1 UNITED ST ATES E N VI RON M E N T A L PR OTE C TION AGE NCY

WAS H INGT ON D. C. 204 60

OFFI CE OF THE A D M I N ISTR A T OR
SCI E NCE A D VI SORY BO A RD

June 25, 2008

EPA-CASAC-08-015

The Honorable Stephen L. Johnson

Adm i nistra tor
U.S. Environm ental Protection Agency 1200 Pennsylvania Avenue, N.W

. Washington, D.C. 20460

Subject: Clean Air S c ientific Adviso ry Comm ittee’s (C ASAC) Peer Review of EPA’s Integrated Science A ssessm e nt (ISA) for Oxides of Nitrogen – Health Criteria (Sec ond External Review Draft)

Dear Adm i nistrator Johnson:

The Clean Air Scientific Advisory Co mm ittee (C ASAC), augm ented by subjectm a tter-exper t s to f o rm the CASAC Oxides of Nitrogen Prim ary National Am bient Air Quality Standards (NAAQS) Review Panel (herea fter referred to as the panel, roster contained in Enclosure A) held a public m eeting on May 1-2, 2008 to review EPA’s Integrated Science Assessment for O x ides of Nitrogen – Health Criteria (Second External Review Draft) (EPA/600/R-07/093aB, March 2008 ) . The Cha r tered 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 eval uation of the most policy-relevant science”

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

am bient air quality stan dards for review of the prim ary standard for oxides of nitrogen (NO

x ).” Although the CASAC finds that th e second draft IS A was m u ch im proved

com p ared to the first draft reviewed in Nove m b er 2007, the docum e nt in its current state does not provide adequate guidance as to wh at would be expected at current am bient

concentrations. CASAC finds that s c ientif ic data exist with which to an swer th is question, albeit with some level of uncertain ty, so that the docum ent can provide an adequate scientif ic ba sis f o r the exposure and policy assessmen ts during the next stage of the NAAQS review. Perhaps the m o st im portant consideration in im proving the

docum ent is a m u ch better discussion of the significance of the epidem iology data for a potential ris k assessm ent, despite th e un certainties associated with those d a ta. Incorporatin g an analys is of the available epidem iology data will allow estim ation o f the potential un certainties that n eed to be fully described a nd quantified in the risk and

exposure assessm ent. The ISA discussion shoul d consider the effect of co-exposures to2 other pollutants, the relations hip between ambient and personal exposures, and how the problems associated with the available epid emiology studies limit their use for risk assessment. Because of EPA’s accelerated NAAQS schedule for NO

x , 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 IS A 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, cr iteria for study selection, the framework

for scientific evaluation of studi es 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 prep ared that reviews a number of relevant frameworks. The background is a useful founda tion for informing the selected approach for assessing available evidence and shoul d be extended to ju stify the adopted framework. Based on this Annex, the Agency has made changes in Chapter 1 that are responsive to prior critiques. In particular, th ere 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 ev idence for causation is offered.

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

that includes the framework for the document. However, the sections that synthesize the evidence are still somewhat loosely writt en, 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 misnome r). 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 appli cation of the criteria offered by Hill. Nonetheless, the revised Chapter 1 and the a pproach set out repres ents an advance over

the earlier draft.

Additional issues that ar e not considered are public ation and model selection biases, a concern given that many studies addr ess the health effects of air pollution and employ multivariable models to attempt to isol ate the effects of particular pollutants at specific temporal or spatial scales. There ma y 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 thos e experienced by the populations in epidemiology studies. Speci fic consideration needs to be given to the relevance of mechanisms identified in toxicology studies to effects observed in the epidemiology

studies.3 Charge Question 2. To what extent are the atmospheric chemistry and air quality characterizations clearly communicated, a ppropriately characterized, and relevant to the review of the primary NO 2 NAAQS? Are the propertie s of ambient oxides of nitrogen appropriately characterized, incl uding spatial and temporal patterns and relationships between ambient oxides of nitrogen and human exposure? Does the information in Chapter 2 provide a suffi cient atmospheric science and exposure

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

Overall, the description of the atmos pheric dynamics, measurement techniques and ambient concentrations is adequate, t hough aspects are still wa nting. The document would benefit greatly by having summaries at the end of each section with the points most key to providing informa tion that will be used in technical documents supporting the rulemaking for NO 2 , in particular those that info rm the rest of the ISA and the risk/exposure assessment (REA) and delineate wh at matters. The Pane l still view s that a quantitative summary of sources would be beneficial. The REA relies heavily on the application of various m odeling techniques, includi ng AERMOD and an empirical approach for estimating on-road NO 2 concentrations. Consequently, the needed background information on their scientific funda mentals, and their ability to reproduce observed concentrations, should be covered in the ISA. Along those lines, given the importance of on-road concentrations, that s ection of the ISA should be enhanced, with additional attention given to street canyon concentrations. Siting characteristics of

monitors should be incor porated into all analys es of monitoring data.

The Panel found that the section on measurem ent interferences c ontinues 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 NO 2 levels and annual averages and identifying whether the interferences pose an important issue for exposure and epidem iology studies). Give n the potential that the REA may depend more heavily on the epidemiology results, the ISA should more comprehensively assess how NO 2 levels correlate with air quality variables besides particulate matter (PM) mass (either PM 10 or PM 2.5 ), ozone and sulfur dioxide, e.g., addressing the correlations with elemental carbon, organi c carbon and other combustion products. It is known that carbon pa rticles will adsorb NO 2 when they are exposed to high concentrations of the gas in the lab. EPA s hould consider the extent to which this may occur in the atmosphere

. .

In the last section on dosimetry, there is little progress to re port on extrapolation modeling since the 1993 Criteri a Document. Nevertheless, the established dosimetry models could be applied to the many of the ke y 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 conditio ns in the epidemiological studies.

Charge Question 3. To what extent is th e discussion and integration of evidence from the animal toxicology and cont rolled human exposure studies and epidemiologic studies technically sound, appropriately balanced, and clearly

communicated? What are the views of th e Panel on the conclusions drawn in the4 draft ISA regarding the strength, consis tency, coherence and plausibility of NO 2 - related health effects?

