U.S. ENVIRONMENTAL PROTECTION AGENCY

SCIENCE ADVISORY BOARD STAFF OFFICE

CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE (CASAC) OXIDES OF NITROGEN (NOx)PRIMARY REVIEW PANEL

PUBLIC MEETING

MARRIOTT AT RESEARCH TRIANGLE PARK

4700 Guardian Drive

Durham, North Carolina 27703

MAY 1, 2008

EPA CASAC MEETING 05/01/08 CCR#15905-1	2

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1	U.S. ENVIRONMENTAL PROTECTION AGENCY

2	SCIENCE ADVISORY BOARD STAFF OFFICE

3		CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE (CASAC)

4		OXIDES OF NITROGEN (NOx)PRIMARY REVIEW PANEL

5	May 1, 2008

6	DR. NUGENT:    Good morning, everyone.  I

7  think it's time to start the formal time of the

8  meeting.  And, I know we have people on the telephone

9  line and I -- this is Angela Nugent, and I'd like to

10   make a brief statement in my role as Designated Federal

11   Officer for the Clean Air Scientific Advisory Committee

12   Oxides of Nitrogen Primary NOx Review Panel.  So

13   welcome, everyone.

14	This is a public meeting of the panel,

15   which is a subcommittee of the Clean Air Scientific

16   Advisory Committee.  I am Angela Nugent from EPA

17   Science Advisory Board Staff Office, and my job is to

18   support the committee.  I'd like to make a few brief

19   remarks in my capacity as DFO before I introduce our

20   Office Director, Dr. Vanessa Vu, and the Chair of the

21   Committee, Dr. Rogene Henderson.

22	This subcommittee, this panel, is a

23   panel of the Clean Air Scientific Advisory Committee,

24   and by law and EPA policy it operates under the

1  Nitrogen or Nitrogen NO2.

2	I'd like to take this opportunity on

3  behalf of the Agency to thank Dr. Rogene Henderson and

4  the distinguished members of this -- the CASAC -- the

5  Clean Air Scientific Advisory Committee, as well as the

6  distinguished members of this panel, which will be

7  providing the independent advice to the Administrator

8  of EPA regarding the health standards for the National

9  Ambient Air Quality Standards for Nitrogen Oxides, or

10   Oxides of  Nitrogen, which include all the other

11   nitrogen species.

12	I would like to thank Dr. Ila Cote and

13   Dr. Mary Ross  from the Office of Research and

14   Development, National Center for Environmental

15   Assessment and RTP for their interaction presentation

16   today -- the next two days -- regarding the second

17   draft ISA.  And also, the team from the Office of Air

18   Radiation, head by the -- represented today, including

19   Dr. Stephen Graham, Harvey Richmond, and Scott Jenkins

20   for their presentation today -- interaction with all of

21   you regarding the second draft -- first draft of the

22   Risk and Exposure Assessment.

23	As Angela indicated that public

24   involvement is a critical component of the deliberation

25   of the advisory process of the Clean Air Scientific

3	5

1  means the deliberations of this committee, this panel,

2  operate in public -- in a public forum. that notice is

3  given in advance of the meeting, that records are kept

4  of the meeting and that minutes are provided to the

5  public within ninety days.

6	There have been four requests for oral

7  comment today.  We have provided the public with

8  opportunities to provide written and oral comments, so

9  we've had four requests for oral comment.  There will

10   be three this morning, one this afternoon.  And there

11   have been sets of written public comments provided that

12   are in the members' packets and that are on the table.

13	I thank all the members of the committee

14   for being here and for their work for the panel, and

15   members of the public and the agency for the

16   preparations, and I'd like to turn the meeting over to

17   Dr. Vu for her welcoming remarks, and then to Dr.

18   Henderson.

19	DR. VU:    Thank you, Angela.  Good

20   morning.  I'd like to welcome everyone to the public

21   meeting of the Clean Air Scientific Advisory Committee.

22   The topic of today's meeting involves the review of the

23   Agency's second draft/Integrated Science Assessment,

24   the ISA, and the first draft of -- EPA's first draft on

25   the Risk and Exposure Assessment for the Oxides of

1  Advisory Committee, and we greatly appreciate receiving

2  comments from interested members of the public, as well

3  as those who will be presenting their public comments

4  today -- I guess this morning and this afternoon, for

5  your consideration.  It's important that the CASAC

6  will have opportunity to review the comments of the

7  public and incorporate into their deliberations for

8  your advice to the Administrator.

9	With that I'd like to, you know, give

10   the floor to Dr. Rogene Henderson.  But one final

11   comment is I'd like to thank Dr. Angela Nugent --

12   excellent DFO for this panel, and appreciate Angela and

13   all the personnel for contractors who support the

14   meeting logistics.

15	Dr. Rogene Henderson.

16	DR. HENDERSON:	Thank you, Vanessa.

17   And welcome again to this meeting for the NOx health

18   panel.  I really appreciate all the hard work each of

19   you are doing on this, and I think it is -- it shows

20   the hard work you're doing in the documents that we're

21   reviewing today, in that I see in the ISA that a

22   product that I think has been much improved by the EPA

23   staff using the advice of CASAC.  So, we'll look

24   forward to looking at that document later on.

25	I'd like, now, for everyone to go around

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1  the table and introduce yourself; saying just your name

2  and where you're from.  And then we'll be sure and

3  include those who are on the telephone to make sure

4  we're aware that they're there.

5	Terry, would you like to start and go

6  around that way?

7	DR. GORDON:    Terry Gordon from NYU

8  School of Medicine.

9	DR. AVOL:    Ed Avol from University of

10   Southern California School of Medicine.

11	DR. HATTIS:    Dale Hattis, Clarke

12   University.

13	DR. PINKERTON:    Kent Pinkerton,

14   University of California Davis.

15	DR. SHEPPARD:    I'm Lianne Sheppard,

16   University of Washington.

17	DR. POSTLETHWAIT:    Ed Postlethwait,

18   University of Alabama, Birmingham.

19	DR. THURSTON:    George Thurston, NYU

20   School of Medicine.

21	DR. SAMET:    Jon Samet, Johns Hopkins

22   Bloomberg School of Public Health.

23	DR. HENDERSON:    Okay.  And, if the EPA

24   staff could introduce themselves.

25	DR. LUBEN:    Tom Luben with NCEA.

1	DR. HENDERSON:	Welcome, John.

2	DR. SCHLESINGER:    Rich Schlesinger.  We

3  can hardly hear you.

4	DR. LARSON:    Tim Larson here.

5	SPEAKER:    No problem here on our end.

6	DR. HENDERSON:    You're coming through

7  loud and clear.

8	DR. NUGENT:	Rich, this is Angela.  I

9  thank you and Tim

10   for sending me an email saying you're having trouble

11   hearing.  Please keep on sending those emails, and

12   we'll work through the problems.

13	I asked everyone here in the room to

14   speak into their mics.  That will help the people on

15   the phone to hear, and also the people on the phone to

16   turn off their speaker phones.  Or if they're going to

17   use their speaker phones, put it on mute.  That will

18   help -- the engineers tell us that will help.

19	DR. BALMES:    So, Angela, you just came

20   across fairly clearly.  You must be talking right into

21   the microphone, but most of the people introducing

22   themselves did not.

23	DR. HENDERSON:	Okay.  So that's our

24   lesson.

25	DR. KINNEY:    This is Pat Kinney at

7	9

1	DR. MENG:    Qingyu Meng, EPA NCEA.

2	DR. KOTCHMAR:    Dennis Kotchmar, EPA.

3	DR. HENDERSON:	And then just come up.

4	DR. ULTMAN:    Jim Ultman, Penn State

5  University.

6	DR. SEIGNEUR:    Christian Seigneur,

7  Atmospheric and Environmental Research.

8	DR. RUSSELL:    Ted Russell, Georgia Tech.

9	DR. KENSKI:    Donna Kenski, Lake Michigan

10   Air Directors Consortium.

11	DR. CRAPO:    James Crapo from the

12   National Jewish Medical and Research Center.

13	DR. WYZGA:    Ron Wyzga, Electric Power

14   Research Institute.

15	DR. KLEEBERGER:    Steve Kleeberger,

16   National Institute of Environmental Health Sciences.

17	DR. HENDERSON:	Thank you, all, very

18   much.  And, now, we'll turn to an introduction of this

19   draft ISA.

20	SPEAKER:	We haven't introduced the

21   people on the phone.

22	DR. HENDERSON:	We forgot the people on

23   the telephone.  Sorry.

24	Okay, who's on the phone?

25	DR. BALMES:    John Balmes.

1  Columbia.

2	DR. HENDERSON:	Thanks, Pat.

3	DR. SCHLESINGER:    Yeah, Rogene, we can

4  hear you very well -- that's about it.

5	DR. HENDERSON:	Who can you hear?

6	DR. BALMES:    You and Angela came across

7  very well.

8	DR. HENDERSON:	Well, okay.  We'll just

9  all speak up then.

10	DR. NUGENT:	So, on the phone there's

11   John and Pat and

12   Rich Schlesinger.  Anyone else on the phone?

13	DR. LARSON:    Tim Larson.

14	DR. HENDERSON:	Okay, now we can go and

15   hear from the -- our EPA folk.  Ila, are you starting?

16	DR. COTE:	Yeah.

17	DR. HENDERSON:	There you are.  You

18   were standing right there.

19	DR. COTE:	How about --

20	DR. HENDERSON:	It's for this

21   presentation.  And I would like to say,  I was quite

22   impressed with your -- the improvement in this.

23	DR. COTE:	Thank you.

24	How's the sound level for people on the

25   phone?

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1	SPEAKER:	Good.

2	DR. COTE:	Okay.  We're going to spare

3  you the overview slide that you've seen 37,000 times at

4  this point, and we're going to jump right into the

5  charge questions.  The way we've structured this talk

6  is to put up the charge questions and then talk a bit

7  about each one.

8	The first charge question was focused on

9  the characterizing the search strategy for identifying

10   literature criteria for study selection and the

11   framework for evaluation studies and causal

12   determination.  Appendix -- or Annex A lays out the

13   search strategy for the literature and criteria for

14   study selection, as well as talks about the framework,

15   but I think the framework is the most important part of

16   the charge question, and so I'm going to focus on that

17   particular aspect.

18	As we had talked about at the last time

19   we all met, we had a framework and some guidelines that

20   we were using internally for making decisions within

21   the document and to ensure we had consistency in the

22   document.  We hadn't articulated those in the document

23   itself and made those explicit.  So the committee I

24   think quite strongly felt that that needed to be done,

25   and we agreed.  So we've made a pretty significant

1  written on causal determination.

2	Next slide.

3	Here are the factors for judging

4  causality .  These are essentially modified Hill

5  criteria that we're using.  As all of you know, the

6  Hill criteria are used widely throughout science and is

7  a common feature of all the documents that I've just

8  mentioned, as well as the Agency's guidelines on

9  cancer.

10	Next slide.

11	There's a two-step process that these

12   documents use.  One can think of it as a hazard I.D.

13   dose response, although that's a little simplistic, but

14   it's not -- it's a useful construct.  The first step is

15   to determine causality.  Can this chemical cause this

16   effect.  In the most simplistic form you think of it --

17   can it cause this effect irrespective of the

18   concentration of exposure.  I think that concept has

19   been modified in the scientific community by

20   essentially a consensus that we're not using extremely

21   high concentrations, but focusing on the lower end for

22   the dose response rate when we talk about causality.

23	We're using a five category descriptor

24   for causality.  Sufficient to infer a causal

25   relationship.  Sufficient to infer a likely causal

11	13

1  effort to incorporate more explicitly this.

2	We -- you know, the other thing I want

3  to mention is if for those of you that are familiar

4  with the smoking and health report, as well as the

5  recent Institute of Medicine report, you will see a

6  great deal of similarity in the language.  We tried to

7  either copy or plagiarize language so we had a

8  consistency across these documents rather than

9  reinventing another description of how to do this.

10   Both of these efforts a lot of thought and effort went

11   into them and so we thought it would be -- I thought it

12   would be a mistake to kind of invent new language.  So,

13   if you see a similarity in language, you're on your

14   toes.

15	But, anyway, the intent of this was to

16   establish a more uniform language concerning causality

17   and bring a greater specificity and I would say rigor

18   to our findings.  This helps it to -- we feel this

19   would help us to assess both the separate and combined

20   lines of evidence, as well as classify and characterize

21   the data to evaluate causality.  And as I noted in this

22   last slide, we've drawn heavily on the Surgeon

23   General's smoking reports, as well as the IOM document.

24   The IOM document is very new.  It's probably the most

25   sophisticated of the various documents that have been

1  relationship.  Suggestive, but not sufficient,

2  inadequate, or suggestive of no causal relationship.

3	The smoking and health document, as well

4  as the IRM document, use a four category, can we have a

5  pointer, okay, we use a four category scheme with this

6  -- and they don't include the sufficient to infer a

7  likely causal relationship. So that is not included in

8  the smoking and health and the IRM documents.  There

9  are two reasons that we put it in.  One, we liked it.

10   It felt better to us in the sense of the gap between

11   suggestive and sufficient to infer a causal

12   relationship seemed very broad to us, and we wanted a

13   more nuanced kind of description.

