at the close of each chapter to re-emphasize or 

focus on the critical points raised? 

Agency ISA Charge Questions 

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

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

of studies and causality determination? 

Everything seems appropriate and well –described, except for the operational 

assignments for causality (P1-16, lines 22-23). I agree with the utility of a gradation of 

confidence in conclusive statements, but it’s a bit confusing as to the clear distinction 

between “sufficient to infer a causal relationship” and “sufficient to infer a likely causal 

relationship”. Isn’t the clarification currently present (“more likely than not”) the 

definition for the next lower level of confidence (“suggestive but not sufficient to infer a 

causal relationship”)? 

2. To what extent are the atmospheric chemistry and air quality characterizations clearly 

communicated, appropriately characterized, and relevant to the review of the 

primaryNO2 NAAQS? Are the properties of ambient oxides of nitrogen appropriately 

characterized, including spatial and temporal patterns and relationships between ambient 

oxides of nitrogen and human exposure? Does the information in Chapter 2 provide a 

sufficient atmospheric science and exposure basis for the evaluation of human health 

effects presented in later chapters? 

In general, yes...However, P2-7 through P2-10, Section 2.3 provides useful (and much 

appreciated) information regarding the various approaches to measurement of ambient 

levels of nitrogen-containing species, but does not provide any succinct conclusions or 

directed message for the reader. Perhaps a closing paragraph or bullet to provide a “takehome” message would be valuable? What discrete message(s) are you are trying to 

convey in this section? 

3. To what extent is the discussion and integration of evidence from the animal 

toxicology and controlled human exposure studies and epidemiologic studies technically 

sound, appropriately balanced, and clearly communicated? What are the views of the 

Panel on the conclusions drawn in the draft ISA regarding the strength, consistency, 

coherence and plausibility of NO2-related health effects? 
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This portion is generally excellent - well-written, thoughtfully presented, and 

meticulously designed. The summary figures, visually presenting the results of numerous 

studies to gauge consistency of response for a given outcome, is a noteworthy 

accomplishment that adds to the accessibility of the document. The summary of evidence 

sections at the close of each section are invaluable and much-appreciated. 

(P3-4, line 24) – A comment made here that “Relatively few new clinical and animal 

(NO2) toxicologic studies have been published since 1993...” seems inconsistent with a 

review of the literature. A PubMed search reveals over 200 publications reporting on 

NO2 health outcomes, animal studies, etc...? Please clarify or correct this sentence. 

4. What are the views of the Panel on the characterization of groups likely to be 

susceptible or vulnerable to NO2 and the potential public health impact of NO2 

exposure? 

(P4-9, Section 4.3 and elsewhere) A brief but clear delineation of the operational 

differences between susceptibility and vulnerability in this document would be useful; 

this is likely to otherwise create some confusion. Is vulnerable being used to describe “a 

lack of defenses against” or something more? Is susceptible being used to describe being 

“prone to a certain response” or something more? This section discusses children and 

older adults as being “...particularly susceptible to air pollution...”, but aren’t they more 

vulnerable? If they were missing a specific gene (in the oxidant stress pathway) or had 

pre-existing disease (such as emphysema, asthma, or possibly diabetes), then they would 

be susceptible. 

5. What are the Panel’s views on the adequacy of this second external review draft ISA to 

provide support for future exposure and policy assessments? 

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

assessments. 

Specific Comments 

Chapter I - IntroductionP1-13, Fig 1.6-2 – shouldn’t “Mediated Effect” arrows from PM 

to NOx to O3 go in both directions? NOX can affect PM formation which can then have 

an effect on observed outcomes, and O3 can affect NOx levels which will affect the 

entire chain of events. Similarly, shouldn’t there be a “Surrogate” arrow from NOx to 

Other Pollutants? 

Chapter 2 – Source to Tissue Dose 

P2-18, line 1 – (spelling error in San Bernardino, and I don’t think I have ever heard this 

region referred to as the San Bernardino “Valley”...??) 

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

Chapter 3 - Integrated Health Effects of NO2 Exposure 

(No additional specific comments other than those above) 

Chapter 4 – Public Health Significance 
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(No additional specific comments other than those above) 

Chapter 5 – Integrative Summary and Conclusions 

This chapter is an excellent compilation of the assembled data. 
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Comments from Dr. John Balmes

Agency Charge Question 3. To what extent is the discussion and integration of evidence 

from the animal toxicology and controlled human exposure studies and epidemiologic 

studies technically sound, appropriately balanced, and clearly communicated? What are 

the views of the Panel on the conclusions drawn in the draft ISA regarding the strength, 

consistency, coherence and plausibility of NO2-related health effects? 

GENERAL COMMENTS 

The second external review draft of the NOx ISA is much improved. In particular, the 

discussion in Chapter 1 on the “EPA Framework for Causal Determinations” provides an 

integrative approach to how the agency will assess the evidence presented in the 

subsequent chapters. Given that this is the first ISA to be produced under the agency’s 

new process for reviewing a “criteria” pollutant NAAQS, it is important to provide such 

an integrative approach as a precedent. My major concern about this draft of the NOx 

ISA is that in certain summaries of sections of Chapter 3, the framework described in 

Chapter 1 is insufficiently applied. I will provide specific examples below. 

In my opinion, the discussion of healthy effects of short-term exposure to NO2 in 

Chapter 3 is appropriate and fairly well integrated. My major concern with this 

discussion involves a statement is made on p. 3-14 and repeated on p. 3-15, 3-61, and p. 

5-12 that “the onset of inflammatory responses in healthy subjects appears to be between 

100 and 200 ppm-min, i.e., 1 ppm for 2 to 3 h.” Figure 3.1-1 is presented to demonstrate 

this threshold graphically, but appears to be the wrong figure, perhaps an alternative 

version of Figure 3.1-2. In any event, Figure 3.1-1 presents studies of the effect of NO2 

on allergen-induced lung function and inflammatory responses not the studies of the 

airway inflammatory effect of NO2 alone that are described on pp. 3-12 to 3-14. This 

figure needs to be replaced with one that actually supports this important statement. 

The discussion of respiratory effects associated with long-term exposure to NO2 is 

important since several prospective cohort epidemiological studies have been published 

since the 1993 NOx NAAQS review that reported adverse effects on growth of lung 

function. There is a subsection on “Toxicological Studies” on p. 3-89 and 3-90 that is 

apparently intended to provide mechanistic support for the results of the epidemiological 

studies. However, the discussion on pp. 3-95 and 3-96 of “Animal Studies of Long-Term 

Morphological Effects to the Respiratory System” is both more comprehensive and 

concise. I would delete the subsection on p.3-89. 

On p. 3-90, the concluding paragraph for section 3.4.1 on “Lung Function Growth” 

provides no assessment of the strength of the association between long-term exposure to 

NO2 and decreased rate of growth of lung function among children. This paragraph 

merely states that the epidemiological studies og long-term exposure to NO2 aqre likely 

confounded by other ambient pollutants. Unfortunately, section 3.4.5, which is supposed 

to be the summary and integration of evidence on “Long-Term NO2 Exposure and 

Respiratory Illness and Lung Function Decrements” also does not provide an assessment 

of the strength of the association. This is a critical deficiency given the relative 

importance of the issue of potential respiratory effects of long-term NO2 exposure. The 
15

section also does not directly assess the strength of the association for either “Asthma 

Prevalence and Incidence” or “Respiratory Symptoms”. It is not until Chapter 5 that the 

strength of the association for long-term exposure to NO2 and respiratory morbidity is 

assessed. 

Another concern that I have regarding section 3.4.5 is the long discussion on animal 

toxicological studies that have found effects of NO2 on host defense against respiratory 

infections on pp. 3-98 to 3-100. While I believe that this discussion is technically 

accurate, I find that it is unnecessary and distracting given the relative lack of discussion 

of the strength of the epidemiological evidence on long-term exposure to NO2 and 

asthma and the total absence of such discussion regarding respiratory symptoms. 

Agency Charge Question 4. What are the views of the Panel on the characterization of 

groups likely to be susceptible or vulnerable to NO2 and the potential public health 

impact of NO2 exposure? 

Chapter 4 does an adequate job of discussing the public health significance of exposure to 

ambient NO2. The chapter Summary (4.5) indicates that persons with preexisting 

respiratory disease (especially asthma), children, and older adults may be more 

susceptible to the effects of NO2 exposure. I agree with this assessment of the evidence. 

There is one statement in section 4.5, however, with which I am uncomfortable. The 

final sentence on p. 4-16 states that “evidence, albeit inconsistent, exists for a gender-agebased difference in susceptibility” regarding the effects of NO2 on children with asthma. 

I find this statement to be too strong. While I agree that there is evidence that the 

incidence of asthma differs between boys and girls with age, the evidence for a genderage-based difference in susceptibility to effects of NO2 exposure in asthmatic children is 

too limited to draw any conclusions. I would delete this sentence. 

The major problem I have with Chapter 5 is that the relatively strong evidence for an 

effect of long-term exposure to NO2 on growth of lung function in children reported by 

both the Sothern California Children’s Health Study and the Mexico City study (RojasMartinez et al.) is diluted by combining discussion of these studies with those on asthma 

and respiratory symptoms. In my opinion, the issue of the strength of evidence for a 

long-term effect of NO2 on growth of lung function needs to be dealt with more directly 

in the document, in both Chapters 3 and 5. 

SPECIFIC COMMENTS 

3-11, line 5 “...increases inflammation in children with asthma.” 

3-14, line 8 This statement would better reflect the studies discussed on the 

previous pages if it were worded “...NO2 concentrations ≤2.0 ppm 

in healthy adults.” 

Figure 3.1-1 wrong figure 

3-16, line 3 “Challenge with “specific allergens” can be performed in allergic

asthmatics.” 
16

3-20, line 28 delete second “of” in this line 

3-22, line 7 “By 72 h, bronchopulmonary hyperreactivity was comparable.” 

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

3-61, lines 7-10 This statement would better reflect the data summarized if worded 

as follows: “Controlled human exposure studies provide consistent 

evidence for airways inflammation at a NO2 concentration of 2.0 

ppm (one study found airway inflammation at a concentration of 

1.5 ppm); the onset of the inflammatory response...” 

