24  periods, relatively short periods of time overlaid on

25  their other expose   you know, on kind of a background.

Page 105

1  term effects are strong and that there are likely peak

2  effects as well.

3	And while we're on the exposure chapter

4  we're going to talk about that because I think

5  ultimately we're going to talk about whether the

6  standard or the recommended change in the standard,

7  what type of a standard it ought to be, what the form

8  ought to be.

9	And as we have this discussion of form

10  here and the data that would underlie that, which I

11  think is going to become a profound question at the end

12  of the day.

13	So I think from the point of view of

14  exposure we ought to see the data expressed in a form

15  that tells me more about the excursions and the

16  shortened effect, the difference between cities in

17  terms of the   for example if you have an average

18  annual level which we talked about at the beginning

19  which is about fifteen parts per billion, if you

20  lowered the national standard to that level, how many

21  cities would be out of conformance with it and what

22  would be the peaks and would that have an effect on all

23  the adverse health effects we're starting to see?

24	I'm sitting her wondering if the

25  exposure data is going to really support us looking at

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Page 106

1  the form of the standards.

2	DR. HENDERSON: And that's the kind of

3  information we need for this to tell us, to support the

4  standard setting process.

5	I'd like to   did the Air Office want to

6  say something?

7	DR. ROSS:    One of the things we really

8  aren't directly in the ISA trying to choose a standard

9  or a form.  The form is actually less influenced by

10  science.  It's sort of a hybrid of science and policy.

11	What we're trying to is develop the

12  evidence that can inform, like what are the effects of

13  exposure to short term exposures and what are these

14  exposure, 24 hour, a one hour peak, what information is

15  available that we can summarize for the Program Office.

16	I'm not sure, I think we're getting some

17  helpful feedback from people in the audience.  I think

18  some of the recommendations, some of reasons we didn't

19  some of the things that are discussed is it was just

20  lack of data.

21	So we would welcome any input from CASAC

22  about data that are available to further expand on

23  these issues like extrapolation from animals to humans

24  for example.

25	Just a follow up statement is that much

Page 108

1  concentrations of oxygen for literally weeks and weeks

2  and weeks at a time.

3	Now, the pediatric community considers

4  that to be "safe".  One can make arguments about that

5  but you're still talking 5 parts per million.

6	What are the environmental NO exposures

7  relative to what it requires on a therapeutic basis to

8  induce peripheral vasodilation?

9

10	So I think some context along those lines

11  if you're going to go down that road I think that that

12  context needs to be included in terms of this dose

13  issue.

14	DR. GORDON: Oh, I agree, it's just we're

15  including some NO2 studies that are private and the

16  relative NO to NO2 emissions could be brought into play

17  in your concept.  I agree.

18	DR. HENDERSON: When you monitor, you

19  monitor both NO2 and NO, correct?

20	DR. PINTO: Yeah, but the NO isn't

21  deposited into the air quality system, you know, that's

22  been available to the public.  That's the problem.

23	DR. GORDON: The data was required in the

24  report.

25	DR. HENDERSON: Well that could be

Page 107

1  of the exposure analysis that we're talking about, you

2  probably will see that it'll be in the risk and

3  exposure assessment that comes from the Air Office.

4	DR. HENDERSON: Okay.  Go ahead, Terry.

5	DR. GORDON: Yeah, even though I'm a non-

6  chemist I wanted to emphasize a couple of points that

7  were stated earlier.

8	Given that NO is so biologically potent

9  and given the fact that all the health effects appear

10  to be on NO2 and that's what's discussed, I'm just

11  wondering if it's the cart or the horse, and that maybe

12  we should really and seriously encourage the EPA to

13  include NO and other temporal species in the routine

14  monitoring.

15	Otherwise we're going to drive it and

16  continue to drive it to NO2 which may or not be

17  appropriate, but we don't know until we have more data

18  NO in particular.

19	DR. HENDERSON: Okay, Ed.

20	DR. POSTLETHWAIT: I'm a little concerned

21  about the use of the word potent.

22	In most clinical situations

23  therapeutically delivered NO is administered in the

24  range of 5 to 10 parts per million and it's given to

25  premature infants on respirators with high

Page 109

1  changed, right, if it was deemed necessary.  I'm just

2  saying, could it be made available?

3	DR. PINTO: I don't know, what's the

4  regulation for it?  Mary, do you have that?

5	DR. ROSS: We're not the right people to

6  speak to the monitoring network.  Out colleagues in

7  OAQPS I'm sure could find out.

8	DR. PINTO: It might be a better question

9  for tomorrow.  Seriously.

10	DR. HENDERSON: Okay.

11	DR. LARSON:  Back to the point about the

12  relationship between the short term and the long term

13  averages.  This is Tim Larson again.

14	I think you would find that that might

15  be different depending on proximity to source, in this

16  case the most ubiquitous sources being near major

17  roads.  And as you know some of those monitors are

18  sited as far away from major roads as possible, but

19  still fairly close in these urban areas.

20	So if you're going to be looking at that

21  later on, you probably already have, but it's useful to

22  try to qualitatively separate out those monitors in

23  that regard because they get very different temporal

24  patterns.

25	DR. WYZGA: I think one simple thing

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Page 110

1	SPEAKER: We can't hear you.

2	DR. WYZGA: Oh, I think one simple thing

3  that can be done to reorganize some of the material in

4  the tables to the extent it's available, is that what I

5  think in terms of trying to sort out the epidemiology,

6  I think that the big issue is the whole issue of

7  surrogacy and so it's very important to look at

8  correlations between NO2 and some of the other

9  pollutants.

10	And it's going to be very dependent upon

11  where the monitor is.  I suspect that if the monitor is

12  sort of source neutral, you're going to get a different

13  set of correlations than if your monitor is near a

14  roadway.

15	And to the extent that that can be

16  separated out I think would be useful.  And I think

17  also temporally too.  I think that annual average

18  correlations could be very different from some of the

19  peak average, peak correlations.

20	So to the extent that we can separate

21  these out I think it would be particularly informative

22  and help us in understanding the epidemiology studies.

23	Because one of the problems we face

24  about it is we don't know who is responding.  Is it the

25  people who are near the roadways or people who aren't?

Page 112

1  and clarification, because I think, you know, it gets

2  confusing when people start seeing that the personal

3  exposures may not correlate with the central site.

4	But what we're looking at is, does the

5  central site correlate with people's personal exposure

6  to out   you know, to NO2 or not, I should say, of

7  outdoor origins.

8	So I don't know if I said that clearly

9  enough, but I think we need to make those distinctions

10  in the document to make it more useful.

11	And then a second comment.  Really I

12  wanted to pick up on Doctor Crapo's argument just in

13  general I think, that throughout the document, starting

14  right at the beginning, the thought has to be, well,

15  how is this useful, you know, what is presented?  How

16  will this be needed for the standard setting process?

17	And a lot of the information is very

18  interesting, but it might not be what is needed at the

19  end.

20	So, you know, throughout the document I

21  get the feel that each   and you know, I'm sure it's

22  true   each section was written independently but I

23  think we need to do another iteration where everybody

24  says, okay, this is what we really need, this is the

25  endpoint we've got to get to and you need to give me

Page 111

1  We just don't know from a lot of these studies.

2	So it's useful to have both in mind.

3	DR. HENDERSON: Oh, George, do you have

4  something?

5	DR. THURSTON: I'd like to take a moment

6  just to talk about the question of indoor and outdoor

7  exposure and I think that we need clarification in the

8  document about the exposure, the personal exposures to

9  outdoor NO2, because EPA is regulating outdoor NO2.

10  It's not going to regulate indoor NO2.

11	I think indoor NO2 is important vis-a-

12  vis, especially vis-a-vis studies that have been done

13  of it.  I think the point was made earlier that some of

14  the most instructive studies about the effects of NO2

15  have been indoor studies.

16	But in terms of the epidemiology and

17  standard setting processes that I think are largely

18  relying on epidemiology, backed up by the other, or not

19  backed up, you know, by the other disciplines, you

20  really need to differentiate the exposures and

21  distinguish in the discussion between NO2 of outdoor

22  origins, personal exposures to NO2 of outdoor origins

23  versus personal exposures to NO2 of indoor origins.

24	And I think that was done in the PM

25  document and I think it was a very helpful discussion

Page 113

1  the information that's most relevant to this end, you

2  know, the endpoint of the process that we're involved

3  in.  And make it most directly relevant, you know, the

4  things like the exposures, who is getting them and what

5  are the various levels of exposures, source of

6  background.  I know that example, that'll be covered

7  later in the next document.

8	But I think throughout that theme has to

9  be there.  How is this useful to the end goal?

10	DR. HENDERSON: Okay.  Thank you.  And Ed

11  has been wanting to talk and I haven't seen him, so Ed.

12	DR. AVOL: Yeah, thank you, this is Ed

13  Avol.  Just one comment on Ron Wyzga's sort of claim

14  that we don't know who is responsive in terms of NO2

15  and whether it has to do with roadways.  I mean there

16  are studies coming out and in fact the studies in

17  Southern California for example, have shown pretty

18  clearly that it's the kids that are closer to the

19  roadways that we see increased incidence of a number of

20  things, symptoms, low lung function, asthma, et cetera.

21	So I think that information is starting

22  to become available.  So it's not quite   I agree the

23  jury is still out, but there is information becoming

24  available.

25	DR. HENDERSON: Thanks Ed.  Now, are

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Page 114

1  there other comments regarding the first three charge

2  questions?  I haven't heard   oh Dale, hi.

3	DR. HATTIS: Hi, hello.  Yeah, I think

4  the vertical gradient in NO2 exposures and therefore

5  being where you have exposure to the higher up are less

6  than the exposures at ground level, and that people

7  have to be located more close to the ground level than

8  the monitors do, I think that's a terrific problem for

9  the interpretation of the epidemiological data in the

10  context of this Australian study which is based upon

11  actually personal measurements, or at least areas,

12  measurements indoors.

13	So in order to translate between these

14  two we have to have an idea of how, of what that

15  vertical gradient is, how often, and how many monitors

16  are located how high.

17	So, you know, the interpretation of the

18  EPI studies in particular is going to be greatly

19  modified by what your analysis is of that business and

20  the distribution of those differences in the people

21  that have been studied.  And I think that reinforces a

22  point that I think you were making, Donna.

23	And so I think that that's really the

24  central issue for the interpretation of how distorted

25  the epidemiological studies are, because you have both

Page 116

1	Did I hear you right?

2	DR. SEIGNEUR: Yes.  Well, maybe I can

3  take a quick example or an extreme example.  Let's say

4  that the existing technique will estimate by a factor

5  of two, then you do an epidemiological study to really

6  understand that based on that measurement technique.

7	Then if you introduce a new technique,

8  which then would give you values which would be higher

9  for what you had before, you may have areas which would

10  be in non-attainment with the old technique which

11  suddenly would turn into attainment.

12	The EPI study would tell you that you

13  would have problems, you know, on the health effects

14  analysis.

15	So I think it's important to be

16  consistent between the EPI studies and the measurement

17  techniques.

18	DR. HENDERSON: Yes, Ted.

19	DR. RUSSELL: If I might, I think it

20  comes down to more not necessarily changing the

21  measurement, but understanding it better.

22	And my advice certainly would be to

23  provide a more thorough assessment of what the

24  uncertainties are with the various measurement metrics

25  of NO2.  Not necessarily saying go and start changing

Page 115

1  systematic error from the differences, the overall

2  differences between the outdoor related exposures to

3  the people relative to the monitoring measurements.

4	And likely quite a bit of random error

5  introduced by the fact that there's some correlation

6  but by far, a far from perfect correlation between

7  what's being measured in the monitors and what's being

8  experienced at least for the outdoor exposure, related

9  exposure of the people.

10	So I think that, you know, that is,

11  because of that difference, the different pollutants in

12  particular, you have a really good chance of

13  distorting, you know, the attribution of effects

14  between pollutants of different kinds.

15	So I think in order to do an

16  quantitative analysis you at least have to have that

17  feature pretty thoroughly quantitatively analyzed, even

18  though the data may well be very sparse to do such an

19  analysis at the moment.

20	DR. HENDERSON: Thank you, Dale.  I would

21  like to hear someone summarize what our advice is on

22  monitoring.  I think I heard you say, Christian, that

23  since the past monitoring has been with this

24  chemiluminescent technique, that to switch would cause

25  problems.

Page 117

1  our measurement method, though it would be nice if we

2  had one that was truly specific to NO2 in the long run,

3  but right now saying, this is the current measurement

4  technology, this is the level of NO2 we usually get, at

5  which time and which season, and this is the likely

6  level of interference and bias that we have in it.

7	Not necessarily throw out the whole

8  thing but really understand what it's trying to tell us

9  at this point.  And I think that information is

10  available.

11	DR. HENDERSON: That sounds like very

12  wise advice.  Are we answering the questions that you

13  wanted to have answered and is there anything we

14  haven't discussed that you were hoping we would

15  discuss?

16	DR. ROSS: Yeah, I think it's been very

17  helpful and it should help us improve on the document

18  for the second draft.

19	DR. HENDERSON: Okay, I'm sorry, go

20  ahead, Ellis.

21	DR. COWLING: I wanted to be sure, is

22  there a consensus among this group that NO2 is the

23  indicator of choice for oxides of nitrogen?

