### 202-234-4433 Neal R. Gross & Co., Inc. Page 1 U.S. ENVIRONMENTAL PROTECTION AGENCY + + + + + CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE

CARBON MONOXIDE NAAQS REVIEW PANEL

+ + + + +

PUBLIC MEETING

+ + + + + TUESDAY, MARCH 23, 2010 + + + + + The Panel met in Salon ABC of the Marriott Research Triangle Park, 4700 Guardian Drive, Durham, NC, at 8:30 a.m., Joseph Brain, Chair, presiding.

CASAC MEMBERS PRESENT:

JOSEPH BRAIN, Chair

PANEL MEMBERS PRESENT: PAUL BLANC THOMAS DAHMS MILAN HAZUCHA JOEL KAUFMAN

MICHAEL KLEINMAN FRANCINE LADEN ARTHUR PENN BEATE RITZ PAUL ROBERTS STEPHEN THOM

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SCIENCE ADVISORY BOARD STAFF:

KYNDALL BARRY, Designated Federal

Officer

ANTHONY MACIOROWSKI, Deputy Director

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TABLE OF CONTENTS

AGENDA ITEM PAGE

Response to PA Charge Question 7-8 3

Dr. Stephen Thom

Response to PA Charge Questions 9-10 48

Dr. Paul Roberts

Response to PA Charge Question 11 56

Dr. Paul Roberts

Summary and Next Steps 167 Dr. Joe Brain

### 202-234-4433 Neal R. Gross & Co., Inc. Page 4 1 P R O C E E D I N G S 2 (8:32 a.m.) 3 CHAIR BRAIN: Good morning, 4 everyone. I think we are in good shape to 5 finish by Noon, but we do have multiple tasks.

6 We want to look at the comments that were 7 produced by all of you and assembled by 8 Kyndall, and they will be distributed in hard 9 copy sometime during the next half-hour or so. 10 The other thing we need to do is 11 to continue our initial discussion of the 12 charge questions to the PA document. 13 So in the absence of the letters, 14 why don't we continue with that. So I think 15 we are up to you, Mike. Is that right?

16 DR. KLEINMAN: Yes. 17 CHAIR BRAIN: I think that is 18 right. So we are now talking about the Policy 19 Assessment document, Charge Questions 7 and 8, 20 and Mike will lead us through that discussion. 21 DR. KLEINMAN: I am bringing the 22 text up on my computer. Okay, sorry for the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 5 1 delay. 2 I put this together pretty late 3 last night. So it definitely needs some 4 editing. But I think the staff has done an 5 extensive analysis of the adequacy of the 6 current and potential alternative primary CO

7 standards. 8 So the current standard, just to9 remind us, is a one-hour average and an eight10 hour average standard. The one-hour is 35 11 ppm. The eight-hour is nine ppm. The form of 12 the standard is that the levels are not to be 13 exceeded more than once a year. 14 In reviewing the adequacy of the 15 standards and the recent literature, the staff 16 has commented that the -- and I am going to 17 quote this, "the much expanded epidemiological 18 evidence provides support for previous 19 conclusions regarding cardiovascular disease, 20 related susceptibility, and indications of air 21 quality conditions that may be associated with 22 ambient CO related risk."

### 202-234-4433 Neal R. Gross & Co., Inc. Page 6 1 They conclude that a causal 2 relationship is likely to exist between 3 relevant short-term exposures to CO and 4 cardiovascular morbidity. 5 Having said that, there were 6 several studies, epidemiological studies, that 7 were cited in Table 2.1 which, when you look 8 at it, is really not as many studies as it 9 appears to be, because it was broken up in

10 terms of health outcomes. 11 After reviewing those studies, 12 staff concluded that -- Well, let me back up. 13 So the table contains studies that have 14 ischemic heart disease, congestive heart 15 failure, and other cardiovascular diseases 16 broken out as separate categories. 17 Several of these studies, three of 18 them, are from the same city, Atlanta. So 19 there is a Tolbert study, a Peel study and a 20 Metzger study. Each of those studies were 21 studies that were done during periods when the 22 standards were not exceeded, and I believe it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 7 1 was the eight-hour standard that they were 2 focusing on. 3 There was one additional study on 4 that page which did not exceed the standard, 5 and that was a congestive heart disease -- 6 congestive heart failure study, Wallenius. So 7 that one also was done during a period when

8 there was no excedence of the standard. 9 There were four other studies in 10 which, in fact, there were excedences. So I 11 think the bottom line was the staff concluded 12 that there was not enough epidemiological 13 data, since two of the Atlanta studies didn't 14 show a statistically significant outcome, 15 whereas one of them did, and they also said 16 that the congestive heart failure studies were 17 less useful, because congestive heart failure 18 has multiple causes, and it would be more 19 difficult to identify CO as a causal agent. 20 So in reviewing this, it seems 21 apparent that we need a better way to look at 22 the epidemiological studies, and what has been

### 202-234-4433 Neal R. Gross & Co., Inc. Page 8 1 done in the PM sector and what has been done 2 with nitrogen oxides has been to use meta 3 analyses and other more sophisticated 4 reanalytical approaches to the epidemiology to 5 help develop concentration-response 6 relationships. 7 In this case, I think the data may 8 lend itself very well to that, because we have 9 studies, and even the studies where work was 10 done where it exceeds the standard -- those 11 can be used to help define a dose response 12 curve or a concentration response curve. 13 The beauty of it is you actually 14 don't have to extrapolate, as we often do with 15 toxicology studies, because we have lower 16 level studies that had significant effects. 17 So I think one of the things that we need to - 18 - or that would be useful to bring out is that 19 there is a need for a more thorough analysis 20 of the epidemiological database. 21 The other thing to point out is

22 that the document calls out that there have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 9 1 been no new controlled human studies, 2 especially to look at some of the more recent 3 endpoints that are being brought up through 4 the epidemiology, like the field 5 susceptibility, things like that, and the 6 likelihood of being able to do controlled 7 human studies with these very susceptible 8 groups is extremely low. 9 So it may be that there will be no 10 new controlled human studies going forward in 11 the future. Therefore, epidemiology is what 12 we are going to have left to work with. 13 So again, I think we need to focus 14 on possibly suggestions for improving the way 15 that epidemiology can be used in these policy

16 assessments. 17 The staff put out -- Their keynote 18 was they said that the data provides support19 for retaining or revising the current eight20 hour standard, which one of the members of the 21 Panel termed ambiguous. 22 It would seem that, if we gave

### 202-234-4433 Neal R. Gross & Co., Inc. Page 10 1 more weight to the epidemiological evidence, 2 one might conclude that the health effects are 3 accruing at levels below current standard, and 4 we have large numbers of individuals which 5 really haven't been tallied that are more 6 susceptible possibly than people with coronary 7 artery disease. 8 Therefore, the evidence might lean 9 -- could be taken to lean in the direction of 10 revising the current standard. 11 So that kind of brings us to the 12 Charge Question 8. So I think we do agree 13 that the data presented does support a range 14 of policy options or at least consideration of 15 a range of policy options, and the question is 16 how to approach that. 17 A number of proposals were raised, 18 and I personally found it sort of difficult to 19 keep track of which proposal was which, but I 20 think there are a number of approaches that 21 were brought out. 22 So, for example, the eight-hour

### 202-234-4433 Neal R. Gross & Co., Inc. Page 11 1 standard: So one possibility is retain the 2 eight-hour averaging time, and give 3 consideration to levels within a range of 4 three to nine ppm, which is quite broad and 5 based on the concentration response 6 relationships derived from the coronary artery 7 disease studies, or consider revising the 8 current standard to a different form -- for 9 example, taking the 99th percentile of the 10 fourth highest maximum instead of the current 11 statistic that is being used.