3-75, line 12 “...mortality in 28 of the same cities...” 

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

Figure 3.4-4 Use decimals rather than commas for the y axes. Explain “study 

phase” in the legend. 

3-88, line 4 “The association between long-term exposure to NO2 and 

decreased PEF was comparable to that found in the CHS, but 

associations with forced volumes were considerably weaker.” 

3-89 and 3-90, Toxicological Studies I would eliminate these three paragraphs. 

The summary of the toxicological literature on 3-95 and 3-96 is 

better. 

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

summary. 

3-95, line 1 “The association of NO2 with dry cough at night observed in the 

German study...” 

3-98, line 25 “...major cohort studies, the CHS in southern California and a

birth cohort study in the Netherlands,...” 

3-98, line 29 to 3-100, line 2 I would eliminate this discussion on potential 

mechanisms of NO2 effects respiratory illness because the first 

sentence on p. 3-98 (lines 29-30) is at odds with the summary of 

the epidemiological evidence for respiratory symptoms on p. 3-95 

(lines 23-26). The information discussed here also does not relate 

to long-term NO2 exposure and asthma prevalence which was the 

subject of the preceding paragraph on p. 3-98. 

3-100, line 23 “...an OR of 1.10 for lung cancer...” 
17

3-100, lines 28-31 “Exposure to 10 μg/m3

 (5.2 ppb) of NO2 was associated with an 

OR of 1.08 for lung cancer (95% CI: 1.02, 1.15); exposure to ≥30 

μg/m3

 (15.7 ppb) was associated with an OR of 1.36 (95% CI: 

1.01, 1.83). However,...” 

3-104, line 13 “...with other NO2

-

 sources...” 

3-106, line 29 “...exposed to 2.0 and 1.0 ppm...” 

3-112, line 8 “...examined associations between...” 

3-113, line 18 “are suggestive of a traffic-related air pollution effect on mortality, 

but...” 

4-7, line26 “limitation of this experimental animal work...” 

4-11, line 8 “Several glutathione S-transferase (GST) genes have common...” 

4-13, line17 delete “biologically” from this sentence 

4-16, lines 30-32 This statement is a bit of a stretch based on the evidence presented. 
18

Comments from Dr. Douglas Crawford-Brown

The primary question addressed in this review is in reference to Chapter 5, Integrative 

Summary and Conclusions, and focuses on the adequacy of the ISA (especially Chapter 

5) to provide support for future exposure and policy assessments. I begin by noting that 

this second draft is a significant improvement on the first. The authors have dealt with the 

majority of my comments on the first draft, and have responded to the majority of 

comments made by the committee as a whole in our earlier review. There is beginning to 

emerge a vision for what the ISAs in general are intended to accomplish, so this is a 

positive step forward for the EPA staff. 

On the primary issue of adequacy as a basis for exposure and policy assessments, my 

comments are of two kinds. First, Chapter 5 does indeed summarize the information from 

earlier chapters that would be relevant to exposure and policy assessments. The authors 

have done a good job of both accurately reflecting that earlier material and choosing the 

material that is most relevant. They have drawn appropriate conclusions from that earlier 

material, including assessments of the strengths and limitations of the conclusions. While 

I might still have some quibbles over the lack of formal assessment of the epistemic 

strength of conclusions, I fully agree with the judgments they have made as to whether 

the evidence for each category of effect is conclusive, supportive, inconclusive, etc. I 

don’t think I could trace the judgments of the authors back to any specific reasoning they 

have done, because the only reference to that reasoning is a vague citation of the Hill 

criteria (criteria that seem to me woefully inadequate as a philosophical basis for rigorous 

assessments of epistemic status). But the judgments of the authors nonetheless appear to 

be the correct ones based on the available evidence. 

The second issue is whether Chapter 5 not only summarizes accurately the information in 

earlier chapters (which it does) but also provides an adequate basis for exposure and 

policy assessments. Here I am less comfortable the chapter, or even the entire document, 

has met the target. It is certainly the case that both the document and the chapter point the 

reader in directions that will be important for exposure and policy assessments. The 

reader is guided to judgments on the appropriate sensitive subpopulations that should be 

considered; on the specific effects that should be considered; on issues related to the 
19

relationship between ambient monitoring results and personal exposures; and on the issue 

of whether epidemiological studies are confounded by exposures to the mix of air 

pollutants that normally accompany exposure to oxides of nitrogen. An assessor will, 

therefore, find much useful information in the document and in Chapter 5. 

However, neither the chapter nor the document provides an adequate basis for performing 

exposure and policy assessments quantitatively. It is not possible from the document 

alone to see what the levels of exposure will actually be to any specific population in any 

specific geographic location. I realize this level of detail may not be what is intended by 

an ISA, but then I am left wondering what could be meant by asking whether the 

document provides an adequate basis for exposure assessment. The only way it could do 

that, in my mind, is to summarize the actual exposure information available, guiding the 

reader to understanding how well that information will allow accurate estimates of 

exposure to specific subpopulations in specific geographic areas. The ISA does not 

summarize exposure information, or even monitoring information, but instead 

summarizes the strengths and limitations of that information. The latter is an important 

goal, as it will place caveats on the use of more detailed information in later exposure 

assessments. But it leaves the task of assembling the information on concentrations, and 

converting these to estimates of exposure, to a later step in the assessment process. As a 

result, I am not comfortable that the ISA provides an adequate basis for subsequent 

exposure and policy assessments, but rather provides an adequate basis for these 

subsequent steps to understand the strengths and limitations of the available data. 

Having said that, this may be all that the ISAs are intended to accomplish, in which 

case the current document would be judged adequate. 

I also was looking for some sort of scientific statement as to how the information 

available ought to be used in conducting an exposure or policy assessment. This can be 

done without wandering into policy decisions. Are the authors suggesting that no 

exposure-response curve can be developed, and hence the assessments must be conducted 

in ways similar to non-cancer risk assessments (with a presumed threshold of effect)? 

Should an uncertainty factor be applied? Would the goal of an assessment be to estimate 

the number of people in the U.S. population exposed at levels above the threshold (or 
20

with a hazard quotient above 1)? Should there exposure be averaged over an hour, or 4 

hours or a day or year? These are questions that will crucial in a future assessment and 

can be answered scientifically without getting into the policy realm, so I expected to see 

them here if the document is to provide an adequate basis for exposure and policy 

assessments. 

I then have a series of specific issues to raise. 

1. I continue to be less than convinced by the epistemic assessments performed, or at 

least the formal descriptions of the assessments. The reference on page 5-1 is to the Hill 

criteria (which are completely inadequate philosophically in my view) and to “other 

pertinent frameworks”. No reference is provided to these other frameworks, so I have no 

idea what they are. I realize the ISA is not a philosophical document, but some better 

guidance as to how the specific judgments of the quality of conclusions are developed is 

needed. There is no problem in stating that they are informed judgments based on some 

set of criteria (and then stating these criteria). Having said that, I do agree with the 

conclusions drawn and so will not push this point too strongly. 

2. The fourth bullet on Page 5-1 asks whether new data affect the plausibility of 

judgments about oxides of nitrogen causing adverse health effects. I had expected to see 

some further qualification such as “adverse health effects at levels of exposure of at 

levels found in the environment”. 

3. On Page 5-3, the bullets don’t seem to follow at all from the opening sentences of the 

paragraphs. I agree with what is contained in the bullets, but they seem to me 

unconnected to the sentences that presumably introduce them. I have read this paragraph 

several times and just don’t see the link. 

4. In that same list of bullets, 6th bullet, the authors talk about artefacts. There is no 

explanation as to what an artefact means, how it affects exposure or policy assessments, 

what a positive artefact would be (presumably in contrast to a negative one), etc. 
21

5. The listing of issues in section 5.2.2 is a good one, and is certainly useful to anyone 

conducting an exposure assessment. But I point back to my earlier comment that even if 

the issues raised here are the correct ones, it is not possible to take this and form a basis 

for an exposure assessment because specific data are not provided and summarized. I also 

expected a bullet suggesting how exposures SHOULD be estimated, rather than simply 

listing the limitations in any exposure measures. I would expect a recommendation as to 

the ratio of personal to ambient levels in specific settings, the time period over which 

exposure should be averaged, etc. I also expected some conclusion as to whether it is 

even valid to use ambient monitoring results, from the network set up for regulatory 

monitoring, as a starting point for estimating exposures. 

6. The last paragraph in section 5.2.2 cautions against strict conclusions being drawn 

based on the epidemiological studies due to a lack of conclusive evidence that ambient 

and personal exposures are completely correlated. The implications of a lack of complete 

correlation depend on the differences in exposure levels between the different exposure 

categories in the study. The implications become more significant as the exposure 

groupings are closer together in exposure, in which case there can be significant 

misclassification and therefore bias towards the null (generally at least). I think a more 

nuanced conclusion here is needed. 

7. I found the summary tables quite useful, so the authors are to be applauded for 

developing them in this coherent fashion. 

8. In the sections on effects, it would be useful if the authors were to provide information 

as to whether an increase in exposure changes the fraction of people with effect, the 

frequency with which a subset of people develop the effect, the severity of the effect, etc. 

I realize that this distinction may not be so important in a regulatory decision (where one 

person getting the effect N times counts the same as N people getting the effect once), 

and that the available exposure-response information may not allow development of 

exposure-response curves, but some comment on this issue would be useful. 
22

9. In the last paragraph (Page 5-22), the authors correctly conclude that it is plausible to 

believe that effects are occurring at levels of exposure below the current NAAQS. But the 

question here is “how far below?”. I should think that the science assessment (this 

document) would be the place where the EPA states clearly the answer to this crucial 

scientific issue – an issue that will greatly affect the policy assessment. 
23

Comments from Dr. Terry Gordon

Charge Question 3. To what extent is the discussion and integration of evidence from the 

animal toxicology 

and controlled human exposure studies and epidemiologic studies technically sound, 

appropriately balanced, and clearly communicated? 