24	We're talking about alternative methods

25  of getting to NO2, but that involves the original

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Page 118

1  assumption that the wisest choice, the most adequate

2  way for this country to understand exposure to oxides

3  of nitrogen, is to get accurate measurements of NO2.

4	DR. RUSSELL: If I might?

5	DR. HENDERSON: Yes, go ahead.

6	DR. RUSSELL: Actually Ellis, I think

7  your question is not as looking at exposure to oxides

8  of nitrogen, but looking at the relevant health

9  effects.  That's what we're trying to assess.

10	So I think that has to come from the

11  people who can tell us which oxides of nitrogen is

12  likely to be given the ambient concentrations one's

13  exposed to.

14	DR. COWLING: No, this isn't just a

15  chemical question.  It is fundamentally a public health

16  question.

17	And I accept your comment, but we have a

18  number of people who are very skilled in health

19  research here.

20	Do you who are skilled in understanding

21  what America ought to do about management of oxides of

22  nitrogen, do you who understand the health effects as

23  thoroughly as possible, just as Ted is suggesting, do

24  you believe that NO2 is the indicator of choice to

25  protect people from oxides of nitrogen?

Page 120

1  NO is a pulmonary vasodilator, it's a pulmonary

2  vasodilator in healthy people as well as sick people,

3  it's just a, it's a smooth muscle relaxant.  Just that

4  it doesn't seem to have any adverse effects when you

5  inhale it over the short term.  But that really hasn't

6  been examined in clinical studies or in long term

7  studies, neither NO2 or NO.

8	But in terms of its irritant

9  inflammatory effects, NO2 has a much stronger action

10  than NO.

11	And I would make the comment that I

12  think the more important thing to be monitoring or

13  considering as a confounder, and this has been

14  mentioned previously, is not NO per se but its particle

15  member, or ultra fine particle counts, because I think

16  many of the indoor studies which look at effects of

17  NO2, the things that produce NO2 indoors are the things

18  that produce ultra fine particles as well, including

19  natural gas combustion.

20	And it's very possible that many of the

21  symptom effects that have been associated with NO2 in

22  indoor studies are in fact studies of particle exposure

23  where it wasn't counted.

24	So I think looking for confounding with

25  PM 2.5 really does not address the issue of whether

Page 119

1	DR. COTE: One of the   I'm about to step

2  into quicksand because this is not my area of expertise

3  at all, but there was a lot of discussion in house that

4  in fact what is really monitored is NOX and what people

5  are really exposed to are NOX and that, you know, we

6  might be better served by simply it that as opposed to

7  NO2.

8	DR. FRAMES: Can I make a comment?  Mark

9  Frames, I'm from the University of Rochester.

10	I mean my understanding certainly of NO2

11  is the regulated pollutant in the NAQS and not NO.  And

12  I think most of that comes from a fairly extensive body

13  of literature, both in vitro and in animal studies and

14  some studies in humans of sort of direct cellular

15  effects but also respiratory and irritant effects of

16  NO2 are much stronger than NO at a given concentration.

17	For example I think Ed made the point

18  that, you know, we're using NO therapeutically at

19  ranges of 5 to 8 and sometimes higher ppm and those

20  kinds of concentrations of NO2 are definitely

21  irritating and cause symptoms and cause lung function

22  changes in some people and cause inflammatory effects

23  as well.  And NO does not.

24	The thing that hasn't been examined are

25  the cardiovascular effects and this was mentioned.  And

Page 121

1  what we're seeing with NO2 effects is in fact ultra

2  fine particle effects.

3	DR. COWLING: Can we infer from your

4  comments that you think   well, let's ask the question

5  directly.  If you were Administrator of EPA, would you

6  endorse the idea that has been with us for 36 years,

7  that the most useful indicator of exposure to oxides of

8  nitrogen is in fact NO2?  And do you think that the

9  present system that we've devised is reasonable?

10	After all, that's why we're here, is to

11  examine the scientific evidence for a decision about

12  whether to keep the standard we've had for all these

13  years, or to alter it in some way.  And I mentioned

14  these four important indicators, the averaging time,

15  the concentration, and what's the fourth one, I can't

16  remember   form, right.

17	If you were Administrator, what would

18  you recommend?

19	DR. FRAMES: You're all fortunate that

20  I'm not the Administrator.

21	DR. COWLING: I know.

22	DR. FRAMES: And I am too I think.

23	DR. ULTMAN: I don't know about that

24  actually.

25	DR. FRAMES: I'm sorry?

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Page 122

1	DR. ULTMAN: I don't know about that, I

2  think I'd rather have you.

3	DR. FRAMES: Thanks, but I'm not ready to

4  pronounce my opinion on whether the standard ought to

5  be changed.

6	But your questions about whether NO2 is

7  the appropriate indicator, I'm not aware, at least from

8  the evidence that I'm aware of, I don't think we have

9  evidence to change whether NO2 versus NO is the

10  indicator.

11	I don't have, I don't see any evidence

12  that pushes us to say NO ought to be one of the

13  regulated criteria of pollutants.

14	On the other hand, you know, how do we

15  know unless we have data to look at?  And if there's

16  going to be some additional studies of cardiovascular

17  effects in the future, particularly epidemiology and

18  panel studies, it would be very helpful to have NO

19  concentrations in order to gather that information.

20	DR. COWLING: NO of course is only one of

21  the many different oxides of nitrogen and I appreciate

22  what you've just said, and you're demurring from taking

23  the responsibility if you were Administrator.

24	But I think this question, what is the

25  indicator of choice and how should we measure whatever

Page 124

1  the health effects.

2	And I think again the issue that kept

3  coming up in my mind as I read the document, is the

4  fact that there is often good correlation with other

5  pollutants related to combustion sources.  And I think

6  it would behoove us, even we don't have a specific way

7  to, a specific recommendation about a new approach, to

8  say that a new approach needs to be considered, because

9  I really think that we somehow spend a lot of time,

10  waste a lot of time, trying to pin health effects down

11  to a specific group when it's really the pollutant

12  mixture causing the health effects.

13	And so that regulating the pollutant mix

14  should be a goal for the future.

15	DR. HENDERSON: Thank you, John, I think

16  that's a goal of many, many people.  Ed?

17	DR. POSTLETHWAIT: It's Ed Postlethwait.

18  I think there's been various speakers that have touched

19  on this, but we have to remember that as Mark pointed

20  out, the standard is for NO2 yet what we're measuring

21  really is non-NO/NOX.

22	And so the exposure estimates based on

23  that for NO2 are probably only going to overestimate

24  the exposure, not underestimate the exposure.

25	So as long as the catalytic reductants

Page 123

1  it is that we will measure in order to administer a

2  standard for the nation, that is a fundamental issue

3  that we ought to try to wrestle with.

4	DR. BALMES: This is John Balmes.  May I

5  say something?

6	DR. HENDERSON: John Balmes, are you, is

7  that you on the

8	DR. BALMES: Yes.

9	DR. HENDERSON: Okay.

10	DR. BALMES: Can you hear me?

11	DR. HENDERSON: Yeah.

12	DR. BALMES: So I'm glad that Ellis

13  raised the basic question, not so much because I want

14  to get into a discussion about NO2 versus other ways to

15  measure oxides of nitrogen per se, but to get the

16  larger issue of the fact that we currently are

17  regulating pollutant at a time.

18	I don't have a ready suggestion about

19  how to change that, but I do recall from the ozone

20  discussion and it's actually even in our letter to the

21  Administrator, we've written a letter, that we can, the

22  Agency should consider ways to deal with oxidant

23  pollutants in total and not pollutant by pollutant,

24  because it's really probably the burden of oxidant

25  pollutants that are responsible for at least some of

Page 125

1  continue to be used, you're actually measuring by and

2  large the entire population of NOX.  You're just not

3  getting recordings of NO reported.

4	DR. AVOL: This is Ed Avol.  I think

5  there are two other issues echoing this part of John

6  Balmes' comments about the mix.

7	And that is that you remember at the

8  earlier workshop there was a lot of discussion about

9  whether NO2 standard setting was useful in the context

10  of separating it from particulate NOX or nitrates and

11  going at the health effects and even control

12  strategies.

13	And so in terms of thinking about the

14  mix it's not the NO2.  It may or may not be the NO2 and

15  in fact from the community of epidemiology, you know,

16  many times that's what's pointed out, the correlations

17  and the association of the combustion exhaust involves

18  both particles and the gases, so it's often difficult

19  to separate those out.

20	So it really is a more complicated issue

21  that even just talking about NO/NO2.

22	From the epidemiological sense I would

23  also, or the standpoint, I would also point out that in

24  terms of understanding public health and looking at

25  trends in public health, it may or may not be the case

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Page 126

1  that we want to go forward with NO, or pick up NO and

2  continue with NO2.  I think if we do go forward with

3  NO, we don't, because of the fact that it hasn't been

4  reported all these years, we don't know much about NO

5  nationally.

6	DR. HENDERSON: That's true.  Perhaps,

7  you know, this idea of the multi pollutant is something

8  we may want to address in our letter because it's such

9  an important point.  It's not an answer to a charge

10  question but it's a very important point.

11	So I have noted that we've mentioned

12  that.  George?

13	DR. THURSTON: Well, a couple of

14  comments.  George Thurston.

15	One is I think a start for that would be

16  something that I've mentioned in my written comments

17  and something I mentioned at our last meeting, and

18  other people have alluded to, and that is to start with

19  the interaction of NOX and PM and particulate matter.

20	And start with that, you know, I think

21  that would be a big step forward and it's doable within

22  the context of this document.

23	Parts of it are already in the document

24  here and there, but it's just a matter of organizing it

25  and trying to see that as a theme throughout the

Page 128

1  published studies of exposure.  There aren't any

2  studies that have used children in exposure studies.

3  There are panels for other specific groups that I think

4  we've discussed.

5	One of the things I will mention though

6  is tomorrow we'll be discussing the exposure assessment

7  and we'll be some models and available data to try to

8  estimate exposure to children and other groups like

9  that possibly.  There's data that we'll be commenting

10  on tomorrow.

11	So we can look at what studies and what

12  data are available and I'm not sure that there were any

13  data available on children.

14	DR. KIM: When you use the specific term,

15  susceptible population, in Chapter 2, but if you look

16  at table, especially Table 2.5 or a, a lot of studies

17  are focused on the children and senior groups.

18	DR. COTE: The other thing I'm sure

19  everybody is aware of is HEI has this large effort

20  ongoing that they are hopeful they can share with us

21  before the final draft that's focused more on roadways

22  and transportation issues.

23	DR. HENDERSON: You're concentrating on

24  the exposures near roadways, is that what you're

25  saying?

Page 127

1  document.

2	There was one other thing.  Oh, and that

3  was with the exposures.  Is there a place here to look

4  at the exposures of susceptible populations?  As we get

5  to the end of the document we're focusing on

6  susceptible populations, people with asthma, children,

7  people who live near traffic, actually those are all

8  three pretty much the same people, because a lot of

9  children with asthma live near traffic in the United

10  States.

11	So what are their exposures and how are

12  they   you know, we can characterize exposures

13  throughout the United States in the general population,

14  but this is a very large group of people that will end

15  up I think being a focus of the evaluation at the

16  endpoint, protecting public health.  Are we protecting

17  the health of children with asthma in inner city

18  locations?

19	And so I think we might want to have

20  information about their exposures in the exposure

21  section or just in general exposures of susceptible

22  populations to outdoor air pollutants, outdoor NOX.

23	DR. HENDERSON: Okay.  Can I ask, Mary,

24  do we have data to do this?

25	DR. ROSS: Well I believe there are no

Page 129

1	DR. COTE: I think that's right.

2	DR. HENDERSON: Yes, I think so.  Ed?

3	DR. AVOL: I'd just ask for one

4  clarification from Mary coming from the children's

5  health study in California.

6	Did you say there are no children's

7  studies?

8	DR. ROSS: There are children's studies.

9  But I was commenting on the personal exposures and

10  ambient concentrations.

11	DR. HENDERSON: The Australian studies

12  have too.  I thought those were very impressive.

13	Are thee other questions?  Yeah, Dale?

14	DR. HATTIS: Yeah, I've been taking a

15  quick look at the data that are in one of the annex

16  tables, AX 3.1, and I think in the context of looking

17  at the relationship of the existing data to the

18  standard, I think there are some facts in that table

19  that are helpful.

20	First is that, off all of the monitors

21  in CMSA in urban areas there aren't any that get even

22  close to the current .053 annual average, okay?  That I

23  think might be a fact that's more prominent.  So if in

24  fact you think that the current epidemiological studies

25  are detecting effects, then you must believe there are

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1  effects below the current standard, okay?

2	The second is that, you know, one of the

3  things that I've been doing just sort of on the side

4  here is to try to look at the difference in the

5  variations between averaging times.  And so I've got a

6  figure that does that but maybe this isn't the right

7  time to show you that.  But basically the shorter

8  averaging times that you expect have more variability

9  than the longer averaging times.

10	And we can know how much that is and

11  that seems to me one of the things that could go into

12  the decision as to how to structure the standard.  But

13  of course, even more important is, okay, what is the

14  averaging for the actual causation of the biological

15  effects.

16	And I don't have a clear idea of the

17  existing discussions of the health effects yet, what

18  that is.

19	DR. COTE: Rogene, I have two quick

20  questions.