14	This five category scheme is also

15   consistent with what the Agency has articulated in the

16   guidelines for cancer risk assessment.  Thank you.  And

17   so at least by using the five category scheme, we are

18   -- EPA is internally consistent and it is consistent

19   across cancer and non-cancer in terms of the descriptor

20   -- the five category set of descriptors.

21	The second sub -- once you've made some

22   decision about what you think the nature of the causal

23   relationship is -- is the dose response part.  And so

24   if evaluating the population dose response, the shape

25   of the dose response, susceptibility, those factors

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1  come into consideration.

2	For those people who are

3  epidemiologists, you will instantly recognize that

4  epidemiologists often are sort of  doing both of these

5  things at the same time.  Where the experimental

6  community is often kind of doing them as a clearer one,

7  two step process.

8	Next slide.

9	And so that's essentially what we've

10   done on the framework, and we've articulated it in the

11   document.  And I would really love to have -- this is

12   going to be the framework that we use for every one of

13   our documents.  So it's really important and we want to

14   get it right, so I'm really looking forward to quite a

15   bit of discussion on the framework.

16	So what we're going to do next is this-

17   is the team of people that's worked on the NOx tox

18   document, and Tom Luben who -- one of our crack

19   epidemiologists, is now going to talk about if you take

20   the framework and you apply it to the available

21   evidence, what are your conclusions.

22	Tom?

23	DR. KOTCHMAR:	Actually, we're going to

24   have Dr. Meng talk about the --

25	DR. COTE:	Oh, I'm sorry.

1  here are related to the key question, how well can we

2  use the ambient concentration as a surrogate for

3  population exposure?  Also, these issues can help us

4  better understand health sciences findings.

5	Next, please.

6	Here comes the first issue, ambient

7  measurement methods and ambient concentrations, there

8  are two key points associated with this issue.  The

9  first one is ambient level of  N02, and the second one

10   is the errors associated with the ambient measurement

11   method.

12	In response to CASAC comments, we

13   provided the information on the distribution -- the

14   trends -- the NO2, Ambient NO2, across the United

15   States as shown in the figure on the left.  The solid

16   white line is the mean of the concentration, and the

17   bottom upper borders of the blue area are the tenth and

18   90's percentile of the distribution.

19	In the past 26 years, the Ambient NO2

20   concentrations have been declining.  The figure on the

21   right shows the distribution of Ambient NO2 measured in

22   all the metropolitan statistical areas with NO2

23   monitors from 2003 to 2005.  The current Ambient

24   concentration, annual concentration is about 15 ppb,

25   which is well below the current National Ambient Air

15	17

1	Tom will talk about applying the

2  framework, but Dr. Meng is going to talk next on the

3  atmospheric/chemistry exposure.

4	DR. KOTCHMAR:	And, also, this

5  represents the scientific staff from the office that's

6  worked on the document, but obviously we have support

7  staff producing the documents and various expert

8  contractors.  But at this time, let's move right along

9  with Dr. Meng, and then Dr. Luben are going to present

10   some of the background information on the revised

11   document.

12	DR. COTE:	Do you want to stand or do

13   you want to do it

14   from there?

15	DR. NUGENT:	And a reminder, please to

16   -- pull the mic

17   fairly close and speak into the mic, please.

18	SPEAKER:	We can't hear.

19	DR. MENG:    I haven't spoken yet.

20	Good morning.  This is Qingyu Meng from

21   NCEA.  I'm going over Chapter 2, which is covered by --

22   next please -- which is covered by Charge Question 2.

23   Next, please.

24	I'm not trying to give a comprehensive

25   review of Chapter 2, but three issues I'm talking about

1  Quality Standard, which is .053 ppm or 53 ppb, but the

2  one hour maximum concentration could be a three or even

3  four times higher than the annual concentration.

4	We should always keep in mind that these

5  numbers are associated with positive interferences

6  caused by nitric acid and PANs.  So in response to

7  CASAC comments, we extended our discussion on this

8  positive interferences issues.  Since the interferences

9  -- the positive interferences are larger during the

10   summer than winter, and also larger in remote sites

11   than the sites close to NO2 sources on a routed basis.

12	Next, please.

13	The second issue is spatial and temporal

14   variation in Ambient NO2 concentrations.  The questions

15   here are can we capture the spatial and temporal

16   variation with a current NO2 Ambient monitoring

17   network?  If the answer is yes, how does the spatial

18   variation of NO2 look like in the urban scale, and how

19   does spatial variation of NO2 look like in a near road

20   small scale.

21	The table here shows the, in response to

22   CASAC comments, actually we provided the information on

23   the distribution of NO2 monitoring network across the

24   United States -- with the declining of NO2

25   concentrations, the number of NO2 monitoring size has

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1  been decreasing.  So, very few cities have more than

2  five NO2 monitoring monitors.  So the table shows here

3  are the spatial variation of NO2 in urban scale.

4  Cities listed here are the cities with more than five

5  NO2 monitors.  We can see from the table that the

6  spatial variation of NO2 can be quite large in an urban

7  scale.

8	"R" is the -- the column "R" shows the

9  range of Pierson  correlation coefficient between NO2

10   concentration between each individual part --

11   individual site pairs across all possible pairs of

12   sites.  And the mean concentration of that column shows

13   the overall mean of NO2 in an urban site, and also, in

14   the parentheses, shows the range of NO2 concentration

15   at each individual site across all sites.  We can see

16   the mean concentration at each individual site varies

17   by a factor of 1.5 to 6.

18	In response to CASAC comments, you also

19   provided the, and illustrated with new figures the

20   spatial -- the large scale spatial NO2 concentration

21   across the United States and also a seasonal and

22   diurnal variations of NO2.  Also for the small scale

23   near-road variations, we just illustrated with new

24   figures that people near-road or on a road can be

25   exposed to elevated NO2.

1  that's what I just said -- infiltration factor and

2  Alpha are very important to understand Ambient

3  contribution to indoor and personal exposure.  The

4  infiltration factor ranges from .4 to .7 and Alpha

5  ranges from .3 to .6.

6	The last issue in the personal exposure

7  assessment is the multi pollutant personal exposure

8  issues.  Personal exposure to NO2 can be associated

9  with personal exposure to other co-pollutants due to

10   the common sources like traffic, and also due to

11   chemical reactions in the Ambient air and in the indoor

12   air.

13	With that, I'll turn it to Dr. Luben.

14	DR. LUBEN:	Thank you.

15	My name is Tom Luben, and I'm going to

16   talk about Charge Question 3 through 5, which cover

17   Chapters 3, 4, and 5.  So in chapters three, four, and

18   five, we really tried to address CASAC comments by

19   tightening up the language, making the format or the

20   style of the chapters more consistent, adding summary

21   sections to the end of each section, and really

22   focusing on the integration.

23	But one of the large overarching topics

24   that we wanted to address was this issue of NO2 as a

25   component of a mixture.  We know that NO2 does not

19	21

1	Next, please.

2	The third issue is the association

3  between the personal exposure and Ambient

4  concentrations.  There are two key points in this

5  issue.  One is the Ambient contribution to personal

6  exposure, the other is the correlation between the

7  personal exposure and Ambient concentration.  During

8  the last review CASAC suggested us to expand our

9  discussion on the relationship between the

10   indoor/outdoor and personal NO2 concentrations with an

11   emphasis on two key parameters.  One, is the

12   infiltration factor, the other is Alpha or Ambient

13   exposure factor.  And also CASAC suggested us to

14   reorganize the discussion of the correlation

15   coefficient between personal exposure and Ambient

16   concentration to reflect the exposure study features in

17   the context of different epidemiological studies.

18	So we did that, and the first -- shown

19   here are the figures 2.5 for A and 2.5 for B on page

20   241.  Basically, we calculate -- recalculated the

21   correlation coefficient and the confidence interval for

22   each study based on the feature of the exposure study

23   -- different exposure study designs.  And also we

24   interpreted this correlation coefficient in the context

25   of different types of epi studies.  Two parameters --

1  occur by itself in the atmosphere, and when we're

2  looking at epidemiologic studies we're not looking at

3  NO2 by itself.  We're looking at NO2 and people are

4  being exposed to NO2 and this combustion related

5  pollutant mixture, as we wanted to discuss this

6  throughout the document.

7	We believe that there are effects,

8  health effects, adverse health effects associated with

9  NO2, and it's really difficult to quantify these

10   effects and also to disentangle the effects that are

11   attributable directly to NO2 by itself compared to

12   those that are attributable to the pollutant mixture.

13   Still, we believe that there is enough evidence to

14   support an independent effect of NO2, and the reason we

15   believe this is because we believe the results for the

16   epidemiologic studies are consistent and coherent and

17   that the animal toxicological studies and human

18   clinical studies provide biological plausibility for

19   these respiratory effects.  We also believe that the

20   addition of other pollutants and multi-pollutant models

21   provide further evidence of an independent effect of

22   NO2.

23	If I could have the next slide, please.

24	So this is a summary figure that we've

25   been working on to kind of address the range of

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1  respiratory effects that we see.  And if you start on

2  the left, we were looking at respiratory symptoms here.

3  Let me mention that the studies that are in black are

4  U.S. and Canadian studies.  The other colors are

5  studies outside the U.S. or Canada.  All the red

6  studies are the respiratory symptoms, and if we look at

7  all the epidemiologic studies that looked at

8  respiratory symptoms, we see that all of the central

9  estimates are above one.  So we think that this shows

10   consistency in the studies.  Some of them are

11   statistically significant, some are not, but overall,

12   they are showing a positive effect with respiratory

13   symptoms and exposure to NO2.

14	As we kind of progress along and move

15   over towards the right, we look at the emergency

16   department visits and hospital admissions. Again, the

17   majority of the studies here have a positive central

18   estimate.  Again, some are statistically significant,

19   some are not, but by-and-large, we believe that this

20   shows consistency in the evidence that epidemiologic

21   studies are showing an effect of hospital admissions or

22   ED visits among adults, children, older adults, for all

23   respiratory diseases and for asthma.

24	DR. HENDERSON:	For those people on the

25   phone, can you tell them what page in the document this

1  before, that looking at co-pollutant or multi-pollutant

2  models are not the best tool that we have to try to

3  disentangle the independent effects of the criteria

4  pollutants from one another, but right now, they're the

5  best tool that we have.  They're available in much of

6  the published literature.

7	This slide looks at the addition of PM

8  species, different size fractions of PM into the model

9  with NO2, and we see that the central estimates do not

10   move very much at all.  There's one case, the Yang

11   study that was in Taiwan where the addition of PM 10

12   increased the central estimate.  That was only when --

13   during days when the temperature was above 25 degrees

14   Celsius.  Other than that, the studies that looked at

15   the addition of PM to the model, including NO2, did not

16   show any significant change leading us to believe that

17   there is an independent effect of NO2.

18	Next slide, please.

19	So with that I'm going to kind of show

20   you the key conclusions that we draw from the document.

21   The key conclusions are the same as what we had in the

22   first draft.  We have changed the language to kind of

23   bring it back to the framework that Dr. Cote was

24   talking about at the beginning.  For respiratory

25   morbidity with short term exposure, we believe that the

23	25

1  graph is on?

2	DR. LUBEN:	It's figure 5.1, so it

3  would be the first figure in Chapter 5.

4	DR. HENDERSON:	Okay.

5	DR. LUBEN:	I can have a page number in

6  just a minute.  I'm sorry.  Page 5.9, thank you.

7	As we progress all the way to the right,

8  we look at the studies that looked at respiratory

9  mortality.  So these are studies that looked at

10   mortality that could be attributable to respiratory

11   disease.  Again, we find that the majority of these

12   studies have a positive central estimate.  Not as many

13   are statistically significant, but we still believe

14   that this shows a consistent positive effect with NO2

15   and respiratory mortality.

16	When we look at all of these together,

17   we believe that this shows a coherence across the

18   severity of respiratory effects, starting with

19   respiratory symptoms, progressing through hospital

20   admissions or ED visits and then ending unfortunately

21   in respiratory mortality.

22	Next slide, please.

23	We also -- excuse me -- we also looked

24   at the addition of co-pollutants into the models.  We

25   know that, and we've talked about it here at CASAC

1  evidence is sufficient to infer a likely causal

2  relationship.  For cardiovascular morbidity and short

3  term exposure, we believe that the evidence is

4  inadequate to infer the presence or absence of a causal

5  relationship.  And for short term mortality, we find

6  that the evidence is suggestive, but not sufficient to

7  infer a causal relationship.

8	When we move on to long term exposure,

9  we found that for respiratory morbidity the evidence is

10   suggestive, but not sufficient to infer a causal

11   relationship.  For other morbidity, including pre-natal

12   and birth outcomes, as well as cancer, we found that

13   the evidence was inadequate to infer the presence or

14   absence of a causal relationship.  And finally, for

15   long term mortality, we also found that this evidence

16   was inadequate to infer the presence or absence of a

17   causal relationship.

18	I hope that we have sufficiently

19   addressed CASAC's comments and we look forward to

20   discussions this afternoon.  Thank you.

21	DR. HENDERSON:	Thank you.  Is that

22   everything on the --

23	DR. KOTCHMAR:	This concludes our

24   presentation.

25	DR. HENDERSON:	This concludes.  Okay.

EPA CASAC MEETING 05/01/08 CCR#15905-1	8

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1  Thank you, very much.  That was very helpful.