 The ISA document is a tremendous improvement over the first draft. There are 

appropriate-length discussions of key studies and the overall message of the ISA is 

clearly communicated. There are, perhaps, sections of the animal toxicology data that 

have too much detail given the high(er) concentrations of NO2 used in some studies. As 

mentioned in past discussions by the Panel, animal toxicology studies should be included 

in the ISA only when they are of relevant concentrations. 

What are the views of the Panel on the conclusions drawn in the draft ISA regarding the 

strength, consistency, coherence and plausibility of NO-related health effects? 

 

 The development of the guidelines to evaluate the strength, consistency, 

coherence, and plausibility of NOx-related health effects is critically important to the 

ISA. In a similar fashion, the use of structured language to describe relationships 

between exposure to NOx and adverse health effects is an important improvement to the 

ISA. The 5 descriptor categories appear well thought out and appropriate, but discourse 

on these categories may bring modifications to future ISAs if not this one. 

Minor Comments: 

Disclaimer page 

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

Page ii, para 2 – typo for (4) before “to set....”? 

Page 1-17, para 2 – Why would tox and cancer have a linear response? Many researchers 

say otherwise. What does dose-transitional mean? 

Page 2-4, last line – ‘at low temperature’ is imprecise; does this mean ambient 

temperatures? 

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

Page 3-6, table 3.1-1 – Under peripheral blood, ‘Total macrophages’ should be (re)moved 

as they are in the lower airways. 

Page 3-8, para 3 – The 3 to 9 ppm 2 week study has little relevance to the toxicity of 

exposure to peak ambient levels of 0.05 or 0.1 ppm NO2. Also, it is unbalanced to give 

the details and results of this high dose study and then say that alveolar macrophages are 

a sensitive target for NOx’s effects and give no refs on macrophages and just refer the 

reader to the Annex. 

Page 3-12, figure 3.1-1 – The figure legend needs more details (e.g., what are the + and – 

on the Y-axis for; what does the * mean?; what do the 3h and 6h mean? Some of this is 

explained later in the legend of figure 3.1-2. 

Page 3-22, first and second line – Needs a ref. 
24

Page 3-22 – There is a lot of detail here for high dose (5 ppm and 20 ppm NO2) animal 

studies. Please consider cutting the long paragraph and summarizing in a couple of 

sentences. 

Page 3-24 – Add ‘Nonspecific’ before ‘Airways’ in the title for consistency with the last 

2 subtitles. 

Page 3-25, para 2 – Delete ‘of’ before ‘as low as....’. Having stated that effects can 

occur at 0.26 ppm, why include the 1-sentence results of a 5 ppm study? 

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

Page 3-47 – I may be reading this all wrong but some of the bars on the figure make no 

sense: on the preceding page, it says the Tolbert study had a 2% increase with a 95% CI 

of 0.5, 3.3. The figure shows a significant box with error bars totally dissimilar the 

reported 95% CI. The same goes for the Barnett (2005) study which says something 

different in the text (page 3-47) than is in the figure. Should all data be re-checked? 

Page 3-59, second line – insert ‘for asthma’ after ‘.... or ED visits’. 

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

Page 3-62, lines 4, 5 – I’m not sure what is meant by ‘....NO2 effects to be mediated by 

other pollutants or exposures;’ 

Pages 3-62, 63 – Although the physiology descriptions are good, the text has 15 lines 

describing HRV and then 5 lines to say there have been mixed results. The same goes for 

the repolarization section – 5 lines to describe what it is and then 1 line to say there was 

no effect. Condense? 

Page 3-79, 2nd para – The statement regarding animal studies and mortality as an 

endpoint in acute studies is not correct. Several studies have looked at LC50 values for 

NO2 in different species. 

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

section. 

Page 3-96, para 1 – A mention of the higher doses used in animal tox studies could be 

added to qualify the last sentence. 

Page 3-111, para 3 – Add ‘a’ before ‘sensitivity’. 

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

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

chapter? 

Page 4-8, para 1 – Adding a conclusion sentence for this section on asthma would be 

appropriate. The same goes for the other susceptibility sections. 

Page 4-12, para 1 – The sentence states that in-vehicle concentrations are 2 to 3 times 

‘ambient’. Does this mean that it’s higher in the vehicle than just outside the car? Or 

does it mean compared to non-traffic ambient levels? 

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

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

Page 5-26 – The title for the table is unclear – Legend of Figure 5.3-1?? 
25

Comments from Dr. Dale Hattis

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

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

evaluation of studies and causality determination? 

I used a few different methods to evaluate the results of the literature search. First I read 

through all of the references cited at the end, noting the frequency of 2006-2008 

references, and selecting in particular titles that appeared highly relevant to the analysis 

of health hazards. From the large numbers of 2007 references and the occasional 2008 

citation, it is clear that the authors have brought their literature searches up to date as of 

the present. I then retrieved the abstracts for about a dozen interesting recent references 

and checked how the revised ISA reported on them in the main text or tables. In every 

case I found that the description in the text or tables corresponded reasonably to the 

abstract. 
26

Comments from Dr. Donna Kenski

Charge Question 2: To what extent are the air quality characterizations and analyses 

clearly communicated, appropriately characterized, and relevant to the review of the 

primary NO2 NAAQS? Are the properties of ambient oxides of nitrogen appropriately 

characterized, including spatial and temporal patterns and relationships between 

ambient oxides of nitrogen and human exposure? Does the information in Chapter 2 

provide a sufficient atmospheric science and exposure basis for the evaluation of human 

health effects presented in later chapters? 

This second draft ISA is much improved from the first draft ISA and it was gratifying to 

see the panel’s suggestions from the last review incorporated to a large extent. The 

discussions of measurement interference and its spatial and temporal variability were 

much better, as was the discussion of ambient concentrations of NO2. The paragraph on 

NO2 increases in other countries was somewhat irrelevant (p. 2-13, lines 25-30) and 

could be deleted or moved to the section on policy-relevant background concentrations. 

Sec. 2.4.5 on concentrations of NOz species is still quite limited and I think more 

information on these various species and their interrelationships would be helpful. Data 

are admittedly sparse but there are more papers that could be usefully summarized. Two 

that I know of are: 

Continuous wet denuder measurements of atmospheric nitric and nitrous acids during the 

1999 Atlanta Supersite, Atmospheric Environment, Volume 37, Issues 9-10, March 2003, 

Pages 1351-1364 

Zhang Genfa, Sjaak Slanina, C. Brad Boring, Piet A. C. Jongejan, Purnendu K. Dasgupta 

Measurements of gaseous HONO, HNO3, SO2, HCl, NH3, particulate sulfate and PM2.5 

in New York, NY, Atmospheric Environment, Volume 37, Issue 20, June 2003, Pages 

2825-2835, 

Abdul Bari, Vincent Ferraro, Lloyd R. Wilson, Dan Luttinger, Liaquat Husain 

Section 2.2.1 on sources of NOx still needs to be augmented with a shortened version of 

Annex Table AX2.6-1 (the old AX2-3) giving quantitative data on emissions 

contributions from major source categories. Fig. 2.2.1 is nice but just doesn’t convey any 

quantitative sense of emissions. 

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

information. 

In the previous CASAC review, we requested that chapter 2 in particular include section 

summaries, as was done so effectively in later chapters. It doesn’t seem like this has been 

accomplished, but it would help tie up this chapter and make the conclusions drawn from 

it in Chapter 5 more obviously connected to the relevant sections. 

Aside from these fairly minor tweaks, I found this section of the ISA satisfactory and I 

think (together with the supporting documentation in the annexes) that it provides a 

suitable basis for the Risk and Exposure Assessment. 

Other comments: 
27

Chapter 5 is great; it gave a fair and balanced presentation of the studies reviewed and the 

conclusions drawn. Very helpful. 

In our review of the first draft ISA, we requested that EPA consider multipollutant 

approaches to managing air quality. While acknowledging that changing the traditional 

one-pollutant-at-a-time approach is likely to take considerable time and effort to 

implement, I’d like to encourage EPA to move in that direction with the ISA process. 

The inclusion of data for multiple N species as well as some sulfate and oxidant 

chemistry was a step forward. 

p. 2-17, Fig. 2.4-6d, title of figure should be Weekend, rather than Weekday 
28

Comments from Dr. Steven Kleeberger

The document reads very well. I have very few comments that would not be considered 

only editorial- or style-related. However, I found the Figures 3.1-1 and 3.1-2 to be 

somewhat confusing. While the information presented is very useful, I would suggest 

that the data would be better presented in tabular form rather than figures. At first glance, 

the +/- on the y-axis suggests a degree or quantitation of positive or negative finding. It 

would be simpler simply to list the studies in a table with negative and positive 

categories. 
29

Comments from Dr. Timothy Larson

General Comments: 

I am limiting my comments to the exposure issues covered in Chapter 2 and parts 

of Chapter 6. In general, this document is much improved on the first draft and the 

authors should be commended. The issues raised by the committee upon review of the 

first draft have been addressed for the most part. I think the Chapter 6 summary of the 

topics in Chapter 2 is reasonable and consistent. The discussion of NO2 infiltration 

seems a little long. 

However, I disagree with the statement beginning on page 2-31 about street canyons 

being complicated and modeling their effects to be “highly problematic”. In fact, recent 

work has shown that both CFD and much simpler integral models provide reasonable 

predictions (c.f. Di Sabatino S, Buccolieri R, Pulvirenti B, et al. (2008) Atmos. Environ. 

41 (37) , 8316-8329). In addition, there are a number of recent studies showing good 

prediction skill with these simpler models (c.f. Mensink C, Cosemans G (2008) Env. 

Modeling & Software. 23 (3) , 288-295; Berkowicz R, Ketzel M, Jensen SS, et al. (2008) 

Env. Modeling & Software. 23 (3), 296-303; Ghenu A, Rosant JM, Sini JF (2008) Env. 

Modeling & Software. 23 (3), 314-321). This seemingly minor point is in fact rather 

important to the interpretation of the spatial heterogeneity of NO2 in built up urban areas. 

These studies and others (e.g. Vardoulakis S, Gonzalez-Flesca N, Fisher BEA, et al. 