The second draft ISA is s ubstantially 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 in corporated into this ISA dr aft. Substantial new findings

have occurred since 1993 that are relevant to th e issue of health risk s related to oxides of nitrogen. These include animal toxicol ogy 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 eff ects that can be attributed to NO 2

.

Panel members concur with the primary conclusions reached in the ISA with regard to health risks that are associated with NO 2 exposure. In particular, the Panel agrees with the conclusion that the current sc ientific evidence is “sufficient to infer a likely causal relationship between short term NO 2 exposure and adverse effects on the respiratory system.” The strongest evidence in support of this conclusion comes from epidemiology studies that show genera lly positive associations between NO 2 and respiratory symptoms, hospitalizations or emer gency department visits, as summarized in Figure 5.3.1. Furthermore, we would concl ude that the epidemiology studies show significant effects related to NO 2 exposure that are robust in some cases, even when adjusted for co-pollutants. One limitati on of the available epidemiology studies, however, is an inability to establish a definitive NO 2 exposure level that can be specifically associated with the observed a dverse health effects. Consequently doseresponse relationships are di fficult to establish for NO 2 , however best estimates and their uncertainties should be discussed. Separately and for future consideration, there is a recognized need to consider re gulatory approaches to comple x mixtures of air pollutants rather than considering e ach pollutant individually.

The human clinical studies reviewed in the ISA need to be interpreted with caution. The lowest reported effect of NO 2 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 si milar or higher levels of NO 2 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 advers e effect. Epidemiology studies more directly

address these adverse health effects and provide evidence id entifying health risks related

to ambient NO 2 exposures. In summary, the new scie ntific literature reviewed in the second draft of this ISA document provides a number of strong indi cations of possible

NO 2 health effects, but confounding or exacerb ating co-pollutants a nd variable findings in human clinical studies remain problem atic. Of special concern are potential interactions with particulate matter, potentially increasing lung NO 2 dosages above what

would occur with NO 2 alone. These aspects should be addressed in considering a revised

criteria standard for NO 2

.5 Charge Question 4. What are the views of the Panel on the characterization of groups likely to be susceptible or vulnerable to NO 2 and the potential public health impact of NO 2 exposure?

Overall, the draft ISA does an adequate job of discussing the public health significance of exposure to ambient NO 2 . The chapter 4 summary indicates that persons with preexisting respiratory disease (especia lly asthma), children, and older adults may be more susceptible to the effects of NO 2 exposure. While the panel agrees with this assessment, other subpopulations may also be at increased risk of adverse health effects from exposure to ambient NO 2 . Specifically, there is evidence in the ozone and PM

health effects literature that individuals who have poor dietar y intake of antioxidants, are obese, or have certain genetic variants, as we ll as premature or low- birth-weight infants, may be more susceptible to these pollutants. Since NO 2 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 subpopulatio ns that are likely su sceptible to adverse effects of exposure to NO 2 and to identify the research that indicates that susceptibility.

The panel recommends that the draf t ISA more clearly communicate the distinction between “susceptibility ” and “vulnerability.” Sus ceptibility as used in the latest draft ISA appears to describe those factors that may be considered “host” or

“intrinsic” while vulnerabil ity appears to be related to an interaction between susceptibility (risk-based on intrinsic risk fa ctor) and increased risk of exposure. As currently used in the document, these terms ha ve 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 bot h accurately reflected that earlier material

and chosen the material most re levant 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 th rough the improvements we have suggested in our review. Chapter 5 does indicate directions that are important fo r exposure and policy assessments: towards sensitive subpopulations that should be considered; towards specific health effects that should be c onsidered; 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 be6 provided so that a risk asse ssor 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 inad equate basis for performing exposure and policy assessments quantitatively, or even summa rizing the information that will be used

in such assessments. The draft is uninformativ e as to what the levels of exposure are for any specific population in any specific geogr aphic location. The authors should have summarized at least the ambient exposure in formation available (alluded to in the previous chapters) and then dr awn 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 i ndoor exposures). This summary and its interpretation can be offered without m oving into the policy domain or even unduly specifying the tasks of further exposure a ssessors. 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 w ith 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 ambien t 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 impor tant conclusions to be drawn from the document. Some statement with regard to th e degree of certainty in the occurrence of effects at ambient levels is needed, no ma tter 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 NO 2 and health responses in epidemiology studies result from NO 2 exposures per se or whether NO 2 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 w ould greatly improve the draft.

Finally, to meet that goal, the draf t ISA should be improved through a better discussion of the significance of the epidem iology data for a potential risk assessment despite the uncertainties associated with thos e data. Incorporating an analysis of the available epidemiology data into the risk a ssessment will allow estima tion of the potential uncertainties that need to be fully descri bed and quantified in the risk and exposure

assessment. The ISA discussion should cons ider the effect of co-exposures to other pollutants, the relationship between ambi ent and personal exposures, and how the limitations of the epidemiology studies im pact their use for risk assessment.In closing, the CASAC was pleased to revi ew this second draft of the ISA for the prim ary NO

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

im portant task.

Sincerely,

/Signed/

Dr. Rogene Henderson, Chair

Clean Air S c ientif ic Advisory Comm ittee

Enclosures

Enclosure A : Roster of CASAC Oxi d es of Nitrogen Prim ary NAAQS Re view Panel

Enclosure B : Com p ilation of Individual Pa nel Mem b er Comments on EPA’s Integrated

Science Assessm ent (ISA) for Integrated Science Assessm ent for Oxides of Nitrogen – Health Criteria (Second External Review Draft)

7Enclosure A 

### U.S. Environmental Protection Agency Clean Air Scientific Advisory Committee Oxides of Nitrogen Prim ary NAAQS Review Panel

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

CASAC MEMBERS Dr. Ellis B. Cowling , * University Distinguished Profe ssor At-Large, Emeritus, Colleges of Natural Resources and Agricultur e and Life Sciences, North Caro lina 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, Departme nt of Environmental Sciences and Engineering, Carolina Environmental Program, Un iversity of North Carolina at Chapel Hill, Chapel Hill, NC