2	So we can now move to the public

3  comments; correct?  I'm sorry, we'll turn the mic over

4  to Angela, who will facilitate the public comment

5  period.

6	DR. NUGENT:	I have not greeted

7  personally our public commentors.  Is Dr. Long in the

8  room?  Welcome, and Dr. Vu is offering you her seat, so

9  thank you, Vanessa.

10	I'd like to introduce Dr. Christopher

11   Long from Gradient Corporation.  And you have

12   presentation slides?

13	DR. CHRISTOPHER LONG:    I do.  Yeah, I

14   think.  Yeah, there they are.

15	My name is Chris Long.  I'm a senior

16   scientist at Gradient Corporation in Cambridge,

17   Massachusetts.  I'm presenting comments on behalf of

18   the utility air regulatory group.

19	Next slide, please.

20	Our comments deal principally with

21   Chapter 5 in the NOx ISA.  And the overall theme of our

22   comments is that Chapter 5 does not provide sufficient

23   integration and analysis of the different lines of NOx

24   health effects evidence.  And, you know, in our written

25   comments, we support this theme with several different

1  subject specific correlations are negative and they

2  highly -- you know, they highly vary and overall the

3  correlations are very weak.  These studies show that

4  there are really no improvements in these correlations

5  when subjects were stratified by the presence of indoor

6  sources and by home ventilation.  Generally, these

7  studies showed much stronger personal to Ambient

8  correlations for other pollutants, such as fine

9  particles.  And interestingly they observed a good

10   correlation between Ambient NO2 levels and personal PM

11   2.5 concentrations.

12	You know, based on study findings such

13   as these, it can be asked how the epidemiological

14   evidence can be judged to be consistent and coherent

15   when there remains large uncertainty regarding the

16   validity of the exposure metric.

17	Next slide, please.

18	In addition, recent studies provide

19   compelling evidence for Ambient NO2 acting as a

20   surrogate.  These are our figures from the Brook, et

21   al. publication, and, you know, the two figures show

22   strong correlations between Ambient NO2 concentrations

23   and concentrations of a number of gaseous and

24   particulate phase species.  Including in the left

25   panel, it shows strong correlations between Ambient NO2

27	29

1  lines of analysis, including number one, a figure, you

2  know, by disregarding the NO2 concentrations at which

3  health effects associations have been observed, figure

4  5.3-1 gives an incomplete and misleading picture of the

5  epidemiological evidence for short term exposure NO2

6  health effects.

7	Secondly, the association between

8  Ambient NO2 concentrations and personal NO2 exposures

9  is complex and remains poorly understood raising

10   questions regarding the proper interpretation of the

11   reported NO2 epidemiologic associations.

12	Number three, USEPA still does not

13   sufficiently consider the fact that NO2 may be acting

14   as a surrogate for other pollutants.  And lastly, USEPA

15   should quantitatively contrast the dose levels typical

16   of Ambient NO2 epidemiological studies versus those

17   used in human controlled exposure studies.  In the next

18   few minutes I'll develop a few of these ideas.

19	Next slide, please.

20	This figure is from a recent publication

21   by Sarnett, et al., and it illustrates the idea that

22   Ambient NO2 and personal NO2 correlations are poor and

23   vary widely.  This figure shows subject specific

24   personal to Ambient NO2 correlations for four U.S.

25   cities.  And generally, you can see that a lot of the

1  and acid-aldehyde, as well as for b-tex compounds.  And

2  in the right panel, it shows very strong correlations

3  between Ambient NO2 and Ambient PAH concentrations;

4  including specifically benzo(e)pyrene in the figure.

5	You know, based on correlations such as

6  these, Brook, et al. concluded that the strong effect

7  of NO2 that they observed in Canadian Time Series

8  Mortality Studies could be due to its serving as a good

9  surrogate for other toxic air pollutants.

10	Next slide, please.

11	You know, as discussed a few minutes

12   ago, the ISA seems to dismiss the NO2 surrogate idea

13   based on the conclusion that NO2 associations generally

14   remained robust in two pollutant models.  But in

15   general, you know, the multi-pollutant model results

16   are very limited and conflicting. You know, of the two

17   pollutant model results provided in the two figures in

18   the ISA, only one of the models adjusting for particle

19   concentrations adjusted for fine particles with most

20   adjusting for PM10.  Only two of the studies included

21   adjustments for a gaseous pollutant other than ozone or

22   SO2.  None of them adjusted for aldehydes, PAHs, or

23   particle-bound organics.  And none of the cited studies

24   are for U.S. locations.

25	You know, recently, several published

EPA CASAC MEETING 05/01/08 CCR#15905-1	9

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1  multi-pollutant model results, including those of

2  Tolbert, et al., McKreaner, et al., and Delphino, et

3  al., they contradict the EPA conclusion that Ambient

4  NO2 is robust in multi-pollutant models.

5	Next slide, please.

6	And lastly, you know, as shown in this

7  figure, epidemiologic associations are generally

8  reported for NO2 doses far below human clinical

9  toxicology no effect levels.  In this figure the

10   colored symbols represent different types of

11   epidemiology studies that used one hour maximum NO2

12   concentrations as exposure metrics.  The dotted lines

13   represent no effect levels from clinical toxicology

14   studies, and in general they show a discordance, you

15   know, that still remains between the human clinical

16   toxicology and the epidemiological  associations.

17	And last slide, please.

18	A few recommendations for EPA.  Merely

19   acknowledging uncertainties is not sufficient.

20   Uncertainties must be quantified and affect the weight

21   that is placed in particular study findings or

22   particular lines of evidence.  Secondly, the supportive

23   or non-supportive role of clinical and experimental

24   studies at the specific Ambient concentrations in

25   question should be more directly addressed.  And

1	I thought the slide you presented showed

2  a grouping of clinic, of epidemiological studies where

3  the concentrations were below a no effect level in the

4  clinical study.  So how did you determine when there

5  was no effect in the clinical studies -- that's what

6  I'm asking?

7	DR. CHRISTOPHER LONG:    Yeah, actually, I

8  guess I should rephrase.  Those aren't -- those are the

9  doses at which effects were observed, so those would be

10   sort of the lowest.

11	DR. ULTMAN:    Oh, I see.  Okay.

12	DR. CHRISTOPHER LONG:    I'm sorry, if

13   that was confusing.

14	DR. ULTMAN:    So, it wasn't a specific

15   NOAEL that was found?  Okay.

16	DR. CHRISTOPHER LONG:    No, no.  I'm

17   sorry.

18	DR. HENDERSON:	Okay. If there's no

19   more questions.

20	DR. NUGENT:    Our next public speaker is

21   on the teleconference line.  It's Mr. John Heuss.  I

22   hope I'm saying that right.  From the Air Improvement

23   Resources -- Resource Inc., on behalf of the Alliance

24   of Automobile Manufacturers.

25	Are you on the line, please?

31	33

1  lastly, Chapter 5 needs to be less of an introduction

2  of ideas and recitation of selected study findings and

3  more of an integrated synthesis that can inform policy

4  makers.

5	Thank you for your attention.

6	DR. HENDERSON:	Are there questions

7  from the panel for Dr. Long?

8	DR. ULTMAN:	The dotted line in the no

9  effects level; where did that come from?

10	DR. CHRISTOPHER LONG:    That came from --

11   actually, from chapter 5 where they discuss, you know,

12   findings from different human clinical toxicology

13   studies.  And, you know, basically, I took the

14   concentrations, the exposure durations and calculated

15   the NO2 dose.  Those come directly from chapter 5.

16	DR. ULTMAN:	When did you determine the

17   zero effect?

18	DR. CHRISTOPHER LONG:    I don't believe

19   there was a zero effect dotted line.

20	DR. ULTMAN:    I thought you concluded

21   that there was no effect, the epidemiological studies

22   there was no effect

23	DR. HENDERSON:	Jim, you need to speak

24   in the mic if you want the

25	DR. ULTMAN:    Oh, I'm sorry.

1	MR. HEUSS:	Yes, I am.

2	DR. NUGENT:	Thanks.  Speak up.  And I

3  think we can hear you in the room.

4	MR. HEUSS:	Thank you.

5	My name is John Heuss with Air

6  Improvement Resource.  We provided detailed written

7  comments earlier this week.  We noted a number of

8  changes and improvements in the second draft,

9  particularly commending the introduction of the

10   application of the framework for making causal

11   determinations.  However, we believe the following

12   areas can be improved through the continued attention

13   of staff and CASAC.

14	First, although the framework is

15   generally applied throughout the second draft, its

16   application is not as rigorous or complete as it should

17   be.  Particularly in the way consistency is evaluated

18   in the acute respiratory epidemiology is less than

19   scientifically rigorous.  The ISA notes that there are

20   about 50 publications in this area.  Only selected

21   single pollutant results are included in the main data

22   presentations in the figure.  However, the ISA also

23   notes there are additional studies that show negative

24   or null results, and notes still others that are

25   characterized as studies that could not inform the

EPA CASAC MEETING 05/01/08 CCR#15905-1	10

34	36

1  associations.  The rationale for why some studies are

2  highlighted in the text and included in figure 5.3-1;

3  others are relegated to tables in the annex is not

4  clear.

5	All these studies implicate pollutants

6  other than or in addition to NO2, but this fact is not

7  discussed adequately in the ISA.  Since NO2 occurs in

8  conjunction with other common air pollutants, issues of

9  confounding and surrogacy plague the interpretation of

10   this literature, therefore it's particularly important

11   to carefully consider the results of the controlled

12   studies throughout the ISA.

13	Second, the draft still focuses on

14   single-pollutant model results rather than evaluating

15   the results in the context of the full suite of air

16   pollutants.  This can lead to double or triple counting

17   of health effects as different pollutants are reviewed.

18   In the recent PM and Ozone reviews, single-pollutant

19   model results were used to show the strength and

20   consistency of the association and used in the risk

21   assessment.  However, single-pollutant models are known

22   to be biased high.  If selected single-pollutant model

23   results are also used to claim the same health effects

24   caused by NO2, it will be a clear case of double or

25   triple counting.

1  approach is insufficient to establish consistency or

2  coherence.  A more holistic and rigorous evaluation of

3  this observational literature is needed if double and

4  triple counting of health effects is to be avoided.

5	Biological plausibility involves two

6  considerations, both the effects the pollutant can

7  cause and then the concentrations that can cause the

8  effects.  All these effects are non-specific.

9  Questions of NO2 acting as a surrogate are prevalent,

10   therefore the ISA should address the plausibility for

11   NO2 along with the plausibility for other anthropogenic

12   and natural materials in the air causing these various

13   potential health effects.

14	Fourth, the ISA mischaracterizes the epi

15   findings in the prior review when it indicated, quote,

16   "The main conclusion was that there was insufficient

17   epidemiologic evidence for an association between short

18   term exposure and health effects," unquote.  A 1995

19   staff paper did not indicate there was insufficient

20   evidence for an association, rather it noted issues

21   that limit the use of the available associations in

22   evolving a basis for the NAAQS..  Our written comments

23   document the errors.  By mischaracterizing the extent

24   and interpretation of epi studies in the previous

25   review, the draft now sets up a false comparison

35	37

1	Third, the ISA should further address

2  the issues of publication bias and model selection

3  uncertainty that hinder the interpretation of these

4  studies.  During the ozone review, CASAC pointed out

5  where systematic analysis have been carried out as in

6  NNMAPS, Steve, et. al, 2002 and 3 and Ito, 2003.

7  Similar patterns of associations are reported for many

8  pollutants. While there are many more observational

9  studies and available in the prior review, there's an

10   implausibly wide-range of results from positive to

11   negative in systematic analysis.  This is not just

12   heterogeneity since there's substantial portion of

13   negative associations.  The ISA needs to acknowledge

14   and consider the wide-range of associations with regard

15   to both biological plausibility and the limitations on

16   the use of time series studies to set Ambient

17   standards.

18	One implication of the variability

19   documented in our written comments is it's not

20   surprising to find some positive NO2 associations in

21   the literature for any health endpoint that's

22   evaluated.  Even for endpoints where there is no

23   underlying effect.  This raises a serious question

24   about the approach in the ISA of documenting any and

25   all NO2 associations in the literature.  Such an

1  between the state of knowledge in the previous review

2  and that in the current review.

3	Fifth, the conclusions in section 5.4

4  for acute respiratory effects are overly broad.  While

5  there is evidence for acute respiratory effects from

6  NO2, the evidence for which there was strong causal

7  support is similar to that in the last review.  The

8  only potential respiratory health effect for which

9  evidence is markedly different in the current review is

10   emergency department visits and hospital admissions for

11   respiratory causes.  However, as detailed in our

12   written comments, the pattern of results is implausibly

13   wide, similar to that for other pollutants, the results

14   are inconsistent for specific respiratory diseases, and

15   the authors of these studies themselves do not focus on

16   NO2.  All this makes the assumption of likely NO2

17   causality highly suspect.

18	Thank you.

19	DR. HENDERSON:	Are there any questions

20   for Dr. Heuss?

21	Yes, Frank Speizer.

22	DR. SPEIZER:    Dr. Heuss, you -- this

23   table -- this figure, 5.3-1 is quite full as it is, and

24   I think staff would be greatly helped if you could

25   indicate specific articles that you think have been

EPA CASAC MEETING 05/01/08 CCR#15905-1	11

38	40

1  left out that would contribute to the, a better view of

2  this picture.