12 The one-hour standard: One of the 13 options is to retain the current standard, 14 which will provide protection against more 15 infrequent acute exposures, and consider a 16 range of five to 15 ppm instead of the current 17 35 ppm. That could be combined with choosing 18 a 99th percentile or a fourth highest maximum 19 as the statistic. 20 Alternatively, they suggest it 21 might be possible if the eight-hour standard 22 is made more restrictive than perhaps the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 12 1 and that would be the controlling standard,

2 and the one-hour standard could be revoked.

3 So to what extent does the 4 document provide sufficient rationale for this 5 range? We talked about this yesterday, but 6 the rationale was based on choosing ranges of 7 carboxyhemoglobin benchmarks, 1.5, 1.8 and 2.0 8 percent carboxyhemoglobin, as levels to 9 protect against, and then using the Coburn 10 force obtained relationship, going back and 11 back-calculating what the exposures would be

12 that would reach that. 13 I think, because we don't have a 14 dose response or a concentration response 15 relationship based on epidemiology, this is 16 what we have at present. I think we should 17 encourage EPA to try to find some way of 18 developing relationships for the 19 epidemiological data similar to what has been 20 done before PM, and that may give us a clearer 21 idea of what the options could be. 22 Another thing that I think would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 13 1 be very useful for the PA would be to 2 summarize the options, perhaps in a table, and 3 list what are the pros and what are the cons 4 of each of the options, so that the 5 Administrator can look at one place and have 6 at least a snapshot of what the consequences 7 of each decision might be. 8 The staff does mention that 9 retaining the one-hour standard might provide 10 protection independent of the type of 11 protection provided by the eight-hour 12 standard, but the discussion surrounding that 13 statement really was not very clear. So a 14 little more discussion about that would be 15 useful to include in the document.

16 Does the Panel have 17 recommendations regarding additional 18 considerations which should inform 19 characterization of these options? 20 I don't know if this is something 21 that we would normally do, but it might be 22 useful to indicate with each of the options in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 14 1 terms of pros and cons how many areas might 2 become out of compliance under each option. 3 It might be something useful to at least have 4 some information on. 5 I think, as I said, a clearer 6 summary of the options' pros and cons would be 7 very helpful in evaluation of how 8 representative the risk analysis, which is 9 based on two selected cities -- how 10 representative is that of the rest of the 11 country? I think that needs to be discussed 12 a little bit in the document, and in terms of 13 setting the standard -- some mechanism or some 14 concept of how to deal with the spatial 15 heterogeneity of CO exposures, for example, in 16 near-roadway things. How is that going to be 17 incorporated into these discussions? 18 So I think those were the primary 19 views that came out of the individual

20 comments. 21 One other individual, Ann Sweeney 22 -- I presume Ann is not on the line -- raised

### 202-234-4433 Neal R. Gross & Co., Inc. Page 15 1 the issue that there is a social justice 2 parameter to carbon monoxide. I was thinking 3 about that, because it doesn't -- I don't know 4 how that fits into primary standards, but I 5 was wondering whether social justice might be 6 considered later on as part of a rationale for 7 discussing a secondary standard. 8 It would be very interesting to 9 set a secondary standard, for example, that 10 would protect against very high levels near a 11 roadside, which would have an interesting side 12 effect; because if we had a secondary standard 13 that could be applied at roadsides, should EPA14 start to establish roadside sampling or near15 road sampling? 16 Violations of the primary standard17 might not necessarily accrue from the near18 road sampler being out of compliance, which it 19 may well be, even at the current standard. 20 So those are my comments. We 21 should open it up to everybody else, I guess. 22 CHAIR BRAIN: I am impressed that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 16 1 you are talking really about the heart of the 2 matter, and this is a really important part of

3 our letter. 4 So you comment on the range of 5 alternatives and present some new ones. Do 6 you think we should be expressing a preference 7 in terms of -- you mentioned keeping it as it 8 is, going from three to seven. How do you 9 come down? Do you just want to comment on the 10 suite of alternatives that are presented and 11 they are adequately presented or do you think 12 the Panel should be expressing a preference 13 for overall direction of the form? How do you 14 feel about that, and then let's hear how 15 everyone else feels. 16 DR. KLEINMAN: My feeling is that 17 the data suggests that the current standard is 18 not adequately protective and that a new 19 standard should be somewhat lower than it 20 currently is. Now -- 21 CHAIR BRAIN: So that is a nice, 22 concise summary. Is there general agreement

### 202-234-4433 Neal R. Gross & Co., Inc. Page 17 1 with that? Any dissenters? 2 DR. KLEINMAN: Okay. I will add

3 that. 4 CHAIR BRAIN: So it sounds like 5 that should be clear. In fact, that sounds 6 like something that should be up front in the 7 covering two-page letter as well. 8 DR. KLEINMAN: Okay. 9 CHAIR BRAIN: You were in the 10 middle of continuing. 11 DR. KLEINMAN: Yes. I think that 12 we can certainly -- I think that the ranges of 13 concentrations that have been proposed by the 14 staff have relative merits. Since we don't 15 really suggest standards per se -- we just 16 advise the direction of things -- providing 17 that range of standards, but suggesting that 18 the range should not be as high as the current 19 standard. So we should trim the range to 20 something below the current level. 21 DR. HAZUCHA: Forgive my 22 ignorance, but what is social justice

### 202-234-4433 Neal R. Gross & Co., Inc. Page 18 1 parameter? Apparently, everybody knows, but 2 somehow I do not know what it is. 3 DR. KLEINMAN: Well, in this 4 particular case, the properties in areas where 5 there is more pollution, and notably roadsides 6 are one among them, or areas next to 7 industrial emitters, the people who are living 8 in those areas tend to be from the lower 9 socioeconomic class. Hence, they are 10 receiving more pollution, because they have 11 lower incomes and, therefore, it is a social 12 justice issue. 13 DR. HAZUCHA: Oh, okay. 14 CHAIR BRAIN: But it is probably a 15 component to almost every environmental 16 standard we can think of. 17 DR. KLEINMAN: Absolutely. 18 DR. HAZUCHA: So it is basically 19 socioeconomic status. 20 DR. BLANC: Yes, which you brought 21 up, although again just to come back, for 22 example, to the issue that you also brought up

### 202-234-4433 Neal R. Gross & Co., Inc. Page 19 1 of endogenous CO production: If poverty is 2 concentrated in part in African American 3 communities in the United States and if that 4 is where sickle cell disease is and that is 5 where higher metabolic rates are, and that is 6 who lives near roadways, there are scenarios 7 that you can describe that make operational 8 theoretical social justice concerns in this 9 particular example more concretely than in

10 some others.

11 CHAIR BRAIN: Other comments? We 12 also welcome our early bird on the West Coast, 13 Beate Ritz. Do you want to make any comments 14 on policy questions seven and eight? 15 DR. RITZ: I actually think my 16 colleague knows very well, and the only 17 addition I have to make here is that we really 18 have to think it through to go to spatial 19 heterogeneity being included or making a 20 recommendation for the inclusion. 21 Clearly, there will be groups that 22 are much more affected, and there is a source,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 20 1 a heavy source component to CO. If we really 2 believe that COHb has a lot to do with the 3 health effects, then that is very, very 4 relevant, but we probably also have to 5 consider newer sources of CO. 6 If we think in the future there 7 may be other sources, then constructing a 8 whole measurement network based on roadways 9 right now may not do us much service, if that 10 is something we are worried about in the 11 future -- that the sources may change.

12 CHAIR BRAIN: Now how do others 13 feel about -- Do we actually want to suggest 14 a secondary standard focusing on roadways, or 15 just -- It was an interesting possibility. 16 Should it be left out or mentioned casually?