(2005) Atmos. Environ. 39 (15) , 2725-2736) indicate that street canyons are similar in 

NO2 concentrations to on-road values in otherwise open areas, i.e., enriched by about a 

factor of 2 above measurements taken away from the road in more open areas. Including 

a discussion of the skill level of these models in similar applications and a multiscale 

approach that includes street canyons seems appropriate (c.f. the Danish forecast system 

at http://www2.dmu.dk/1_viden/2_Miljoe-tilstand/3_luft/4_spredningsmodeller/5_Thor/default_en.asp). 

This adds another dimension to the exposure assessment, namely the fact that pedestrians 

spend time walking in these canyons and having windows opening onto these canyons 

and can therefore experience exposures for equal or greater times than they do on roads 

in transit (they may not even own cars in dense urban areas). 

Specific comments: 

Page 2-25 line 26 and page 2-26 line 6: Text seems to arrive at different conclusions 

about passive samplers without comment. 

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

levels. 

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

Page 2-51 line 16: The NO2 east-west spatial variation in greater Los Angeles varies 

broadly with distance from the coast due to well known meteorological and chemical 

phenomena. NO2 levels in Riverside are determined in large part by pollution 

transported from upwind urban areas to the west. 

Page 2-55 Table 2.5-9 is presented without comment. 
30

Comments from Dr. Kent Pinkerton

Agency Charge Question 3. To what extent is the discussion and integration of evidence 

from the animal toxicology and controlled human exposure studies and epidemiologic 

studies technically sound, appropriately balanced, and clearly communicated? What are 

the views of the Panel on the conclusions drawn in the draft ISA regarding the strength, 

consistency, coherence and plausibility of NO2-related health effects? 

General Comments: 

The organization and improvement of the second draft ISA document for Oxides of 

Nitrogen – Health Criteria, compared to the original draft are excellent. The revised 

document has addressed a number of concerns expressed by CASAC for the original 

draft document. In my opinion, the content, flow, presentation and logic of materials are 

well done. New publications from the scientific literature since 1993 incorporated into 

this ISA draft are extensive and impressive. The majority of these papers cited in the 

document are highly relevant from an environmental perspective. A number of the new 

toxicology documents provide biologic plausibility, however, exposure concentrations in 

these studies are typically well above ambient conditions (greater than or equal to 5 

ppm). The addition of new epidemiologic and human clinical studies to this second draft 

of the ISA is highly impressive and far exceeds new animal toxicology studies. 

However, those new toxicology studies included demonstrate effects as low as 0.4 ppm 

(in a lung vitamin deficit model in the guinea pig). Airway hyperresponsiveness 

following repeated NO2 exposure at 1 and 2 ppm for up to 12 weeks in guinea pigs has 

also been demonstrated. Each of these studies adds further validity for the biologic 

plausibility of NO2 health effects. Human studies also provide strong evidence for health 

effects at NO2 levels in the 0.04-0.08 ppm range as 1 hour peaks. New data to 

demonstrate greater sensitivity to NO2 in the form of increased airway responsiveness 

(approximately 10-fold) for asthmatics vs. healthy individuals further emphasizes the 

importance for consideration of susceptible populations and children in consideration of 

setting the NO2 standard recommendation. In summary, the second draft of the ISA 

document represents an excellent compilation and reasonable interpretation of new 

research findings that should greatly aid in formulating decisions for setting the next 

criteria standard for oxides of nitrogen. Summary statements made for many of the 

sections under Chapter 3 were very helpful. I feel the conclusions made in the ISA 

document using integrative analysis of epidemiologic, human clinical and animal 

toxicological evidence provide strength, consistency, coherence and plausibility for NO2-

related health effects. 

Minor Comments: 

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

concentration in the future? 

2) P2-40: this section provides an excellent detailed description on the relationship 

of personal exposures to ambient concentrations. 

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

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

exacerbates airway symptoms. 
31

5) P3-12: Figure 3.1.1: It would be helpful to more completely label the y axis. 

Perhaps “observed response” could be added. At first examination, the meaning 

of the symbols + and – is not clear. Does + mean increased or adverse response; 

does – mean no change from control or a reduction of response from control? 

6) P3-18: Figure 3.1.2: Same comments as for Figure 3.1.1., although the text 

referring to this figure clarifies the meaning of + and – for the y-axis. 

7) P3-25: Excellent comparison of NO2 concentrations leading to increased airway 

responsiveness in healthy and asthmatic humans and animals. 

8) The intervention study of Pilotto et al (2004) provides striking evidence for health 

effects among asthmatic children for NO2 concentrations at extremely low levels. 

The only concern for the interpretation of this study remains the possibility that 

ultrafine particles, rather than NO2 may be driving this effect. 

9) There appears to be strong evidence of NO2 effects on physician-diagnosed 

asthmatic children (Pilotto et al., 2004). Although it may be difficult to 

completely rule out the effects of ultrafine particles, multi-pollutant models 

continue to demonstrate robust NO2 health effects when adjusting for other 

pollutants such as CO, O3 and PM. 

10) P 3-50, line 29: the term “not sensitive” in this sentence is unclear. Does this 

mean co-pollutant regression analysis does not work or that other co-pollutants do 

not confound NO2 effects? 

11) Excellent studies are included throughout the document to demonstrate positive 

associations between ambient NO2 concentrations and health effects among 

young children and older adults (65+ years). 

12) There continues to be a concern relative to confounding of co-pollutants, as well 

as NO2 being a surrogate for other pollutants. However, there appears to be 

consistent data throughout more recent publications to suggest NO2 can elicit 

health effects at current ambient levels. 

13) Susceptible populations are clearly an important group to consider for NO2 health 

effects. The Southern California Children’s Health Study clearly points to NO2-

related changes with reduction in lung growth function in children. 

14) Excellent summary and integration of scientific evidence for all aspects of health 

effects of NO2 throughout the document. 
32

Comments from Dr. Edward Postlethwait

1. In general the document shows considerable improvement over the initial draft 

and thus the EPA staff should be commended. 

2. The issue of endogenous NO2 generation appears not to have been addressed as a 

potential contributor to uncertainties with regard to data interpretation, thresholds, and 

assessing posited mechanisms of action. This is especially important for three of the 

posed question in section 5.1 regarding has new information altered support for 

occurrence of health effects, at what levels of NOx do health effects of concern occur, 

and plausibility of adverse health effects. 

3. On page 2-61, the section dealing with modeling NO2 dose should be clarified 

with regard to NO2 flux. The term “NO2 flux to air-liquid interface” does not accurately 

describe the net movement of NO2 from the intrapulmonary gas phase into the surface 

lining layer, or potentially epithelial cells. If NO2 flux occurs as written, there is a 

disconnect between the sites of focal injury and mass transfer from the intrapulmonary 

gas phase. 

4. To this reader, there is a consistent ambiguity in the way NO2 thresholds are 

presented. As written, it is not especially clear in the document whether the lack of 

documented thresholds means that NO2 related effects can be extrapolated to zero [NO2] 

in a linear fashion or that threshold concentrations have not been identified due to the 

numerous confounding factors. The document would be strengthened if this issue was 

revised throughout to unequivocally present a consistent interpretation. 

5. It is somewhat curious that the document supports causal relationships between 

NO2 exposure and acute but not chronic health effects. If NO2 is able to induce short 

term effects at the denoted concentrations, one would anticipate that individuals residing 

in the same geographic locale would also experience long term impacts. Thus, it may be 

useful to consider whether this represents an inconsistency or is due to any number of 

mitigating factors. 

6. Per discussions from the initial review meeting, the document does not 

extensively link the potential occurrence of short term NO2 spikes and health 

outcomes. A more thorough discussion in the summary chapter (Chapter 5) of 

the possible occurrence rates, NO2 spike concentrations and thus exposures 

relative to the current long term average values, and observed effects would 

strengthen the document and provide the impetus to help support a shorter 

term standard if warranted. 
33

Comments from Dr. Armistead Russell

Post-Meeting Amendment

Given the redirection of the REA, I think it is particularly needed that the ISA highlight 

(further stress and discuss) epidemiologic studies that have included multi-pollutant 

models with NO2, particularly those that have included other combustion byproducts like 

EC, Total Carbon (TC) and CO. In doing so, they need to provide caveats on the 

interpretation of such studies, but also recognize their importance. They should note that 

PM2.5 and O3 are poor indicators for exposure to combustion emissions. If there are 

studies demonstrating how PM might act as a carrier for NO2 that should also be 

assessed. 

Original 

Again, like the first draft, the 2nd Draft ISA is an effective document for providing the 

information needed to conduct the risk and exposure assessments. It is substantially 

improved from the last draft. However, I was a bit disappointed that some pieces did not 

get changed between the 1st and 2nd drafts. 

1. I still think there should be a table of sources in Section 2.2.1. There is no Table 

2-3 in the Annex: it is Table 2.6-1. Having a table in the ISA might help OAQPS 

note that their commercial air craft estimate for Philadelphia does not look right. 

They should also note that being an elevated source also leads to the emissions 

being more dispersed. Indeed, the highest NO2 levels found in cities are not from 

EGUs. 

2. In the chemistry section, a bit more should be said about NO to NO2 

transformation as NO2 is the apparent indicator species. 

3. The measurement section is still a bit biased when highlighting the Mexico 

studies. Mexico City is a unique place, so I tend to downplay those results. 

Switzerland is more appropriate. There really should be some US-based studies. 

4. The section on ambient concentrations presents an appropriate level of 

information on NO2 levels in the US at the country/urban scales, but should 

provide more information on NO at the same time. I would treat them together, 

with much of the transport discussed as transport and decay of NOx. If one looks 

at the REA, an important issue is roadway levels. This is hardly treated here. 

This section should discuss roadway levels of NO2 and NO, as opposed to 

covering it later in 2.5.4. A major missing component of ambient characterization 

is that of other pollutants. It is important to show the correlation between NO2 

and some other species (e.g., EC) and I think it belongs here as opposed to later in 

2.5.8. It would seem to fit more naturally here. 

5. 2-31. It is not apparent that a 15 m monitor will lead to an underestimate of what 

people are breathing given that in cities (e.g., NY) air inlets in to homes may be 

that high. Also, as noted in the REA, very few of the monitors are at 15m. Give a 

balanced presentation. 