3	Now, I don't -- I tried to look through

4  your comments, but I couldn't quickly figure out

5  whether you had indicated the specific articles that

6  you think have been left out.

7	MR. HEUSS:    Well, I think there's a

8  whole list of articles in the ISA where it says could

9  not inform for both asthma and all respiratory, so

10   those obviously are there.  And I guess one of the

11   things I did was, for example, used Ross Anderson's

12   1998 article where he specifically looked at 15 earlier

13   articles and studies, and concluded they weren't

14   consistent.  Some of them showed ozone effects and some

15   did not, some showed NO2 effects, some did not, some

16   showed PM effects, some did not, et cetera.  He looked

17   at it more holistically at that point in time with 15

18   studies and concluded that, you know, there were

19   associations because there's different age categories

20   and different respiratory categories.  So I used those

21   sorts of things.  But I think, you know, if there are

22   indeed 50 studies, then, you know, they really ought to

23   look at all of them and try to figure out not only are

24   there NO2 associations, but what those authors actually

25   concluded relative to air pollution or PM or Ozone or

1  the first external draft.  At that time, API provided

2  several recommendations to improve the ISA.  Subsequent

3  API followed up with more detailed written comments

4  filed to the docket.  API's objective was to have the

5  NOx ISA accurately reflect the current state of the

6  science.

7	As Dr. Henderson and others have already

8  mentioned today, the second external draft is much

9  improved.  While we find that there are many of the

10   concerns identified by API that are now included, the

11   connections -- the corrections are mentioned but are

12   not necessarily in our opinion given the proper weight

13   as conclusions are developed.

14	Specifically, the ISA relies extensively

15   on epidemiological studies that suffer from a number of

16   significant limitations making them an insufficient

17   basis for ISA's conclusions regarding association

18   between NOx exposure and health effects.  I think

19   you've already heard that comment today.  Let me save

20   you time -- so I'm not repeating things.

21	Yeah, I guess, the other thing we wanted

22   to talk about is to -- I guess first of all, we will

23   follow up with more detailed written comments to the

24   docket on the issues that we found in the secondary

25   external review.

39

1  NO2 or whatever.

2	DR. HENDERSON:	Are there any responses

3  to that from EPA that you want to make?

4	DR. LUBEN:	In the ISA when it says an

5  article could not inform the decision, that usually

6  means that the author said there were or were not

7  statistically significant effects but did not present

8  quantitative results.  And with no quantitative results

9  there was no way that we could plot them on the graph.

10	DR. HENDERSON:	Thank you.  Any more

11   questions for Dr. Heuss?  Okay.

12	DR. NUGENT:    Our third and last

13   commentor for this morning is Mr. Ted Steichen from the

14   American Petroleum Institute.  I understand he's here

15   to join us and provide comments at the meeting.  Please

16   take a seat.

17	MR. STEICHEN:    Thank you.

18	I'll get close to the microphone here.

19   Good morning.  I'm Ted Steichen, and I'm with the

20   American Petroleum Institute.  API represents about 400

21   members related to all aspects of the petroleum

22   industry.  We appreciate the opportunity to comment on

23   the second external draft of Oxides of  Nitrogen ISA.

24	On October 24 of last year, Howard

25   Feldman of API provided comments before CASAC regarding

41

1	But I did want to talk about our concern

2  with the process for the review of the Oxides of

3  Nitrogen NAAQS.  As many of you know or may know, that

4  API's participated in reviews of the NAAQS for several

5  such reviews from the beginning of each review.  As we

6  all know, EPA has over the years unfortunately not been

7  able to meet its five year deadlines for completing the

8  NAAQS reviews.  API is therefore very supportive when

9  EPA decided, or it was announced by the Deputy

10   Administrator, Marcus Peacock, in December of '06 and

11   modified in April of '07, to the extent that the

12   revised process increases the likelihood that the

13   agency will be able to complete the reviews in a timely

14   manner while maintaining the scientific integrity of

15   the reviews.

16	We are concerned, however, about the

17   application of the process in the present review of the

18   primary Oxides of  Nitrogen.  While the new process

19   sets forth an ambitious time line to complete the NOx

20   review within five years after a workshop is held on

21   the science policy issues, this review for the Oxides

22   of  Nitrogen is being conducted on an even more

23   abbreviated schedule.  EPA's schedule, which we would

24   definitely acknowledge, is driven at least by a consent

25   decree has compressed that review basically to three

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1  years.  And most of the time that's being saved is

2  being taken from time that others would be -- that

3  otherwise would be allocated to the critical science

4  and risk exposure assessment processes.

5	The generic NAAQS review process

6  announced by the Deputy Administrator provides 33

7  months from the start of a review until the issuance of

8  a final integrated science assessment.  In this case,

9  however, the agency plans to complete that process in

10   just 17 months according to the integrated review plan.

11   Similarly, while the generic NAAQS review process

12   contemplates 18 months between the release of the

13   Agency's plan for conducting a Risk and Exposure

14   Assessment and the issuance of that final Risk and

15   Exposure Assessment, that process has been reduced to

16   14 months for the current review.

17	The shorter time for the science review

18   in this case is not necessarily cause for concern.

19   However, when the shorter time-line leads to a less

20   than careful presentation of the scientific record,

21   this can cause alarm.  And again, as I think has been

22   indicated, there have been substantial progress made in

23   this second external draft, but I think, you know, in

24   the short term it's like -- I think the first draft --

25   we'd like to see the first draft better, so we can

1  schedule, it was first identifying 17 days for public

2  comment, and we asked for an extension and it was

3  granted for 45 days.  Again, you know, we think 60 is

4  where we'd like to be, and the model schedule would

5  typically allow that.  So, again, recognizing that

6  there are constraints both related to the, you know,

7  consent decree issues, and also, just resources in

8  general, I want to identify that, you know, the better

9  we can see it in  the first round hopefully the more

10   useful our public comments can be, and we can get it in

11   in a time that does not lead us to have certain

12   decisions already identified in future documents.

13	So essentially, that's my statement, and

14   I appreciate the opportunity to speak today and if

15   there were any questions about that I'd certainly try

16   to answer them.

17	DR. HENDERSON:	Are there any

18   questions?

19	Thank you.

20	MR. STEICHEN:    Thank you.

21	DR. COTE:	I'd actually like to make

22   one correction.  It is incorrect that the regulatory

23   evaluation will be done on the first draft.  It will be

24   done on the final draft.  And obviously -- or there

25   would be no point in doing these second and final

43	45

1  provide more useful comment at that time because we

2  recognize that, again, the way the schedule is set up,

3  that the first draft is really informing on the Risk

4  and Exposure Assessment that we'll be talking about in

5  the rest of your meeting, or you'll be talking about

6  the rest of your meeting.

7	The CASAC panel, in fact, concluded in

8  its November 29th letter that the first draft was

9  inadequately described the NOx review process including

10   EPA's approach to literature identification and

11   evidence evaluation, and further noted that the first

12   draft did not appear to have developed by a process

13   that approaches the current state-of-the-art around the

14   development of systemic reviews for decision making

15   purposes.  And, again, the point is not to belabor

16   something that's already been resolved, but it's simply

17   to make the point that with a compressed schedule, it

18   becomes even more critical that the first draft really

19   be of highest quality possible.  And that's really the

20   comment that I'm trying to make here.

21	And finally, we'd just like to identify

22   that we did have a little concern about the opportunity

23   for public comment on the Risk and Exposure Assessment

24   document, which when it was released and that's really

25   the first document that was released somewhat off

1  drafts.  But we communicate this information to OAQPS

2  on a very rapidly and efficiently, and so that their

3  evaluations are done on the, really on the final draft

4  -- the final rulemaking will be done.

5	MR. STEICHEN:    Well, I'm looking at the

6  generic NAAQS schedule.

7	DR. COTE:	You know that -- that

8  schedule when we put that up is a little bit -- as you

9  can see the Risk and Exposure Assessment lags the --

10   lags the ISA.  And, you know, if there's -- if the

11   schedule -- the generic NAAQS schedule doesn't reflect

12   that, please point that out, because we would like to

13   correct that.  But, in fact, the rulemaking will be

14   done on the final document.

15	MR. STEICHEN:    Yeah, and I don't think

16   it's so much of the process is that it's simply that

17   what we're going to talk about in terms of the Risk and

18   Exposure Assessment can only really be identified from

19   the first draft of the ISA, and that's why we're simply

20   making the point that having the ISA a little stronger

21   the first draft --

22	DR. COTE:	That's not correct.  We --

23   there's kind of this continuous flow of information, so

24   they will be using the information the second draft.

25	DR. HENDERSON:	Okay. That is our final

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46	48

1  question.

2	DR. ROSS:	Rogene, can I also clarify

3  the schedule?

4	DR. HENDERSON:	Yes.

5	DR. ROSS:	A part of the -- this is

6  Mary Ross.  This is Mary Ross with NCEA, and part of

7  the generic process involves approximately sixty days

8  of review for the ISA documents and approximately

9  thirty days of review for the Risk and Exposure

10   Assessments.  And we've been pressed with the schedule

11   and will acknowledge it's a court ordered schedule,

12   it's been difficult, but we have been keeping to

13   approximately that schedule and so that's consistent

14   with a generic process that we have set-out initially.

15	DR. HENDERSON:	Okay. Thank you.

16	MR. STEICHEN:	With the extension, yes.

17   Yeah, we're there.  Thank you.

18	DR. HENDERSON:	Thank you.

19	MR. STEICHEN:	Okay.

20	DR. HENDERSON:	And thank you.

21	Okay.  I appreciate those good public

22   comments.  I heard a lot of comments about the problem

23   of addressing multi-pollutant atmospheres and that's a

24   problem that we all are concerned with, and it's not an

25   easy problem to solve.  It's something that I think

1  of the peer review.  So just a comment, and I think it

2  would be useful to see if others feel the same way.

3	Turning to Charge Question 1, we saw

4  substantial changes in response to comments made with

5  regard to the first review.  The annex provides

6  extensive coverage of other documents.  It probably

7  would be useful to know just how much of that is

8  actually drawn straight from those documents with

9  proper quotation and citation.  I did have a sense of

10   deja vu, in fact, of authorship as I read some of that

11   material.  And I think you probably should be careful

12   just so you don't -- if you will get called-out and I

13   think that should be --

14	DR. COTE:	We tried to do that, but

15   we'll go back and --

16	DR. SAMET:	Yeah, I think I'd just be

17   really -- really careful.

18	DR. COTE:	Often, we change a few words

19   in there, so we don't have that problem, but we'll go

20   back and look at that.

21	DR. SAMET:	And I certainly agree with

22   the approach of saying that, you know, a number of

23   groups have set-out these procedures and protocols for

24   evidence evaluation.  You don't need to reinvent that.

25	Now, so that said, so having set-out the

47	49

1  will be a focus in the future as we try to improve our

2  management -- assessment and management of our air

3  quality.

4	But let's move on now to a discussion by

5  the committee on the Agency Charge Question 1 related

6  to -- that's going to be led by Jon Samet.  Jon, are

7  you ready to go?

8	DR. SAMET:	Sure.

9	So, in reference to Charge Question 1,

10   first, I just made some general comments that I

11   thought, as others have already said, that the second

12   draft is improved over the first.  I'll just tuck-away

13   the comment that it certainly would be easier to review

14   these documents if there was some way to know what

15   changes had actually been made from document to

16   document.  And I don't know -- that's a generic

17   comment, but on spending hours plowing through this and

18   trying to understand what had changed in this

19   electronic age, it's certainly possible to indicate

20   what has been made and to provide some sort of covering

21   memo or something indicating the major changes.  And I

22   think that would be useful I think for the committee's

23   efficiency, and also perhaps to document what has

24   actually happened from version one to version two, and

25   it would be consistent with I think the usual practice

1  framework in Chapter 1 there's I think several issues;

2  is it the right framework and is it on track, and I

3  guess there's a few issues there.  One is the, sort of

4  the use of the so-called Hill Criteria.  My other

5  comment is please don't rename these as decisive

6  factors.  We definitely do not need EPA renaming what

7  has been around for decades.  So, if you could, please,

8  please, take that out.

9	But the question is whether the Hill

10   with its nine categories and criteria are needed versus

11   some of the simplifications of the Hill that have taken

12   place.  And that's probably worth consideration.  I

13   mean, I think if I really pushed you on analogy

14   experimentation, plausibility coherence and said what's

15   the difference, we would all probably flunk that --

16   flunk that test.

17	The -- another related issue,  and I

18   didn't comment on this specifically, but it's in part

19   triggered by, again, seeing Ila's presentation, it's

20   the question of the five categories and what exactly

21   you mean.  And the second one I think is important,

22   because these categories are going to be defined in the

23   sense by the way you use them in applications, sort of

24   by their cases.  If you will, I think if I were to ask

25   you what is a, you know, sufficient to infer with the

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50	52

1  top level without likely, and the distinction in sort

2  of where you would place your massive certainty.  I

3  think it would be useful.  You know, there are those

4  pictures in the IOM report that are sort of I think a

5  useful guide to talking about classification of

6  evidence when you are less than certain what you have

7  -- that you're not a hundred percent certain let's say

8  of a causal relationship as with let's say active

9  smoking and lung cancer, and then you sort of become

10   less and less certain.  I'm not sure that you right now

11   know where the distinction lies.  It might be useful to

12   talk about that a little bit and even provide some case

13   examples.