21	DR. HENDERSON: Okay.

22	DR. COTE: I thought I heard in answer to

23  Doctor Cowling's question, that there wasn't a

24  substantial argument for moving away from NO2 as an

25  indicator.  I think that's what I heard as a consensus.

Page 132

1  favorable things about doing uncertainty analysis.

2	DR. COTE: Yeah, I think that's   okay,

3  Mary has clarified that that was really meta-analysis

4  rather than uncertainty analysis.

5	DR. ULTMAN: Those are two different

6  things.

7	DR. HENDERSON: No, I think uncertainty

8  analysis is favorably

9	DR. ULTMAN: Is Lianne on the phone,

10  because that's one of her areas of special expertise?

11	DR. SHEPHERD: Yeah, I am on the phone.

12  I don't know that I have anything to add to that now.

13  It'll probably come up a lot more tomorrow.

14	DR. HENDERSON: Okay, is that Lianne?

15	DR. SHEPHERD: Yes.

16	DR. HENDERSON: Okay, I thought we needed

17  a comment.

18	DR. SHEPHERD: I don't have anything to

19  add right now.

20	DR. HENDERSON: Okay, she said she --

21	DR. ULTMAN: More later.

22	DR. HENDERSON:   would have more later,

23  yeah.

24	DR. SHEPHERD: Right.

25	DR. COTE: Okay, that was all that I

Page 131

1	DR. HENDERSON: I thought I heard that

2  there is not now good evidence to move away from NO2,

3  though there is concern about the multi pollutant

4  effects and how you handle that, which probably goes

5  way beyond the scope of this panel.

6	DR. COTE: We're concerned about that

7  too.  We've been discussing that a lot.

8	DR. HENDERSON: Yeah.

9	DR. COTE: I don't want to get into a

10  long discussion but the second question I had, I just

11  wanted a little feedback on is, you know, a number of

12  people have said, have mentioned looking at the

13  uncertainties around a number of these factors.

14	And my questions is there's, you know,

15  I'm sort of of the school of uncertainty analysis, but

16  there is a deep seated feeling in the organization that

17  CASAC in the past has not particularly looked favorable

18  on uncertainty analysis.

19	Now maybe that has more to do with how

20  the uncertainty analysis was done versus a general

21  dislike of it.  But maybe Mary can shed a little more

22  light on that.

23	Meta-analysis, Mary says it was meta-

24  analysis, not

25	DR. HENDERSON: I think I've heard very

Page 133

1  wanted to know.

2	DR. SHEPHERD: I do have a comment though

3  about

4	DR. HENDERSON: Okay.

5	DR. SHEPHERD:   Chapter 2 with respect

6  to this comparison and discussion of correlation

7  coefficients.

8	I just couldn't make sense out of it,

9  there are so many different correlations being compared

10  and they weren't clearly defined and there were so many

11  factors that would make them different, like seasonal

12  restriction and so on.

13	And that was tried, attempted to be

14  addressed, but that whole piece needs to be reworked

15  because I didn't think that we could draw any

16  conclusions from the data as presented.

17	DR. HENDERSON: Thank you, Lianne.  Ron?

18	DR. WYZGA: Just one thing.  I think this

19  is in response to the issue about what's the

20  appropriate indexing method, you know, NO2 is thought

21  to be appropriate.

22	But I would still urge that to the

23  extent the Agency can update the report NO data, it

24  would be particularly for people with a deeper

25  analysis.

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1	So I think that's something we don't

2  want to let go of.

3	DR. HENDERSON: Okay, thanks, Ron.  Ted,

4  you look like you're about to say something.

5	DR. RUSSELL: Yes.  I was going to ask

6  Ellis, I actually got the feeling you were pushing

7  maybe the Agency looking at something like the nitric

8  acid or something like that.  And I'm not sure if

9  that's

10	DR. COWLING: No, I have biases of course

11  over the two, but I have no special bias towards the

12  nitric acid simply raising the question, what is the

13  appropriate measurement technique and what is the

14  appropriate monitoring design and what is it, as you

15  pointed out yourself, what is it that worries the

16  health people in terms of their experience in dealing

17  with humans that suffer from asthma and all the other

18  difficulties that observed?

19	The Academy of Sciences has urged that,

20  in its most recent management of air quality in the

21  United States report, urged consideration of multiple

22  pollutant, multi effects ways of approaching the air

23  quality management.

24	And this discussion about what about the

25  connection with ozone, what about the connection with

Page 136

1  pollutant at a time.  So I think we will eventually go

2  to the multi pollutant system.

3	DR. ARNOLD: I just want to say just one

4  thing, this is Jeff Arnold.

5	DR. HENDERSON: Can you speak into the

6  mike so we can hear you?

7	DR. ARNOLD: I just want to say that one

8  of things we are trying to do with the discussion about

9  the monitoring of NO2 in itself, and this bears

10  directly on both of Ellis' points, is that we were

11  talking generally about the uncertainty in the NO2

12  measurement and whether or not NO2 is the indicator

13  chosen to go forward, because we thought it was

14  important to have that information available to people

15  who are working on health effects.

16	The other side of this whole thing, we

17  were talking about the more general measurement in

18  trying to get to a characterization of the mix is the

19  reason that we were looking at and talking about the

20  measurement of NOI together because it's a fairly

21  simple transformation to make mechanically.  And some

22  measurements are actually in place in the network now

23  and we can understand what those relationships look

24  like.

25	And that NOI then captures more of the

Page 135

1  PM, emphasizes exactly why that committee strongly

2  urged, and why Europe is in the process of accepting

3  that recommendation.

4	We have a bias in this country to doing

5  one thing at a time and we're biased also to not do

6  anything until there's a crisis.

7	I presume they were interested in the

8  crisis in 1971 relating to oxides of nitrogen and that

9  that's where we got the standard that we now have and

10  have continued to use for 36 years.

11	So we should take a wiser choice, a

12  wiser, make a wiser series of recommendations.  And

13  certainly as Rogene said a few moments ago, we'll

14  probably have to deal with that multiple pollutant, but

15  Amen.

16	So I'm asking in the most general way,

17  what is it that CASAC ought to recommend to the

18  Administrator with regards to management of oxides of

19  nitrogen?  And if that means what they ought to do

20  about ozone and PM at the same time   by all means.

21	That is a bias, I am biased toward the

22  notion that managing air quality is a much bigger job

23  than managing one pollutant at a time.

24	DR. HENDERSON: Well as far as consuming

25  time it certainly takes more time to do it one

Page 137

1  actual oxides of nitrogen mix than we do with the NO2

2  measurement which has got an unknown and varying amount

3  of interference.  It varies both spatially and

4  temporally at all the measurements that are in there.

5	And so as part of the point of getting

6  to a multi pollutant strategy, which I'm not

7  recommending that we try to do at this point in this

8  meeting, but that was part of the idea of looking at

9  NOI because it characterizes more of the oxides of

10  nitrogen.

11	DR. HENDERSON: Thank you.  Now, we're

12  going to be breaking for lunch.

13	Before we do as we discussed earlier, we

14  have a little new process at the end, so Angela is

15  going to try to summarize what we want to say to the

16  Administrator, the key points.

17	And so those of you who have, your name

18  is underlined, I'm hoping that you will be able to get

19  a written summary of our, the panel's answer to those

20  charge questions to Angela by email.

21	There's two important things, monitoring

22  Ted, will you put that in, and you had I think a good

23  summary of   you and Christian together, be sure that

24  monitoring is in there.

25	And then Ellis, could you write up a

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Page 138

1  little sentence on that we need to start addressing

2  multi pollutants?

3	DR. COWLING: I would be happy to.

4	DR. HENDERSON: Thank you.  And send

5  these snippets to   Tim Larson, are you on the phone?

6	DR. LARSON: Yeah.

7	DR. HENDERSON: You may not realize

8  you're supposed to be writing something up.

9	DR. LARSON: Yes.  So you'd like me to,

10  would you like me to try to summarize some of these

11  points about the sufficiency for evaluation?

12	DR. HENDERSON: Okay, I could barely hear

13  you but if you would send us that email, to Angela,

14  she's going to collate them.

15	DR. LARSON: Okay, can you hear me?

16	DR. HENDERSON: Yeah, when you speak up I

17  can hear you.

18	DR. LARSON: Okay, I don't know what the

19  phone is but I'm sort of yelling into it.

20	DR. NUGENT: Rogene is asking for this by

21  tonight.

22	DR. HENDERSON: Oh yeah, this is not in

23  the future, this is today.  Today.

24	DR. NUGENT: Today.

25	DR. HENDERSON: And tomorrow morning

Page 140

1  letter to be 50 pages long, but you know.

2	DR. THURSTON: And Angela said she wanted

3  it at the latest by 10:00 p.m. eastern time, is that

4  daylight I guess, we're still on daylight, right?

5	DR. HENDERSON: And I really thank Angela

6  for being willing to pull this all together for us.

7	Okay, let's have lunch.  The restaurant

8  is what are we going to do?

9	SPEAKER: Vanessa knows.

10	DR. VU: Lunch for CASAC members is where

11  you meet for breakfast, the Raleigh Room.

12	DR. HENDERSON: So we will convene at

13  1:00 and there are people here who are going to be on

14  the phone, so let's be back.

15  (WHEREUPON, the morning session was concluded at

12:03

16  p.m.)

17	DR. HENDERSON: The next three charge

18  questions are all related to health, the Charge

19  Questions 4, 5 and 6.

20	So I think, and we have many health

21  experts here to comment on this.  This is a very

22  important section, quite critical and I hope everybody

23  has read the bottom line that was on the last paragraph

24  of Chapter 5, because it tells you that the Agency

25  considers that there's sufficient evidence to, that the

Page 139

1  we're going to pass this around and we're going to

2  decide whether this is something that we can agree on

3  as far as the letter to the Administrator and how we

4  think this document needs to be changed to improve it

5  or whether we can't.

6	If we can't we have a conference call

7  later on.

8	DR. LARSON: Rogene, what would you like

9  me to emphasize and what part of the discussion?

10	DR. HENDERSON: What did you say?

11	DR. RUSSELL: What would you like him to

12  emphasize.

13	DR. HENDERSON: Oh.

14	DR. LARSON: What part of the discussion

15  do you want me to try to summarize?

16	DR. HENDERSON: Well, Charge Question 3

17  but that's, I know what you mean, that's kind of, it

18  involves everything under, in Chapter 3.

19	The indoor/outdoor or maybe NO as the

20  surrogate for, I mean NOX, NO2 as the surrogate for

21  nitrogen oxide.  That's something we want to have in

22  there.

23	DR. LARSON: Okay, okay.

24	DR. HENDERSON: Just a paragraph, short,

25  short and sweet because the letter, we don't want the

Page 141

1  standard should be strengthened as I understand what's

2  written up there.

3	But we need to put this in context as we

4  go through these different charge questions.

5	We'll see how it goes, we may want to

6  combine some of these discussions.  I think they will

7  combine themselves almost automatically but we'll start

8  out with Charge Question 4, which is really at the

9  heart of the whole thing.

10	To what extent is the discussion and

11  integration of evidence when the animal toxicology in

12  controlled exposure human experimental studies and

13  epidemiologic studies technically sound, appropriately

14  balanced and clearly communicated?

15	So that's going to be headed by Terry

16  Gordon.

17	The man who is writing down what we are

18  saying would like for us to identify ourselves before

19  we start talking, and particularly those who are on the

20  telephone.  So if you don't mind doing that, that would

21  be helpful.

22	And Terry Gordon is speaking first.

23	SPEAKER: Rogene, I can't hear anything.

24	DR. HENDERSON: Well nobody's talking

25  right now.  That's good.

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Page 142

1	SPEAKER: That's good, okay.

2	DR. HENDERSON: We have to speak up into

3  the mike.

4	SPEAKER: Okay, all right.

5	DR. GORDON: There's a great deal of good

6  work here in this Chapter 3 and 4 and I feel that the

7  health relevant studies have been presented.  This is

8  really loud to me.

9	Obviously this long, long chapter was a

10  multi author effort and the inconsistencies in

11  integration across the different sections is what I

12  feel is the main problem with this chapter, this

13  Chapter 3, in terms of answering the Charge Question

14  number 4.

15	So the proper degree of integration and

16  study discussion in terms of relevance to our task of

17  reviewing the science of NOX health effects, it's

18  presented in a few places, mostly in the descriptions

19  of the clinical studies.  But adequate integration is

20  most absent in the animal tox descriptions and

21  sometimes I feel the EPI studies were not integrated,

22  they just tend to wander.

23	So part of me was thinking that a single

24  or maybe two at the most authors should be charged with

25  the next step of condensing and integrating this

Page 144

1  might be easier to give a full interpretation and

2  integration of the EPI studies and then mention briefly

3  in each one of those sections afterwards, how the

4  clinical and animal tox data supports or refutes the

5  EPI data, rather than how it is now.  It's a little bit

6  separate.

7	Then, and this is just out in left

8  field, I was wondering is Chapter 4 necessary, the

9  susceptible sub-populations, even though it's something

10  I actually do research on a lot.  It seems it's partly

11  duplicative of what's going on in 3.

12	Why would you pull out the most

13  sensitive sub-population effects into a separate

14  chapter?  Shouldn't that be in the Chapter 3?

15	And in summary I think is like a key if

16  not the key chapter and it's needs better balance

17  between providing the details of the central studies

18  and the overall integration with health effects.