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

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

Dr. Jonathan M. Samet , Professor and Chair of the Depa rtment of Epidemiology, Bloomberg School of Public Health, Johns H opkins University, Baltimore, MD

CONSULTANTS

Mr. Ed Avol , Professor, Preventive Medi cine, Keck School of Medicine , University of Southern California, Los Angeles, CA

Dr. John R. Balmes , Professor, Department of Medi cine, Division of Occupational and Environmental Medicine, University of California, San Francisco, CA

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

Dr. Dale Hattis , Research Professor, Center for Tec hnology, 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 MeetingDr. Steven Kleeberger , Professor, Lab Chief, Labor atory of Respiratory Biology,

National Ins titu te of Environm ental Health Scie nces, Nation a l Ins t itutes of Health, Research Triangle Park, NC

Dr. Timothy V. Larson , Professor, Departm e nt of Civ il and Environm ental Engineering, University of W a shi ngton, Seattle, WA, USA

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

Health and the Environm ent, Unive r sity of California, Davis, CA

Dr

. E d wa r d P o s t l e t h wa i t , Professor and Chair, Departm e nt of Environmental Health Sciences, School of Public Health, Univers ity of Alabam a at Birm ingha m, Birm ingham,

AL

Dr. Richard Schlesinger , Associate Dean, Departm e nt of Biology, Dyson College, Pace University, New York, NY

Dr. Christian Seigneur , Vice President, Atm o spheric & Environm ental Research, Inc.,

San Ra m on, CA

Dr. Eliz a b eth A. (Lianne) Sheppard , Research Professor, Biostatistics and

Environm ental & Occup a tiona l Health Sc iences, Public Health and Community Medicine, University of Washington, Seattle, WA

Dr. Frank Spei z er , Edward Kass Professor of Medici ne, Channing Laboratory, Harvard Medical School, Boston, MA

Dr. George Thurston , Professor, Environm ental Me dicine, NYU School of Medicine, New York University, Tuxedo, NY

Dr. James Ultman , Professor, Chem ical Engin eering, Bioengineering P r ogram , Pennsylvania State Universi ty, University Park, PA

Dr. Ronald Wyz g a , Technical Executive, Air Quality Health and Risk, Electric Po wer Research In stitu te, Pa lo Alto, CA

SCIENCE ADVISORY BOARD STAFF Dr. Angela Nugent , Designated Federal Officer, 1200 Pennsylvania Avenue, NW 1400F, W a s h ington, DC, Phone: 202-343-9981, Fax: 202-233-0643, ( nugent.angela@epa.gov )

910 Attachment B: Compilation of Indi vidual Panel Member Comments on EPA’s Integrated Science Assessment (ISA) for In tegrated 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. Do uglas 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 ................................................................................. 5311 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-wri tten and with sufficient detail and reference to provide readers with useful guidance and docum entation, 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 exampl e, in Chapter 3). Although an excellent summary of the chapters appears as Chap ter 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 ch aracterization of the search strategy for identifying literature, criteria for study sele ction, 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 utilit y 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 relationshi p” and “sufficient to infer a likely causal relationship”. Isn’t the clarification curre ntly present (“more likely than not”) the

definition for the next lower le vel of confidence (“suggestive but not sufficient to infer a causal relationship”)?

2. To what extent are the atmospheric chemis try 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 evaluati on of human health effects presented in later chapters?

In general, yes...However, P2-7 through P2-1 0, Section 2.3 provide s useful (and much appreciated) information regarding the vari ous approaches to measurement of ambient levels of nitrogen-containing species, but doe s not provide any succinct conclusions or directed message for the reader. Perhaps a cl osing paragraph or bullet to provide a “takehome” message would be valuable? What di screte 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 studi es and epidemiologic studies technically sound, appropriately balanced, and clearly communicated? What are the views of the

Panel on the conclusions drawn in the draf t ISA regarding the st rength, consistency, coherence and plausibility of NO2-related health effects?12 This portion is generally excellent - well-written, thoughtfully presented, and meticulously designed. The summary figures, visually presenting th e results of numerous studies to gauge consistency of respons e 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 secti on 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 l iterature. A PubMed se arch 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 susceptibil ity and vulnerability in this document would be useful; this is likely to otherwise create some confusi on. Is vulnerable bei ng 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 “...partic ularly susceptible to air pollu tion...”, 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 e xposure and policy assessments?

Overall, this document provides sufficien t support for future exposure and policy

assessments.

Specific Comments Chapter I - IntroductionP1-13, Fig 1.6-2 – shoul dn’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. Si milarly, shouldn’t there be a “S urrogate” arrow from NOx to

Other Pollutants?

Chapter 2 – Source to Tissue Dose P2-18, line 1 – (spelling error in San Bernardi no, and I don’t think I ha ve ever heard this region referred to as the San Bernardino “Valley”...??) P2-21, Figure 2.5-1 (spelling e rror, “In a residence”(68.7%)

Chapter 3 - Integrated Hea lth Effects of NO2 Exposure (No additional specific comm ents other than those above)

Chapter 4 – Public Health Significance13 (No additional specific comm ents other than those above)

Chapter 5 – Integrative Summary and Conclusions This chapter is an excellent compilation of the assembled data.14 Comments from Dr. John Balmes

Agency Charge Question 3 . To what extent is the discu ssion and integration of evidence from the animal toxicology and controlled human exposure studies and epidemiologic studies technically sound, appr opriately balanced, and clearly communicated? What are

the views of the Panel on the conclusions dr awn in the draft ISA regarding the strength, consistency, coherence and plausibility of NO 2 -related health effects?