14	Then, the other issue is having set out

15   this framework, is it well-applied throughout the

16   document?  And there I think I do see the document as

17   coming up short.  I think some of my other colleagues

18   made the same comments that they do, in fact, set this

19   out.  But then when you come back in these sort of

20   integrated discussions, I don't know whether it's just

21   that it was not carried through, that there were

22   different teams doing the writing of these chapters

23   from those who set-out Chapter 1, but I did not see the

24   kind of I think more rigorous application of these that

25   should be made.  And if you look at the use, for

1  more difficult.

2	I don't know on this question -- I

3  should know -- but whether the St. George's database,

4  which I think is a useful compilation of least of time

5  series studies and others -- whether -- what the group

6  has put in for Nitrogen Oxide.  But that would be one

7  potentially useful way to try and understand what's

8  gotten into the literature.

9	I think that's it, Rogene.

10	DR. HENDERSON:	Thank you.  Is there

11   any need for clarification from NCEA?  You understood

12   that?  Okay.

13	DR. COTE:	I wanted to -- the only

14   reason we kind of were renaming the Hill Criteria

15	DR. HENDERSON:	Can you talk in the

16   mic, because I'm sure the phone

17	DR. COTE:	This is Ila Cote.  I was

18   just looking -- trying to pull up the Hill paper as we

19   were speaking. And I'm not sure he used criteria in the

20   original paper.  But what we were trying to avoid was

21   having criteria for the criteria.  So that we thought

22   was a little awkward.  So I don't know if you want to

23   have discussion about if we could --

24	DR. SAMET:    Well,  I don't know.

25   Decisive factor sounds a little too decisive I think.

51	53

1  example, of these criteria and the Surgeon General's

2  reports where there are very comprehensive sections at

3  the end of evidence reviews on evidence synthesis, I

4  think you would find useful models.  Now, I comment on

5  that later.

6	I do think one issue that's come up

7  already and that I do comment on that's not adequately

8  addressed and I think is potentially problematic for

9  the literature on Nitrogen Dioxide is publication bias.

10   And I think of -- concern here is that -- that there

11   have been many multi-pollutant studies, many time

12   series studies, where, you know, sets of pollutants

13   have been used.  Maybe very often there's been a

14   primary emphasis on particulate matter or ozone.  NO2

15   has been available as an indicator.  It's been put in

16   the models.  And I think you have to be concerned that

17   those studies in which something was found that was

18   either high or statistically significant there was more

19   likely to be mention of a coefficient or something for

20   NO2.  And, in fact, I think just looking at the figure

21   5.1, I think the high estimates, not surprisingly,

22   have very wide confidence bounds -- very much as you

23   would anticipate.  So, I think that issue needs to be

24   certainly mentioned.  The extent to which you want to

25   explore the possibility of publication bias is I think

1  That's all.

2	DR. HENDERSON:	Okay.

3	DR. COTE:    Point taken.

4	DR. HENDERSON:	Okay, Dale.

5	DR. SPEIZER:    Can I comment on this --

6	DR. HENDERSON:	Oh, sure.  Frank.

7	DR. SPEIZER:    -- Hill criteria business?

8	DR. HENDERSON:	Yeah.

9	DR. SPEIZER:    I haven't seen the IOM

10   report and maybe it's done a better job.  But I recall,

11   and I'm using my memory, in reading the Hill criteria

12   in 1965 and subsequently, that there's another

13   paragraph underneath that says these are not rigid

14   criteria. These are suggestions of how to look at data.

15   And, certainly, judgment still needs to be there in

16   doing it.

17	Now, I don't know whether the IOM  has

18   come up with a different set of criteria.

19	DR. SAMET:	So just a comment, actually

20   Hill has.  It's a wonderful paper if you haven't read

21   it.  And he actually concludes at the end, in fact,

22   that you need judgment evidence -- it's always

23   uncertain, and you still have to make decisions and go

24   ahead.  And this same comment is actually made -- the

25   Surgeon General's report in '64 I think has five or six

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1  criteria -- makes the same.  These are not, by any

2  means, a check list.  And I think everyone who has

3  written about these has said that.  And I think that's

4  one more reason that you don't want to call them

5  decisive factors.  They're just points to line-up how

6  much you know.  And I think that Frank's point has been

7  made repeatedly and everybody has proposed these kinds

8  of systems.  And, in fact, those calls of philosophers

9  -- think about this -- argued that you must have

10   temporality, but all else is not necessary for

11   causation.

12	DR. HENDERSON:	Okay. We're going to

13   move on to Dale.  Where is Dale?

14	DR. HATTIS:    Yeah.  Here.

15	DR. HENDERSON:	Okay.

16	DR. HATTIS:    So, I focused on the

17   literature search rather than this --

18	SPEAKER:	Dale, could you speak into

19   the mic?

20	DR. HATTIS:    Yes.

21	I've focused on the literature search,

22   and I basically started by reading the document from

23   the reference section.  And what I did note was that

24   there are a large number of 2007 references and a

25   smattering of 2008.  So that really suggests that this

1  the framework was on target.  I felt like the document

2  read very much like a first draft.  And there were a

3  lot of concepts mentioned but they were very brief, and

4  a lot of them were incomplete or weren't well justified

5  as to why you made the modifications.  I learned a

6  little bit more today about, you know, wanting a little

7  bit of nuance that I would have liked to have seen

8  directly in the document.

9	I went back to the annex and the

10   transitions weren't there either.  I thought it was

11   great that the annex had all of the source information

12   and you could look and see what all the documents were

13   that were pulled from, but I didn't see the transition

14   I wanted to -- the conclusions that were stated in

15   Chapter 1.

16	Let's see.  Then, there were a couple

17   places where I wanted to see some changes.  For

18   instance, there's a brief discussion of features of

19   study design and later there's details about the study

20   design, so there's some reorganization that's needed,

21   but then I thought there were some details missing.

22   For instance, in experimental studies, one of the

23   problems with them is they are experiments and you

24   can't do five million experiments to replicate natural

25   conditions, and that piece wasn't mentioned as a

55	57

1  is, in fact, quite a recent literature search and that

2  the results are there.

3	Then I selected what I thought were a

4  dozen or so of the most, you know, facially important

5  sounding titles and went and retrieved the abstracts

6  from Library of Medicine Sources, and then I checked

7  the way in which the authors described their results

8  compared to the way the -- they were summarized in the

9  document.  And in every case I found that there was a

10   good correspondence between what the ISA document had

11   said about the references and what the abstracts seemed

12   to say.  Although I didn't review the articles in

13   depth, it appeared that the literature search had done

14   -- had been thorough and reasonably accurate in

15   reporting what the authors had reported about their

16   findings.

17	DR. HENDERSON:	Thank you, Dale.  When

18   I read your comments, I said I was very glad that you

19   did such a thorough review.  So, thank you.  That's a

20   help to the committee.

21	And, Lianne, you have a comment?

22	DR. SHEPPARD:    Yeah, I focused

23   predominantly on the framework side of the question, a

24   little bit less on the literature review.  And I

25   thought -- I thought it was a great improvement; that

1  limitation of the experimental literature.

2	The measurement error discussion was

3  derived from the Zieger, et al. paper, but it wasn't

4  cited, and it really only applies to the time series

5  design.  It doesn't apply to all observational studies

6  of air pollution.  And literature, at this point, isn't

7  really complete on that area.

8	And, I wasn't really clear on how much

9  the section should be a general review versus a

10   specific application to the air pollution context. For

11   instance, Table 1.6-1, which talks about the Hill

12   criteria and has modifications, I would say it would be

13   better to directly summarize the sources and then

14   comment on how they should be different in this context

15   in the text.  And then I would also agree with Jon that

16   we need to bring out more clearly the issue of

17   publication bias.

18	So those are my main comments.

19	DR. HENDERSON:	Thank you, Lianne.

20   George?

21	DR. THURSTON:    Yes.  My comments really

22   focused on the last part of the question, which had to

23   do with the framework for scientific evaluations of

24   studies and causality determination.  And, you know, I

25   felt that they did a good job looking at the

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58	60

1  epidemiology, and I don't think really publication bias

2  is the problem that others seem to feel it is.  I think

3  that they've done a good job on the document of

4  summarizing what's there, and the evidence is pretty

5  strong and the epidemiology.  The place where I really

6  felt needed work in the criteria in the document, which

7  I think is a very good document, but the thing -- the

8  gap that I see is between the epidemiology and the

9  toxicology.  And looking at the epidemiology, you see

10   very strong evidence at ambient levels, and then the

11   toxicology finds effects only at much higher levels.

12	And, so, I think that the thing that's

13   missing is something that we do have a fair amount of

14   understanding of and needs to be put into the document

15   is the interaction of particles with gases.  And this

16   is something that I did bring up at our last meeting

17   and I really was disappointed that it was not looked at

18   more.  And I even provided in my comments a paper by

19   Boren from 1964, I believe it was.  It's actually a

20   paper that talks about carbon particles as a carrier

21   for gases and their effects.  And I found this not in

22   Pub Med, because if you look in Pub Med it's not there.

23   There was this young investigator who wrote a summary

24   document of the evidence, Frank Speizer, and he

25   referred to it.  So, when I looked at that I said,

1  them aspects that should be considered.  He asks, what

2  aspects of that association should we especially

3  consider before deciding that the most-likely

4  interpretation of its causation.  And at the end of it

5  I think it's maybe worth looking -- if I can flip to

6  the end of the paper -- at what he concludes at the end

7  -- "All scientific work is incomplete whether it be

8  observational or experimental.  All scientific work is

9  liable to be upset or modified by advancing knowledge.

10   That does not confer upon us the freedom to ignore the

11   knowledge we already have or to postpone the action

12   that it appears to demand at a given time. Who knows,

13   asks Robert Browning, but the world may end tonight,

14   true, but on available evidence most of us make ready

15   to commute on 8:30 the next day."

16	So, I guess what he's saying is use

17   these criteria or aspects -- consider these aspects and

18   then move forward with a decision.

19	DR. HENDERSON:	That's a great quote.

20   I'll have to remember that.  Thank you.  But is there

21   any response from EPA?  I know there's a section -- I

22   would be hard pressed to find exactly where it is --

23   where they did discuss the difference between the tox

24   and the epi, but I don't recall whether they had the PM

25   in there.

59	61

1  well, let me go find that.  And, so, I went through our

2  old library and found this paper.  And just because

3  something has not been published since the beginning of

4  the Internet does not mean it does not bear relevance

5  to this.

6	And, so, I think we really have to look

7  far and wide for -- but I think this is something that,

8  you know, I -- we know.  And it's not an indictment of

9  NO2.  You know, there seems to be this thing, oh, well,

10   you know, there's co-pollutants and these are

11   confounders.  Well, no, actually, they may not be

12   confounders, they may be co-conspirators in this

13   effect.  And that particles are known to be carriers of

14   gases and can make -- be a vector for them reaching

15   deeper in the lung.  And I think that that connection

16   needs to be considered in the document and is not.

17	So -- and then to make that connection

18   between the epidemiology and the toxicology.  And also,

19   I think to identify where, you know, okay, we do have

20   these studies that have been done, but where do we need

21   more information.  So this is an opportunity here for

22   us to see where there are gaps in knowledge.  What we

23   do know and what we don't know.

24	Now, with regard to Hill, I did pull up

25   his paper, and he doesn't call them criteria.  He calls

1	Do you all -- I'm sure you all have it

2  memorized.

3	DR. ROSS:	We certainly did look for

4  the toxicological studies that looked at the

5  interactions between the two, and there aren't many.

6  But we do take your heart -- your concern to heart and

7  we'll try to expand our discussion of NO2 and PM --

8  potential interactions in the upcoming document.

9	DR. THURSTON:    Because I think too often

10   this statistical finding that they're correlated is

11   seen as a negative, you know, that oh, well, then we

12   can dismiss this.  But, actually, it makes a lot of

13   sense when you understand the biological action of

14   these gases and particles.

15	So, I think that the document needs to

16   bring that information to bear and into the

17   understanding of the what seems to be a disparity

18   between the toxicology and the epidemiology, which I

19   see as not -- you know, I'm not surprised that looking

20   at just pure NOx in a toxicology study you don't see

21   effects down to the same level you see it in the real

22   world where there are particles present.  And that

23   makes all perfect sense, and, you know, in my written

24   comments, I talk about the example of ozone, where we

25   had toxicology studies of pure ozone in chambers and

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62	64

1  they said, well, you can't see lung function decrements

2  below 120.  So when we came out, and Frank I'm sure

3  remembers this, we did our studies of children in the

4  '80's, and we showed lung function decrements down

5  well-below a hundred, and they said, well, you must

6  have a confounder or something.  And then when they did

7  the -- redid the experiments to be more like the real

8  world with multi-hour exposures and people exercising,

9  they were able to replicate the epidemiology.

10	So, I think there's a real example there

11   of how by thinking about the disparities between the

12   toxicology and epidemiology you can bring it together

13   and understand better what's going on.