19	And as Ellis said this morning, it needs

20  to be made a much more efficient communication device.

21  And it's most important to have an integrated analysis

22  that draws the key conclusions from the available data

23  sets, and I stole this from Dale, and include the

24  magnitude of the concentration response for the

25  different health endpoints.

Page 143

1  chapter.

2	And for example there are several

3  redundancies in these studies, things repeated two

4  pages later.

5	So in general I just have four short

6  bullets and I feel it's important

7  that only the key studies that support or refute the

8  NAQS should be included.  And unlike Chapter 2

comments

9  we heard earlier where they wanted to bring some of the

10  annex information into Chapter 2, I think a good bit of

11  information in Chapter 3 should go back to the annex,

12  and more integration and discussion devoted to the key

13  health relevant studies.

14	And then because it's such a large

15  chapter, and I don't know if anybody is going to

16  suggest splitting it up, it seems it should have a

17  summary at the end of each section that discusses the

18  relevance of that section as it relates to adverse

19  effects with concentrations, something that was brought

20  up before and something that's missing.

21	And in this latter point it's key across

22  all the study types, especially the EPI studies which I

23  think are driving the NAQS review.

24	And therefore if the EPI studies, if

25  it's decided the EPI studies drive the NAQS, I think it

Page 145

1	And that's probably the key to this

2  whole chapter and it's only there as I said in a few

3  places.

4	And to reemphasize what Jim Ultman said

5  earlier, that the exposure concentration in studies,

6  the EPI ones of course, should be put in context

7  throughout during the summary at the end of the chapter

8  in the context of the current standard with respect to

9  reviewing is it appropriate or not.

10	DR. HENDERSON: Thank you, Terry.  John,

11  are you ready to give your comments?

12	DR. SAMET: Yes, it's Jon Samet or John

13  Balmes?

14	DR. HENDERSON: Oh, I'm sorry, it's Jon

15  Samet

16	DR. SAMET: Okay.

17	DR. HENDERSON:   and not John Balmes,

18  I'm sorry.

19	DR. SAMET: Just checking.

20	DR. HENDERSON: I was thinking J-O-N, but

21  you can't tell the difference.

22	DR. SAMET: Yes, so I wrote fairly

23  lengthy general comments that I think speak largely to

24  this charge question.

25	So my general comments were that I did

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Page 146

1  not see this document succeeding in meeting what it was

2  called, integrated.  And that this problem really

3  reflects sort of a failure of process which I think

4  sort of comes through in the last comment and some of

5  the other comments.

6	There are models for doing systematic,

7  integrated reviews and I don't really feel that this

8  document looked to those models, the authors looked to

9  those models, the Agency looked to those models in

10  setting out on a process.

11	And then I think that comes through

12  because the methodology is rather opaque for me in sort

13  of achieving the integration.  Terms like coherence,

14  plausibility, consistency pop up but they're not really

15  clear as to the intent of those terms as they're

16  reviewed.  They're sort of convenient to use.  The word

17  is integration is used without integration taking

18  place.

19	So I will say that as a general model

20  for how to proceed to do integrated summaries, I'm

21  concerned about this as a starting point.

22	And then that reflects back of course on

23  question 4, on Charge Question 4 because that is the

24  one where the integration is supposed to come in.  And

25  I just don't see that the methodology was set out.  I

Page 148

1	So I saw problems and the problems don't

2  relate to necessarily these were picked out in how they

3  were represented, but really whether they were

4  integrated or not.  And as I say right now my view is

5  that the integration and synthesis that was needed here

6  has not been accomplished.

7	And so much of this sort of reads   I'm

8  sorry to say this   but sort of like a mini criteria

9  document with sort of recitations of studies with, you

10  know, paragraphs starting of with, you know, Schwatz,

11  et al shows and so on, so that it's, I just don't think

12  the model's integration has been met.

13	So that means that the answer for the

14  charge question is that this has not yet been done

15  adequately.

16	DR. HENDERSON: Okay Jon, was that all

17  you had for this charge question?

18	DR. SAMET: Yeah, and I think again I've

19  laid out a lot of general thoughts in my comments.

20	DR. HENDERSON: Yes, you sent extensive

21  comments.  Well now let's go to John Balmes.

22	DR. BALMES: Okay.  So first of all I

23  apologize for not submitting written comments yet.

24  I've been working on a grant and that's had to take

25  priority.  But I will submit those by the end of

Page 147

1  mean there's sort of these little mini reviews of that,

2  the mini reviews of some tox that might be viewed as

3  relevant.  But it's not really brought together.

4	I was concerned, and I think I saw some

5  of this in George Thurston's comments as well about

6  sort of the underlying framework and ideas.  And I

7  think the interpretation of effects attributable to NO2

8  and NOX is very difficult because of the links back to

9  common sources of other pollutants, the contributions

10  of NOX and PM, the role in ozone generation.

11	And these sort of simple underlying

12  causal models that seem to play throughout the document

13  may not be correct.  And again in my comments I sort of

14  outlined some of the different models and there's some

15  little figures there that are the kind of thinking that

16  I think ought to come up front in the document.

17	Because again, the document has to make

18  clear that NO2 is the right indicator itself, that

19  reduction of NO2 could be reasonably expected to have

20  benefits, which is the causal model and potentially

21  some of the other models.

22	But again if we're working to lower PM,

23  and that is one way that NOX is in fact mediated, we're

24  sort of going after the same sources twice obviously

25  and I think that that could be acknowledged.

Page 149

1  tomorrow.

2	I didn't hear the start of Terry's

3  comments but I heard the end and I heard of Jon's.

4	And, you know, the question for charge 4

5  has four, excuse me, three specific components, is the

6  discussion integration of the evidence from different

7  types of studies technically sound, appropriately

8  balanced and clearly communicated?

9	So on the technically sound part I would

10  say that my major concern was just articulated by Jon

11  and also George Thurston in his written comments, that

12  I think there need to be clearly communicated criteria

13  about how steady the epidemiologic studies in

14  particular were selected.  And then how the results are

15  evaluated.

16	I thought Jon and George both

17  articulated that well.  So that's on the technically

18  sound thing.

19	With regard to appropriate balance, I

20  guess I was a little concerned that two negative

21  studies that I've coauthored didn't appear in the

22  discussion.  And I think while neither one of these

23  studies is earthshattering, given the relative dearth

24  of information with regard to nitric acid vapor, our

25  1993 study which I think is one of the very few studies

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Page 150

1  to compare filtered air and nitric acid vapor, the

2  controlled human exposure study, the fact that's not

3  even mentioned, and it has been published since the

4  last criteria document, should be mentioned.

5	Again it's a negative study.  There's

6  also a study that was published in 2005 by my group

7  which was a negative study about NO2's affect on

8  allergic inflammation using induced sputum rather than

9  bronchoalveolar lavage.  There's a brochoalveolar

10  lavage study mentioned.

11	I only point out these two studies

12  because those are ones I knew about because I'm the

13  coauthor.  I am a little bit concerned that even though

14  we need a shorter document than the old criteria

15  document, that there may have been some cherry picking

16  in terms of studies to the exclu   you know, which, to

17  the exclusion of some relevant information.

18	I don't know that for a fact but I'm

19  concerned about it.

20	And, you know, in terms of the clear

21  communication, I don't think it cuts it.  The chapter

22  is repetitive about mechanisms for sure.  I don't think

23  the mechanistic information is well integrated with the

24  epidemiologic information.

25	You know, an example would be when the

Page 152

1  they're taking, that the authors are taking what the

2  original studies probably used, but it would be nice to

3  have a common metric when you're going back and forth

4  between studies.

5	And I also think that the tables and

6  figures, which I like, at times need better labels or

7  legends because they really should sort of stand on

8  their own so you don't have to go back into the text

9  and figure out what's there.

10	So those are two picky things.

11	I guess one more, sorry, there is a

12  section on the effects of NO2 on allergic responses in

13  synthesized individuals which I think is an important

14  set of, it's an important section, but that important

15  section in my mind doesn't make it into the integration

16  with a focus on asthma.  And I think it should because

17  that may be an important way by which asthma is

18  exacerbated by NO2.

19	That's all I have to say --

20	DR. HENDERSON: Thanks, John.

21	DR. BALMES:   at this point.

22	DR. HENDERSON: Thank you very much,

23  those are very helpful comments.  And Ron?

24	DR. WYZGA: Let me first of all

25  apologize, I've been in the office two days in the past

Page 151

1  long term exposure and morbidity sort of integrated

2  summary of that piece is done, the first paragraph is

3  about, it mentions respiratory illness and growth of

4  lung function, and then there's like three or four

5  paragraphs about respiratory illness, potential

6  mechanisms by which respiratory illness in kids might

7  be increase by NO2 exposure.

8	And then there's a little, there's very

9  little about possible mechanisms for the observed

10  effect on growth of lung function from the Children's

11  Health Study.

12	And I just think you could do a much

13  better job of integrating the toxicologic information

14  with the, in support of various epidemiologic results.

15	So I would have to agree with Jon that

16  the 150 pages or whatever it is that are there are,

17  while better than a criteria document, it's kind of a

18  mini criteria document, it's not really an integrative

19  summary that I think can inform policy makers with

20  clear communication.

21	And the one final sort of picky thing

22  that I think would make it easier for   or two things

23  in terms of policy makers reading this.  It goes back

24  and forth between micrograms per meter cubed and parts

25  per billion and parts per million.  I realize that

Page 153

1  six weeks due to personal and professional activities.

2  So I have not had a chance, had access to all of my

3  files and all of my data, but I depended very heavily

4  on what I know and sort of grabbing a couple of things

5  when I was in the office.

6	And it's difficult, we don't want a

7  criteria document but we really want to include what's

8  relevant and it's sort of hard to decided what the

9  dividing line is.

10	But the first issue I asked myself is,

11  what's here, is it comprehensive?  And the idea is we

12  don't to be as comprehensive as a criteria document,

13  but where do we stop?  I don't know.

14	But I'll say that I was very

15  disappointed that it's not comprehensive.  Thinking

16  about studies that I've been involved in, there are

17  some very key studies that have been published that are

18  not listed.

19	They were negative studies that looked

20  at a whole range of pollutants, including NO2, the

21  findings were negative and the studies aren't referred

22  to at all, including one looking at physician visits

23  for childhood asthma.

24	I grabbed a couple of papers as I was

25  leaving the office that had NO2 in them and I looked at

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Page 154

1  them on the airplane.  They weren't referenced either.

2  And one of the studies was a study in Southern

3  California that looked at VOCs and NO2 and basically

4  when the two are looked at together they show nothing

5  for NO2 and it's very hard to discern on both of them.

6	So I felt that it wasn't comprehensive.

7	And the second thing is, again thinking

8  about the studies that I know well, I didn't feel that

9  they were accurately reported and there were just parts

10  of them reported.

11	An example, as part of the area study,

12  Peel, et al looked very extensively at respiratory

13  endpoints.  And when they looked, she looked at single

14  pollutant models she found association with NO2 and

15  respiratory, hospital admissions for respiratory

16  diseases.

17	When she looked at multi pollutant

18  models she found that NO2 went away and the ozone

19  seemed to dominate everything.

20	Now, there are problems with multi

21  pollutant models and you have to wave your hands a

22  little bit and explain them, but I felt at least the

23  document should have presented the multi pollutant

24  results and not only the single pollutant results.

25	The same is true of the area study by

Page 156

1	And for that reason I think that multi

2  pollutant studies are particularly important.  How

3  robust is that association if you look at other

4  pollutants?

5	And I think this document needs to look

6  at it more systematically and sort of talk about what

7  are the co-pollutants under different circumstances?

8  If you're near a roadway in general.

9

10

11

12

13

14	And I think more weight should be given

15  to those studies that tend to look at co-pollutants

16  rather than studies that look at a single pollutant.

17  And this is why I think it's also important to tie it

18  in with the clinical studies and the toxicology studies

19  because in the controlled exposures we know exactly

20  what people and animals were exposed to and tie them

21  together.

22	So I would ask that one go back and see,

23  are you missing other important studies?  Are you

24  treating them fairly when they deal with co-pollutants?

25  Are you emphasizing that?  And then ask yourself other

Page 155

1  Metzger which looked at cardiovascular disease and

2  admissions.  You know, NO2 is reported in an earlier

3  data set, NO2 was reported and then they spoke about

4  results of NO2 and CO together where NO2 was still

5  important.  But in a later data period where we had

6  much more extensive data, NO2 went away, EC and carbon

7  particles were much more important as was CO.

8	Again, these results were not reported.

9  I was involved in a long term study with mortality with

10  Lipford where we found associations with NO2.  And

11  again when we looked a multi pollutant context it was

12  dominated by ozone and it went away.

13	And the study that's in here reports the

14  single pollutant results and does not report some of

15  these multi pollutant results.

16	Now there are caveats in dealing with

17  them and I think they can be handled and discussion,

18  but I think it's fair to get them.

19	I think the major problem we have to ask

20  ourselves with NO2 is clearly in single pollutant

21  models we see a lot of evidence of association with

22  health effects.  And the really big question is, is NO2

23  serving as a surrogate for something?  And that's

24  something we really have to, you know, dig into and

25  think about it.

Page 157

1  questions too.