GENERAL COMMENTS

The second external review dr aft of the NOx ISA is much improved. In particular, the discussion in Chapter 1 on the “EPA Framewor k for Causal Determinations” provides an integrative approach to how the agency will assess the evidence presented in the subsequent chapters. Given that this is th e first ISA to be produced under the agency’s new process for reviewing a “cr iteria” 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 secti ons 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 in tegrated. 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 ap pears 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 inflam matory 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 associ ated with long-term exposure to NO2 is important since several prosp ective cohort epidemiological studies have been published since the 1993 NOx NAAQS review that re ported adverse effects on growth of lung

function. There is a subsection on “Toxicol ogical Studies” on p. 3-89 and 3-90 that is apparently intended to provide mechanistic s upport 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 th e association between long-term exposure to NO2 and decreased rate of growth of l ung function among children. This paragraph merely states that the epidemiological studi es og long-term exposure to NO2 aqre likely confounded by other ambient pollutants. Un fortunately, 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 Decremen ts” also does not provide an assessment of the strength of the association. This is a critical deficien cy given the relative importance of the issue of pot ential respiratory effects of long-term NO2 exposure. The15 section also does not directly assess the strength of the a ssociation for either “Asthma Prevalence and Incidence” or “Respiratory Sympto ms”. It is not until Chapter 5 that the strength of the association for long-term e xposure 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 belie ve that this discussion is technically accurate, I find that it is unnece ssary and distracting given th e 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 di scussion regarding respiratory symptoms.

Agency Charge Question 4 . What are the views of the Panel on the characterization of groups likely to be susceptib le or vulnerable to NO 2 and the potential public health impact of NO 2 exposure?

Chapter 4 does an adequate job of discussing the public health signifi cance 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, howev er, with which I am uncomfortable. The final sentence on p. 4-16 states that “evidence, albeit inconsistent, exists for a gender-agebased difference in susceptibili ty” regarding the effects of NO2 on children with asthma. I find this statement to be too strong. Wh ile 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 eff ects 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 HealthStudy 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, th e issue of the strength of evidence for a long-term effect of NO2 on growth of lung func tion 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 e xposure studies provide consistent evidence for airways inflammation at a NO2 concentration of 2.0 ppm (one study found airway inflam mation at a concentration of 1.5 ppm) ; the onset of the in flammatory response...”

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

Figure 3.4-1 The x axis in the lowe r 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 w ould eliminate these three paragraphs. The summary of the toxicologica l literature on 3-95 and 3-96 is

better.

3-90, lines 8-16 There is a lack of assessment of the streng th 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 el iminate this discussion on potential mechanisms of NO2 effects respir atory 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 di scussed 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 μ g/m 3 (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

μ g/m 3 (15.7 ppb) was associated with an OR of 1.36 (95% CI: 1.01, 1.83) . However ,...”

3-104, line 13 “...with other NO 2 - sources...”

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

3-112, line 8 “...examined association s 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. Do uglas 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 signifi cant improvement on the first. Th e 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 genera l are intended to accomplish, so this is a

positive step forward for the EPA staff.

On the primary issue of adequacy as a ba sis 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 reflectin g that earlier material and choosing the

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

material, including assessments of the streng ths and limitations of the conclusions. While

I might still have some quibbles over the la ck 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 th at 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 j udgments 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 doe s) but also provides an ade quate 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 th at both the document and the chapter point the

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

reader is guided to judgments on the appropr iate sensitive subpopulatio ns that should be

considered; on the specific effects that should be considered ; on issues related to the19 relationship between ambient monitoring results and persona l 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 informati on in the document and in Chapter 5.

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

exposure and policy assessments quantitativel y. 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 rea lize this level of detail may not be what is intended by

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

document provides an adequate basis for e xposure 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 sp ecific 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 th e 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 streng ths 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 scient ific 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 decisi ons. Are the authors suggesting that no

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

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

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

the number of people in the U.S. population e xposed at levels above the threshold (or20 with a hazard quotient above 1)? Should ther e exposure be averaged over an hour, or 4

hours or a day or year? These are questions th at 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 complete ly inadequate philosophically in my view) and to “other

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

idea what they are. I reali ze the ISA is not a philosophica l 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 crit eria). 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 whethe r new data affect the plausibility of

judgments about oxides of nitrogen causing adve rse 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, 6 th 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 (presuma bly 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 b ack 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 measur es. I would expect a recommendation as to

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

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

even valid to use ambient monitoring resu lts, 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 conc lusions 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 expos ure levels between th e 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 th e 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 usef ul if the authors were to provide information

as to whether an increase in exposure cha nges the fraction of pe ople 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 gett ing the effect once),

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

exposure-response curves, but some comme nt 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 shoul d 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 di scussion 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, se ctions of the animal toxicology data that have too much detail given the high(er) concentr ations 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 conclu sions drawn in the draft ISA regarding the strength, consistency, cohere nce and plausibility of NO -related health effects?

The development of the guidelines to evaluate the strength, consistency, coherence, and plausibility of NOx-related hea lth effects is critical ly important to the ISA. In a similar fashion, the use of stru ctured language to describe relationships between exposure to NOx and adverse health effects is an important improvement to the ISA. The 5 descriptor cate gories 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 macr ophages’ 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 st udy and then say that al veolar macrophages are a sensitive target for NOx’s effects and gi ve no refs on macrophages and just refer the

reader to the Annex. Page 3-12, figure 3.1-1 – The figure legend need s more details (e.g., what are the + and – on the Y-axis for; what does the * mean?; wh at 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 Tolb ert study had a 2% increase with a 95% CI of 0.5, 3.3. The figure shows a significant b ox 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 ‘d iseases’ 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 desc riptions are good, the text has 15 lines describing HRV and then 5 lines to say there have been mixe d 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 regardi ng animal studies and mortality as an endpoint in acute studies is not correct. Se veral studies have looked at LC50 values for NO2 in different species. Page 3-90, para 3 – This paragraph on epidemio logy appears to be misplaced in this tox

section. Page 3-96, para 1 – A mention of the higher do ses 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 th e 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 con centrations 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 ch aracterization of the search strategy for identifying literature, criter ia for study selection, the framework for scientific evaluation of studies and causality determination?