6. 2.5.4: This section is fine, but could go deeper to provide the detail that is 

ultimately needed in the REA. It should discuss the conversion of NO to NO2 

with information as to conversion rate and how quickly NO falls off and NO2 
34

rises. The current REA uses little from this section, instead deriving its own fit to 

the decay. It is also not apparent how the REA used the information about 

intrusion of the vehicles own exhaust in to the cabin. 

7. 2.5.8. This is a very important section, and I think it does a reasonable job of 

providing the type of information needed to see how NO2 correlates with other 

important species, including EC. One of the problems with having this section 

much later in the document is that they then go over points discussed earlier (e.g., 

diurnal variation). 

8. Conclusions: 

a. P5-3, L19. In the body of the ISA, they never use 25%... even though I 

think the 50% value given earlier is extreme, whatever number chosen 

here should be supported in the ISA. 

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

so. 

c. 5-3, L30: Precise is not the correct word here. Possibly accurate, but I 

would say that it may be accurate enough for the job at hand, so I would 

back off on this statement altogether. 

d. P5-5, L7: While true, we find out in the ISA this is not a real problem 

since most monitors are not at 15m. 

Something to think about for future ISA’s: you should have a section discussing the 

models that might be appropriate for estimating ambient levels and, possibly, exposure. 

In this case, it would be AERMOD and APEX. This section should provide the model 

formulation, inputs and an evaluation of its capabilities. Modeling is discussed to some 

degree in the NOx-SOx SNAAQS ISA, which is good (though the committee wanted 

more evaluation). 

 
35

Comments from Dr. Jonathan Samet

General Comments:

The second draft ISA for oxides of nitrogen (NOx) is improved and responsive in many 

respects to concerns raised by CASAC members, including myself, at the review of the 

first external review draft. The Agency’s staff has attempted to be responsive in setting 

out a better framework for evidence identification, evaluation, and synthesis. I am 

hopeful that continued progress will be made to sharpen this process, in order to address 

issues that are still unsolved. Additionally, I think that the peer review process would be 

enhanced generally by the preparation of a note to CASAC that sets out the Agency’s 

responses to major concerns raised by the CASAC reviewers. Such responses would be 

consistent with usual practice of peer review, and would provide a trail, documenting 

how comments made by CASAC were taken into account. 

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

specific comments. 

Charge Question 1:

In response to comments with regard to the Agency’s approach to literature 

identification, study selection, and synthesis of the evidence, as well as causal inference, 

an extensive annex has been prepared that reviews a number of relevant frameworks. 

The background is a useful foundation for justifying the selected approach. The Agency 

has made a number of changes in Chapter 1 that are responsive to prior critiques. In 

particular, there is a description of literature selection, an approach to evaluating evidence 

for inferring causality is provided, and a reasonable set of descriptors of the strength of 

evidence for causation is offered. 

On reading the draft ISA, there has been some impact throughout the document of having 

a better prepared first chapter and this framework. However, the sections that synthesize 

the evidence are still somewhat loosely written, and do not systematically apply the 

guidelines offered by Bradford Hill, and adopted by the Agency. (Note, that these should 

not be renamed as “decisive factors”, a misnomer). Too often, sections that are offering 

judgments as to the strength of evidence use such language as “taken together or 

“integrating” without a more specific application of the criteria offered by Hill. 

Nonetheless, the new Chapter 1 and the approach set out represents an advance over the 

earlier draft. Discussion is needed as to whether the list developed by Hill should be 

replaced with the shorter set used in the Surgeon General’s Report. Perhaps, a 

comparison could be made with a test case. 

One issue that is left unaddressed is publication bias, a reasonable concern given that 

many studies address the health effects of air pollution and employed multivariable 

models to attempt to isolate the effects of particular pollutants. There must have been 

some tendency on the part of investigators to report positive associations. This topic 

needs to be mentioned, as the existence of publication bias would be difficult to set aside 

for some of the epidemiological studies. 
36

Charge Question 3: 

This charge question relates to the integration of evidence from the various lines of 

investigation. Of particular concern is the plausibility of effects observed in 

epidemiological studies in the context of animal and human toxicology. There is no 

doubt that high levels of NOx can injure the lung and other organs. For setting the 

NAAQS, the plausibility of effects at ambient concentrations is particularly relevant. I 

am concerned that the draft ISA has only partially addressed the plausibility of effects at 

current ambient concentrations and at those investigated in a number of the 

epidemiological studies. The ISA appropriately notes that both clinical and animal 

studies are carried out at doses well above those that are typical for population exposures. 

The document would be improved if more attention could be given to considering the 

relevance of mechanisms observed at higher levels to effects at ambient levels. 

Charge Question 4:

Chapter 4, “Public Health Significance”, provides as overview of populations potentially 

at increased risk from exposure to NOx. 

The listing of susceptible subgroups covers those of both particular relevance and of 

general relevance. The various groups identified are appropriate, although I have concern 

that EPA will follow the same template for all pollutants without giving sufficient 

consideration to the relevance of particular subgroups for particular pollutants. 

Charge Question 5:

The revised document is greatly improved. It identifies health effects associated with 

exposure to nitrogen oxides and the strength of evidence supporting causality of 

associations. It makes an attempt to assess whether effects would be expected at current 

ambient concentrations. This is one of the weakest aspects of the current draft. Consider, 

for example, the conclusory language from page 5-22: “integrating across the 

epidemiologic human clinical and animal toxicological evidence presented above, we 

find that it is plausible that current exposures can result in adverse impacts to public 

health at ambient concentrations below for current NAAQS for NO2.” This sentence 

addresses the most critical matter around the need to revise the NAAQS: are there effects 

being observed at current ambient concentrations? The sentence addresses plausibility. 

Some statement with regard to the degree of certainty is needed, no matter how difficult it 

may be to characterize uncertainty. 

Specific Comments:

Page # Line # Comment 

1-7 5 Not certain this is true! 

1-10 2 Along with considerations of plausibility 

1-10 24 That may lead to confounding. 

1-10 28 “...homogeneous groups with of the confounding...” 

1-12 22 What does this mean? 

1-13 1 Note, the following discussion refers to statistical models. The 
37

Page # Line # Comment 

word “model” has many uses. 

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

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

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

3-1 24 “obscured” What does this mean? 

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

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

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

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

3-7 5 At what concentration? 

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

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

forest plot. 

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

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

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

3-26 5 Isn’t this inconsistent with an NO2 effect? 

3-40 4 Well-recognized 

3-46 6 “pneumonia” is a LRI 

3-46 19-22 “Collectively...” a conclusion—out of place 

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

3-101 1 Certainly, the possibility that traffic-related carcinogens are the 

etiologic agent needs to be raised. 

3-106 11 Why confounding, implying underlying causation? 

3-107 13 “(2000...” ) and earlier 

4-5 29 Be careful not to overinterpret 

5-1 28-29 ? 

5-22 21 “Integrating across the epidemiologic” How? What does this 

mean? 
38

Comments from Dr. Richard Schlesinger

Overall, this is a very good document that clearly integrates the essential concepts 

required to make a judgment related to health effects from NO2. 

p. 1-16, line 22. It may be better to change the first bullet to “sufficient to infer a definite 

causal relationship” since this would make it more consistent with the second bullet 

indicating a “likely” causal relationship. The way it is written, it is not clear what the 

difference is between “causal relationship” and “likely causal relationship.” 

p. 5-13, line 15. The 5 ppm exposure is quite high and its relevance to the document is 

not clear. 

p. 5-16, lines 13-14. Does this sentence mean that the effects observed could have been 

due to NO2 or are most likely due to confounder pollutants? 

Table 5.3-1. This is an excellent table. 
39

Comments from Dr. Christian Seigneur

Charge question 2: 

To what extent are the atmospheric chemistry and air quality characterizations clearly 

communicated, appropriately characterized, and relevant to the review of the primary 

NO2 NAAQS? 

The second external review draft has been considerably improved in that regard. For 

example, Figure 2.2-1 is more accurate; the variability of the NO2 fraction of NOx

emissions is now correctly discussed, and the spatial variability of NO2 concentrations 

near sources (in particular, roadways) is properly described. 

Are the properties of ambient oxides of nitrogen appropriately characterized, including 

spatial and temporal patterns and relationships between ambient oxides of nitrogen and 

human exposure? 

The spatial and temporal patterns of NOx and NO2 are appropriately described. As 

mentioned above, the strong spatial gradients observed near roadways are discussed. The 

temporal variability of NOx and NO2 concentrations is also well characterized with 

sufficient detail being provided in the Annex (e.g., diurnal and seasonal variability). 

Does the information in Chapter 2 provide a sufficient atmospheric science and exposure 

basis for the evaluation of human health effects presented in later chapters? 

There is one aspect of the link between atmospheric science and exposure/health effects 

that needs to be better discussed in the ISA. Currently, measurement error is highlighted 

early on in the document (Section 1, p-1-11) as important when adjusting for spurious 

associations. The difference between true and measured ambient concentrations is 

identified as one of the components of measurement error. Such measurement errors are 

then discussed in detail in Section 2.3 for outdoor measurements and in Section 2.5.2 for 

indoor measurements using passive samplers. Some estimates of measurement 

uncertainty are provided. For outdoor measurements with the Federal Reference Method 

(FRM), an average interference from NOz compounds of 22% is given for Mexico City 

data with peak interference of 50%. A comparative study in Switzerland is reported to 

have shown average errors of 10% in winter and 50% in summer. This section concludes 

that the interference is likely to be on the order of 10% or less in winter, but much larger 

in summer. It is also stated that the interference from NOz compounds is less significant 

near the emission sources (because there has not been enough time for NOz species 

formation). Passive samplers used in individual exposure studies are described in Section 

2.5.2 as being within 10% of the FRM. 