14	DR. HENDERSON:	Thank you, very much,

15   George.

16	I would -- before I open it up for

17   everybody else who may have some comments on Charge

18   Question 1, I want to bring up something Ellis Cowling

19   asked me to say, because Ellis is a charter member of

20   CASAC, and he was just feeling very, very guilty that

21   for the first time in all of these years on service at

22   CASAC, he didn't get his written comments in.  So, he

23   asked me to verbally mention one thing.

24	He liked the way you put the policy

25   relevant questions in in the introduction and in the

1  atmospheric chemistry measurement and the like.  I

2  think it is effective.  I thought the first draft was

3  effective, and we provided some points that could be

4  improved.  And I think you've addressed most of those.

5  I think there's still a few points that, at least on my

6  end, could -- a next draft, or actually, I guess it

7  would no longer be a draft -- a final document might

8  improve -- that I'd still like to see the -- at least a

9  brief list of sources somewhere in the actual document.

10   I just think that would be helpful.  It would highlight

11   what are the major sources such that someone who is

12   reading this document without reading the annexes would

13   have a real feel for where things are and, you know,

14   that it's not just mobile, on-road traffic, which a lot

15   of people think.  And, in fact, when you start looking

16   at the next document, the REA, you see that one of the

17   issues that comes up is things like the airports, and

18   you can also start thinking about railroads, et cetera;

19   in terms of transportation corridors.  And I think that

20   would be good to show that up front.

21	Likewise, and this also comes up from

22   now reading the REA, and I didn't put -- I don't think

23   I put this in my initial review of the -- the first

24   draft of the ISA, but you start seeing that in the REA

25   that models are playing a bigger and bigger role in

63	65

1  Chapter 5, and I also like that.  And he suggested that

2  at some point in the process that they be answered

3  directly.  In other words, you have a list of the

4  question and then you list directly the answers.  And

5  this is not from Ellis, this is from me, I was thinking

6  that might go in the policy assessment document or

7  something, you know, at a later stage.  But his comment

8  was that those were great questions and we need a

9  specific spot in part of the processes that gives the

10   answers.

11	And now I will open up the discussion.

12   Does anyone else have comments on Charge Question 1?

13	Okay.   Jon, you know you're the one

14   that's going to pull all this together and develop

15   eventually a short paragraph or two for the letter to

16   the Administrator?

17	That's what the lead discussant is

18   doing.

19	Okay, let's move on then to Charge

20   Question 2.  And, Ted Russell is the lead discussant.

21	DR RUSSELL:    Thank you.  And, I do like

22   to give my congratulations to what I think is a

23   substantially improved document.

24	Looking at Charge Question 2, which

25   deals primarily with how the document covers

1  terms of what they're addressing their task.  And when

2  I started thinking about that, I really think that

3  those models that they're mentioned in the annexes, but

4  should come up in the document itself, albeit short,

5  but still a good synopsis of what models are available

6  and what are their likely limitations, uncertainties,

7  and how they might be applied in a scientific realm in

8  the risk exposure -- risk and exposure aspects of the

9  next document.

10	I think this is particularly true when,

11   again, this is sort of looking forward to the next

12   document, when you see how they essentially figured out

13   what concentrations might be near the roadway.  And

14   they have -- they come up with a formula that, you

15   know,  it would have been nice to have that sort of

16   issue more vetted in the ISA.  What sort of approaches

17   one might actually take to come up with what are the

18   peak on-road or near-road concentrations based upon

19   ambient monitors and a greater evaluation of such,

20   which I don't think that -- I think it's somewhat not

21   fully vetted in the REA document.

22	Another comment I'd still make is that

23   it doesn't -- this draft, the issue of the monitor

24   interferences, it's, I think, better characterized, but

25   I'm still worried that one gets the wrong impression

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66	68

1  how important those interferences might be, in that if

2  you start looking at the endpoints of concern here,

3  that being both the average, but more likely the peak

4  concentrations of NO2, it's unlike -- you know, one

5  gets the feeling, okay, that the interference could be

6  as much as 50 percent, but that 50 percent first is

7  generally taken from -- well, in this case you referred

8  to a Mexican study, and I'll tell you Mexico City is

9  very different than the U.S., and then a Swiss study,

10   and you correctly state that that's typically -- you

11   get the maximum interferences during the summer, in the

12   afternoon, when you have the high levels of the

13   interference, as in nitric acid and the PANs, but

14   that's also not when you typically have the higher

15   levels of NO2 that are going to weigh-in on either the

16   maximum concentrations in an area which are really

17   going to be not during the middle of the afternoon,

18   they're going to be more in the morning or the later

19   afternoon typically.  And then they also probably would

20   not be during the middle of the summer.  And so I think

21   you get this wrong impression there.  And, also, even

22   on the averages is probably going to be somewhat

23   decreased, so I would recommend that that be considered

24   further -- is that the interferences in terms of how

25   they might be -- how they might come up in terms of

1  worth.

2	And also, like Ted, we had requested in

3  the first round of reviews that this document

4  incorporate some additional quantitative information on

5  sources and, you know, oddly, there was a nice

6  paragraph or two in the risk assessment document that

7  was more quantitative than what was in the ISA, you

8  know, not counting the annex -- the table in the annex.

9  So, something along those lines may be a little -- with

10   a little more detail would be very helpful.

11	And another sort of carry-over from the

12   previous review was that the summaries -- I thought

13   Chapter 3 incorporated a lot of nice summary statements

14   at the ends of sections and sort of made your

15   discussions, and that would have been helpful in this

16   Chapter 2, as well.

17	Just one item that wasn't in my written

18   comments, but became more clear as I was reading

19   through the Risk Assessment, in light of the emphasis

20   on on-road concentrations.  I think that Section 2.5.4

21   could be -- or should be -- sort of additionally

22   supported by some analysis of the distribution of

23   on-road concentrations, or near-road concentrations.  I

24   guess I was somewhat uncomfortable with the model used

25   in the Risk Assessment documents.  So, you know, going

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1  assessing a standard -- probably just not as great.

2	Other than that, I've got some other

3  individual -- oh, one other thing I'd note is again in

4  the REA, it notes that very few of the monitors that

5  are used are at 15 meters, though in the ISA there's

6  still the issue of this monitor -- monitors being

7  between 15 meters and more like four meters, is an

8  issue.  And, so I think there's a couple of things that

9  come up here that would suggest, you know, maybe

10   belatedly, that if you start looking at the REA how you

11   might -- how that might reflect on this draft of the

12   ISA, and to make them more consistent.

13	Thank you.

14	DR. HENDERSON:	Thank you, Ted.  Donna?

15	DR. KENSKI:	Yeah.  Thanks.

16	Like Ted, I thought this was a much

17   improved document, and I guess I'd like to thank the

18   EPA folks for incorporating so many of our comments

19   from the first round.  So, just a handful of comments

20   for me, too.

21	I thought the section 2.4.5 on

22   concentrations of the NOz species was still pretty

23   limited and could benefit from a little additional

24   information on those other related species.  So, I

25   suggested a couple of references there for what it's

1  back to this section, you know, I understand that the

2  data are scarce, but what are there I think could be

3  incorporated in this document to help -- I don't know

4  -- help me believe the models that are used in the Risk

5  Assessment portions.  So I would like to see data

6  specifically on the distribution of those on-road and

7  near-road concentrations to the extent that it exists.

8	DR. HENDERSON:	Thank you, Donna.

9	Is Tim Larson on the phone?

10	DR. LARSON:    Yes.

11	DR. HENDERSON:	Okay, we can hear you

12   fine.

13	DR. LARSON:    Great.  Thank you.

14	I  second the comments so far that this

15   is a much-improved draft over the first one.  I

16   sympathize with EPA's attempt here to do this risk

17   assessment given the sort of sparsity of the monitoring

18   network, and not only is it fairly sparse, but it's

19   dwindling, which is a challenge.  Add to that the fact

20   that the focus or the interest seems to be moving more

21   from a long-term average to a short-term exposure and

22   the network and its spatial intensity becomes even more

23   of a challenge because, as we know, spatial variation

24   is not only greater over these shorter time scales.

25	I really liked Ted's suggestion about

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1  adding a section to the ISA to summarize the models

2  that are used in the risk assessment, especially

3  extrapolating from the long-term average to monitor

4  values to the shorter term peak exposures.  Because

5  there's a number of issues that are difficult to

6  untangle not only for the average reader but for the,

7  for those who are more familiar with this area.  And,

8  so, I think that's a great idea because it lays out

9  better what the options are.

10	To that end I made a comment in my -- in

11   my written comments I provided some more recent

12   references on some of the integral models that are used

13   in confined urban areas because there was a statement,

14   albeit a passing one, in the ISA that said that the

15   only way you can do this is with some complicated

16   computational fluid dynamics model, and it was sort of

17   intractable.  But if you look at that literature, it --

18   there's a number of papers -- I think I had four in

19   there from the last year -- three or four of them in

20   2008 even that are pretty encouraging, and if this has

21   its own literature, but I think it would be certainly

22   something that would be worth discussing in the ISA in

23   a more summary form as Ted suggested.

24	One idea -- I like the idea in this

25   memorandum that was sent around of looking at the

1  that aren't, and you made the classification, which

2  seemed reasonable, a hundred meters.  And I'm wondering

3  if there's any information -- if that information sort

4  of carried through the interpretation of any of those

5  epi studies?

6	DR. ROSS:    The memorandum you're

7  referring to is about the Risk and Exposure Assessment;

8  is that right?

9	DR. LARSON:    Well, it is in its detail,

10   but I mean there was also an analysis made of the

11   monitors and which ones, you know, information is

12   available on which ones are right next to roads.

13	DR. HENDERSON:	Maybe we can wait 'til

14   we get to that.

15	DR. ROSS:    So what you're suggesting

16   though is interpreting the epi studies?

17	DR. LARSON:    Right.

18	DR. ROSS:    Looking at the monitors used

19   in those

20	DR. LARSON:    I mean, I don't know to

21   what extent the epi studies that are summarized there

22   had monitors that were right next to roads versus were

23   away from roads, and I'm just wondering since you had

24   that information in another analysis, in another part

25   of the document, whether or not any of that was

71	73

1  monitors near the roads versus those that are further

2  from the roads as sort of a classification scheme.  And

3  I'm wondering whether or not any of that information

4  was translated into the epidemiological

5  interpretations, because it seems like for either the

6  long or short term numbers there's sort of a

7  qualitative difference in those monitors.  And I don't

8  really have a sense of which of the epi  studies may or

9  may not have used some of those monitors that are

10   seemingly different.  I don't know if that's possible,

11   but it might be something that's illuminating.

12	DR. HENDERSON:	Would you like for us

13   to -- for EPA to respond to that now?  I mean, you were

14   asking EPA a question.

15	DR. LARSON:    Yes.

16	DR. HENDERSON:	I mean, relating the

17   roadway values in the memorandum that went around to

18   epi?

19	DR. ROSS:    Can you restate the question?

20   Because I'm struggling to think of where this fits.

21	DR. LARSON:    Yeah, there's -- at least

22   the memorandum that was sent around, and there was some

23   passing reference to it in the document for the EPA

24   monitors there were near-roads, there's a number of

25   them that are close to major roads and there's others

1  included in your summary or interpretation of that

2  data?

3	DR. THOMAS LONG:    Dr. Larson, this is

4  Tom Long from NCEA.

5	DR. LARSON:    It didn't seem to be in

6  there, so maybe it was a suggestion that   it might be

7  useful. I don't know.

8	DR. ROSS:    First, let me recognize that

9  there are very few epi studies that were done in the

10   United States, and we wouldn't have that kind of

11   information for studies done in Europe or even actually

12   Canada at our fingertips.  But Tom can address

13	DR. THOMAS LONG:    Yeah, I think the --

14   this is a very interesting question of how the monitors

15   used in the epi studies influenced the interpretation.

16   And it probably can only be addressed -- even with this

17   detailed analysis that was done in the memorandum -- it

18   probably could only be looked at in a qualitative

19   manner.

20	DR. LARSON:    Yeah.

21	DR. THOMAS LONG:    For the reason that

22   Mary just mentioned, and also, the epidemiology studies

23   are done over quite a long time period, and monitors

24   come in and out of the network and those sorts of

25   things.  But, I think it would be interesting for us to

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1  at least look at it in the qualitative manner.

2	DR. LARSON:    I think that's about all

3  you can do.  I agree that would be interesting.

4	So, anyway, I guess that's all I have to

5  say at the moment.  I thought it was an improved

6  document for sure.  And I really like the idea of a

7  fairly short document that's to the point and there's

8  been a lot of thought gone into it.  Thank you.

9	DR. HENDERSON:	Thank you, Tim.

10	DR. MENG:    This is -- may I say

11   something about this?

12	DR. HENDERSON:	Okay, you, and then

13   Frank.  Okay. Go ahead.

14	DR. MENG:    Okay. This is Qingyu Meng

15   from NCEA.  I just want to mention that you've seen a

16   ambient monitor as a surrogate for population exposure

17   in epi-studies.  Actually, qualitatively we have

18   addressed that issue in the annex with the exposure air

19   part.  So you've seen the ambient monitor as a

20   surrogate for population exposure related to the

21   spatial variation of NO2 and also the personal

22   activities.  So how does that affect the epi results --

23   we mentioned something in the annex.