2	In looking at some studies, in looking

3  at results, you know, people looked at different lags

4  and I found, you know, it wasn't always consistent.  In

5  some cases it was a very short lag that's important.

6  In other cases the lag was several days out.

7	Is that meaningful or not?  I don't know

8  but I think it's something that needs to be

9  entertained.

10	Those are my major comments and I'm

11  happy to answer further questions and I'll send you

12  those specific references as soon as I get back to the

13  office.

14	DR. HENDERSON: Thank was my first thing,

15  I wanted to be sure that we will have those copies of

16  the reports you're talking about.

17	Can you off the top of your head say why

18  some of these negative studies were not included?

19	DR. ROSS: Well I've been looking in the

20  document because cheery picking is obviously something

21  we take very seriously.  And all I can say is we did a

22  systematic literature search using source terms that we

23  worked out with the librarian and worked over.  And I

24  think we tried to gather information.

25	For Peel and Metzger I'm looking at the

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Page 158

1  multi pollutant figure we put together and as I recall

2  the results were in figures and not quantitative

3  results that we could pull into to a figure ourselves.

4	So I think we tried to look at those

5  studies as much as we can.

6	I don't have any reason, I don't know

7  all the specific studies people are mentioning, but we

8  certainly tried to include as many as we can and we

9  welcome any   we will look very seriously and do

10  another literature search and make sure we didn't miss

11  something.

12	But please, you know, submit references

13  that you think we missed.

14	DR. SAMET: Rogene, this is Jon.  Can I

15  make two follow up comments?

16	DR. HENDERSON: Sure.

17	DR. SAMET: Yeah, just one on the

18  literature search strategy, I think it has to be more

19  transparent than it is.  And I think, I'm sympathetic

20  to trying to have a list, but when it's not clear and

21  replicable how studies are being selected you'll always

22  be subject to enquiries like, why wasn't whatever study

23  included?

24	And I think that that's a problem with

25  the document.

Page 160

1  was very briefly mentioned about endogenous NO

2  production, I thought in terms of trying to put the

3  experimental results, both in toxicology and

4  epidemiology into a biological plausibility context,

5  that the endogenous production of reactive nitrogen

6  species was pretty absent from the discussion.

7	In the field of free radical biology

8  it's been recognized now for many years, that NO2 is

9  produced endogenously anytime you have an inflammatory

10  response.

11	How you put that into context relative

12  to the low ppb NO2 inhalation exposures we're talking

13  about, especially in the epidemiology studies, I don't

14  have an answer to.  But to equate causality to

15  something that is 10, 20 parts per billion relative to

16  the exact same molecule that's produced from a

17  peroxidase reaction and uses nitrite and hydrogen

18  peroxide, I think somewhere in this document that whole

19  issue has to be addressed.

20	Now as I said, putting that in terms of

21  quantifiable amounts of NO2 is an extraordinarily

22  challenging thing to do.  But I think on a relative

23  term at least, that should appear.

24	Likewise when in the document when we're

25  talking about some of the co-pollutant stuff, nothing

Page 159

1	I just want to have a caution, and this

2  comes in light of the little figure, that

3  interpretation of the multi variant models here is very

4  complicated, because of the possibility of direct

5  pathways, indirect pathways and confounding.

6	And I think that this issue needs very

7  careful intellectual attention up front.  And how you

8  do interpret these models and when effects come and go

9  depending on what variables are included, the

10  interpretations are not so simple as either the

11  document portrays them or very often how authors

12  interpret them.

13	So I would urge some real thinking about

14  how to interpret these multi pollutant models.  And of

15  course if in fact NOX is acting through other

16  pollutants and you put those pollutants in a model and

17  the NO2 goes away, that does not mean it's not having a

18  causal effect.  Just as one example.

19	So I think you need to build a better

20  framework up front for interpreting the evidence you're

21  going to present.

22	DR. HENDERSON: Thank you, Jon.  Yeah,

23  Ed?

24	DR. POSTLETHWAIT: Yeah, this is Ed

25  Postlethwait.  In Chapter 3 and Chapter 4, although it

Page 161

1  was said about the endogenous production of carbon

2  monoxide and CO now is recognized as a second, and in

3  fact it's being used in preclinical trials.  And so

4  they're delivering CO to people that ten years ago we

5  would have thought was just nuts to do.  And now it's

6  shown to have some anti-inflammatory and other types of

7  efficacies.

8	And so the connection between the known

9  mechanisms of action and biological plausibility, et

10  cetera and the outcomes that were reported in the

11  document, I think could really be tightened up.

12	DR. HENDERSON: Okay.  Ed, those are some

13  important points and I thank you for bringing it up.

14	Ed Avol has a comment and then I want

15  Kent Pinkerton to come in because Kent at one time was

16  not going to be here and so he inadvertently got left

17  off this list, so he's going to speak after Ed Avol.

18	DR. AVOL: Thank you.  So I just have a

19  couple of comments to get at the charge question

20  related to clear communication.

21	And it seemed to me the heart of the

22  issue in this document is the understanding and

23  relating in terms of the public health context.  And

24  there are threads throughout the different chapters,

25  this one included, that get at how we interpret what we

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Page 162

1  do.

2	But clearly because NO2 and NOX is so

3  closely associated with combustion exhaust and other

4  pollutants, for example ultra fine particles that Mark

5  Frampton measured and mentioned earlier.

6	I think we need to sort of think about

7  how this is communicated and the context really in

8  which it's reported throughout the document.  So it

9  goes back to what Ted Russell had said earlier about

10  sources, because I think if there is an overriding

11  writer that sort of integrated many of the chapters

12  because there were many different writers and

13  contributors to this document, understandably, but

14  there's sort of a theme that underlies all of these

15  facets that goes from the sources and the fact that we

16  need to identify it, its multi pollutant nature I guess

17  and then look at the pollutants and health effects and

18  understand that in fact we have these potentially

19  confounding issues that might be able to be uncoupled

20  by multi pollutant models by some of these studies and

21  to what extent we believe that the studies have

22  successfully demonstrated that.

23	And then finally to conclusions later on

24  that say, that talk about this rather than just a

25  sentence here or there that sort of says, allows it as

Page 164

1  higher than the epidemiological studies that are

2  beginning to show effects, especially in children with

3  asthma.

4	And so I think that kind of integration

5  and interpretation of how do we use the animal tox

6  studies, if at all in the creation of the next

7  rendition of this criteria document.  Is there a place

8  for that in the document?

9	I think it's also really important,

10  since this criteria that has been established for NOX

11  is on the order of 36 years that I thought I heard

12  earlier today, you know, where do we go with that?

13  Because it seems as though with the current standard as

14  it is, there is very rare exceedances of the standard

15  as it exists today.  Yet how do we take into account

16  that there are health effects in children exposed to

17  incremental levels that are on the range of 10 to 20

18  ppb levels?

19	So those are things that I think are

20  really critical for the integration for this document.

21	And really, before Ron mentioned

22  anything and as well as John Balmes, I thought the

23  review of the literature seemed to be really good and

24  that it was, you know, with new literature and things

25  that are there, but again it sounds like it would be

Page 163

1  a possibility.  I think that would help the overall

2  document and make it clearer to the user of this

3  document as to what it means and how the document

4  itself is integrated.

5	DR. HENDERSON: Thank you, Ed.  And now

6  Kent, it's your turn.

7	DR. PINKERTON: Thank you.  What I'm

8  about to say will echo much of what has already been

9  stated.

10	But as an animal toxicologist I think

11  that it's very important to me to better understand how

12  we integrate animal toxicology to human clinical

13  experimental studies as well as epidemiological

14  studies.

15	And I think that with the document,

16  although it's really been a great effort to pull

17  together a lot of the literature and perhaps there are

18  other sources of literature that still need to be

19  considered, but a concern is the fact that in order to

20  produce toxic effects in animals we're usually dealing

21  with an order, the two orders of magnitude, higher

22  concentrations of nitrogen dioxide than we need to use

23  in the human clinical studies.

24	And then even with the human clinical

25  studies they tend to be usually an order of magnitude

Page 165

1  good to take advantage of the things that we're

2  learning today about other literature, other studies

3  that may be pertinent to helping us with this criteria

4  document.

5	And finally I would like to think that,

6  you know, there really is a lot of pressing issues here

7  from the perspective of whether this document needs to

8  be changed or not in terms of a new standard.

9	And so again these discussions and the

10  way you put together the document will be critical.

11	And I would just like to also emphasize

12  the fact that it is very important because it seems to

13  be a recurring theme throughout the document, that the

14  health effect that are attributed to NO2 may always be

15  confounded by the association of other co-pollutants or

16  it may be that NO2 is just serving as a surrogate for

17  other pollutants.

18	So again that's another point again that

19  I would emphasize that needs to be really clearly

20  defined in this document.

21	DR. BALMES: This is John Balmes again.

22  I wanted to thank Kent for bringing up a point that I

23  had meant to bring up but I forgot to and that's a key

24  point.

25	With regard to ozone we have good

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Page 166

1  experimental data, both from clinical human studies and

2  animal toxicologic studies to support inflammatory

3  effects at levels at least close to ambient.  But we

4  don't have that with NO2.

5	So that it makes the integration of the

6  epidemiologic literature with the toxicologic

7  literature, both human and animal, you know, very

8  important.

9	And I think that insufficient attention

10  has been paid to that as Kent pointed out.  I think

11  there has to be an acknowledgment that both the animal

12  and human studies that show acute effects are at higher

13  levels than ambient.

14	So that sort of brings up again the

15  issue of how NO2 is acting to, in its association in

16  the epidemiologic studies with health effects.  Is it

17  direct NO2 effect or not?  Or is NO2 a surrogate?  You

18  know, the various models that Jon Samet included in his

19  written comments.

20	But I'm repeating Kent because I want to

21  underscore, think that's very important and I think one

22  of the public comments this morning already brought up

23  the relative lack of support from the toxicologic

24  studies for the epidemiologic evidence.  And so I think

25  we have to sort of, I think the Agency needs to deal

Page 168

1  these comments that are brought up that indicate that

2  we may not have been thorough in picking up all the

3  negative studies.  And so if there's a positive, it's

4  not a publication bias but a positive bias for finding

5  the positive studies is in there, so it's also very

6  important for us consider in coming to that conclusion.

7	And then I wanted in particular to draw

8  your attention to a section that hasn't been talked

9  about yet, it's on page 3-126 on cancer incidence.

10  I've been puzzling over this since I read this section

11  since I really hadn't watched these two articles real

12  closely when they came out.

13	But one from Sweden and one from Norway

14  in which they looked at incidence of cancer and

15  correlated it with air pollution.  In this case it's

16  translated all the way down to NO2 being the driving

17  agent to it.

18	But they, because they actually, if this

19  is correct and I convert the micrograms per cubic

20  meter, basically divide it by two to get parts per

21  billion, you're talking about exposure levels that they

22  say is, by Nyberg's article in 2000, exposure a the

23  98th percentile to an ambient level of NO2 was

24  associated with a odds ratio of 1.44 for cancer, for

25  lung cancer.  And the other study came up with an

Page 167

1  with that head on.

2	DR. HENDERSON: James Crapo.

3	DR. CRAPO: I'd like to sort of partially

4  weigh in, I think the major issue that we need to

5  provide advice on as a committee, and that is if you

6  read this document the way it's written right now

7  there's a very persuasive argument that there's a

8  profound effect of NOX exposures on many tests of

9  mortality, ER admissions or asthma admissions, cancer,

10  lung growth and development and, you know, a lot of

11  studies that support it with a lot of consistency and

12  coherence.

13	But I think we need to give advice and

14  I'm not sure what the advice ought to be as to whether

15  or not in fact we're looking at a confounding issue and

16  it's surrogate for something else that's doing this or

17  whether the NO2 is doing it directly.

18	And so we need to have some real depth

19  in our knowledge to put those two things together that

20  Kent and John have just talked about.

21	But I think we need to be very concrete

22  in our recommendations to the Agency about conclusions

23  that can be drawn from this and the power that relates

24  to it.

25	It's, I'm a little concerned by some of

Page 169

1  incidence of 1.36.

2	So you're talking about a possibility

3  if you then extrapolate this backwards, if you were

4  able to reduce the, you know, if you attributed this

5  all to NO2 and then reduced it by 20 parts per billion

6  I guess is what they're standardizing this to, it's

7  kind of hard to reduce from 15 to, by 20, but

8  nevertheless it raises the point that if you could make

9  a profound decrease in NO2 you could have a profound

10  impact on the incidence of lung cancer, and on other

11  cancers as well which is also part of the study.

12	My instincts are this is not correct.

13  It's probably a substantial bias in it to create such a

14  profound effect because I've not seen anything that

15  could reduce lung cancer by that kind of a magnitude.

16	And I wonder if this kind of   well, I'd

17  like other people's comments on this data.  But if this

18  were correct it would mandate that we have to do

19  something abut the NO2 levels.

20	But my interpretation of this is that

21  it's probably a surrogate for air pollutants and I'm

22  not sure what the pollutant is in that area.  Although

23  these are two good countries where you should expect

24  good epidemiology and good data.

25	But the only correlation is to where the

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1  people live and to a correlation of air pollutants.