I used a few different methods to evaluate the re sults of the lite rature search. First I read through all of the references cited at the end, noting the fr equency of 2006-2008 references, and selecting in particular titles th at appeared highly relevant to the analysis of health hazards. From the large numb ers of 2007 references and the occasional 2008 citation, it is clear that the authors have brought their literature search es up to date as of the present. I then retrieve d 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 corresponde d 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 characteri zed, and relevant to the review of the primary NO2 NAAQS? Are the properties of ambient oxides of nitrogen appropriately characterized, including spatial and tem poral patterns and relationships between ambient oxides of nitrogen and human exposur e? 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 revi ew incorporated to a large extent. The

discussions of measurement interference and its spatial and temporal variability were much better, as was the discussion of ambien t concentrations of NO2. The paragraph on

NO2 increases in other countries was some what 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 in terrelationships 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 atmo spheric nitric and nitr ous acids during the 1999 Atlanta Supersite , Atmospheric Environment, Volume 37, Issues 9-10, March 2003, Pages 1351-1364 Zhang Genfa, Sjaak Slanina, C. Brad Bori ng, Piet A. C. Jongejan, Purnendu K. Dasgupta

Measurements of gaseous HONO, HNO3, SO 2, 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) gi ving quantitative data on emissions contributions from major source categories. Fig. 2.2.1 is nice but ju st 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 s eem 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 conne cted 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 document ation 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 shoul d be Weekend, rather than Weekday28 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 us eful, I would suggest that the data would be better pr esented in tabular form rather than figures. At first glance, the +/- on the y-axis suggests a degree or quan titation 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 cons istent. 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 simp ler integral models provide reasonable predictions (c.f. Di Sabatino S, Buccolie ri 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 he terogeneity 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 ot herwise open areas, i.e., enriched by about a

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

a discussion of the skill level of these mode ls in similar applications and a multiscale approach that includes street canyons seems a ppropriate (c.f. the Da nish forecast system

at http://www2.dmu.dk/1_viden/2_Miljoe-tilstand/3_luf t/4_spredningsmodeller/5_Thor/default_en.asp ). This adds another dimension to the exposure as sessment, namely the fact that pedestrians spend time walking in these canyons and having windows opening onto these canyons and can therefore experience exposures for e qual 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 arri ve at different conclusions about passive samplers without comment.

Page 2-35 line 13: This sentence needs a re ference 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 spatia l variation in greater Los Angeles varies broadly with distance from the coast due to well known me teorological and chemical phenomena. NO2 levels in Riverside ar e 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 discu ssion and integration of evidence from the animal toxicology and controlled human exposure studies and epidemiologic studies technically sound, appr opriately balanced, and clearly communicated? What are

the views of the Panel on the conclusions dr awn in the draft ISA regarding the strength, consistency, coherence and plausibility of NO 2 -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 concer ns expressed by CASAC for the original draft document. In my opinion, the content, fl ow, presentation and l ogic of materials are well done. New publications from the scientif ic literature since 1993 incorporated into this ISA draft are extensive and impressive. The majority of these papers cited in the document are highly relevant fr om an environmental perspective. A number of the new toxicology documents provide bi ologic plausibility, however, exposure concentrations in these studies are typically well above ambien t 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 incl uded demonstrate effects as low as 0.4 ppm (in a lung vitamin deficit model in the guinea pig). Airway hyperresponsiveness following repeated NO 2 exposure at 1 and 2 ppm for up to 12 weeks in guinea pigs has

also been demonstrated. Each of these st udies adds further validity for the biologic plausibility of NO 2 health effects. Human studies al so provide strong evidence for health

effects at NO 2 levels in the 0.04-0.08 ppm range as 1 hour peaks. New data to demonstrate greater sensitivity to NO 2 in the form of increased airway responsiveness (approximately 10-fold) for asthmatics vs. h ealthy individuals fu rther emphasizes the importance for consideration of susceptible populations and children in consideration of setting the NO 2 standard recommendation. In su mmary, the second draft of the ISA document represents an excellent compila tion and reasonable in terpretation of new research findings that should greatly aid in formulating d ecisions for setting the next

criteria standard for oxides of nitrogen. Summary statem ents 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 ep idemiologic, human clinical and animal toxicological evidence provide strength, cons istency, coherence and plausibility for NO 2

- related health effects.

Minor Comments:

1) P 2-35, line 15 Will increased use of bioma ss fuels lead to an increase in NO 2 concentration in the future? 2) P2-40: this section provides an excellen t detailed descripti on 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 summari ze the proposed mechanisms whereby NO 2 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 a dded. 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 NO 2 concentrations leadi ng to increased airway responsiveness in healthy and asthmatic humans and animals. 8) The intervention study of Pilo tto et al (2004) provides striking evidence for health effects among asthmatic children for NO 2 concentrations at extremely low levels. The only concern for the interpretation of this study remains the possibility that ultrafine particles, rather than NO 2 may be driving this effect. 9) There appears to be strong evidence of NO 2 effects on physician-diagnosed asthmatic children (Pilotto et al., 200 4). Although it may be difficult to completely rule out the effects of ultrafine particles, multi-pollutant models

continue to demonstrate robust NO 2 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 NO 2 effects? 11) Excellent studies are included throughout the document to demonstrate positive

associations between ambient NO 2 concentrations and health effects among young children and older adults (65+ years). 12) There continues to be a concern relativ e to confounding of co- pollutants, as well

as NO 2 being a surrogate for other pollutant s. However, there appears to be consistent data throughout more recent publications to suggest NO 2 can elicit

health effects at current ambient levels. 13) Susceptible populations are clearly an important group to consider for NO 2 health

effects. The Southern California Childr en’s Health Study clearly points to NO 2

- related changes with reduction in lung growth function in children. 14) Excellent summary and integr ation of scientific evidence for all aspects of health

effects of NO 2 throughout the document.32 Comments from Dr. Edward Postlethwait

1. In general the document shows consider able improvement over the initial draft

and thus the EPA sta ff should be commended.

2. The issue of endogenous NO2 generation appears not to have been addressed as a potential contributor to uncertainties with re gard 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 concentr ations have not been identified due to the numerous confounding factors. The document would be strengthened if this issue was revised throughout to unequivocally pr esent a consistent interpretation.

5. It is somewhat curious that the document supports causal relationships between NO2 exposure and acute but not ch ronic 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 expe rience long term impacts. Thus, it may be

useful to consider whether th is represents an inconsistenc y or is due to any number of mitigating factors.