17 Does EPA have a comment? 18 DR. MURPHY: I just want to 19 perhaps provide clarification, and I was a 20 little confused by this point that was raised 21 by Dr. Kleinman. 22 With regard to the standards, you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 21 1 were speaking in terms of -- I thought you 2 were perhaps saying that an excedence of the 3 primary standard would not count, or 4 something. I want to assure you that it

5 would. 6 Where we have the data indicating 7 that the standard is not met in ambient air,

8 that would be an excedence of the standard. 9 It would trigger a variety of control options, 10 and that is how the standards work. 11 You also made a comment with 12 regard to the secondary. I might alert you to 13 chapter three which talks about the secondary 14 and quotes from the anecdotes as to what the 15 secondary in intended to protect against. 16 Rather than protection of public health, it is 17 protection of public welfare, and it lists a 18 variety of things which are considered in 19 that, and social justice would not 20 necessarily, I believe, fall within that 21 category. It is closer to the public health 22 protection, of course, with adequate margin of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 22 1 safety. 2 So just to make sure you 3 understood that an excedence of the primary 4 standard is definitely something we take 5 seriously. 6 CHAIR BRAIN: I thought he was 7 saying that, even though the primary standard 8 may be met, that along roadways there may be 9 higher levels. So I guess, is that more of a 10 monitoring issue than we are just not 11 measuring it in the right -- 12 DR. KLEINMAN: What I am saying is 13 that, if the monitoring is changed to include 14 near-road samplers, those near-road samplers 15 are very likely to produce much higher levels 16 than the samplers that are out there in the 17 general public area. 18 So the question is: If, for 19 example, EPA does place roadway samplers or 20 near-road samplers out there or in areas where 21 there is really very non-homogeneous carbon 22 monoxide concentrations -- and that can occur

### 202-234-4433 Neal R. Gross & Co., Inc. Page 23 1 in canyons, in cities, urban canyons; we know 2 that those things occur, and in fact, 3 placement of samplers generally avoids those 4 kinds of hot spots. 5 So the issue is, if we are going 6 to include hot spot samples or samplers, are 7 they going to be treated in exactly the same 8 way as all the other samplers or can they be 9 given sort of a secondary role for monitoring 10 these very high levels that may occur in very 11 localized areas? 12 The other point in terms of the 13 social justice, I realize that it is supposed 14 to be property issues and welfare issues. 15 What I am thinking is that the root source of 16 the social justice argument is the property 17 values are degraded because of the presence of 18 pollution. 19 So it is a little circuitous, but 20 it is not untenable to make that claim. 21 MR. ORLIN: My name is David 22 Orlin. I am with EPA's Office of General

### 202-234-4433 Neal R. Gross & Co., Inc. Page 24 1 Counsel, and I just wanted to clarify a little 2 bit, because we do have -- You know, primary 3 and secondary have commonly understood 4 meanings, but for the Clean Air Act, you know, 5 we do have a definite understanding for the 6 NAAQS that the primary would be the health 7 based standard, and the secondary would be the 8 welfare or sort of ecological standard. 9 It is sort of theoretically 10 possible that you could define a standard in 11 terms of its monitoring siting criteria. So 12 that you would say, you know, we are not 13 going to consider monitor results that are 14 near a roadway. And if the Panel thought that 15 was important, then they could provide advice 16 on that, but as a general practice, EPA's 17 strong preference has always been to set the 18 NAAQS across an area and to look at all the 19 relevant monitoring data. 20 As Dr. Murphy said, as a general 21 matter, once we set the standard, we will look 22 at any valid data, and we don't like to look

### 202-234-4433 Neal R. Gross & Co., Inc. Page 25 1 at data and then say, you know, even though 2 this is above the level of the standard, we 3 are not going to consider it a violation. But 4 if the Panel is concerned about treatment of 5 hot spots, one way or the other, then they 6 could provide some advice on that. 7 CHAIR BRAIN: I confess, I just 8 need to be educated about the way the current 9 monitoring network is working. If you have a 10 city and you have 50 monitors, and just one of 11 them is above the standard, is that a 12 violation or not?

13 DR. MURPHY: Yes. 14 CHAIR BRAIN: It is? 15 DR. MURPHY: Yes. And if I might 16 add, my understanding of the network for CO is 17 the intention is that they be near roads. Now 18 as I mentioned yesterday, in the current 19 monitoring network there are many monitors 20 which are not near roadways, and that is one 21 thing that happens as we review the standards. 22 We get another look at the monitoring network.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 26 1 So we will be looking at that 2 again, and the monitoring folks will be 3 deciding if they need to modify the monitoring 4 regulations. But my understanding of the 5 current monitoring regulations is they do 6 require that monitors be near where we expect 7 there to be CO at concentrations which might 8 exceed the standards, and clearly, those would 9 be near roadways. 10 DR. PENN: Just one question. 11 When you had the PM meeting a couple of weeks 12 ago and you talked about -- we talked about it 13 yesterday -- did they bring up or address this 14 argument in terms of PM monitoring near 15 roadways or was that not a consideration? 16 CHAIR BRAIN: I think it was 17 mentioned. There, certainly, was discussion 18 of traffic, dust. 19 DR. PENN: Because that is a big 20 part of the papers that have been produced 21 recently. 22 DR. ROBERTS: Joe, I thought Mike

### 202-234-4433 Neal R. Gross & Co., Inc. Page 27 1 brought up something interesting, and I 2 wondered if staff had looked at numbers of 3 sites that might exceed the suggested range, 4 like the three ppm eight-hour or applied 15 5 one-hour proposed possible? 6 DR. MURPHY: Right. In terms of 7 considering a decision, providing information 8 on what might support options for a standard, 9 that would normally not be something that we 10 ought to consider, and that is not something 11 that the Administrator would consider in 12 setting the standard. However, it is not 13 unusual for that information to be available 14 and, for example, at the time of proposal 15 there are some public communication materials 16 which make clear what the impact might be, but 17 to date we have not developed that type of 18 material.

19 DR. DAHMS: It seemed to me that 20 the current monitoring network is positioned 21 based on actual exposure, projected exposure 22 and times of exposure, or for modeling

### 202-234-4433 Neal R. Gross & Co., Inc. Page 28 1 purposes. In other words, you would expect 2 that, if eight percent of a person's time is 3 on a highway, that eight percent of the 4 monitors might be within 50 meters of a 5 highway, but that is not the case. There is 6 no -- In other words, there is no way of 7 making that assumption. 8 I would think that in the future 9 it would be -- You know, what is the point of 10 having a monitor in an urban canyon in L.A. 11 when less than 100 to one percent of the 12 people spent any time in that canyon. It then 13 becomes not very representative of very many 14 people's exposure. 15 There are people that -- I don't 16 know what you do. You post a sign: You are 17 entering a place of high risk; do it on your 18 own? You know, how do you -- We are talking 19 about definitely placing things where there is 20 going to be excedence of standards. 21 CHAIR BRAIN: Is there a paradigm 22 for how monitors are deployed? Again, does it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 29 1 represent -- Is it intended to best represent 2 the average human exposure or do you look for 3 the worst places? What is the philosophy or 4 is it just willy nilly and a matter of 5 history? 6 DR. MURPHY: Are you asking EPA? 7 CHAIR BRAIN: yes. 8 DR. MURPHY: Okay. So the answer 9 would be, in terms of required monitors, as 10 part of the standard we tend to have 11 requirements for monitors to try to identify 12 areas where the ambient air has the potential 13 to exceed the standard; because, of course, we 14 do not want the ambient air to exceed the

15 standard. 16 So we would -- and in CO -- it is 17 my understanding that the regulations, which 18 date back a bit, but their requirement was to 19 put the monitor near the places where we 20 thought the standard would be exceeded, which 21 in the case of CO, as you all well know, is 22 near roadways. So that is a requirement.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 30 1 Now over the years, you know, 2 evolution happens in terms of states having a 3 variety of reasons that they put monitors out. 4 Some of them may be to meet that requirement 5 of the National Ambient Air Quality Standards. 6 Some of their needs for the standard may be 7 that they want to have a sense of what are the 8 CO concentrations in very populated areas. 9 So when you then look across where 10 are the monitors today, they may represent a 11 variety of objectives, but the objective in 12 terms of the NAAQS is to make sure we are 13 monitoring in places where the standard has 14 the potential to be exceeded. That is the 15 purpose for the EPA regulations requiring 16 those monitors. 17 Beyond that, people may have 18 objectives. Researchers may have objectives. 19 States may have objectives. So the actual 20 network may look a little different, and you 21 might not realize an underlying objective for