The epidemiological studies presented in Section 3 have used in most cases NO2

measurements from FRM instruments or passive samplers. Therefore, one may imply 

that there may be significant uncertainties associated with the results of those studies 

because of the FRM interference errors discussed in Section 2. However, this aspect of 

the health effect uncertainty does not appear to be discussed. In reality, I anticipate that 

most NO2 exposure occurs near emission sources where NOz concentrations are low and, 
40

therefore, interference error is small. Also, the seasonal variability of NO2 concentration 

shows that in most cities higher concentrations occur in winter when the interference 

error is 10% or less. It may, therefore, be possible to consider that the NO2 measurement 

error is not a major source of error in health effects studies. However, such a point needs 

to be made clearly in the ISA. One possibility is to provide a more definitive discussion 

of the implication of the interference of the FRM at the end of the introduction of Section 

2.3 (p. 2-9). The fact that NOz species concentrations are low when NO2 concentrations 

are high (near emission sources, in winter) and the reasons why (not sufficient time for 

reaction, low photochemical activity) should be explicitly stated. Then, the implications 

for the health effects studies need to be articulated clearly. 

Annex 2.7.1. Chemistry-transport models 

This Annex section has been rewritten and a discussion of local-scale dispersion models 

has been added. This Annex section is overall well written and very useful. There is, 

however, one part, which requires some revision. On p. AX2-67 (at the end of the 

discussion of local-dispersion models), it is stated that (1) emissions from roadways are 

usually not in steady state and (2) that buoyant plume rise differs for point and line 

sources. The unwritten implication is that AERMOD, the model used in the exposure 

and risk assessment, would not be appropriate to simulate NO2 concentrations from 

roadways because (1) it uses steady-state assumptions and (2) it is a point source model 

and does not treat, for example, vehicle-induced turbulence. The text then goes on to 

discuss CALPUFF, a non-steady-state model that can treat dispersion from surface 

sources. The implication is that CALPUFF is a better model to simulate NO2

concentrations downwind of line sources such as roadways. This paragraph needs to be 

rewritten because (1) the limitations mentioned for AERMOD are not entirely correct and 

(2) the description of CALPUFF as a better model for line source dispersion is incorrect. 

In my earlier comments on the Methods document, I raised some concerns regarding the 

use of AERMOD for line source modeling and asked why a line source model such as 

CALINE would not be used. EPA replied that CALINE was no longer supported by the 

developer and that AERMOD was an acceptable model because it could be adapted for 

line sources. Although further development of AERMOD to become a true roadway 

dispersion model is warranted, I agreed with EPA that, given the dispersion models 

currently available, AERMOD was an appropriate choice. The statement made in the 

Annex regarding the non-steady-state nature of roadway emissions is not relevant 

because AERMOD is used to calculate downwind concentrations within a few hundred 

meters from the roadway and the travel time will be less than one hour (i.e., the time 

typically used for meteorological and emission inputs). The statement regarding the 

inappropriate treatment of the initial plume dispersion characteristics for a roadway in 

AERMOD is misleading as CALPUFF does not treat such roadway initial plume 

dispersion either. Furthermore, one must note that the current CALPUFF versions that 

are publicly available (e.g., versions 5.8 and 6) include a coding error that leads to 

incorrect NO2 concentrations near the source. 
41

Therefore, the last two sentences of that paragraph (“In contrast, there are models that are 

non-steady-state...”) should be deleted and the limitations of AERMOD when applied to 

line sources such as roadways should be rewritten in a more objective light. 
42

Comments from Dr. Elizabeth “Lianne” Sheppard

Final comments: Generally the document is much improved and the revisions have been 

responsive to previous CASAC comments. 

Charge question 1: 

Conceptually the framework outlined in Chapter 1 is on target. However it reads 

very much like a preliminary incomplete draft. Section 1.6 needs to be thoroughly 

revised. It has many of the right concepts mentioned, but often briefly, incompletely, or 

without good justification for the proposed modifications. For instance, Annex AX1 

contains a thorough compilation of previous work on evidence classification, but details 

on the translation into Chapter 1 are absent – there is no evaluation, interpretation, or 

justification for the modifications proposed on page 1-16 of the ISA. As another example 

Table 1.6-1 is an adaptation from two previous documents, but the details of and reasons 

for the adaptation are not discussed in the Chapter or Annex. 

Detailed specific comments: 

• P 1-8 section on scientific evidence used for identifying causality: There is a brief 

discussion of features of study designs and a later discussion of details of study 

designs (p 1-10). These should be combined. Also key points are missing. One 

is that the challenge with experimental studies is to create conditions that reflect 

the complexity of the naturally occurring exposures. Another is that observational 

studies represent conditions experienced by the population but inference from 

them is limited because of the absence of experimental intervention. Another is to 

mention cross-species extrapolation. 

• P 1-9: The footnote seems out of place in this chapter since the notation and 

concepts haven’t been introduced. 

• P 1-10 l 2: Is this what is meant?: “Developing evidence for going beyond 

association to causation involves integration of multiple sources of information 

into a coherent paradigm.” 

• P 1-10 l 10: Revise sentence. What does “Done properly and setting aside 

randomness” mean? 

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

• P 1-10 l 18 Experiments are stronger causally than observational studies tub 

much more limited in the realistic conditions that can feasibly be studied. 

• P 1-10 l 21 Confounders are only one consideration of causal inference from 

observational studies. 

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

• P 1-11 measurement error discussion is derived from the Zeger et al paper (not 

cited) and applies to the time series study design. It does not apply to all 

observational studies of air pollution, but the literature as yet does not have 

similar papers for other designs. 

• P 1-11 l 18 Replace “producing the findings” with “biasing the results” 

• How much should section 1.6 be a general review vs. specific application to the 

air pollution context (e.g. table 1.6-1)? It would be safer to directly cite the 

sources and then comment on features for this application in the text. 
43

• P 1-14 l 8 How about “Model averaging attempts to incorporate model selection 

uncertainty into the target parameter estimate...” 

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

• Publication bias should be addressed explicitly. Air pollution studies estimate 

small effects so some issues become relatively more important in this area: model 

selection, subgroup analyses, appropriate design and analysis approach (e.g. 

referent selection in case-crossover studies or panel study approach to analysis). 

• Table 1.6-1 Replace “decisive factors” and revise explanations, e.g. #8 drop 

reference to observational studies. 

• AX1-5,1-7 criteria for study selection: All studies are more or less successful on 

these criteria. Consider how to best address systematically evaluation and 

discussion of these for individual studies. I suggest moving towards a 1-2 page 

evaluation for each key study to be included in the annex. This evaluation will be 

much more detailed than the current appendix tables and addresses study features. 

• AX1-8 l 5-6 Is this regardless of analysis and reporting of results? For instance, 

an analysis that adjusts for measurement error will have wider confidence bands 

than one that doesn’t. Should the study that goes beyond common practice by 

adjusting for measurement error be given less weight? 

• AX1-9 l 21: Stay away from statistical significance as a criterion. Magnitude and 

precision of estimates should be enough. 

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

Charge question 2: Air quality and exposure 

The discussion of correlations is much improved although I would like to also see 

the formulas documented (e.g. in the annex) instead of just described. However, now that 

the discussion is clearer, it becomes even more questionable in my mind whether the 

comparisons across studies and study designs are useful. Correlations are standardized 

quantities that depend on multiple features of the data. In a correlation, not only is the 

linear “relatedness” (covariance) of the two quantities important, but so is the variability 

of each. Thus two estimates of correlation could be very different just because one is 

restricted to a single season (with less variability) while the other captures data from an 

entire year. Since I expect this feature is extraneous to the interpretation goal, should it 

be part of the comparison? More work is needed to make the comparisons across studies, 

populations, pollutants, types of correlation, etc. really useful. This is a difficult task 

since the literature doesn’t give clear guidance on how to summarize these studies. That 

said, I was surprised to see an apparently reasonable summary of this information in 

Chapter 5. 

Monitor siting is an important and often hidden feature in all of the NO2 data. It 

could be critically impacting the epidemiological studies and their interpretation. This 

feature potentially pervades much of the summarized literature and could be affecting 

conclusions. Any revisions to the document that can be done to directly and openly 

address monitor siting and its effects on results and interpretation will improve the ISA. 

Unlike PM, oxides of nitrogen vary dramatically as a function of distance from road and 

some monitors are sited near roads. Plus much NO2 data are being analyzed at the 

hourly time scale. Low correlations between monitors could be completely driven by the 

local sources. For instance, the analysis summarized in Table AX3.2-2 is focused on 

spatial variability but does not identify the locations or siting features of the monitors. 

Scatterplot summaries would also be revealing, particularly appropriately included in the 
44

annex. Further analyses of data may suggest features that should be highlighted in these 

comparisons. 

Specific comments: 

• Figures 2.5-4: Clarify the meaning of the sampling time (is this duration or 

averaging time?), the meaning of the information in the Fisher’s Z-transform 

column, and that the reported correlations are shown on the native (not 

transformed) scale. Consider separating figures by study design or type of 

correlation reported (including averaging time) rather than location of study. 

Sorting by high vs. low air ventilation season may be important also. 

• Section 2.5.6: Incorporate understanding of monitor siting into this discussion as 

appropriate. 

• 2-45 l 11-13: Is this a better sentence?: “The relationship between personal 

ambient NO2 exposures and ambient NO2 concentrations found in different types 

of exposure studies have distinct implications for different types of epidemiologic 

studies. 

• 2-45 l 30: I wouldn’t classify the relevant features of exposure to be the same for 

time series and long-term cohort studies. The cohort studies are mostly relying on 

spatial variation in a long-term average pollutant while the time series studies are 

relying on day-to-day variation in daily average. 

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

regarding health 

I found the integration and presentation of evidence in Chapter 3 to be generally 

good. However there are a number of details in the presentation I think need to be 

clarified to support the intent of the chapter. It is also critical that staff continue to refine 

and improve the information presented in the Annex tables. (I recognize this represents a 

massive effort.) The organization of these tables has been much improved, but I did not 

find that they include much more pertinent information. In trying to discern my 

agreement with the interpretations in Chapter 3 I often found I wanted to evaluate more 

detail on a particular study but this wasn’t available in the annex. I was trying to answer 

questions such as “did this study properly adjust for confounding”, or “what is the 

seasonal variation in the data”. There are also some misleading features in the uniform 

approach to summarization (such as the change in a 4-point symptom scale in the 

Chauhan et al (2003) study that appears to be reported as an OR in the appendix and does 

not include units in Chapter 3 (3-5 lines 21+)). Another important feature of the Chauhan 

et al study that is discussed in Chapter 3 but completely absent from the Annex summary 

is that it was conducted over a 13-month period. In looking ahead to future iterations of 

this ISA process, it is important to consider how to revise the approach. One suggestion 

is to prepare an annex to the annex with a much more thorough and less constricted 

summary of each study. Quite likely at least a page or more of abstracted information 

will be needed for each study, at least for the studies that end up providing the greatest 

weight of evidence for the inference. Finally, both for the current version and in future 

versions, better indexing and cross-referencing is needed so the supporting information 

can be found efficiently. 