24	DR. HENDERSON:	Thank you.  And Frank?

25	DR. SPEIZER:    Yes, I guess I was kind of

1  where they are in terms of where the measurements are

2  made.  Because, in fact, that's the criteria they use,

3  is distance from the road.

4	DR. ROSS:    Well, there actually are

5  different sets of studies.  And some of the

6  epidemiologic studies are associating effects with NO2

7  from the monitors and they don't necessarily say where

8  the monitors are.  And we could find out where they are

9  in the United States, but not at these others.

10	DR. HENDERSON:	Okay, Christian, you

11   have comments?

12	DR. SEIGNEUR:    Yes, we'll also find that

13   the draft seems to be an improvement of the previous

14   draft.  The comments that were made in the previous

15   meeting I think went very nicely otherwise.  So I only

16   have two comments.

17	The first one actually Ted touched upon

18   that a little bit, and that's the issue of the

19   uncertainty associated with the difference in the NO2

20   measurement technique.  In Chapter 1, there is

21   description of uncertainties and how they affect of

22   course the results of the health effects studies, and

23   then we move to section two where there is a very nice

24   complete description of all the uncertainties

25   associated with the NO2 measurement technique.

75	77

1  shocked by Mary saying that because it's in Europe and

2  Canada, you don't have the data.  I'm surprised.  I'm

3  not sure what you're saying.

4	DR. ROSS:    We don't know where the

5  monitors are in those studies.  We can identify them in

6  the United States and we can tell you which ones are

7  close to roads.

8	DR. SPEIZER:    Okay. But most of the

9  epi-studies really indicate the effects that are

10   related to proximity to roads.  So, at least in terms

11   of what the epi-data shows, it really indicates that

12   the closer you are to the roads, the greater the

13   effects that are seen.  So that tells you one thing.

14   One of the criticisms I was going to come back to later

15   with regard to the 18 page memo was it would really be

16   nice to know what is the population concentrations that

17   are within that 100 meters that you use versus, that

18   you're throwing out as terms of being too close to the

19   roads, are there populations there.  And if there is

20   nobody living there that's fine.  I mean, that's

21   perfect, and that's the right thing to do, but we

22   really ought to have some indication of what the

23   population load is in those spaces.

24	But in terms of the -- it seems to me

25   the studies that have indicated effects have indicated

1	As Ted mentioned, some of those

2  circumstances under which you have large uncertainties

3  may not be relevant -- actually, it was health effect

4  studies -- where typically you have high NO2

5  concentrations for your results and typically in

6  wintertime -- the appendix shows nicely that you tend

7  to have higher NO2 concentrations in winter compared to

8  summer.  I mean, it's an oversimplification but

9  perfect.

10	And of course as you move away from the

11   source, you have atmospheric dispersion and then you

12   have, you know, conversion of NO2 to nitric acid and

13   organic nitrates.  So the implication is that when you

14   have high interference, most likely, you don't have

15   high NO2 concentrations.  But that's not being said

16   explicitly at the end of section 2.

17	And then if the reader move to section

18   3, you clearly decided that you may have large

19   uncertainties due to the NO2 measurement technique,

20   which I don't think would be the case.  So my

21   recommendation would be that at the end of section 2,

22   you know, you bring closure to this issue of

23   interference and whether or not it does have an impact

24   on epi studies, which in my opinion, it probably does

25   not have a major impact.

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78

1	The second comment is actually related

2  to an appendix.  In the previous meeting, we discussed

3  air mode,  which was used for the exposure and risk

4  assessment.  And there was a discussion of  CMAC and I

5  brought up the point that if we're going to use air

6  mode we should describe air mode.  And now the appendix

7  has a nice description of air mode including, you know,

8  the pros and cons of the model.  But when I read that

9  section I was a little bit perturbed because, first of

10   all, there are some limitations of air mode which are

11   being brought up and some I don't think are very

12   pertinent to what we are doing here.  Air mode is a

13   steady-state model, which means that you assume the

14   wind direction to be constant for one hour, which I

15   don't think to be that major limitations because we are

16   looking at NO2 concentration in proximate sources in

17   most cases.

18	And then that paragraph in the appendix

19   ended up bringing up SCAMP F which is another

20   dispersion model implying that SCAMP F actually could

21   be a better model to be used for that type of study.

22   And I'm not sure I would agree with that because there

23   are problems with SCAMP F .  SCAMP F doesn't do the NO2

24   calculation correctly for instance.  So, either that

25   appendix will have a complete review of all dispersion

80

1  when you're trying to read it.

2	So, I'm going to -- I spend a little bit

3  more time on the dosimetry part of things since that's

4  my background, and the other sections in the chapter.

5  And first of all, there wasn't -- there really wasn't

6  much work to do there because there hasn't been much

7  progress since the last, last ozone, OS and NOx review.

8  So the appendix seems to include all the relevant

9  references.  There's considerable -- most of the new

10   work has to do more with what I would consider the

11   biochemical aspects of dosimetry rather than the

12   extrapolation modeling aspects that try to determine

13   internal dose from exposure, and try to extrapolate

14   that across different exposure conditions and different

15   species of animals.  So there hasn't been much progress

16   there.

17	Now, in this particular review that

18   posed no obvious problem because the actual health

19   effect that was chosen for risk assessment turns out to

20   be taken from clinical studies, or it'll say it's a

21   health effect that there's been a lot of clinical work

22   on in humans, so that it was possible just to use the

23   exposure conditions of the experiments directly rather

24   than extrapolating.  So, I'm not sure this is good or

25   bad.  I have this feeling in the back of my mind that

79	81

1  models; including air mode, SCAMP F and the other ones

2  like SCAQMD, which I think would be overkill or we

3  simply, I think my recommendation would be to eliminate

4  the comments based -- eliminate the comments on SCAMP

5  F.  Rewrite a little bit air mode in a more positive

6  light with respect to the application we have here, and

7  then I think then we would have a nice appendix

8  presented -- presenting the model that's being used in

9  the assessment.

10	DR. HENDERSON:	Thank you, Christian.

11	Jim?

12	DR. ULTMAN:    I agree with everybody else

13   in the sense that this chapter has vastly improved

14   since the first draft.  It was much more inclusive and

15   much more readable, I thought.

16	I have one very minor point, but it's a

17   nagging point.  It has to do with document development.

18   When you print out a color coded contour plot in black

19   and white, it just messes up all the data.  So, for

20   example, the background -- the plotted background

21   levels, I mean, you can't tell what's low and what's

22   high.  So there must be a way of overcoming this

23   problem when you print the documents out.  This was the

24   same problem that appeared in the ozone document, as

25   well.  It's a minor point, but it is -- it's disturbing

1  there's a kind of an implicit bias when choosing health

2  effect as a basis for risk assessment in choosing

3  something where human data exists so that you can --

4  you don't have to worry about extrapolation issues.

5  And as I said that's the good thing because it makes

6  the risk assessment very clean.  It's a bad thing

7  because you may miss some important issues because --

8  that have been uncovered in animal studies, because you

9  haven't gone through the trouble of trying to do the

10   proper extrapolation modeling.

11	So, the only -- the only real suggestion

12   that I have here is to possibly extend some of the

13   calculations that were done already in this document,

14   in terms of perhaps the cumulative inhaled dose that

15   was present in different studies, both animal and

16   human, and maybe display them in some type of a tabular

17   form.  In other words, there's various end points that

18   were measured in both human and animal studies.  And,

19   you know, the hours of exposure, the concentration

20   levels, the patterns of exposures, are roughly known.

21	So that you could get at least an

22   overall inhaled dose in those studies. And you could,

23   dose could be listed for animal and human studies as

24   well.  As I say, I know you've done some of that, I

25   think, for the human studies already, but not for the

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1  animal studies.

2	It would be nice to go one more step,

3  and that would be to use existing literature on

4  dosimetry to see if some of the animal studies could be

5  at least roughly extrapolated to what that would mean

6  in terms of human concentration.  And I realize in some

7  cases it's kind of irrelevant because some of the

8  effects in the animals were seen at very high exposure

9  concentrations and even if extrapolated, it wouldn't

10   make any difference.

11	But some of the animal studies, the ones

12   having to do with infectivity and things of that

13   nature, immune system compromise, some of those were

14   seen at very low exposure levels.  So it might pay to

15   do a, if it can be done on a basis, as I say, of

16   published studies, to try to do a rough extrapolation

17   to what it might mean in a human.  So as I'm saying, my

18   suggestion to the table that it at minimum would try to

19   estimate for the different types of endpoints and the

20   different species, you know, rats and humans, for

21   example, what the cumulative doses were for comparison

22   in the various studies. And I'm not suggesting you have

23   to do this in every study but rather maybe divide it

24   according to the particular endpoints we're talking

25   about.  And then it maybe even push the envelope a

1	So why am I bringing this up under this

2  charge question?  Well, because I think the issue is so

3  important that it shouldn't be held off until the risk

4  assessment

5  document. I think more has to be said, and you've

6  already mentioned this, more has to be said about how

7  on road data looks, the on road concentration datas

8  look relative to off road data and then even going

9  further.  Just as there are equations in this chapter

10   which, detailed equations on how exposure is

11   calculated, I think it wouldn't hurt to move forward

12   some of the quantitative equations on the on road

13   extrapolations.  To move them forward from the risk

14   assessment to this document and explain them in more

15   detail so that when we do get to calculations such as

16   are in this supplemental memo, that we can really

17   understand what the meaning of those particular

18   calculations are.

19	So those are the two major, major

20   comments I had.

21	DR. HENDERSON:    Thank you, Jim.  Now I

22   would open it up for anybody who has further comments

23   on Charge Question 2.  Lianne, is your hand up?

24	Okay.

25	DR. SHEPPARD:    I wanted to also talk

83	85

1  little further and see if the animal overall doses

2  could be extrapolated down to or up to what it would be

3  in human.

4	So that was one of my comments.  The

5  other comment has to do with the, I think, I'm

6  following on a comment that was already made that had

7  to do with the on road concentrations of NOx and NO2 in

8  particular.  This turns out to be, as we all saw, a

9  very important component of the risk assessment

10   document and I have to admit, I was really, I thought

11   the explanation in the risk assessment document of the

12   extrapolation method, by which you go from, you know,

13   ambient monitored data to roadside was not clearly

14   written.   I mean, I couldn't really follow it very

15   clearly.  But apparently there is an assumption in

16   there, for example, about not having the influence of

17   the roadside concentrations affect the calculations.  I

18   couldn't even, I couldn't follow that, and maybe it's

19   just my own thickheadedness, but I consider myself at

20   least an average reader.   So I thought the explanation

21   in the risk assessment document of the extrapolation

22   method was weak.  Now maybe if I had gone to the annex

23   and read it in a lot more detail, I would have caught

24   on more, but I did go to the annex and it really didn't

25   help me.

1  about this whole problem of monitor siting and the

2  data, interpretation of the data.  It, as you

3  mentioned, Jim, it's really important in the exposure

4  risk assessment document and as Tim mentioned, it

5  potentially has great implications for the

6  interpretation of epi studies.

7	Unlike particulate matter, oxides of

8  nitrogrn vary very highly as a function of distance

9  from road, and so some of these weak correlations that

10   we're seeing are presumably driven completely by that,

11   particularly when you're looking at hourly data,

12   because there can be huge differences due to wind

13   direction and the road and so on and so forth, that can

14   be driving that.  And that could be affecting

15   interpretations and abilities to actually make imprints

16   about health effects.  Very, very dramatically, I

17   think.  And it could also be very dramatically

18   affecting the estimates of exceedances in the exposure

19   and risk assessment document.  So it's difficult, but

20   we've got to do a better job with clarifying the

21   importance of monitoring siting and incorporating that

22   into the entire assessment.

23	So that's my main comment.  My other

24   comment is related in the sense that I thought, first

25   of all, I wanted to say overall, there were many good

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1  improvements, the entire document and so any critical

2  comments need to be taken in light of the fact that

3  you've done a great job integrating a lot of things.

4	The discussion of the correlations I

5  thought was a lot better, but I felt like I still

6  wasn't satisfied.  There's a couple of things.  One is,

7  I'd love to see the formulas, I still didn't find the

8  formulas, and the words were better so I felt like I

9  had a fairly good idea of what was being done, but I'd

10   still like to see the formulas, at least in the annex.

11	And I've, maybe I've missed them in

12   there, but, and cross-referencing so that we can find

13   them easily, too.  I mean, correlations are

14   standardized quantities, so I have a difficulty with a

15   comparing them because they're not only about the

16   co-variance of two things, but they're also about the

17   relative variability, and so when you, for instance,

18   look, compare correlations from annual data compared to

19   season restricted data, you can get much smaller

20   correlations in the season restricted just because

21   there's less variability within one season, there is

22   across a year.  But I don't think that's what we care

23   about  when we're trying to compare these correlations.

24   I don't think that's what the purpose of  our inference

25   is.