22 the standard.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 31 1 CHAIR BRAIN: That is very 2 helpful. It is interesting, isn't it? So a 3 redeployment or more monitors in high level 4 areas, in a sense, represents a de facto 5 tightening of the standard, doesn't it, to

6 some extent? 7 DR. PENN: But one question. It 8 is the states that decide where the monitors 9 ultimately are placed, is it not? 10 DR. MURPHY: The states place the 11 monitors, but the EPA has regulations 12 requiring certain things about monitor 13 placement as a minimum requirement. 14 For example, we require that the 15 states place monitors where there is -- 16 generally speaking, where the ambient air has 17 the potential to exceed the standard, and in 18 the CO -- I wish I had in front of me the CO 19 monitoring requirements, but it is my 20 understanding that they be near -- I mean, for 21 some of the pollutants, there are phrases 22 like, area of maximum concentration. That is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 32 1 a phrase for the lead standards -- lead 2 monitors, for example. 3 So there is an underlying federal 4 regulation that directs where we require there 5 be monitors placed, but the states are the 6 ones with the responsibility to place those 7 monitors. So they may place them additionally 8 in other locations. 9 DR. PENN: But you would suggest,10 for instance, that there might be places on I11 5 where there should be a monitor placed or 12 you just make it more general in terms of 13 roadways, and then California can decide if 14 they want to put it down, you know, Long Beach 15 or if they want to put it up higher? 16 There is a lot of leeway, it 17 seems. You guys make the suggestions, but it 18 is still ultimately where the states decide to 19 put it, or do you actually say we think there 20 should be something along the West Side 21 Highway in Manhattan? 22 DR. MURPHY: No. the regulations,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 33 1 of course, would not be that specific. 2 CHAIR BRAIN: Mike, do you have 3 enough guidance? 4 DR. ROBERTS: Can I add a couple 5 of things there? So I think what staff has 6 said is what the goals are. There are a 7 couple of things going on now. 8 The states -- All the agencies are 9 in a five-year cycle of evaluating their 10 networks. They are required to do this as 11 part of EPA requirements, and there are 12 multiple objectives for all monitoring sites, 13 including population exposure and high 14 concentrations. You know, there is a long 15 list of that.

16 We have done some of these for 17 some areas. Traditionally, there are not very 18 many near-roadway CO monitors, as we talked 19 about earlier with the ISA. The ratings in 20 the official system aren't actually very good, 21 but there are only a couple of sites in the 22 country -- I think, three -- that are within

### 202-234-4433 Neal R. Gross & Co., Inc. Page 34 1 50 meters of the edge of the roadway, which is 2 what the new NO2 requirement is, for example. 3 People want tradition. They want 4 what is the trend in CO to understand the CO 5 emissions inventory improvements, and things 6 like that. So there is a range of objectives, 7 but there have been a few monitors that have

8 been excluded from standards. 9 I know Las Vegas had a monitor on 10 the sidewalk on the Strip at the MGM Grand for 11 years that was excluded from -- it was a hot 12 spot monitor. It was excluded from the 13 standards. Now that was placed there when 14 they were actually exceeding the standard of 15 nine, but now they no longer do either. 16 So I think in the current every 17 five-year network evaluation, I think they are 18 all due July 1st this year. So this is the 19 first real time that real serious quantitative 20 analysis of monitoring networks is being done, 21 and everybody is required to do that. So I 22 think that will improve the CO monitoring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 35 1 network as well as others. 2 I know it is not really part of 3 our evaluation, because I think our evaluation 4 of where the standard should be -- Mike very 5 eloquently discussed what Table 2.1 is,

6 etcetera. 7 I actually suspect that near-road 8 50 meter monitors will not exceed a lowered 9 standard. I just finished a year in Las Vegas 10 with three monitors, one monitor within 50 11 meters and a couple within -- well, two within 12 50 meters and one within 120 meters of the 13 roadway. 14 So I suspect that, if we are 15 worried that, gee, that will throw a whole 16 bunch into non-attainment, I don't think that 17 will happen, especially with the continuing 18 downward trend. There is still a strong CO 19 downward trend here. It hasn't really

20 bottomed out as much as some of the other 21 pollutants. 22 DR. THOM: Joe, aren't we dealing

### 202-234-4433 Neal R. Gross & Co., Inc. Page 36 1 with the future? Shouldn't we be? We are 2 dealing with the science that we've got in

3 front of us? 4 CHAIR BRAIN: I think so. This 5 has been an interesting discussion, but let's 6 see if we can wind this up. 7 First of all, is there anybody on 8 the telephone that wants to comment on 9 Question 7 or 8? Hearing none, let's hear 10 from Paul, and then let's go back to Mike. 11 Tell us whether you have enough guidance from 12 the Panel to write the final version of your

13 answer. Paul? 14 DR. BLANC: Although I think 15 inherent in the comments was appropriate 16 critique of the approach taken with Table 2.1, 17 I don't think it actually goes far enough. I 18 was impressed by Steve's comments regarding 19 the previous question in which you also review

20 Table 2.1. 21 I think you should share your 22 comments, because otherwise there will be a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 37 1 disassociation between -- 2 DR. THOM: The one thing I should 3 say is, when I wrote that, it was after 4 scanning Table 2.1. In Mike's analysis, 5 actually there are only four of those 6 citations where there is no violation of the

7 current standard. 8 The point more generally is that 9 Mike and I both commented that Table 2.1, I 10 think, supports the argument rather strongly 11 that the epidemiological data drives one to a 12 conclusion that the current standards should 13 be lowered, that there is indeed a risk for a 14 variety of cardiovascular decompensations to 15 arise from ambient CO in the range of only 16 several parts per million. That was one of my

17 comments. 18 The other, I think, sort of major 19 message for our charge to Question 6 was that, 20 whereas the controlled clinical data clearly 21 justifies an emphasis on cardiac 22 decompensation, individuals with coronary

### 202-234-4433 Neal R. Gross & Co., Inc. Page 38 1 vascular disease, that they may not be the 2 most sensitive individuals. 3 In particular, there is a fair bit 4 of data to suggest that the fetus is 5 particularly at high risk from very low levels 6 of carbon monoxide. Although that data do not 7 rise to the level where you can change 8 standards -- the science isn't quite there yet 9 -- the clinical data implicates, and the basic 10 science toxicological data strongly suggests

11 that. 12 Therefore, our opinion is that 13 some of that information should be included in 14 the Policy Assessment, and it further supports 15 an argument to modify the current standard. 16 Although it doesn't give you a number, again 17 it supports the notion that something needs to 18 be done based upon the science as it stands 19 today, with the caveat that as we move 20 forward, the science presumably is going to 21 get better in terms of a clearer understanding 22 of pathophysiology. The science, however,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 39 1 today does support a strong recommendation to 2 modify the standard.

3 CHAIR BRAIN: That sounded to me 4 like a consensus view and not inconsistent 5 with anything that Mike said. It does add 6 that we really continue to want to highlight 7 possible effects on gestation and on the 8 fetus, and that should be mentioned. Does 9 that resonate with you? I think so. 10 DR. BLANC: Yes, it does. 11 CHAIR BRAIN: I also want to point 12 out another epidemiologic point or 13 biostatistical point about overly discounting 14 a positive relative risk association in a 15 study where a few days may exceed the 16 standard, and thus that was a study performed 17 in an area not in compliance. 18 It is very unlikely that the 19 excedence days in such a study over a long 20 period of time would explain the statistical 21 association unless there was a relative risk 22 of 1,000 on the days in which the excedence

### 202-234-4433 Neal R. Gross & Co., Inc. Page 40 1 occurred. Therefore, it is likely that the 2 epidemiologic association -- It is more than 3 not that the epidemiologic association is 4 explained arterial to all the days in which, 5 in fact, the exposures as experienced were 6 within the standard. 7 So there is, on the one hand, a 8 sort of purely regulatory assessment of an 9 area as having not been completely in 10 compliance, but that shouldn't be, therefore, 11 used to misinterpret the epidemiologic 12 association as being attributable to very high 13 exposures. It is more likely than not that 14 the effect that we are seeing is explained by 15 exposure days within the standard. 16 CHAIR BRAIN: Does everyone agree 17 with that? I think so. I think we, in 18 general, want them to be somewhat more 19 positive about these epidemiological studies 20 and not discount them because there are a few 21 excedences, and I think that is common for the 22 literature for many other criteria of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 41 1 pollutants as well.