6. Per discussions from the initial re view meeting, the document does not extensively link the potentia l 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 aver age values, and observed effects would strengthen the document and provide th e impetus to help support a shorter

term standard if warranted.33 Comments from Dr. Armistead Russell

Post-Meeting Amendment

Given the redirection of the RE A, I think it is particularly needed that the ISA highlight (further stress and discuss) epidemiologic studies that have included multi-pollutant

models with NO 2 , particularly those that have in cluded other combustion byproducts like EC, Total Carbon (TC) and CO. In doing s o, they need to provide caveats on the interpretation of such studies, but also rec ognize their importance. They should note that PM2.5 and O3 are poor indicators for exposur e to combustion emissions. If there are studies demonstrating how PM might act as a carrier for NO 2 that should also be

assessed.

Original

Again, like the first draft, the 2 nd 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 1 st and 2 nd drafts.

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

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

note that their commercial air craft estim ate for Philadelphia does not look right. They should also note that being an elev ated 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 rea lly 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 le vels 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 impor tant 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 monito r will lead to an underestimate of what people are breathing given that in cities (e.g., NY) air in lets 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 pr ovide 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 NO234 rises. The current REA uses little from th is section, instead deriving its own fit to the decay. It is also not apparent how the REA us ed the information about

intrusion of the vehicles ow n 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 co rrelates 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 estima ting 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 (NO

x ) is improved and responsive in many respects to concerns raised by CASAC member s, including myself, at the review of the first external review draft. The Agency’s st aff has attempted to be responsive in setting

out a better framework for evidence identi fication, 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 revi ew, and would provide a trail, documenting how comments made by CASA C were taken into account.

My responses to the charge questions from th e 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 re levant frameworks. The background is a useful foundation for jus tifying the selected approach. The Agency has made a number of changes in Chapter 1 th at are responsive to prior critiques. In particular, there is a descript ion of literature selection, an approach to evaluating evidence for inferring causality is provi ded, and a reasonable set of descriptors of the strength of

evidence for causation is offered.

On reading the draft ISA, there has been so me impact throughout the document of having a better prepared first chapter and this fram ework. However, the sections that synthesize the evidence are still somewhat loosely wr itten, 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 misnom er). 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 appli cation of the criteria offered by Hill. Nonetheless, the new Chapter 1 and the appro ach set out represents an advance over the

earlier draft. Discussion is needed as to whether the lis t developed by Hill should be replaced with the shorter set used in th e Surgeon General’s Report. Perhaps, a comparison could be made with a test case.

One issue that is left unaddr essed is publication bias, a r easonable concern given that many studies address the health effects of air pollution and employed multivariable models to attempt to isolate the effects of pa rticular pollutants. There must have been some tendency on the part of i nvestigators to repo rt positive associa tions. This topic needs to be mentioned, as the existence of publ ication bias would be difficult to set aside for some of the epidemiological studies.36 Charge Question 3:

This charge question relates to the integra tion of evidence from the various lines of investigation. Of particular concern is the plausibility of effects observed in epidemiological studies in th e context of animal and human toxicology. There is no doubt that high levels of NO

x 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 partia lly addressed the plausi bility of effects at

current ambient concentrations and at t hose investigated in a number of the epidemiological studies. The ISA appropriate ly notes that both clinical and animal

studies are carried out at doses well above those that are t ypical for population exposures. The document would be improved if more atte ntion could be given to considering the relevance of mechanisms observed at highe r 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 NO

x .

The listing of susceptible subgr oups covers those of both pa rticular relevance and of general relevance. The various groups identified are appropr iate, although I have concern that EPA will follow the same template fo r all pollutants without giving sufficient

consideration to the relevance of particular subgr oups for particular pollutants.

Charge Question 5:

The revised document is greatly improved. It identifies health effects associated with exposure to nitrogen oxides and the streng th 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 w eakest 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 co ncentrations below fo r current NAAQS for NO 2 .” This sentence

addresses the most critical ma tter around the need to revise the NAAQS: are there effects being observed at current ambient concentra tions? 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 considerat ions 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 re fers to statistical models. The37 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 uncerta inty 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 informativ e 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 NO 2 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 epid emiologic” 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 fi rst bullet to “sufficient to infer a definite causal relationship” since this would make it more consistent w ith the second bullet indicating a “likely” causal relationship. The way it is written, it is not clear what the

difference is between “causal relations hip” and “likely causal relationship.”

p. 5-13, line 15. The 5 ppm exposure is quite hi gh and its relevance to the document is

not clear.

p. 5-16, lines 13-14. Does this sentence mean th at 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 chemistr y and air quality characterizations clearly communicated, appropriately characterized, and re levant to the review of the primary

NO 2 NAAQS?

The second external review draft has been c onsiderably improved in that regard. For example, Figure 2.2-1 is more accu rate; the variability of the NO 2 fraction of NO

x emissions is now correctly discusse d, and the spatial variability of NO 2 concentrations near sources (in particular, ro adways) is properly described.

Are the properties of ambient oxides of n itrogen appropriately characterized, including spatial and temporal patterns and relationships between ambient oxides of nitrogen and human exposure?

The spatial and temporal patterns of NO

x and NO 2 are appropriately described. As mentioned above, the strong spatial gradients observed near roadways are discussed. The temporal variability of NO

x and NO 2 concentrations is also well characterized with sufficient detail being provided in the Anne x (e.g., diurnal and s easonal 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 atmo spheric science and exposure/health effects

that needs to be better discu ssed in the ISA. Currently, m easurement error is highlighted early on in the document (Secti on 1, p-1-11) as important wh en adjusting for spurious

associations. The difference between true and measured ambient concentrations is identified as one of the components of measur ement 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. Fo r outdoor measurements with the Federal Reference Method (FRM), an average interference from NO

z 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 summ er. This section concludes that the interference is likely to be on the or der of 10% or less in winter, but much larger

in summer. It is also stated that the interference from NO

z compounds is less significant near the emission sources (because there has not been enough time for NO

z species formation). Passive samplers used in indivi dual exposure studies ar e 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 NO 2 measurements from FRM instruments or passive samplers. Therefore, one may imply that there may be significant uncertainties a ssociated with the resu lts of those studies

because of the FRM interference errors discusse d in Section 2. However, this aspect of the health effect uncertainty doe s not appear to be discussed. In reality, I anticipate that