2	Anyway, this kind of correlation is

3  what's, what we're talking about throughout the whole

4  study.  And we need to come to this conclusion

5  concreted, before we can start making conclusions about

6  the overall study and where it ought to go and what

7  ought to happen with it when it goes up to the

8  Administrator for a decision.

9	DR. HENDERSON: Yeah, go ahead Steve.

10	DR. KLEEBERGER: This is Steve

11  Kleeberger.  I'd like to follow up on James' comments,

12  I think those were outstanding.  And actually I was

13  going to save this for when it was time for me to speak

14  but I think I'll start now.

15	What I got from reading Chapters 3 and 4

16  is that while there are a number of interesting

17  observations, there are very few that substantiate

18  initial observations and that it's very difficult to

19  make any concrete conclusions based on the very few

20  studies addressing questions related to susceptibility

21  for instance.

22	And it made me think about what our

23  charge is here.  And that is, are we charged only with

24  evaluating what is there in order to make

25  recommendations?  Or can we as a group also make

Page 172

1	DR. SAMET: Oh Rogene, this is Jon, let

2  me comment.

3	DR. HENDERSON: Yeah.

4	DR. SAMET: The Nyberg study I know well

5  and I mean I think the author's intent on that study

6  was that the NO, the model of the NO variable, the NO2

7  variable was a surrogate for air pollution as I think

8  perhaps James suggested.

9	And there are many epidemiological

10  studies that point to air pollution in general as

11  contributing to the burden of lung cancer, the Six

12  Cities Study and the American Cancer Society's study

13  most notably.

14	So I don't think this is new news, I

15  don't think anyone though has felt that there's a way

16  to do anything other than to point toward the general

17  combustion mix as contributing to the causation of

18  cancer.

19	And again I, you know, I think in

20  looking at the evolution of the epidemiological

21  literature on NO2, if you look back, a long time ago

22  there was emphasis given to just a very few outdoor

23  studies where there was the thought that there was a

24  pure NO2 exposure that was higher for some people.

25  That was the same as the Chattanooga study that Carl

Page 171

1  recommendations for future studies to address these

2  kinds of questions, these gaps in the literature if you

3  will, that will help us or inform us in actually making

4  some concrete conclusions about the literature that's

5  already there?

6	DR. HENDERSON: Well I think we should

7  feel free to make recommendations for future studies to

8  fill data gaps.  However, the regulation has to be set

9  of what's available now.

10	But I'm trying to think of an example

11  where we've recommended future studies, but there's

12  nothing wrong with making recommendations for future

13  studies.

14	Our main charge is to say, is this

15  document, is the science in this document sound enough

16  to be used in the standard setting process based on

17  what's available now?

18	I am very curious about these studies

19  too but I'm kind of like James, intuitively, gosh, I

20  can't believe that NO2 is causing that much cancer

21  around the country.

22	But I don't know, John Samet, did you

23  look at the, are you familiar with those studies?  He's

24  probably muted.  Has anybody read those studies that

25  could critique them and will add

Page 173

1  Shie did back in the '70s.

2	And then there was the emphasis on the

3  indoor studies because that was NO2 independent of the

4  rest of the outdoor combustion mixture.

5	And I think what is new in this review,

6  and again I think this goes back to the problems I

7  highlighted of interpretation, is that people are now

8  turning to times series studies or some other studies

9  where multi variable models have been used to try and

10  tease out NO2 as a mixture component.

11	And to me the heart of the interpretive

12  argument lies in how well you can, how well you can do

13  that.  And I think again, just to reiterate, this is

14  something the document needs to deal with.

15	And this is where the integration with

16  the toxicology becomes so important in my mind.

17	DR. CRAPO: But can I add further on

18  that.  Jon, if you look at the Table 3.   no 5.5-3 at

19  the very end of Section 5, it is the table in which I

20  thought that they really made a strong and I think a

21  laudable effort to try to correlate, put it all

22  together and come up with an integration of the various

23  risks.

24	And what they do on the right side of

25  that table is calculate the standardized excess risk at

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Page 174

1  the 95% confidence interval for various functions,

2  which go through a whole lot of different functions

3  over this whole table.

4	And it's defined, that function is

5  defined as I think an excess risk attributable to NO2

6  at a, in 20 parts per billion increments.

7	Another question on this table, but I'm

8  wondering if in fact we've gone too far with this table

9  and started to draw conclusions where we're actually

10  concluding here that a 20   because when they say

11  standardized risk, and if you look at the lung cancer

12  one, which is on page   and of course they're all like

13  this, but the lung cancer one is on

14	DR. ROSS: James, can I speak to that

15  point about the 20 parts per billion?

16	DR. CRAPO: Sure, go ahead.

17	DR. ROSS: It's not actually intended to

18  say anything about 20 parts per billion.  What you get

19  from the epidemiology study is a relative risk, it's

20  essentially a slope and what we're doing is

21  standardizing it, because the studies presented for

22  different increments in NO2 and what we've done is

23  standardize to an increment that's sort of high to low

24  range in the ambient air.

25	But it's, that's the way that you could,

Page 176

1  throughout this table or through many of the other

2  problems and it's part of the problem we're talking

3  about.

4	So I particularly wanted Jon's comment

5  about this table.  If this is an appropriate to analyze

6  it?  Does it compare to all these variable studies?

7  Because I like the idea, I'm curious if I can really

8  use it in this context to create an integration across

9  all these very different study designs.

10	DR. SAMET: Well to me the major issue is

11  whether you trust the model and I mean that's really

12  the key to this.

13	And I think that comes in light of what

14  the models can tell you in the sense of how these

15  variables may be correlated and what the potential

16  paths for NO2 to have effects are.

17	So you could estimate these effects but

18  these may be coming under the wrong model and I think

19  that's where the decision has to made about what are

20  the right model or models.  And these are sort of, I

21  mean in a sense these tables apply to causal

22  interpretation.

23	DR. HATTIS: This is Dale Hattis.  Notice

24  that there are distortions that are likely in both

25  directions.

Page 175

1  it's just intended so that if we put them in figures

2  you could see them on a sort of a same scale.

3	DR. CRAPO: Right, I understand that.

4  And I'm feeling ambivalent about what I'm saying

5  because for the last several years I've been sitting in

6  this chair saying, be concrete, give me, take hard

7  stands, interpret this data, put your neck out and

8  we'll, so we can talk about it.  And you've done it,

9  and I'm really proud of you for that, and I like it.

10	But now I'm wondering if we've stretched

11  the statement on NO2 to the point where it's saying

12  something that we probably can't say.  Because when I

13  start translating this down to an absolute risk, in

14  fact I, the lung cancer example is one where I agree

15  with Jon, I think it's related, it's a correlation with

16  air pollution and we don't know what it is, it's a

17  surrogate.

18	And I have real doubts that you can

19  express this as an odds ratio or as a standardized risk

20  relative to parts per billion of NO2.

21	And I'm, so I'm concerned as to whether

22  we can do this for many of these studies.  And the lung

23  cancer is an example that I think is pretty obvious

24  that we probably can't do it.

25	But maybe that same logic applies

Page 177

1	Just because it goes away, the core of

2  the association might go away if you put it in a multi

3  pollutant model, if the NO2 is poorly measured and some

4  other thing is better measured and correlated with

5  whatever the causal agent is, then, you know, the

6  causal agent still could be NO2 and have this affect of

7  going away with the, in the multi pollutant model

8  analysis.

9	So that's partly why you need to do what

10  was suggested earlier, is to have a background

11  intellectual discussion of, okay, what are the

12  distortions?  How quantitatively important could they

13  be with the amount of distortion of the measurements

14  that we know happens for NO2 from the verticality

15  problem and the other problems of assuming that central

16  state monitors are well predictive of the outdoor

17  contribution to personal exposures?

18	So I think that's   sort of we know

19  there are distortions in both directions that need to

20  be to some extent fairly assessed.

21	DR. HENDERSON: Okay, I think we'll let

22  George Thurston talk about Charge Question 5, it's also

23  a health question.  And maybe we're beginning to get

24  into that area a little anyway.

25	DR. THURSTON: Okay, yeah.  The question

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1  is, to what extent does the integration of the health

2  evidence focus on the most policy relevant studies or

3  health findings?

4	And I find when I look at what I wrote

5  down here, a lot of it overlaps with what we've just

6  discussed because I do think these are related

7  questions, very closely.

8	I mean one of the first points is one

9  that Jon Samet brought up.  Well first of all, I guess

10  the answer to the question that I come up with is that,

11  yes, but not well enough.  Okay, so, you know, the

12  obvious answer, right?

13	But the need for a framework of the

14  document, and I'd just reiterate that.  It's been said

15  before, I wrote something along those lines in my

16  written comments, but page 5-7 talks about the strength

17  of evidence categories, good, the, you know, those are

18  good.  But we need a foundation for that.

19	And that was also brought up in some of

20  the public comments before we started, you know, that

21  we need to better say what the meaning of these are and

22  their foundation.

23	And we need to set that out at the front

24  of the document.  And I think the best way to do this

25  of course is to start with A.B. Hill's criteria and

Page 180

1  move that in, you know, combine them.  But again, the

2  susceptibility question is one that should be thought

3  of all the way through the document and from the

4  beginning to end.

5	Who is most exposed and what are the

6  effects that might make people susceptible?  And then

7  what do the studies indicate who are the susceptible

8  people?  And do we see a coherent picture?

9	We need to look at the results, you

10  know, in terms of the policy relevant studies and using

11  it for policy.  We need to look at the results as a

12  function of concentration to be more useful for

13  standard setting.

14	I mean we have this long table and

15  there's a lot of missing information unfortunately, and

16  maybe there are ways to fill this in in terms of   and

17  then rank them and put them in groups, you know, across

18  outcomes in certain categories of concentrations.

19	You know, instead of doing one category,

20  then the next category by health outcome, maybe we

21  could group them by concentration and of exposures and

22  then look across there.

23	Now, you know, the 98th percentile, the

24  99th percentile is, you know, sometimes we've got the

25  maximum, we've got the mean, we have the standard

Page 179

1  figure them into these categories, the strength of

2  evidence categories and say what we expect for the

3  various levels of certainty.

4	So that really is something that needs

5  to be done up front and then carried throughout the

6  document, that each time someone writes a section of

7  evaluates a section they'll say, okay, how does this

8  fit into those criteria and, you know, the coherence

9  questions and so on?

10	And we need to look across disciplined

11  evidence, something we've been discussing about

12  coherence.  You know, are the effects, when we look at

13  the toxicology studies and the exposure studies, are

14  the effects on clearance and immune function that are

15  documented, are they consistent with the epidemiology?

16	And I think that there is some evidence

17  that it is.  In other words, who are we seeing

18  affected?  The children with asthma.  So there is a

19  coherence and I think that needs to be brought out and

20  there needs to be a thematic approach to that where

21  each section is not standing alone, but looking across

22  the document.

23	And, you know, another point was the

24  susceptibility section that's not well linked to the

25  previous chapter.  So someone mentioned maybe we should

Page 181

1  deviation, I think they could probably estimate what

2  these things are from the data or we could go to the

3  original authors and ask them if they have that

4  information.  Or a lot of these studies use ambient

5  data, most of them.

6	And so that data, you know, are

7  available so that you could look at the start at the

8  beginning of the study and look at the NOX data and

9  come up with those numbers.

10	So that could be done to fill that in

11  more so we could better categorize these studies by

12  concentration range, which I think would be more useful

13  for standard setting.

14	So, you know, as we've said before, we

15  need to focus the results on results for the especially

16  susceptible populations and try and work on that,

17  because ultimately those are the groups that you're

18  trying to protect.

19	I mentioned before about the PM and NOX

20  interactions so I won't go into that again and others

21  have brought this up, that NOX may be acting by making,

22  you know, by knocking down the defense of the body,

23  let's say clearance of particles and then enhancing

24  particle effects, so there may be a pathway that way.

25	So that needs to be discussed, how these

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Page 182

1  pollutants might be interacting in the body and causing

2  greater effects than they would if there was only one

3  of them.

4	And just sort of lastly to comment,

5  since I've got the microphone, the discussion about the

6  lack of animal and human exposure, exposures at ambient

7  levels like we have for ozone, well I think it's

8  wonderful we have those studies for ozone, that they've

9  been able to be done and we have them.

10	But I don't think that's absolutely

11  required.  And for example we don't have them for PM,

12  ambient exposures where we can replicate health

13  outcomes in human exposure studies.  You know, there's

14  near ambient and there's, you know, the concentrator

15  studies and that kind of thing, but we don't have the

16  direct at ambient concentrations for PM.

17	So I don't think we should set a higher

18  standard for this than we do for PM and other

19  pollutants.

20	I do think that they're very important,

21  those studies, to learn about the biological

22  plausibility.  And again, if you're doing A.B. Hill's

23  criteria you're going to look and say, okay, we've got

24  this association in epidemiology.  Is it biologically

25  plausible?  Then we turn to the studies we have

Page 184

1  primarily epidemiologic data, that that's wrong to do.

2  That's for us to discuss.

3	But I do think the acknowledgment that

4  the study, the toxicologic studies are at levels higher

5  than ambient needs to be in the document sort of more

6  clearly.

7	That's two different things.

8	DR. HENDERSON: Ed Avol has something to

9  say.

10	DR. AVOL: Just to follow up on a comment

11  that George made with regard to susceptible sub-

12  populations.