2 DR. DAHMS: The controlled human 3 studies are, if you look at it from the 4 standpoint of excedence -- come on. 5 CHAIR BRAIN: Big time. 6 DR. DAHMS: Yes, it is big time.

7 CHAIR BRAIN: Hundreds. 8 DR. DAHMS: Yes, right. But even 9 the effective dose is something obtained in 10 excedence of the standard. So you can't have 11 it both ways. 12 DR. BLANC: Also, I don't think it 13 goes to too much of a level of detail that one 14 of the studies -- or a pair of studies that 15 they do endorse as being within the study 16 within compliance, and then reject because it 17 wasn't a statistically significant elevation 18 of relative risk -- the lower limit of the 19 confidence interval that excludes -- or 20 includes one is 0.9999. So in terms of the 21 possibility of beta error, I think, is -- you 22 know, it is worth noting it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 42 1 CHAIR BRAIN: Can we be certain 2 that both of these, I think, succinct and 3 compelling summaries are included during -- 4 DR. RITZ: Yes. There is one more 5 point, and that is that a lot of these studies 6 actually give you results for different 7 outcomes, and it almost seems like the studies 8 that give you more options of choosing your 9 outcome are being seen more critical, and the 10 ones that just lump all cardiovascular disease 11 together actually get you the significant 12 results; because, of course, they have more 13 subjects. 14 So that is just another point 15 where you have to be careful when you review 16 these studies, trying to make a point that 17 they are not consistent when, in fact, they 18 are consistent if you don't go into the 19 subgroups. 20 DR. HAZUCHA: Well, I don't know 21 whether you will ultimately dissent or not, 22 but I agree with EPA evaluation of epi

### 202-234-4433 Neal R. Gross & Co., Inc. Page 43 1 studies. We all know that there is very high 2 correlation between carbon monoxide levels and 3 PM levels. We have a lot of endpoints for PM 4 effects. Of course, it is inflammatory 5 endpoints, cardiovascular inflammatory 6 endpoints, and so on. 7 For carbon monoxide, we have 8 nothing, basically, because we don't measure 9 COHb. So we have only concentration or LH 10 concentration of carbon monoxide. 11 Because of this collinearity 12 between carbon monoxide and PM, of course, we 13 will get then a sort of high correlation 14 between the endpoints and carbon monoxide. As 15 well, we will get for PM and the endpoints. 16 So I don't know, really, how to 17 separate. Statistically, there is a lot of 18 statistical approaches were used, but still I 19 do not know how physiologically we can 20 separate carbon monoxide effects, if there are 21 any, and the PM effects, which there is plenty

22 of.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 44 1 CHAIR BRAIN: Anybody want to2 respond to that? Certain, the issue of co3 pollutants -- 4 DR. RITZ: Well, when you look at 5 the epi studies, the one agent that always 6 remains in the significant when you put 7 everything together is carbon monoxide. PM 8 actually -- PM-10 often appears much worse 9 than carbon monoxide. 10 The signal for carbon monoxide is 11 incredibly strong for these outcomes in the 12 epi studies. Otherwise, you would have to 13 really, of those, discuss PM, I think, being 14 less strong than the carbon monoxide, and we 15 are having standards for PM based on epi 16 studies. 17 DR. THOM: Is your argument that 18 you cannot fathom a mechanism? Is that your 19 argument? 20 DR. HAZUCHA: Yes, that is 21 correct. It is one of the arguments. 22 DR. THOM: So on that score,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 45 1 number one, I don't think the function of an 2 epidemiologic study is to link it to a 3 biochemical mechanism. I mean, it is just 4 demonstrating some sort of a causality, and 5 that leaves to the basic scientists to do the 6 mechanism. But with regard to the 7 inflammatory component, there is very clear8 evidence that carbon monoxide is a pro9 inflammatory substance.

10 DR. HAZUCHA: At such low levels? 11 DR. THOM: Well, okay. Now so 12 there is a question, but then you come into 13 play some of the issues with regard -- Carbon 14 monoxide is pro-inflammatory, absolutely. 15 There is clear evidence of vascular injury. 16 Now the argument that -- The 17 secondary argument would be, as you just said, 18 well, maybe it is the dose. So the animal 19 studies, our animal studies and our clinical 20 reports that have shown the pro-inflammatory 21 effects of carbon monoxide are done at higher 22 concentrations than the environmental

### 202-234-4433 Neal R. Gross & Co., Inc. Page 46 1 standards, but again the issue becomes -- That 2 doesn't discount the inflammatory component, 3 just says maybe there is more to it. 4 That is to say, a longer duration 5 at a lower level will acquire the same level 6 injury. We can't answer that question now. 7 However, there is clear evidence that it is 8 pro-inflammatory, which -- So I don't think 9 you can discount -- 10 CHAIR BRAIN: I think we need to 11 move on, and we will see how Mike does with 12 this. I think these are -- What you talk 13 about, Milan, are certainly something that the14 Panel has worried about, the issue of co15 pollutants and interactions, and to what 16 extent is CO a surrogate for air pollution in 17 general. 18 So I think that will certainly be 19 part of the document, and we should make sure 20 that that theme is also there, and they are a 21 little bit in tension with each other. 22 Mike, are you reasonably well

### 202-234-4433 Neal R. Gross & Co., Inc. Page 47 1 informed as to what you need to put down that 2 will kind of summarize the discussion? 3 DR. KLEINMAN: I think I can do 4 it. 5 CHAIR BRAIN: Good. Okay.

6 DR. MURPHY: Could I ask a 7 question? Sorry.

8 CHAIR BRAIN: Yes.

9 DR. MURPHY: One of the comments 10 was with regard to -- There was a statement 11 made that I thought I heard. I want to make 12 sure what I heard -- that the CAD population 13 may not be the most sensitive, and while we 14 recognize that there are other -- in ISA, that 15 there may be other populations that are 16 potentially susceptible, including, of course, 17 the fetus, we don't have -- at least my 18 understanding based on the presentation of the 19 evidence in the ISA, that we don't have the 20 evidence indicating that that would be more 21 susceptible than CAD, and it sounded like 22 there was a view that perhaps that was the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 48 1 thought. I wanted to understand what evidence 2 was underlying that. What was the science 3 basis there? Thanks. 4 CHAIR BRAIN: So are we saying 5 that there are just other very susceptible 6 populations?