most NO 2 exposure occurs near emission sources where NO

z concentrations are low and,40 therefore, interference erro r is small. Also, the seasonal variability of NO 2 concentration shows that in most cities higher concentra tions occur in winter when the interference error is 10% or less. It may, therefor e, be possible to consider that the NO 2 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 possibili ty is to provide a more definitive discussion of the implication of the inte rference of the FRM at the end of the in troduction of Section 2.3 (p. 2-9). The fact that NO

z species concentrations are low when NO 2 concentrations are high (near emission sources, in winter) a nd the reasons why (not sufficient time for reaction, low photochemical activit y) should be explicitly stat ed. Then, the implications

for the health effects studies n eed 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 overa ll well written and very useful. There is, however, one part, which requires some re vision. On p. AX2-67 (at the end of the discussion of local-dispersion models), it is st ated that (1) emissions from roadways are usually not in steady state and (2) that buoya nt 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 NO 2 concentrations from roadways because (1) it uses steady-state a ssumptions and (2) it is a point source model and does not treat, for example, vehicle-indu ced turbulence. The text then goes on to discuss CALPUFF, a non-steady-state mode l that can treat dispersion from surface sources. The implication is that CALPUFF is a better model to simulate NO 2 concentrations downwind of line sources such as roadways. This paragraph needs to be rewritten because (1) the limitations mentione d for AERMOD are not entirely correct and (2) the description of CALPU FF as a better model for line source dispersion is incorrect.

In my earlier comments on the Methods documen t, I raised some concerns regarding the use of AERMOD for line source modeling and as ked 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 acceptabl e 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 w ith EPA that, given the dispersion models currently available, AERMOD was an appropria te 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 downw ind 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 emi ssion 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 not e that the current CA LPUFF versions that are publicly available (e.g., ve rsions 5.8 and 6) include a coding error that leads to

incorrect NO 2 concentrations near the source.41 Therefore, the last two sentences of that para graph (“In contrast, there are models that are non-steady-state...”) should be deleted and th e 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 im proved 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 fo r the proposed modifications. For instance, Annex AX1 contains a thorough compilation of previous wo rk on evidence classification, but details on the translation into Chapter 1 are absent – there is no evalua tion, 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 discu ssed 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 a nd a later discussion of details of study designs (p 1-10). These should be combin ed. Also key points are missing. One is that the challenge with experimental st udies is to create conditions that reflect the complexity of the naturally occurring exposures. Another is that observational studies represent conditions experienced by the populat ion 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 mean t?: “Developing evidence for going beyond association to causation involves integrat ion 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 ar e problems – e.g. washout.

• P 1-10 l 18 Experiments are stronger cau sally than observational studies tub

much more limited in the realistic cond itions that can feasibly be studied.

• P 1-10 l 21 Confounders are only one cons ideration 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 de rived 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 fi ndings” 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 exp licitly. Air pollutio n studies estimate small effects so some issues become relatively more important in this area: model selection, subgroup analyses, appropriat e 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: A ll 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 a ppendix tables and addr esses study features.

• AX1-8 l 5-6 Is this regardless of analysis and reporting of re sults? 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) inst ead 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 ar e useful. Correlati ons 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 c ould be very different just because one is restricted to a single season (w ith less variability) while the other captures data from an entire year. Since I expect th is feature is extraneous to th e 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 gi ve clear guidance on how to su mmarize 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 hi dden feature in all of the NO2 data. It could be critically impacting the epidemiol ogical studies and their interpretation. This feature potentially pervades much of the summ arized 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 result s 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 sitin g features of the monitors. Scatterplot summaries would also be revealing, particularly appropriately in cluded in the44 annex. Further analyses of data may suggest f eatures 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 corre lations are shown on the native (not transformed) scale. Consider separa ting figures by study design or type of correlation reported (including averaging tim e) 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 be tter sentence?: “The rela tionship between personal ambient NO2 exposures and ambient NO2 c oncentrations found in different types of exposure studies have dis tinct implications for differe nt 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 po llutant while the time series studies are relying on day-to-day vari ation 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 th e intent of the chapter. It is also critical that staff continue to refine and improve the information presented in the An nex 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 Chapte r 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 al so some misleading features in the uniform approach to summarization (such as the ch ange 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 peri od. In looking ahead to future iterations of this ISA process, it is important to consider how to revise the a pproach. 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. Finall y, 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 chap ter 5 and summarized clearly in Table 5.3-1 looked generally appropriate. I ask st aff 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 es timate. This is not done consistently throughout the document.

• Please downplay the apparent use of stat istical 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 si gnificance. 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, includ e 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 natu ral experiment, not an intervention study. This perspective appears elsewher e in the document(s) as well.

• P 3-4: Is the Shy & L ove paper peer-reviewed?

• P 3-5 l 19, 21: Make sure units are in cluded 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 di fferences in correlations may be due to monitor siting. Any way to a ddress that? Also define the correlation w.r.t. time scale, location.

Charge question 4: This appears to be appropriate. Better distinguish susceptibil ity and vulnerability. I like the idea of listing all likely suscep tible groups and then determining whether there is any information in the literatur e about these groups. This can be a new framework that is applied to all pollutants and allows fo r a very open and transparent evaluation of our focus on particular groups. It also clearly id entifies gaps in the literature with respect to this topic. The concentration-response section 4.2 need s 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, partic ularly with respect to transp arent use of the literature for policy. Additional points from the discussion th at I echo here: Has the document clearly

established what we know and what we don’t kn ow? Clearly state th e 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 conclu sions 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 intr oductory 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 corre lations for hourly average NO2...” and “...twenty-four hour average concentration...”

• P 5-5 bullet starting l 3: Cl arify “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 fair ly reasonable. However I don’t think statistical significance is the right crit erion. Focus instead on the estimates.

• P 5-9 figure: Insert the NO2 increment used. Add a footnot e to caution against overinterpretation of this nice summary: “Studies include diffe rent lag days and adjustment variables”

• P 5-17 l 15: Revise. Statis tical 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, a nd 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 reader s of the ISA to find this information.