13	I mean I think it's important for the

14  document to look at and identify susceptible

15  populations and that's fine.  But I think we don't want

16  to lose sight of the fact that there's, there are

17  ranges of susceptibility.  I mean there are certainly

18  asthmatic children that we're interested in, but for

19  example in lung growth function from the Children's

20  Health Study we don't have any evidence that asthmatic

21  children are losing function any faster than healthy

22  children.

23	In fact healthy children are losing

24  function, have depressed function as well.  And so I

25  think in that sense children are a susceptible

Page 183

1  available.

2	And I think some of the most important

3  studies that were noted in here in that regard, not in

4  terms of setting the standard, but in terms of deciding

5  whether this is a causal relationship, are the

6  intervention study that was mentioned, the indoor

7  studies are very, I thought informative of that

8  question.

9	So we don't have the controlled studies

10  and animal studies that everybody loves.  We do have

11  those indoor studies and an intervention study that

12  wass mentioned.  So I think that's very powerful

13  evidence that needs to be considered.

14	DR. BALMES: So George?

15	DR. THURSTON: Yes.

16	DR. BALMES: It's John Balmes again.  I

17  agree with you that we don't have to have a toxicologic

18  study supporting the EPI findings, but you're correct

19  about PM.

20	But I just think we should acknowledge

21  that up front.  You know, I think it's sort of a little

22  bit obfuscated in the document the way it currently is.

23	So I want' trying to say that before the

24  Agency or before CASAC recommends to the Agency that we

25  have a different standard for NO2 that's based on

Page 185

1  population.

2	Similarly there is some talk in the

3  document about genetic susceptibility and if you look

4  at the penetration of GSTM presence or absence in the

5  population, I mean there are significant numbers of

6  people, which may be a different way of saying the same

7  things with regard to normal or healthy or asthmatic

8  sub-populations, there are large portions that are at

9  increased risk.

10	And so I think that's the issue that

11  needs some gradation or some description and discussion

12  needs to come across in there as well.

13	DR. HENDERSON: I would like to say I

14  agree with you, George, that the EPI studies that were

15  most impressive for me were those intervention studies

16  in Australia as I recall, where they did them indoors

17  and they had, you know, the stoves were taken in and

18  out and he saw changes in the health effects in the

19  children as I recall.

20	Those were very impressive because you

21  have less confounding by the other air pollutants.

22	But I have a question for you.  What is

23  the level in animal studies of, the level of NO2 that's

24  required to cause problems with particle clearance?  I

25  can't remember, I'm asking because I can't remember

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Page 186

1  what those were.

2	DR. THURSTON: Well that's not my area of

3  research.  Terry Gordon, can we put you on the spot

4  here?

5	DR. GORDON: Yeah, Steve, I'll put you on

6  the spot.

7	DR. THURSTON: Yeah, this is his

8  question.

9	DR. KLEEBERGER: You know, I think this

10  gets back to part of the problems with what's out

11  there, is these kinds of studies have not been

12  addressed, or these kinds of questions have not been

13  addressed systematically well enough to answer, or come

14  to a conclusion about that.

15	DR. HENDERSON: Okay.

16	DR. KLEEBERGER: I mean if you would ask

17  me that question in mice, I would say well you need to

18  set up a strain screen, so you start looking across of

19  battery of inbred strains in mice until you actually

20  find that there are, and you almost certainly will find

21  that there are differences across a particular species.

22	DR. LARSON: Rogene, this is Tim Larson

23  again.  Can you hear me?

24	DR. KLEEBERGER: Yep, yep.

25	DR. HENDERSON: Yep.

Page 188

1	DR. KLEEBERGER: Yes.

2	DR. CRAPO: So you're dealing within

3  almost two, three orders of magnitude at higher levels

4  to get acute animal effects that we can measure in

5  small numbers of animals.

6	DR. KLEEBERGER: If there's a generic

7  animal.

8	DR. CRAPO: Yeah, but I mean if it's a

9  generic animal but various ones are reported at 1, 2,

10  3, 4, 5, 10

11	DR. KLEEBERGER: Right.

12	DR. CRAPO:    at 15 parts per million

13  you are causing acute severe injury in an hour of

14  exposure

15	DR. HENDERSON: Oh.

16	DR. CRAPO:    with ARDS following that.

17  But then you, but if you get down to one part per

18  million you're starting to lose all your effects that

19  you can measure acutely.

20	That's what I've read.

21	DR. HENDERSON: That's what my memory

22  tells me and so I think that lessens our concern about

23  ambient levels of NO2 causing

24	DR. GORDON: But this is ignoring all

25  short term, one hour max values which

Page 187

1	DR. LARSON: I had a question about your

2  statement that there was less confounding in the indoor

3  studies.

4	I thought a lot about that and when you

5  really get down to the question of what's confounding

6  about the outdoor studies, you know, the other

7  pollutants may have a, I mean may have confounding

8  effects, but they're not that strongly correlated with

9  NO2 to begin with.

10	Other pollutants which we don't measure

11  outdoors, perhaps are.  And the question really is, are

12  those other pollutants, the black carbon, the ultra

13  fines, are they similarly confounded indoors?

14	I mean I think we might be able to

15  address the question.  We don't discuss it in the

16  document, but I agree that's an important set of

17  studies that seem to be key to isolating the NO2

18  effects in epidemiology.  But we're not addressing that

19  particular question of confounding.

20	DR. CRAPO: I think in terms of the

21  animal studies, my memory is that the animal effects

22  require, for all the various effects require parts per

23  million.

24	DR. HENDERSON: That's right.

25	DR. CRAPO: And not parts per billion.

Page 189

1	DR. HENDERSON: Oh sure.

2	DR. GORDON:   can get up to 100

3	DR. HENDERSON: That's right, yeah.

4	DR. GORDON:   or more ppb in talking

5  about those where the verticality issue or whatever the

6  word is, you know, it could be even higher than 100.

7	DR. HENDERSON: That's right, it could be

8  higher.  If somebody   yeah, Mary, what

9	DR. ROSS: Could I draw your attention to

10  the table on page 5-18, it's a table of toxicology

11  where we tried to draw what appeared to be the lowest

12  concentrations at which some effects were seen.  And

13  they're in the order of .2 to .8 parts per million.

14	So I just welcome any feedback you have

15  on that.  It's table 5.5-2.  And similarly the page

16  before, 5-17 is a human health studies.

17	DR. HATTIS:  I didn't hear that last

18	DR. GORDON: Another variable that's

19  important here is the duration of the exposure.  Some

20  things can have effects over a longer averaging time

21  than others, depending upon the details of the

22  mechanisms.

23	DR. CRAPO: One more number when we are

24  thinking about those, I looked it up online to find a

25  couple of papers to get, the exhaled breath NO for all

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Page 190

1  us normals today, is usually about, a means of about 6

2  to 7 parts per billion.

3	DR. HATTIS: Of NO2?

4	DR. CRAPO: Of NO, NO, in an asthmatic

5  the exhaled breath NO was about 30.

6	So you're saying that the   I'm not sure

7  that NO is a good surrogate for NO2 because NO is a, in

8  my mind a very good molecule except when it interacts

9  with an oxidant like ozone or a super oxide and becomes

10  converted to another species.

11	But clearly you have biological

12  productions of NO in your body that are very close to

13  ambient, airborne levels.

14	DR. HENDERSON: Yeah.  Thank you for

15  looking that up.  And someone was saying today, was it

16  you, George, that the peroxide   who was saying that

17  this could go to NO2?

18	DR. LARSON: You have to scrub the

19  outdoor air before you exhale just to get a legitimate

20  reading.

21	DR. POSTLETHWAIT: Of course the problem

22  with NO2 is it's so reactive once formed endogenously.

23  You're likelihood of finding it in expired air is

24  almost zero to none.

25	But in expired breath condensate they do

Page 192

1  nitrated proteins in the lungs of people with

2  inflammation.

3	DR. POSTLETHWAIT: Absolutely.

4	DR. HENDERSON: Well you can argue that

5  two ways and I've heard it argued both ways.

6	If there's an endogenous source, some

7  people will say, well, a little bit more won't hurt.

8  And others will say, oh, but it does, it's building on

9  an already, you know, bad situation.

10	And so you have to think of it both ways

11  I think.

12	James, you   oh no, Steve Kleeberger,

13  you haven't had a chance.  Steve, do you have some

14  comments you'd like to make?

15	DR. KLEEBERGER: I was just actually

16  doing a pub med search on something here, but hand on a

17  second.

18	So I will echo comments from George in

19  that I think the integration in terms of reflecting

20  health effects is there, but it's probably not very

21  good at this point.  And certainly greater, at least in

22  reading the document, I think greater attention made to

23  efforts regarding the integration are going to be

24  necessary and helpful.

25	I focused mostly on the susceptibility

Page 191

1  find nitrite which is the first, one electron reduction

2  product of NO2.  And in all the studies in AODS and

3  inflammation, et cetera, when you find proteins being

4  nitrated, NO2 is the nitrating species.

5	And so as James brought up, any of these

6  issues with NO reacting with super oxide, the ultimate

7  oxidant that's formed is NO2.  In some cases there's

8  also a thing called a carbonate radical that's also

9  formed.

10	And so you wonder in asthmatics with

11  underlying inflammation if they've got 30 ppb of NO in

12  expired breath, you know, and they've got resident

13  pnn's with peroxidase activity, I have no clue how much

14  NO2 they're making.

15	But if they inhale a little NO2 on top

16  of that, is it really going to tip the balance into

17  sort of a new realm of health effect, or would it be

18  sort of like a smoker who is exposing himself to a ton

19  of NO2 and give him a few ppb and expect to see

20  something?

21	DR. CRAPO: I don't know that, but I've

22  heard that these patients all have enhanced labeling of

23  their lungs of nitrotyrosine

24	DR. POSTLETHWAIT: Right.

25	DR. CRAPO:    so there's a lot of

Page 193

1  of the chapter, Chapter 4, largely because that's what

2  I'm most comfortable with.

3	And my feeling is that the document I

4  think actually discussed the existing literature, but

5  as I had mentioned earlier I think what is a critical

6  issue is the darth (sic) of, or the dearth of

7  information to help us make any meaningful sense of the

8  data that are actually out there in terms of

9  reproducibility and systematically looking at specific

10  susceptibility facts that could be considered in terms

11  of our recommendations.

12	And so it made it a little bit difficult

13  for me to make any real conclusions about the effects

14  of genetic background for instance as Ed brought up,

15  and gender which I don't think was addressed, and

16  preexisting disease.

17	One point that I also wanted to raise

18  about the document per se is that, I think it was on

19  page 4-12 where there was an estimation of the number

20  of asthmatics and the number of   I forget what the

21  other population was   oh, heart disease, I'm not sure

22  how meaningful that particular section of Chapter 4 is.

23  And I'm not entirely sure what it relates to.

24	In fact what they're saying is that, you

25  know, we have a large and growing population of

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Page 194

1  asthmatics, we have a large and growing population of

2  individuals with heart disease, but that doesn't

3  necessarily mean that these people are all going to be

4  susceptible to the effects of air pollution, let alone

5  NO or NO2.

6	In fact there is considerable

7  variability among asthmatics in terms of their response

8  to air pollutants like ozone.  And to make a blanket

9  statement that asthmatics as a whole are going to be

10  susceptible or more susceptible than a healthy

11  individual is probably not true.

12	And so I think we have to be careful in

13  terms of describing or categorizing individuals with

14  preexisting disease as extraordinarily susceptible.

15	DR. COTE: Just a point of clarification

16  on the table.  The implication wasn't that all those

17  people would be affected.  It was just trying to get a

18  handle on the potential at risk population.

19	If you're following up on what George

20  was saying, I think that these kind of disease states

21  would put people at some potential increased risk.

22	DR. KLEEBERGER: Well they could, they

23  could be.  But I'm just saying it has to be

24	DR. COTE: I think the language that

25  needs to be clear.

Page 196

1  to start, let's assume that I accept the fundamental

2  conclusions here, because I do see a lot of coherence

3  of findings when you analyze them in the way that

4  they're done, a lot of coherence from human

5  epidemiology studies, field studies or multiple groups

6  all around the world looking at multiple endpoint,

7  hospital admissions, ER admissions, asthma, COPD,

8  exacerbations of a cough, of other asthma symptoms, of

9  decreased lung growth and development and cancer as

10  we've mentioned, all with powerful correlations in the

11  form in which they're analyzed today.

12	And I've already said that I have

13  concerns that we have a confounding issue going on and

14  we might be, I don't know whether to lower the PM level

15  or lower the NOX level.

16	But I think we're talking about a very

17  real effect.  Better epidemiology and better analyses

18  of all these various groups are finding that there is a

19  profound effect.  And I'm on the fence as to whether I

20  attribute this to NOX or not, I want to put that on the

21  table.  Maybe by the end of this two days I'll have a

22  strong opinion on that one.

23	The, but if we assume that this is

24  correct, then I have several concerns about the

25  document that I think need to be done, because my

Page 195

1	DR. KLEEBERGER:   more clear, yeah,

2  yeah.  And I have a number of other minor comments but

3  I can, I'll have that in my written, it's in my written

4  document.

5	DR. HENDERSON: Okay.  Thank you.  Let's

6  look at Charge Question 6, which is really what we've

7  been discussing.

8	What are the views of the panel on the

9  conclusions drawn in the draft ISA regarding the

10  strength, consistency, coherence and plausibility of

11  NO2 related health effects?

12	And I had asked James to talk about

13  that.