7 DR. KLEINMAN: That was what I was 8 saying. I was saying that there are large 9 numbers of other susceptible groups that 10 aren't captured in the range studies that were 11 done using the benchmarks, because I believe 12 the numbers were specifically organized 13 against -- or around the individuals with 14 coronary artery disease. 15 CHAIR BRAIN: But I don't think I 16 heard a statement about relative 17 susceptibility. We don't really have -- 18 DR. KLEINMAN: I said there were 19 susceptible. 20 CHAIR BRAIN: There are other very 21 susceptible individuals. 22 DR. KLEINMAN: Right.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 49 1 CHAIR BRAIN: Good. Thank you. 2 Let's press on. So now we are up to Questions 3 9 and 10. Nine seems like it is a relatively 4 simple question. Paul, take us through that. 5 DR. ROBERTS: So I guess the only 6 comments I have actually seen -- I didn't see 7 any other compiled comments. 8 CHAIR BRAIN: Was anybody else 9 assigned? 10 DR. ROBERTS: Well, Russ Dickerson 11 sent in a couple of comments. So he and I are 12 the only ones I know that put anything in on 13 this. 14 So Chapter 3 is a fairly short 15 chapter evaluating, looking at the evidence 16 for a possible secondary standard, welfare 17 based. So this is not health based. Right? 18 We had a little discussion about that already. 19 In general, the PA concludes that 20 there is insufficient information at this time 21 to support the consideration of a secondary

22 standard for CO.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 50 1 I think, in general, there is 2 probably enough detail here, and Russ sort of 3 agreed. However, Russ was suggesting as part 4 of -- I don't know if it is really 9, 10 or 11 5 here -- that it would be helpful if the PA 6 said for the potential effects on climate, 7 which by the way, the ISA said there was 8 evidence for that, and we saw that as a panel 9 before, but there is not really enough 10 evidence to figure out how that would really 11 work and what the effect actually is. It is 12 all estimates with large uncertainty. 13 Russ was suggesting it would be 14 appropriate in the last paragraph to add some 15 summary information on what is missing that 16 would allow an evaluation of -- truly of a 17 secondary standard. 18 The kinds of things, I think, that 19 would be in that list are more accurate U.S. 20 but especially global emissions inventories 21 for CO to evaluate the relative contribution, 22 monitoring specified for climate rather than

### 202-234-4433 Neal R. Gross & Co., Inc. Page 51 1 just for standards in exposure, and maybe 2 improvements in localized chemical reactions 3 in the global models to understand CO 4 interactions with methane and ozone; because 5 the interaction with ozone especially is the 6 major potential contributor, and these global 7 models do not look at the details at a local 8 level like around a roadway. 9 That is really where the CO would 10 have this reaction and, therefore, an effect 11 on ozone. It basically, scavenges OH 12 radicals, I guess, and doesn't allow them to 13 scavenge ozone instead. So there is more 14 ozone around, but the global models wouldn't 15 correctly recognize that. 16 So I think Russ and I sort of came 17 down on the side of, more or less, agreeing 18 with what the chapter is saying in terms of 19 what we can't really do at this point. 20 CHAIR BRAIN: So it acknowledges a 21 possible connection with CO and climate 22 change, but it doesn't go beyond that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 52 1 DR. ROBERTS: Right. 2 CHAIR BRAIN: I think it was the 3 general feeling that that was appropriate. 4 DR. BLANC: But I guess what 5 confused me when I heard their presentation at 6 least was that it didn't seem consistent with 7 my memory of what the ISA section said. Maybe 8 that has -- Is what you are saying, that has 9 to do with a nuance between the ISA saying it 10 is -- there is a causative association between 11 CO and climate effects, and the policy 12 document saying, well, that may be true, but 13 there is not enough in addition to that to do 14 anything about that? 15 CHAIR BRAIN: I don't know that it 16 was causative. I think it was more a 17 recognition that CO is involved in air 18 chemistry. 19 DR. BLANC: I thought it was 20 pretty -- 21 DR. ROBERTS: I think the words 22 are fairly definitive, but I think at least

### 202-234-4433 Neal R. Gross & Co., Inc. Page 53 1 some of the argument then is that the 2 uncertainty, though, in those estimates are -- 3 50 percent, I think, is what the ISA quotes. 4 Okay. At least the global models don't 5 actually model this at all. 6 So you have to go do a special -- 7 The EC -- I can't -- went and did some 8 estimates and got the secondary effect numbers 9 that are quoted in the ISA. So that is my 10 remembrance of what it is. Maybe staff? 11 DR. DAHMS: Paul, I think the key 12 thing is on page 3.2 where it says CO is a 13 weak direct contributing greenhouse warming. 14 In my mind, it had a lot to do with the 15 strength of the effect. Just that one 16 sentence indicates that it is involved. It is 17 so minor as to not -- 18 CHAIR BRAIN: It wasn't as though 19 CO is a greenhouse gas, but it is that it 20 affects the production or degradation of -- 21 DR. BLANC: That is in the policy. 22 You are talking about 3.2? But if we go back

### 202-234-4433 Neal R. Gross & Co., Inc. Page 54 1 -- I wish somebody could find easily the 2 statement as it is written in the ISA which

3 seems less muted than that.

4 DR. DAHMS: As I recall that 5 statement in the ISA, it was talking about 6 what was possible and not really quantifying 7 it in any way. 8 DR. BLANC: Can you find it in the

9 ISA? 10 DR. LASSITER: Are you referring 11 to the causal -- the statement of causality?

12 DR. BLANC: Yes. 13 DR. LASSITER: It is in the Policy 14 Assessment as well. A causal relationship 15 exists between current atmospheric 16 concentrations of CO and effects on climate. 17 That is in the Policy Assessment on page 3-2, 18 and that is line 12. So that is directly from

19 the ISA. 20 CHAIR BRAIN: But the magnitude of 21 the effect is unknown, not absolutely 22 described.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 55 1 DR. LASSITER: Right. There is 2 direct and indirect effects and, as you 3 stated, the direct effects are very weak, and 4 the indirect are greater. Yet they are mostly 5 associated with the methane and ozone, not the 6 CO directly. 7 DR. BLANC: Where is it on 3-2? 8 I'm sorry. 9 DR. LASSITER: Line 10. 10 DR. ROBERTS: Well, line 13 and

11 14. 12 DR. LASSITER: Yes, I'm sorry, 13 line 12 and 13. 14 CHAIR BRAIN: I think we will also 15 ask Russ Dickerson and Ted Russell to look at 16 this, because I think they had the most to say 17 about it. So we will sort of put them on 18 notice. 19 DR. ROBERTS: We did have minor 20 comments from Russ, but I thought he was going 21 to call in for this, and he hasn't. 22 DR. BLANC: And then if the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 56 1 interaction with ozone is likely to be in a 2 micro environment near roadways, is that 3 likely to mediate ozone damage to vegetation 4 near roadways? Has that been shown? Is that 5 just a theoretical concern?

6 DR. ROBERTS: I don't know. I 7 think -- I don't know. Do you know? 8 DR. LASSITER: State the question 9 again. 10 DR. BLANC: If there is a micro 11 environmental effect of CO near roadways, that 12 would tend to increase ozone near roadways. 13 Would that be sufficient to have an ozone 14 related vegetation damage effect? 15 CHAIR BRAIN: I don't think ozone 16 gradients near roadways have been described. 17 DR. ROBERTS: So maybe I am 18 exaggerating when I say near roads. 19 Certainly, in urban areas. 20 DR. HAZUCHA: In roadways it would 21 be mostly NOx, nitrogen oxide, which will 22 increase ozone, not CO.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 57 1 CHAIR BRAIN: I think there is 2 clarity. paul, have you dealt with 9 and 10?