The conclusions brought forward into chapter 5 and summarized clearly in Table 

5.3-1 looked generally appropriate. I ask staff and CASAC to consider whether it is 

worth also listing health outcomes that have not been studied in this table. 
45

Specific comments: 

• Make sure all figures and other summaries include the increment of NO2 (or other 

pollutant as appropriate) for the RR/OR estimate. This is not done consistently 

throughout the document. 

• Please downplay the apparent use of statistical significance as a criterion for 

scientific importance throughout. In that vein, change the y-axis for Figure 3.1-2 

to not be an evaluation of statistical significance. The new version of Figure 3.1-1 

appears to be more informative but I wonder if the graphic misleads in the 

ordering and scaling of the y-axis. 

• P 3-2 l 31: Add a sentence like: “Fourth only a limited number of conditions can 

be evaluated feasibly. 

• P 3-3 paragraph 1: If possible, include a comment on which of the limitations in 

toxicological studies are most important in this context. 

• P 3-4 l 5: This is an example of a natural experiment, not an intervention study. 

This perspective appears elsewhere in the document(s) as well. 

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

• P 3-5 l 19, 21: Make sure units are included in this reporting and fix AX6-30 

where the effect estimate appears to be reported as an OR. Furthermore, the 

summary information in the Annex fails to mention that this study covers a 13-

month period – an important feature to consider in evaluating the results. 

• P 3-8 l 3: Why are the findings conflicting? Is this another example of confusing 

statistical significance with scientific evidence? 

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

• P 3-11 l 4: Here is an example where the increment of NO2 isn’t cited but is 

important for interpretation. 

• P 3-11 l 15-16. Here is a case where the differences in correlations may be due to 

monitor siting. Any way to address that? Also define the correlation w.r.t. time 

scale, location. 

Charge question 4: 

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

I like the idea of listing all likely susceptible groups and then determining whether 

there is any information in the literature about these groups. This can be a new 

framework that is applied to all pollutants and allows for a very open and transparent 

evaluation of our focus on particular groups. It also clearly identifies gaps in the 

literature with respect to this topic. 

The concentration-response section 4.2 needs work. Much of the discussion appears 

to have the time series study design in mind, and if this is the case it should be stated (p 

4-4 ll 16-24, l 25). How does the discussion on p 4-5 l 20-29 inform our understanding of 

the shape of the concentration-response function? 

• P 4-5 l 16-17: Does this sentence refer to a nonlinear concentration response 

function? Clarify. 

Charge question 5: 
46

Generally the integration and summarization of the evidence in Chapter 5 was 

quite good, even for cases where I quibble with the details in earlier chapters. The new 

framework for causality supports the goals of the ISA and provides clear-cut criteria for 

health endpoints to bring forward into the Risk and Exposure assessment. More work 

should be done in consistent application of the Hill criteria. The CASAC discussion 

reflects my own concerns about whether this draft provides an adequate foundation for 

preparation of the ERA, particularly with respect to transparent use of the literature for 

policy. 

Additional points from the discussion that I echo here: Has the document clearly 

established what we know and what we don’t know? Clearly state the goals of chapter 5 

in the beginning. Is NO2 the pollutant or the index for the effects? 

Detailed comments: 

• P 5-2 l 7-8: Is the evidence for conclusions only based on the Hill critieria? I 

would include consideration of the overall quality of the studies that are weighed. 

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

• P 5-4 l 28-31 + 1-2 next page: Clarify the details. I want words inserted, e.g. 

“Intersite temporal correlations for hourly average NO2...” and “...twenty-four 

hour average concentration...” 

• P 5-5 bullet starting l 3: Clarify “epidemiological studies.” Not all are the same 

and I presume this bullet statement refers to time series studies. 

• P 5-5 bullet starting l 20: This summary of the difficult to summarize features of 

personal vs ambient correlation is fairly reasonable. However I don’t think 

statistical significance is the right criterion. Focus instead on the estimates. 

• P 5-9 figure: Insert the NO2 increment used. Add a footnote to caution against 

overinterpretation of this nice summary: “Studies include different lag days and 

adjustment variables” 

• P 5-17 l 15: Revise. Statistical significance is not the key feature, for instance a 

statistically significant effect could be in the “wrong” direction. 

Other general comments: 

• There is still overuse of “statistically significant” in this document. This is binary 

summarization of the data that depends on multiple features including magnitude 

of the effect, variability, and sample size. It doesn’t reflect scientific meaning. 

To the degree possible replace focus on statistical significance with more 

meaningful quantities (e.g. effect estimates and confidence intervals). 

• There continues to be a need to more thoroughly reference supporting information 

in the annex and make it easier for readers of the ISA to find this information. 

. 
47

Comments from Dr. Frank Speizer

Chapter 2 

 The setting out of the conceptual model in figure 2.1 provides an excellent overall 

view. The devil is in the details that follow. 

Review of Atm. Chemistry and Air Quality: 

Page 2.3, line 15: It is probably worth indicating that from elevated sources the 

dispersion and dilution results in lower levels albeit more widely dispersed. 

Page 2.3, Line 28 and Figure 2.21: The text suggests right Side outer box is NOz but 

label does not appear in the figure. Needs to be added. 

Page 2.6 para beginning line 10: It might be useful in the paragraph to indicate the 

relative amounts of POM measured. 

Spacial and Temporal pattern of ambient NOx and human exposure 

Page 2.13, Para beginning line 25: Is it worth either indicating (or speculating) that the 

increase in NO2 in other countries (could read Western Europe) is related to increase 

diesel and other mobile source utilization, are there canyon effects, is there a difference in 

fuels or engines, etc.? 

Excellent organized discussion of exposure issues pointing out some of the uncertainty 

that will have to be taken into account. But certainly providing enough evidence that 

subsquesnt risk assessment can be done, at least for selective sites, albeit with less data 

than were available for PM and O3. 

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

Page 2.24, end of line 4: Suggest adding a table of results from McCurdy et al 2000, 

giving assessment of 11 different human activity patterns. 

Page 2.25, line 4 and line 9: Need to rectify the discrepancy between the two statements 

although rest of paragraph provides some insight. I do not know what to believe! 

Page 2.27, Table 2.51: Needs a footnote. Table ought to be able to stand alone rather 

then needing text in lines 1-7. 

Page 2.28: Surely the important thing here is the paragraph beginning on line 18. The 

previous paragraph beginning on line 6 is mostly descriptive of what is in Table 2.5.1 and 

could have been left out. 

Page 2.48, para beginning line 7: Needs editing. Discussion of P, K and a mention of 

twice as not thoroughly investigated.. 

Page 2.50. Summary: Strengths (and weaknesses) of existing data and what inferences 

can be drawn are well described. 

Chapter 3 
48

Intergrated evidence for Toxicology, human studies, and epidemiology 

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

literature. 

Seems to me that a qualitative summary of Hill’s criteria might be created in a table for 

acute effects. Something like: (don’t take my +s and –s seriously). 

Hill Criteria Host Def 

& 

Immunit

y 

Inflammatio

n 

Short 

term 

A.R. 

Resp. 

Symptom

s 

Lung 

Functio

n 

Hosp

. 

Mort

. 

Strength + + (1ppm x2-

3hrs) 

++ Gen. 

Neg 

-- -- 

Consistenc

y 

+ + +/- ++ +/- nul -- 

Coherence ++ +/- (in 

children 

only) 

+/- 

(few 

studies

) 

++ - -- -- 

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

Ditto something for chronic effects where respiratory effects range RR=1.1-1.3, 

consistent, particularly in children and adults >65. Asthma 25% increase. No copollutant effect, COPD mortality no coherent picture. Long term for other morbidity 

concur “inadequate evidence to infer presence or absence of causal relation. 

Sections do not contain references. 

Public Health Implications 

Reasonable brief summary. Potential for some confusion in the use of terms susceptible 

and vulnerable. Sometimes used interchangeably when really means different thinks. 

Just be careful how the terms are used. 

Integrated summary and conclusions. 

Table 5.3.4 might be helped in exposure levels were included. 

Chapter does a good summary that will work for the risk assessment. 
49

Comments from Dr. George Thurston

 In these pre-meeting comments, I will focus upon responding to my assigned 

questions for the ISA. 

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

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

evaluation of studies and causality determination? 

 In reading the NOx ISA document, I found that the epidemiological studies I was 

aware of were considered, and could see no gaps in the epidemiological literature, which 

has greatly strengthened the evidence for an association between acute NOx exposure and 

respiratory health effects. With regard to the toxicological studies, I felt that, considering 

the potential inter-species differences in vulnerability, that it was very appropriate for the 

document to include studies that used exposures on the order of 5 ppm (approximately 10 

mg/m3) to be very appropriate in this document, as such studies (while not useful for the 

estimation of human dose-response estimation) may well provide insights into the 

potential mechanisms of damage that might be caused by NOx. 

 One area that was lacking was a more intensive consideration of the evidence of 

potential impact of the co-exposure of particles and NOx, both in the toxicology and 

epidemiology. While I am not as familiar with the toxicological literature, I note that an 

informative toxicological study by H.G. Boren [“Carbon as a carrier mechanism for 

irritant gases” Archives of Environmental Health, 8, 119-124]. In this paper, a short-term 

exposure to 47 mg/m3 (25ppm) of NO2 or inhalation of fine carbon particles exhibited no 

gross pathological effects in the mouse lung, but when the mice were exposed to carbon 

particles that had previously been exposed to NO2, the mice developed local destructive 

lesions, with loss of cells from the alveolar walls. While just one study with high levels 

of NO2, this study indicates that the co-presence of particles with NO2 can enhance the 

effects of NO2. Since particles are always in co-exposure with NO2 in the real world, 

this may provide an important pathway of effect, but one that is not considered by this 

document, despite my raising this concern early in the process. My question: are there 

more published toxicological studies considering this particle-NOx interaction 

mechanism? This seems well worth another intensive look through the entire literature 

with that focus in mind. 