14	DR. CRAPO: Yeah, and I've already said a

15  lot of what I think on this and I'm trying to   I'm

16  really on the fence, do I really go on the bandwagon to

17  lower the NOX level dramatically?  Or do we say this

18  needs to be revised in terms of what we've said?

19	But the way this document's written it

20  scientifically mandates that  we do everything we can

21  to lower the NO levels and the NOX levels in the United

22  States.

23	And so I'm on the fence trying to have

24  my own recommendation on that on which way to go.

25	But let's assume that I accept, I want

Page 197

1  question would be, how should I lower the standard?

2  And how should I affect the standard?  What should the

3  form of the standard be?

4	And I find that the document doesn't

5  inform me adequately to start to make the next

6  decision.

7	If I assume that the conclusion is

8  correct, then I want to know, I want to have a dose

9  response that tells me about what's going on at the

10  ambient level when I know that I can't drop the levels

11  20 ppb since I'm starting out at 15, and it looks to me

12  like we really, we don't have a very good discussion of

13  the threshold.  And again I think your answer is going

14  to be, we don't have good data on threshold and we

15  can't, we can detect effects that appear to be going

16  towards zero.

17	But we really need a discussion of that

18  because if you, as soon as you accept any of the

19  fundamental conclusions of this document, the one that

20  you mentioned, the last sentences on page, on Section

21  5, of our conclusion that if it stands will man   to

22  me, would mandate action on it.

23	So I think I'd to see the document

24  worked again about to tell me how to do that action and

25  I'd like to analyze the threshold, I'd like to analyze

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1  the lower limits to it, I'd like to look at the peak

2  effects and I'd like to have some data that helps me to

3  analyze that.

4	I mean can I get the benefit by just

5  decreasing the peaks and excursions?  And should it be

6  a   and then I need to begin to ask whether it should

7  be a daily standard or an annual standard and should it

8  have a certain number of excursions in it and does it

9  make a difference on what those are?

10	So those are all the kinds of questions

11  that were discussed in detail on ozone and PM that are

12  not here.

13	And I think that's the   in fact that

14  needs to be looked, even if we decide that this is a

15  surrogate for something else.  We need to begin to

16  understand that set of data to go with it.

17	The   and I think I've said everything

18  else already.

19	DR. HENDERSON: Okay.  I'm wondering,

20  when can expect, I mean several people have mentioned

21  that we're missing any discussion of the form and

22  averaging time, et cetera.

23	Is that something that will come

24  tomorrow in the exposure risk assessment document?  Or

25  are we expecting too much of the ISA?

Page 200

1  let me accept this data, what should I do with it now?

2	And I discovered that I really couldn't,

3  I couldn't find the information I needed to sit here

4  and say, I'd recommend you drop it to .1, or no, 10

5  ppb, and these are the reasons why.

6	And I would need a scientific reason for

7  doing that and I couldn't find it.  I also asked myself

8  if there's any evidence of a lower threshold and I   so

9  those are the kinds of things that I don't think you

10  ought to make the conclusion, but I would like to see

11  the data organized so it could tell me there is or

12  there is not data to help me make that decision.

13	DR. COTE: Maybe this section needs to be

14  expanded, but I think there's only a few studies that

15  specifically tried to look for a threshold.  You know,

16  that's generally not a very successful kind of approach

17  with EPI.

18	So I think you would have to rely on

19  something like modeling.  You know, the LOTUS

20  extrapolation modeling, my understanding is if you're

21  adding to some sort of background process it's

22  generally considered to be linear.

23	DR. CRAPO: Well I wouldn't be surprised

24  if your answer was, we looked at all these factors and

25  we can't do it.  I would accept that, but I want to

Page 199

1	DR. ROSS: The science assistant has

2  never been in the past intended to answer those

3  questions, to say this is what the form should be.

4	We are attempting to organize the

5  information about short term exposures and long term

6  exposures, that then could be interpreted by others

7  and, you know, and we look at ways we could do that

8  better.  To better characterize the 24 hour, one hour

9  and the tox studies with all kinds of exposure levels.

10	But we'll try to organize that as well

11  as we can.  And we'll discuss the levels at which

12  effects are seen and to the extent possible in our EPI

13  studies it's often a range of air   at the distribution

14  of air quality and not a level.

15	But we have not, we were not striving

16  for the integrated assessment, science assessment to

17  have a specific recommendation.  That is usually

18  targeted for the ANPR, the Advance Notice of Proposed

19  Rule Making, where the Agency would be looking at the

20  science assessment and the risk and exposure assessment

21  and then making those recommendations.

22	But we would like to organize the

23  information in a way that can inform those decisions.

24	DR. CRAPO: Yeah, that's what I was

25  looking for because I was sitting here saying, well,

Page 201

1  hear you tried.

2	DR. COTE: Okay.  Yeah, in fact I think

3  we went through that thought process in house but we

4  probably haven't articulated it in the document as

5  clearly as we need to.

6	If it makes you feel any better, we had

7  those same discussions about, is it yes, is it no, is

8  it yes, is it no?  And decided because it was easier

9  for you to respond to that we would present the

10  information kind of going out on a limb, but I guess

11	DR. CRAPO: And I want to, I really like

12  the way you've presented it because you reached out and

13  took a position and that's, I compliment you, this is a

14  very much more productive discussion than the kinds we

15  were having before where we were struggling with what

16  to do with the data.

17	DR. HENDERSON: So that's good.  Now Ed,

18  you were on the same charge question.  Did you have

19  something to add?

20	DR. AVOL: Yeah, I do but Jon Samet is --

21	DR. HENDERSON: Well I was letting him, I

22  was going to bring him in at the end --

23	DR. AVOL: Okay.

24	DR. HENDERSON:   so he could give the

25  final word.

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Page 202

1	DR. AVOL: Okay, that's fine.

2	DR. HENDERSON: So Jon, prepare yourself,

3  after Ed it's

4	DR. SAMET: Yes, okay.

5	DR. HENDERSON:   your turn.

6	DR. SAMET: Okay.

7	DR. AVOL: Okay, that's fine.  Well I

8  also, I mean I think a lot of this we've already talked

9  about in the context of the earlier discussion and

10  questions.

11	Looking at this I did sort of get the

12  sense as Jim Crapo did, that sure, this preponderance

13  of evidence is there that sort of makes you lean in one

14  direction.

15	But I think it is a fair comment that

16  was brought up earlier this morning in public comment,

17  that we need to, in the document we need to be sort of

18  more an objective discussion and layout of what the

19  decision tree is for getting to why something is

20  convincing or suggestive or not.  So that by the time

21  you get to the conclusion section there's a clear and

22  transparent process and it doesn't just sort of come at

23  you from nowhere.

24	I mean I think if we were to do that,

25  some of these, there may well be some readjustment of

Page 204

1  not brought out in broad discussion here but it really

2  is a big issue in terms of being able to tease out and

3  uncouple how important is, or will the public's health

4  be protected by a NOX reduction as opposed to

5  identifying it and relating it to something else.

6	DR. HENDERSON: Thank you, Ed.  Jon

7  Samet.

8	DR. SAMET: Yeah, I'll make a couple of

9  comments.  So I guess I'll interpret this charge

10  question in two ways.

11	So one is, does the draft ISA

12  established strength, consistency, coherence and

13  plausibility as a document?

14	And there I think my answer is, no.  And

15  I will say that just looking at Chapter 5 which should

16  be really, I think where that final bringing it

17  together should be accomplished and I think it's just

18  really weak in doing so.

19	And, you know, just for example at the

20  bottom of page 5-15 there is a sentence that basically

21  says, integrating across all the data, there is

22  plausibility, consistency and so on.  But it's not, the

23  document is not really   does the job let's the way

24  that a Surgeon General's report or other kinds of

25  public health related reviews would do.

Page 203

1  the words that have been used in some of the earlier

2  chapters.

3	I think I gave a number of specific

4  comments about form and substance in the written

5  comments so I won't go through those now.  You can read

6  those.

7	I think again though in terms of the

8  strength, consistency, coherence and plausibility, I

9  think the information is there and   the information is

10  there but it hasn't, it hasn't been so compelling that

11  I'm convinced that all those four pieces are there yet.

12	DR. COTE: I think some definitions would

13  be very useful.  We actually went through   I have on

14  my desk a sheet of paper that has the Rosetta Stones

15  and all of that and we tried to, we tried to read the

16  document to make sure it was consistent, but we can be

17  more explicit about

18	DR. AVOL: Okay.  That would help.  And

19  again I think, you know, a big issue throughout all

20  this is this notion of multi pollutants and confounding

21  the inter-correlation and the relationship of NOX with

22  other species, particularly, or especially

23  particulates.

24	And so I think it's something that, it's

25  sort of the elephant in the room that we sort of, it's

Page 205

1	So I mean I think as a document I don't

2  think that those four features of the evidence are

3  established.  And that is regardless of what the

4  evidence shows.  As a document itself this is a failing

5  of the way the information is brought together and

6  discussed.

7	And again I would urge the office to

8  consider the kinds of discussions that are in other

9  models.

10	So then it comes back to the question

11  of, you know, what do I or we think the evidence shows?

12  And I think when I look at it I go through some of the

13  same sort of agonizing that you've heard already from

14  James and others.

15	And I think that I don't have a personal

16  bottom line yet on whether the sort of strength,

17  consistency, coherence and plausibility are met.  I

18  think if strength means strength of associations and

19  that's the usual way that word is used, I would not

20  really expect there to be particularly strong

21  associations at ambient or near ambient levels.  I

22  would actually look to rather weak associations as far

23  more plausible than strong associations.

24	So I'm not strength, what is even meant

25  by the strength criteria here.  I would not

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Page 206

1  characterize the epidemiological associations as strong

2  either for NOX or for PM for that matter.  They're

3  statistically significant and they're plausible.

4	And there is consistency in let's say

5  among studies.

6	Coherence and plausibility are pretty

7  close cousins so I'm not sure exactly what the

8  distinction is.

9	And so when you look at the body of

10  evidence, and again how the discussion should line up

11  is, in terms of plausibility, what do we have from the

12  toxicologic studies?  And I think here the dose

13  question just has to come in.  And again most of the

14  toxicology is showing effects at exposures, you know,

15  at the some hundreds of ppb and up.

16	There is the question of I think what is

17  the signal from the indoor studies where there's not

18  NO2 as present in a different mixture from what you see

19  outdoors, so I think that's a very useful body of

20  evidence.

21	And I think again there, there is some

22  indication of effects in some of the studies, but not

23  all and I think there is I think more convincing

24  evidence in the experimental study.

25	And then the outdoor work is just very,

Page 208

1  and 6, about any of them that we haven't discussed that

2  people want to bring up?

3	If not I   well I see one, Donna.

4	DR. KENSKI: Well this is not exactly a

5  question but an observation I guess, and it's built on

6  what Steven had to say about, you know, suggestions

7  for, you know, studies that we need to see.

8	But what would be helpful I think in

9  this document is some kind of sort of assessment of

10  what we're missing.  You know, sort of limitations of

11  the current data would be really helpful.

12	DR. HENDERSON: It sounds like a good

13  idea.  Mary, do you usually do that, have limitations?

14  I think you have in the past had limitations of current

15  data.

16	DR. ROSS: We have often followed a

17  criteria document with a research needs document, which

18  was a formal process involving a workshop that followed

19  the production of a criteria document.

20	So research needs to be identified in a

21  process through meetings like this and then it would be

22  a separate document.

23	We haven't always had, we, I don't think

24  we've usually had separate sections on research needs.

25  At times in a particular issue a limitation will be

Page 207

1  very difficult to interpret.  And I think, and this is

2  a major problem beyond these sort of technical concerns

3  I've raised about model interpretation, I think the

4  issue of publication bias has to be considered here

5  because there are, for example in the time series

6  studies there have just been so many done.

7	And I think there's been such an

8  emphasis on PM in '03 that we've only seen perhaps a

9  tendency to report the more positive effects for NO2,

10  and not all.  And that's where the multi city studies,

11  which are emphasized are most important.

12	So I think there's two issues that need

13  to get sorted out.

14	One is the document's handling of these

15  points where I think it's failed right now.

16	And then there's, actually what does the

17  evidence, what does the evidence show?

18	And I think strength probably comes off

19  the table in interpreting the epidemiological studies I

20  believe.

21	So those are my comments.

22	DR. HENDERSON: Thank you, Jon, and thank

23  you for calling in.

24	Are there other comments now about the

25  health charge questions, that's Charge Questions 4, 5

Page 209

1  it wasn't a comprehensive search for a research needs

2  but it might be identified on a case by case basis in a

3  specific area.

4	DR. KENSKI: So is that something we

5  should make reference to in our comments so that you

6  could, you know, incorporate that?

7	DR. HENDERSON:   I think you need to

8  talk into your mike, Donna

9	MR. DOLAN: Oh.

10	DR. HENDERSON:   because I couldn't hear

11  what you were saying.

12	DR. KENSKI: Oh, sorry, I was just

13  saying, is that something we should incorporate in our

14  comments then?

15	DR. HENDERSON: Sure, we could

16	DR. KENSKI: Rather than asking you to do

17  it.

18	DR. HENDERSON:   we can incorporate

19  those ideas in our letter.

20	I suggest if there are no more

21  questions, I want to remind people that if your name is