3 DR. ROBERTS: Yes. I am not sure 4 where the exact comments are, but I've got a 5 draft of this.

6 CHAIR BRAIN: And then 11 sort of 7 wraps it all up. You want to -- Have you 8 dealt with that or do you want to comment on 9 charge question 11? 10 DR. ROBERTS: Well, I think, you 11 know, I guess we have discussed it already, 12 really. I think it is the same. It is the 13 same thing, and I had a hard time separating 14 out my answer for 10.b was different than 11. 15 CHAIR BRAIN: And in general, we 16 are pretty happy with what is said there? 17 DR. ROBERTS: I think so. We can 18 put these words out to the whole committee, 19 including Russ. 20 CHAIR BRAIN: Okay. Great. 21 So I think we have now finished 22 our initial discussion of the charge

### 202-234-4433 Neal R. Gross & Co., Inc. Page 58 1 questions, and the remaining task for the next 2 couple of hours is to look at the draft 3 reports. 4 So I think, let's get started on 5 the REA draft, and then maybe in half an hour 6 or so we will take a break, because we need a 7 break, and also if anyone hasn't checked out 8 of their rooms, it is probably a good time to 9 do that. So let's get started. 10 DR. LADEN: Joe, just one thing. 11 I've got Question 1, and the answer there is 12 not the right -- I didn't send Kyndall the 13 right one. I just resent it. Did you get it? 14 MS. BARRY: And what I will do is 15 I will have that one printed in just a second. 16 DR. LADEN: So we should just --

17 We shouldn't talk about that one. 18 CHAIR BRAIN: So again, let's talk 19 a little bit about process. So what we have 20 or will have are sort of the initial text 21 produced by all of the lead authors last night 22 or this morning.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 59 1 I am thinking that maybe a first 2 cut through this, since we do have limited 3 time, is to ask the lead authors if there are 4 areas of your statement where you are unsure. 5 In other words, where do you need guidance? 6 So maybe we will do that first, if everyone -- 7 Presumably, you already know what is there, 8 but as you were writing it last night or this 9 morning, do you see areas of controversy, of 10 lack of clarity, where you need help from the 11 committee to be really confident that you have 12 produced a consensus summary. 13 So maybe we will do that first, 14 and simply just ask each lead author whether 15 they need help or whether they are pretty 16 satisfied that it is a consensus view. 17 Then we will -- we can also then 18 turn to the entire Panel and ask you to look 19 at each of these, and are there ones that you 20 disagree with. 21 We are hoping that each of the 22 lead authors, by this Friday, can do

### 202-234-4433 Neal R. Gross & Co., Inc. Page 60 1 additional edits that you think are needed. 2 Then we will have about another week for 3 Kyndall and I to look at it, to refine it 4 further, and then we will get it out to you 5 and to Jon Samet for a final review before it 6 goes to the CASAC committee, and they are 7 meeting on April 19. 8 MS. BARRY: So, yes, the CASAC 9 teleconference will be April 19th. So what 10 Joe is proposing, I think, is very reasonable 11 for the leads to have your opportunity to 12 refine the language by this Friday, and then 13 we will turn it around and kick it back to you 14 guys the following week, maybe next Friday. 15 Then we will be looking to have your final 16 comments and get everything posted somewhere 17 in the range of the 9th through the 12th of 18 April. 19 So it is an aggressive schedule 20 but, I believe, one that is very reasonable, 21 given how far we have gotten in our day and 22 half of meetings. Any questions? Okay.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 61 1 CHAIR BRAIN: Great, thank you. 2 Particularly the topic leaders, if you can 3 join us for that CASAC teleconference, that 4 will be very helpful, because questions may 5 come up where you are the authority, and a 6 response from you would be very helpful. 7 So why don't we now look at the -- 8 You know, these are our comments on the second 9 draft REA, and as a first cut -- We will give 10 everyone a chance later, but as a first cut, 11 why don't we simply go through the questions 12 and see whether the author has any unresolved 13 issues. 14 DR. LADEN: I can talk about my 15 unresolved issues, but you can't see what I

16 wrote. 17 CHAIR BRAIN: Okay. That is fine. 18 DR. LADEN: All right. So what I 19 tried to do -- This was -- So the first 20 question is really on Chapter 2, which is 21 really kind of -- I saw that as -- and it is 22 called the Overview Chapter. So I think that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 62 1 what is in that chapter is really reflective

2 of what our comments are later on. 3 So what I tried to do is present 4 that we felt that there was a good overview 5 conceptually, but that there was kind of 6 mixed concern about the presentation of the 7 epidemiology, and that -- So I just wanted to 8 make sure that I presented that correctly. 9 CHAIR BRAIN: And people should 10 not be looking at what is here. 11 DR. LADEN: Don't look at what is 12 there. That is only what I had written. I 13 sent the wrong thing last night. 14 So what I said is that, while some 15 Panel members supported the cautious approach 16 to using the epidemiology data in the risk 17 assessment, overall there were concerns that 18 the current presentation underemphasized the 19 epidemiologic findings. 20 Even if they are not used in the 21 risk assessment, it is important to 22 incorporate them into the discussion of risk.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 63 1 So I wanted to make sure that that -- because

2 I felt that there was some -- not 3 disagreement, but there was some concern -- I 4 guess disagreement about how the epidemiology 5 should be used in the risk assessment. 6 I think -- I haven't had a chance 7 to read the rest of the document, and I am 8 sure that is going to come out more in the 9 subsequent chapters. So what I then said is - 10 - At the end, I said that I felt that this 11 chapter needed to be edited as -- re-edited, 12 as the other chapters are changed. I just 13 want to make sure that is adequate. 14 The other thing that I talked 15 about is the continuing concerns about the 16 choice of the population at risk, and that the 17 choice of modeling risk for the CAD population 18 needs to be further justified and/or expanded 19 to include other susceptible populations. 20 So that is kind of how I 21 summarized the discussion, and I didn't put 22 specific comments in here. So that was my

### 202-234-4433 Neal R. Gross & Co., Inc. Page 64 1 other question: Was this too much of an 2 overview summary? Did people want more of the 3 specific comments that they had put in? In 4 here, was that going to be enough that it is 5 in the addendum? 6 CHAIR BRAIN: Any responses to 7 Francine? It sounds consistent with what the 8 conversation was. 9 DR. BLANC: I just probably 10 wouldn't leave them the out of that, if they 11 want to narrow it to CAD only, they have to 12 better justify it. I just don't think there 13 is a justification. 14 CHAIR BRAIN: And I think there is 15 strong consensus that we want to include other 16 cardiovascular -- 17 DR. BLANC: Not that they 18 shouldn't do their modeling with CAD, but in 19 addition, they need to broaden it. 20 CHAIR BRAIN: So we will have a 21 chance to look at that text probably after the

22 coffee break.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 65 1 Number 2 is Russ Dickerson. So 2 why don't -- He is not here to comment. So 3 why don't we leave that until -- 4 DR. ROBERTS: Well, I think I sent 5 it in. I don't think there is much 6 controversy in that one. 7 CHAIR BRAIN: Sounds good. Then 8 that gets us up to Charge Questions 3 and 4. 9 So I guess the question, Milan, is not to 10 summarize what is there, but are there issues 11 that you want more input from the Panel? 12 DR. HAZUCHA: Not really. I 13 incorporated Beate's and Steve's comments, and 14 unfortunately, I don't have Joel's comments,

15 but I don't know whether he had a chance to 16 read this semi-consensus. But I do not have, 17 really, any additional questions. 18 CHAIR BRAIN: Okay. So again, we 19 will come back to all these and give everyone 20 else a chance. But now we are just sort of 21 touching base with the authors. 22 Paul, questions 5 to 7, any

### 202-234-4433 Neal R. Gross & Co., Inc. Page 66 1 unresolved or controversial issues that you 2 want advice about? 3 DR. BLANC: Well, one thing is 4 that the other contributors should look and 5 make sure that, in ways in which I 6 incorporated your comments, they are 7 appropriate. 8 In order to be coherent, I 9 incorporated other comments within the body of 10 the comments. I didn't do them sequentially. 11 For example, I retained the comments that 12 Appendix C should have some specific 13 illustrations or examples. I want to make 14 sure that is still -- I think it was Dr. 15 Dahms' suggestion -- that you still want that 16 there, and the coupling of the nonlinear CFK 17 in CHAD would more convincing if there were 18 references to validation. 19 I think we heard that it is not 20 possible to validate. So I added some wording 21 that, basically, in the best of all possible 22 worlds, it would be great; but since there

### 202-234-4433 Neal R. Gross & Co., Inc. Page 67 1 isn't, so be it, but that it is still -- we 2 accept the proposition that this is an 3 improvement over previous, which also weren't 4 validated. So we can't hold them to a higher

5 standard. 6 The wording isn't the best, but 7 that is basically what you meant. Right? 8 Okay. 9 Then on number 6: Number 6 is -- 10 I tried to incorporate various comments that 11 were made on endogenous CO production and some 12 questions that the group had about whether the 13 model -- the ranges produced by the model was 14 reflective of certain subpopulations that 15 might be out of that range, but also I think 16 one clear source of confusion to several of us 17 had been the fact that the range that came out 18 by chance with the random subset was narrower 19 than the overall simulation. 20 That doesn't mean that there is 21 something wrong with that. It just probably 22 was randomness, but it might be helpful that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 68 1 the document clarify that. 2 I did also retain in there the 3 issue of providing the estimates for indoor, 4 and I tried to compromise with Joel's view. 5 Joel Kaufman emphasized seeing what the 6 marginal increase from ambient was. So I 7 said, if it showed all three separately and 8 together, then one could interpret it either 9 way. 10 Milan, I left your series of 11 specific comments on some textual things at

12 the end of that.