1	DR. THURSTON:    Yes, I wanted to follow

2  up on what Lianne was talking about, 'cause I too felt

3  this whole issue of personal versus population

4  exposures needs to be clarified. I think, you know, the

5  public comments we had at the beginning clearly showed

6  that what's written in the document is not being fully

7  understood.  I mean, they do address this issue that

8  what's relevant to the population studies is not the

9  correlation with individual NO2 levels, but with the

10   average of the individual levels. And, you know, if

11   you're going to do a personal level individual cohort

12   study, well, the, yes, the personal exposure's

13   important to consider. But if you're doing a population

14   study, what you're interested in is the average of that

15   population and what is found, what has been found is

16   that when you average over a cohort, where it sort of

17   eliminates the noise of each individual person's

18   personal variation in their like, indoor exposures and

19   things, that that average correlates with the central

20   site monitor much better and justifies the use of

21   central site monitors for epidemiology. So I think that

22   needs to be, you know, based on the conversations that

23   I've heard, you know, and the comments, that that needs

24   to be even said more clearly, I think.

25	One of the things is, that Lianne, I

87	89

1	And so these raw comparisons of a whole

2  host of correlations, I just feel like we're just not

3  getting at what we care about, and it's a difficult

4  problem, so, and I think, as I said, I think you've

5  made progress and you're doing a better job than the

6  first draft, but I still think there's a long way to

7  go.

8	DR. HENDERSON:    Thank you, Lianne, and

9  Ron is in my blind spot, so I'll call...

10	DR. WYZGA:    Thank you, Rogene. I think

11   one of the things we're going to be faced with later is

12   basically interpreting and then integrating health

13   information from many different studies and types of

14   studies.  And I think it would be useful to have an

15   explicit section in here that talks about some of the

16   difference in the characteristics of air quality from

17   the outdoor studies and the indoor studies, and you may

18   even want to add some of the clinical studies, in terms

19   of what's the relative composition of the different NOx

20   compounds, and also what are the co-pollutants?

21	There are differences between them, but

22   I think having some explicit articulation of that would

23   help us in interpreting the health studies later on.

24	DR. HENDERSON:    Thank you, Ron, was

25   there somebody else? George?

1  think what Lianne was getting at was, you know, there

2  was sort of mixing up the cases of where there's

3  correlations between individuals and the central site,

4  and the average of the individuals.  It is noted in the

5  table, but I almost think they should be just separated

6  completely and saying, these are the correlations that

7  might be relevant to an individual level study, and

8  therefore, you would need to individually monitor.

9  Which is what epidemiologists do.  So they recognize

10   that if you're going to look at an individual's

11   symptoms, let's say, you need to have that individual's

12   exposures, but if you're going to look at the

13   population of an entire city, then you don't need every

14   person's exposure, what you need is the population

15   weighted, you know, the population average.

16	And so I think that that disparity and

17   distinction in the correlations data, because the way

18   it is right now, it's easy to be confused by it and

19   say, well, look, some of these are quite low and some

20   of them are better, but so we need to make that, I

21   think even more, it is in the document, but clearly,

22   maybe by having a separate table for the two and

23   discussing the implications for the epidemiology might

24   make that clearer to people reading the document.

25	The other, the other thing is the

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1  question of the central site versus the, even when

2  you're looking at that average exposure of the

3  population and then looking at the central site or even

4  just the correlation of the central sites, you're going

5  to find that if the monitor is at a real hot spot, that

6  it's not going to correlate well with population-based

7  monitors.  And so if you look at that correlation then

8  you're gonna, and you do, and then you say well, the

9  correlation could be quite low, but epidemiologists are

10   aware of this, and when we do the epidemiology,

11   generally it's practice, if you're going to do a

12   population weighted exposure, you know, if you're

13   looking for a population exposure, not to use the hot

14   spot.  You use the community-based monitors.

15	And that should be in the papers.  I

16   mean, I'll give you an example.  If you're going to

17   look at hospital admissions, there are scheduled and

18   unscheduled admissions.  And someone could say, my god,

19   why are they doing hospital admissions, you could get

20   really disparate results if you include scheduled

21   admissions. 'cause they're going to happen irrespective

22   of air pollution.  Well, we recognize that when we do

23   the studies and we don't include these scheduled, the

24   people who are scheduled to come in on Tuesday for an

25   operation a month ahead.  Those aren't included in the

1	So I think that some of these

2  correlations could be presented in a way, in a context

3  more thinking ahead to the epidemiology and saying what

4  is general practice in the epidemiology and which

5  correlations relate to which types of epidemiology?

6  And I think that's sort of saying what has been -- you

7  know, what Lianne was getting at, I think, right?  And

8  certainly Tim was getting at that with the

9  epidemiology, that the central site hot spot monitor

10   may not be represented but it's not what is used, so it

11   looks like a bigger problem in the document than it is,

12   I guess.

13	DR. HENDERSON:    Okay, Lianne can respond

14   and then Ed has, is waiting in line here.

15	DR. SHEPPARD:    Just to follow up, it

16   matters quite a bit what the study design is, George.

17	DR. THURSTON:    Yeah, right, good point.

18	DR. SHEPPARD:    And so it can't, I mean

19   the time series studies you want may be a population

20   based monitor by and large, but a lot of the cohort

21   studies of course the focus is on getting that

22   variability that has to do with near roads,

23   capturing that.

24	DR. THURSTON:	Right, so I think that

25   that distinction of types of epidemiology for types of

91	93

1  count.  That would be a problem, but we don't do it.

2	Similarly I think that using a central site

3  hot spot monitor to represent the entire population

4  would be a problem, and generally, you know, as  to my

5  knowledge, nobody does that. So it's not the problem it

6  appears to be from the Table of Correlations.  In other

7  words, you might try what are the correlations of, if

8  you eliminate the traffic hot spot monitors, what's the

9  correlation of the community based monitors?   Which is

10   what someone's going to do with, if they're doing an

11   epidemiol -- now if they're doing a roadway study, sort

12   of what Dr. Speizer's talking about, yes, they would

13   include those and then they would look at the

14   population living very close, that would be a different

15   kind of study.

16	But for the population city-wide, I, my

17   understanding, and it's general practice to not use the

18   hot spot monitors, certainly not just that one. You,

19   what people do is average over, so that's another

20   distinction. If you're going to look at the correlation

21   of one monitor with the personal levels, that's not

22   what people do in the epidemiology, they average, you

23   know, all, especially the community-based monitors,

24   they average them on a day and they use that average to

25   get an idea.

1  data, although it really, you know, I think needs to be

2  made up here in the exposure, because people, you know,

3  in a way to relate it, I mean it's discussed, it is

4  discussed and I think maybe that could be clarified,

5  and make this distinction.

6	DR. HENDERSON:    It was discussed in

7  the --

8	DR. THURSTON:    It is.

9	DR. HENDERSON:	You want just to be,

10   have it clarified --

11	DR. THURSTON:	I think so, yeah.

12	DR. HENDERSON:    It was discussed and you

13   want to just have it clarified and you've been waiting

14   patiently.

15	DR. AVOL:   I just had a few brief

16   comments, some a little bit structural, and then to

17   amplify some things that previous speakers have said.

18   First I agree that the document is much improved and

19   that the terse sort of focused nature of it is welcomed

20   and appreciated, but I think in doing that you also

21   need to sort of present the key important issues and

22   then to provide some measured judgment about what those

23   issues are and I think sometimes that's gotten a little

24   bit away and two areas where I think it's worth

25   nothing.

EPA CASAC MEETING 05/01/08 CCR#15905-1	25

94	96

1	One is in the multi-pollutant

2  considerations.  We've talked a lot in previous

3  meetings and there have been comments and you'll

4  continue to hear comments about the issue of

5  multi-pollutants and how that factors in here and so I

6  think you sort of...you need to sort of talk about that

7  because as George pointed out, there's biological

8  plausibility, both in the chemical transformations and

9  in the physical world as well as in the biological, the

10   receptor effects and so I think it's important to bring

11   that out somewhere in the document, as appropriate in

12   the respective sections.

13	The other thing that I think is an issue

14   of integration, the ISA should take the data and make

15   some measured judgment about things, it seems to be,

16   and particularly in Chapter Two, one of the problems I

17   had was that you talk a lot about the measurements as

18   Ted and Christian both said, you describe the

19   measurement, you describe the potential interferences,

20   et cetera, but in that chapter at the end of it, you

21   don't come to some conclusion about where you are with

22   it.  There's a little bit of that later in Chapter Five

23   at the summary of the whole document but it would be

24   very useful I think in terms of once you get rolling

25   and going with the document, chapter by chapter, and

1  and what we do see in that figure is that at some point

2  there appears to be not really, I hesitate to call it a

3  threshold, but a level at which people do start having

4  an inflammatory response that is statistically

5  significant.

6	Unfortunately the dose response is

7  somewhat unclear above that point as to whether the

8  magnitude of the actual inflammatory response would

9  increase or not.  However, if we moved over to figure

10   3.12 where we looked at increases in airways

11   hyper-responsiveness.  Before I go back or before I

12   move on to that, for anyone that's on the phone that

13   cannot receive a handout, the figure that I just

14   referred to on inflammatory responses, that's figure

15   3.11.  That may be found in the first draft of the

16   document as Annex figure 51.  But moving on to the

17   airways hyper-responsiveness, what we've done in that

18   figure is we've tried to again look at the dose that

19   people received and whether there was a statistically

20   significant effect indicated by the plus sign or not

21   statistically significant effect indicated by the

22   negative sign and it's not really clear that we have a

23   nice dose response relationship at least for airways

24   hyper-responsiveness.

25	I mean there are some reasons for that.

95	97

1  building up the case, as it were, that when you

2  describe this, when you present this, you make some

3  judgment about what do you think about this and then go

4  on.

5	DR. HENDERSON:    Okay, are there other

6  comments?  I want to ask EPA, have our...are they

7  clear, do you need any clarification of these comments

8  for any reason?

9	DR. JAMES BROWN:    I would like to just

10   comment...this is James Brown and I would like to just

11   comment on the dosimetry issues that Dr. Ultman brought

12   up.  I have a few comments there, the first one is that

13   I would like you to know that we are actually working

14   on looking at all the end points in both the animal

15   studies and the clinical studies and trying to see if

16   we can identify a clear dose response relationship.

17	The second thing would be, we have a

18   figure where that works a little bit and Dr. Nugent has

19   that now and that's looking at inflammatory responses

20   in healthy individuals.  Unfortunately, right before

21   our draft went out, the wrong figure became substituted

22   in and some of you noted the...and were a little bit

23   confused by that figure, and in that figure we looked

24   at responsiveness and increased inflammatory responses

25   in healthy individuals, as a function of inhaled dose

1  One thing Dr. Samet brought up in his comments in

2  relation to another chapter where I said that the

3  responsiveness is less in exercising individuals.

4  Well, that clearly goes against an increase in dose

5  with an increase in response.  I think that there are

6  reasons that we might have that perhaps.  It's a change

7  in responsiveness in asthmatics just due to the

8  exercise itself, making the increase in responsiveness

9  to the challenge agent less evident.

10	Another complication in establishing

11   that dose response relationship would be the delivery

12   of the challenge agent, the method of delivery, the

13   dose that's delivered and the underlying sensitivity of

14   the individuals, also limits our ability to establish

15   the dose response relationship.  So we are working on

16   that and we have provided two figures that weren't

17   necessarily included with dosimetry but in the

18   discussion of the clinical studies to address that

19   issue.

20	DR. HENDERSON:    Thank you very much. and

21   I think it's time for a break...

22	DR. SAMET:    Could I make just one quick

23   follow up.  I was really not so much thinking about the

24   dose response issue that you, as you said that you've

25   outlined part of it in the report now as I was the

98	100

1  animal extrapolation issue, and you know, there's

2  nothing on the comparison between the animal dose in

3  experiments where a health effect was seen in the

4  animal versus what you might see in the human and the

5  reason I think that's important is because it's

6  possible that in the risk assessment, we focused on a

7  particular endpoint where there might be another end

8  point that a person's even more sensitive to and the

9  only way to find that out, to compare sensitivity from

10   the animal experiments, would be to do some kind of a

11   dose extrapolation so I'm not even thinking  anything

12   sophisticated as a dose response but just the question

13   that if you compare two different...if you compare

14   different animals...

15	I'm sorry, I'm saying that wrong, if you

16   look at an endpoint that shows some sensitivity or some

17   effect due to NOx and you know the level of exposure of

18   the animal and you can estimate the lung size or the

19   weight of the animal and you can estimate the

20   ventilation rate of the animal, if you do a simple

21   extrapolation to, you know, an anthropometric

22   extrapolation basically to a human, would that be in

23   the same range as some other end point so for example,

24   if you look at the work that was done on the...that's

25   been done on I guess on rats and effect of...I'm sorry,

1  (WHEREUPON,   a brief recess was taken.)

2	DR. HENDERSON:    Okay, it's time to get

3  back together and discuss Charge question three.  For

4  anybody who wants them, there are copies of the slides

5  presented by NCEA this morning, out on the table so if

6  you want copies of those slides they are available.

7  Our helpers have been passing out revised copies of Ann

8  Smith's remarks, so if you find those in your chair,

9  they're to replace what's in your folder and with that

10   we will start off...

11	DR. COTE:    Rogene, could I ask a

12   question?

13	DR. HENDERSON:    Yes, go ahead, Ila.

14	DR. COTE:    I was sitting in the back and

15   continuing to think so I wanted to go back and ask Jon

16   a comment, about the application of the Hill criteria,

17   I mean, what he said is if you look at all those

18   criteria, it's hard to make them all kind of work very

19   well, but by the same token I think there are

20   situations, we're trying to design this so it works for

21   a broad array of chemicals, not just here.

22	So analogy is a perfect example, there