 

3a. To what extent is the discussion and integration of evidence from the animal 

toxicology and controlled human exposure studies and epidemiologic studies technically 

sound, appropriately balanced, and clearly communicated?? 

? 

 This is where my above-noted concern really manifests itself. What we have is a 

wide gap that needs to be bridged between the controlled exposure studies and the 

epidemiological study results. The former show respiratory effects of NO2 only down to 

about 200 ppb, while the latter routinely and robustly document significant NO2-

respiratory associations down at ambient levels. How can that be the case? We 

previously confronted a similar situation in the 1980’s, when our NYU-Harvard study’s 

of children at summer camps documented significant lung function decrements among 
50

children to be associated with ozone exposures below 100 ppb, while the controlled 

exposure studies only showed effects down to 120 ppb. Subsequent more realistic 

controlled exposure studies (with exercise) later confirmed the epidemiology, and we 

now have a more protective ozone standard. 

 With regard to NO2, I suspect that ambient particles, always present in 

epidemiological studies, but not present in controlled NOx exposure studies, may provide 

the vector for the apparently enhanced effects of NOx in epidemiology vs. controlled 

studies, but the evidence for this possible avenue to justify the apparent discrepancy 

between the epidemiology and the controlled-exposure studies is not sufficiently explored 

in this report. In some cases it is noted in the ISA already (e.g., the fact noted that the 

APHEA study found greater PM effects in cities with higher NO2 levels), but needs to be 

brought together to address this specific issue. Thus, while some of the evidence is 

already present, and more may be in literature not yet brought to bear (or not yet 

collected), it is important to identify in the ISA what we do and do not know about this 

potential mechanism of NOx effects, and about other possible factors that may be 

responsible for this apparent disparity between the levels of effects (e.g., that the most 

susceptible subjects may not be considered in controlled-exposure studies, or that 

exercise may be a factor, both of which are mentioned here and there in the ISA). 

 The way to bring this about in the document, I suggest, is to add a section to 

Chapter 5 where the questions asked at the start of the Integrative Summary (on page 5-1) 

are answered to the best we can at this time, and which identify areas of further needed 

investigation to answer the question more definitively. In particular, the most important 

question to be answered is: 

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

 Answering this particular question will expedite the addressing of the gap 

between the controlled-exposure results and the epidemiology results, as well as a 

comprehensive consideration as to why that might be (i.e., Particle-NOx interactions? 

Greater degrees of susceptibility in the general public? Exercise? etc.). 

3b. What are the views of the Panel on the conclusions drawn in the draft ISA regarding 

the strength, consistency, coherence and plausibility of NO2-related health effects 

 While I generally agree with judgments reached by the EPA regarding the 

strength of the evidence regarding causality, there is a need to discuss the concentrations 

where the various effects are applicable, as discussed above. 
51

Comments from Dr. James Ultman

This well-organized and comprehensive document and its appendices provides a critical 

analysis of the newest literature as well as highlighting conclusions make in the 1993 

Criteria Document. The EPA staff and its consultants are to be congratulated for a job 

well done. 

As a second draft of the ISA, the document has effectively incorporated the most 

important suggestions of the NOx Review Panel including better detailing of the criteria 

used to judge causality and the means by which studies were selected for inclusion in the 

document. 

Chapter 1. 

No comment. 

Chapter 2. 

The description of emission sources and of the spatial variation of ambient 

measurements is much improved in this chapter. 

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

The sparseness of monitor sites in Figure 2.4-1 begs the question of how compliance is 

uniformly enforced in all regions of the country. 

Figure 2.4-2 indicates the hourly-average ambient NO2 concentration at current 

monitoring sites almost never exceeds the lowest benchmark level of 200 ppb used in the 

Exposure and Risk Assessment. This underscores the importance of on-road and indoor 

sources that have a small influence on the ambient air measurements but a strong 

influence on personal exposure. 

In figure 2.4-3 and others like it, the image should be coded in gray-scale (rather than 

color) before it is printed out. 

There is an error in the title of figure 2.4-6d. WeekdayÆWeekend. 

In equation 2.5-5, Cnona has a subscript that is inconsistent with the subscript on Cna used 

in the text. 

In the dosimetry section on page 2-59, there is not much progress to report since the 1993 

Criterion Document. Because the Exposure and Risk Assessment is based directly on 

observations made in clinical experiments, the need to use such models for dose 

extrapolation is not necessary for the current ISA. 

Chapter 4. 

No comment. 
52

Chapter 4. 

No comment. 

Chapter 4. 

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

the risk assessment. 

On page 5-3, the key finding that the NO2 concentration is overpredicted by 25% by 

current monitoring methods is probably a good thing since the overprediction is due to 

other NOx and NOy that may also induce a health effect. 

In the Conclusions on page 5-20, it would be appropriate to provide direct, succinct 

answers to the framing questions posed on page 5-1. 

 

Answer to charge question 2. 

I believe that the chapter does meet all the objectives outlined in the charge question. I 

do suggest, however, that material be added that describes and supports the method of 

extrapolating ambient monitor measurements to on-road concentrations. This is too 

important an issue to leave for the brief discussion that currently appears in section 6.2.3 

of the Exposure and Risk Assessment document. 
53

Comments from Dr. Ronald Wyzga

Overall comments: 

This draft is much improved over the previous version. The siting of monitors is 

discussed, and there is a much better understanding of reported ambient measurements 

represent. The review of the health literature is comprehensive and makes it easier to 

achieve a good overall understanding of the health consequences of NOx exposure. The 

summary of the health effects discussed in Chapter 5 is an excellent organizational tool 

that facilitates an understanding of the nature and consequences of ambient exposures to 

oxides of nitrogen. There are a few areas that need further clarification. These are 

presented below in more detailed comments. 

Charge question 2: To what extent are the atmospheric chemistry and air quality 

characterizations clearly communicated, appropriately characterized, and relevant to the 

review of the primary NO2 NAAQS? Are the properties of ambient oxides of nitrogen 

appropriately characterized, including spatial and temporal patterns and relationships 

between ambient oxides of nitrogen and human exposure? Does the information in 

Chapter 2 provide a sufficient atmospheric science and exposure basis for the evaluation 

of human health effects presented in alter chapters? 

I have two suggestions here. The document refers to several studies undertaken overseas, 

several of which focus on distance to roadways as a factor “affecting indoor and outdoor 

NO2 concentration and personal exposure”. To the extent that the overall nature of 

exposure could be quite different from that in the US given differences between the US 

and overseas sources in terms of fleet composition and extent of pollution control, there 

should be some note made about the geographic setting of these studies and whether the 

setting is typical of those found in the contemporary US. Any information on copollutants and concentrations would be particularly helpful. 

Since the strength of the health argument for NO2 health effects is tied to the 

observations that effects are found in studies which consider both indoor and outdoor 

exposures, it would be particularly interesting for this chapter to provide some additional 

information to inform this argument. For example, given the typical sources of indoor 

and outdoor NOx, how does the composition change with respect to the different oxides 

of nitrogen and are the co-pollutants the same or different in indoor and outdoor settings? 

Charge question 3: To what extent is the discussion and integration of evidence from the 

animal toxicology and controlled human exposure studies and epidemiologic studies 

technically sound, appropriately balanced, and clearly communicated? What are the 

views of the Panel on the conclusions drawn in the draft ISA regarding the strength, 

consistency, coherence, and plausibility of NO2-realted health effects? 

One of the difficulties in interpreting the epidemiological study results is that it is often 

unclear whether health responses are due to traffic or to NOx per se, an ingredient of 

traffic-generated air pollution. To the extent possible, the document should attempt to 

indicate those studies where traffic is deemed to have a lesser influence on NOx 

exposure. 
54

I would like to see a more rigorous examination/discussion of the co-pollutant issue; for 

example, which co-pollutants were discussed in which study; which were not. Are there 

any differences in measurement error, etc. I personally share some of the concerns raised 

by Brook et al. (2007) cited in the document. 

In several places studies were not considered because they “did not inform”; this needs to 

be clarified. 

Charge question 5: What are the Panel’s views on the adequacy of this external review 

draft ISA to provide support for future exposure and policy assessments? 

The current draft is a helpful document and a great improvement over the previous draft. 

With the appropriate consideration of the issues raised elsewhere in this review, the 

document would be an excellent resource for future exposure and policy assessments. I 

also believe that the document needs to tackle the issue of whether associations between 

NO2 and health responses in epidemiological studies are a reflection of NO2 exposures 

per se or is NO2 an index surrogate for some other exposure associated with NO2 

sources. I believe the information is scattered throughout the document to help address 

this question, but an explicit and articulate consideration of this issue would greatly 

improve the document. 

Specific comments: 

Page 2-21: Figure 2.5-1 “residence” 

Page 2-29, ll 1-3: Does this mean that local sources and near-source concentrations are 

not to be regulated? I think the wording needs to be changed here. 

Page 2-42, ll. 5-6: statistical significance per se in not as informative as R2

; if the sample 

size is large enough any non-zero correlation will be statistically significant. 

Page 2-52, Table 2.5-7: The paper by Brook et al. (2007) cited later in the document 

should be mentioned here. I find it particularly noteworthy that NO2 is highly associated 

with several organic compounds. 

Page 3-12. Figure 3.1-1: This figure is helpful, but it should also indicate the time and 

concentrations of exposure of exposure in the subtable. See Figure 3.1-2. This would 

allow the reader to judge whether the application of Haber’s law is appropriate and could 

facilitate the interpretation of results. 

p. 3-26, ll 28- : Are there any co-pollutants associated with these exposures? Are they 

different from the outdoor studies? 

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

p. 3-57, ll. 9-14: clarify what is meant by “did not inform”; if a study is not considered, it 

is important to understand why. Similar comments exist elsewhere; e.g., p. 3-58, ll 17-20. 
55