.47 Comments from Dr. Frank Speizer

Chapter 2 The setting out of the conceptual mode l 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 i ndicating that from elevated sources the dispersion and dilution results in lower le vels albeit more widely dispersed.

Page 2.3, Line 28 and Figure 2.21: The text suggests right Side outer box is NO

z but label does not appear in the fi gure. Needs to be added.

Page 2.6 para beginning line 10: It might be useful in the para graph 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 c ountries (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 is sues 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 leas t for selective sites, albeit with less data

than were available for PM and O3.

Atm. Science and exposure provide basi s 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 differe nt human activity patterns.

Page 2.25, line 4 and line 9: Need to rectif y the discrepancy between the two statements although rest of paragraph pr ovides 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 importa nt thing here is the paragr aph 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 edi ting. 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 348 Intergrated evidence for Toxicol ogy, 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 wh ere respiratory effects range RR=1.1-1.3, consistent, particularly in children and a dults >65. Asthma 25% increase. No copollutant effect, COPD mortalit y no coherent picture. L ong term for other morbidity concur “inadequate evidence to infer pr esence 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 interchangeab ly 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 stud y 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 ga ps 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 vulne rability, that it was very appropriate for the document to include studies that used exposur es on the order of 5 ppm (approximately 10 mg/m3) to be very appropriate in this documen t, as such studies (while not useful for the

estimation of human dose-res ponse 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 in tensive consideration of the evidence of potential impact of the co-exposure of pa rticles 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. Bo ren [“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 wa lls. While just one study with high levels of NO2, this study indicates that the co-prese nce of particles with NO2 can enhance the effects of NO2. Since partic les are always in co-exposure with NO2 in the real world, this may provide an important pathway of effe ct, but one that is not considered by this document, despite my raising this concern earl y in the process. My question: are there more published toxicological studies cons idering this partic le-NOx interaction

mechanism? This seems well worth another in tensive look through th e 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 studi es and epidemiologic studies technically sound, appropriately balanced, and clearly communicated??

?

This is where my above-noted concern rea lly 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 s how respiratory effect s of NO2 only down to about 200 ppb, while the latter routinel y and robustly document significant NO2- respiratory associations down at ambient le vels. How can that be the case? We previously confronted a sim ilar situation in the 1980’s, when our NYU-Harvard study’s of children at summer camps documented significant lung function decrements among50 children to be associated with ozone exposures below 100 ppb, while the controlled exposure studies only showed effects down to 120 ppb. S ubsequent 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 av enue to justify the apparent discrepancy between the epidemiology and the controlled-exp osure 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, whil e 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 star t of the Integrative Su mmary (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 defi nitively. In particular, the most important question to be answered is:

• At what levels of nitrogen oxides e xposure do health effects of concern occur?

Answering this particular question will expedite the addressing of the gap between the controlled-exposur e results and the epidemiol ogy results, as well as a comprehensive consideration as to why that might be (i.e., Particle-NOx interactions? Greater degrees of susceptibility in th e general public? Exercise? etc.).

3b. What are the views of the Panel on the c onclusions 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 regard ing causality, there is a need to discuss the concentrations where the various effects are ap plicable, as discussed above.51 Comments from Dr. James Ultman

This well-organized and comprehensive docum ent 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 c onsultants are to be c ongratulated for a job

well done.

As a second draft of the ISA, the documen t has effectively incorporated the most important suggestions of the NOx Review Pane l including better detai ling 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 a nd 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 t itle of figure 2.4-6d. Weekday Æ Weekend.

In equation 2.5-5, C

nona has a subscript that is inconsiste nt with the subscript on Cna used

in the text.

In the dosimetry section on page 2-59, there is not much pr ogress 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 obj ectives outlined in the charge question. I do suggest, however, that materi al be added that describe s and supports the method of extrapolating ambient monitor measurements to on-road concentrations. This is too important an issue to leave for the brief disc ussion 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 unders tanding of reported ambient measurements represent. The review of the health literat ure is comprehensive and makes it easier to achieve a good overall understa nding of the health conseque nces of NOx exposure. The summary of the health effects discussed in Ch apter 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 th at need further clarification. These are presented below in more detailed comments.

Charge question 2 : To what extent are the atmosp heric chemistry and air quality characterizations clearly comm unicated, appropriately characte rized, and relevant to the review of the primary NO2 NAAQS? Are the properties of ambient oxides of nitrogen appropriately characterized, including spatia l and temporal patterns and relationships

between ambient oxides of nitrogen and human exposure? Does the information in Chapter 2 provide a sufficient atmospheric sc ience and exposure basis for the evaluation of human health effects pr esented in alter chapters?

I have two suggestions here. The document re fers 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 geographi c setting of these st udies and whether the setting is typical of those found in the contemporary US. Any information on copollutants and concentrations w ould be particularly helpful.

Since the strength of the health argument for NO2 health effects is tied to the

observations that effects ar e found in studies which cons ider both indoor and outdoor exposures, it would be particularly interesti ng for this chapter to provide some additional information to inform this argument. For example, given the typi cal sources of indoor and outdoor NOx, how does the composition cha nge with respect to the different oxides of nitrogen and are the co-polluta nts the same or different in i ndoor and outdoor settings?

Charge question 3 : To what extent is the discussion and integration of evidence from the animal toxicology and controlled human e xposure studies and epidemiologic studies technically sound, appropriately balanced, and clearly communicat ed? What are the

views of the Panel on the conclusions drawn in the draft ISA rega rding the strength, consistency, coherence, and plausibi lity 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 d eemed to have a lesser influence on NOx

exposure.54 I would like to see a more rigor ous 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) cite d in the document.

In several places studies were not considered be cause 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 futu re 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 po licy 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 scat tered throughout the docum ent 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 loca l sources and near-source concentrations are not to be regulated? I think the wo rding needs to be changed here.

Page 2-42, ll. 5-6: statistical significan ce per se in not as informative as R 2 ; 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 particular ly noteworthy that NO2 is highly associated with several organic compounds.

Page 3-12. Figure 3.1-1: This fi gure 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 whet her 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 e xposures? 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 commen ts exist elsewhere; e.g., p. 3-58, ll 17-20.55