13 Then number 7 -- 14 DR. KAUFMAN: Paul, let me just -- 15 This is Joel. Let me just hop in there. I 16 guess -- and I will suggest some additional 17 text and send it on, but I guess I would make 18 the additional -- First of all, I would 19 indicate to the staff that it was the stuff 20 that was presented in the presentation 21 yesterday that was good, where they actually 22 went the additional steps to model this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 69 1 contribution of ambient; because that wasn't 2 in the written document we reviewed. 3 So it probably worth highlighting 4 that that was a good direction to go in, and 5 they should probably follow that on in order 6 to better understand the increment of the 7 ambient contribution, too, because I think 8 that is going to be a very effective part of 9 the modeling of the concentrations 10 potentially, rather than modeling the final 11 COHb, but to model the increment as a way of 12 assessing the effect of the various 13 concentrations that they are going to use in 14 the final assessment of the standard. Does

15 that make sense?

16 DR. BLANC: Yes. Send me the 17 language. 18 DR. KAUFMAN: Yes. Okay. 19 DR. BLANC: Should I go on to 7

20 then? 21 CHAIR BRAIN: Yes, please.

22 DR. BLANC: Seven comes back to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 70 1 the issue of cardiovascular disease versus 2 coronary artery disease and, I think, reflects 3 what I wrote originally, but I think there was 4 consensus in that regard. I don't recall that 5 -- The other authors' texts were generally 6 fairly brief or went over the same thing. 7 That was the one I did last, and I was 8 starting to fatigue. So you should let me 9 know if you think something needs to be there 10 that isn't. 11 CHAIR BRAIN: Okay. Then we have 12 Charge Question 8 and Paul Roberts. Anything 13 you were unclear about? 14 DR. ROBERTS: Well, I mean, I put 15 in a sentence to recognize Paul's concern 16 about the indoor sources step. So he needs to 17 look at that at the very end. So I was trying 18 to recognize -- Really, the two comments were 19 mine about the modeling and his about that in 20 terms of affecting the ability. 21 CHAIR BRAIN: Great. So here is 22 what we will do. We have now had this first

### 202-234-4433 Neal R. Gross & Co., Inc. Page 71 1 cut. Why don't we now give all of you time to 2 look at the answers, and again Francine 3 Laden's new version has been handed out. 4 I guess, before we give everybody 5 an opportunity to look at what is here and to 6 comment on it, does EPA staff -- Are there 7 issues that, as people review this, that you 8 want us -- I know you haven't had a chance to 9 look at it thoroughly either, but even before 10 that, are there any concerns that you have? 11 DR. MURPHY: One quick question of 12 clarification, I think Dr. Graham has. 13 DR. GRAHAM: Thank you. I don't 14 know if it is quick. Can I go through this 15 page by page, line by line, sort of? 16 CHAIR BRAIN: Probably not line by 17 line, but give us what are the microscopic 18 issues. 19 DR. GRAHAM: Just to help you or 20 save you some time.

21 CHAIR BRAIN: Yes. 22 DR. GRAHAM: On the first page at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 72 1 the very bottom there was discussion about the 2 .5, and we had talked about this, that that 3 was related to an analysis that was performed, 4 and it isn't related to the ambient air 5 quality data that was used as an input. That 6 was in deriving specific ratios or factors 7 that were used in adjusting concentrations. 8 Does everybody recall that discussion? 9 Okay. Being that it was used to 10 derive that relationship, it is unclear to me 11 how that actually impacts what is stated here, 12 the threshold COHb levels, particularly since 13 the benchmark of interest or the endpoint is 14 mostly impacted by higher concentrations, 15 concentrations at the upper end of the air 16 quality distribution. 17 CHAIR BRAIN: Again, your point 18 yesterday is it was really only used to devise 19 the algorithm, but then when the actual values 20 were calculated it was not used. 21 DR. GRAHAM: Right. Absolutely.

22 CHAIR BRAIN: So that needs to be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 73 1 clear. 2 DR. GRAHAM: Or if you are asking 3 for more clarity. 4 DR. ROBERTS: I would just suggest 5 taking that paragraph out. It is not as high 6 level a point here at all. It is not in the 7 main model. 8 CHAIR BRAIN: Or do you want them 9 to clarify what was done? If you were 10 confused, perhaps others are. 11 DR. ROBERTS: Well, I think they 12 can clarify it. I think our individual 13 comments can have things about clarifying 14 exactly, but I don't think it is at the level

15 of the rest of the comments here. 16 CHAIR BRAIN: Okay. So when you 17 produce your next edit -- 18 DR. ROBERTS: Well, I am not the 19 leader, though. Somebody else is the leader 20 in this. Right? Milan or someone. 21 DR. THOM: Yes. They clarified it 22 yesterday.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 74 1 DR. ROBERTS: So I think if they 2 put that in the text, and that will be in our 3 individual comments.

4 DR. GRAHAM: Then on the second 5 page, lines 6 through 9, there is a paragraph 6 asking about what was done for the overlapping 7 air quality zones. I can quickly just say we 8 used the closest monitor. So wherever the 9 resident tracked was, it used the closest 10 monitor. So if there were overlap, it was 11 whichever one was closer. 12 CHAIR BRAIN: Again, should we 13 leave in something asking you to clarify that? 14 DR. GRAHAM: Yes, because that 15 actually wasn't written in the text. 16 CHAIR BRAIN: So maybe you can 17 just modify.

18 DR. HAZUCHA: And then we can take 19 it out. 20 DR. DAHMS: Again, we could put it 21 in our individual -- Put them in this thing or 22 put them in details, too? Where do those

### 202-234-4433 Neal R. Gross & Co., Inc. Page 75 1 comments go? 2 CHAIR BRAIN: If they are large 3 and important, I think they can appear here as 4 things that should be dealt with, and we are 5 reassured that they are going to be dealt 6 with. But I think, again, CASAC will be 7 looking at this whole -- the same documents we 8 have looked at, and so even if we are happy 9 with the anticipated response, it is probably 10 not inappropriate to still point out some 11 things that require greater clarity, even if 12 we have been told that greater clarity is on 13 its way. 14 DR. GRAHAM: Lines 24 to 27, it 15 asks about the micro environments. One and 15 16 were done previously, and we did 8 here. This 17 is actually explained on page 523, lines 2 to 18 five. 19 On page 3 at the very top, we had 20 done some updating of the physiology file --

21 CHAIR BRAIN: Where are we now? 22 DR. GRAHAM: Page 3 at the very

### 202-234-4433 Neal R. Gross & Co., Inc. Page 76 1 top, 1 through 3. That is about the -- Well, 2 it makes a reference to the -- We did a review 3 of the physiology file, and that is at the 4 very beginning of that text in Appendix C, but 5 we also go further in that Appendix to 6 describe the updates that were done for three 7 of the variables. 8 We updated the data for body mass, 9 the normalized VO2 Max, as well as the 10 hemoglobin content. So those contained recent 11 algorithms and distributions. 12 CHAIR BRAIN: Again, I find that 13 paragraph a little unhelpful in that it really 14 doesn't say what data is or are obsolete, and 15 what ones are incorrect. So it seems to me, 16 it needs either greater specificity -- 17 DR. GRAHAM: Yes, that would be 18 great. 19 DR. DAHMS: Joe, could I ask for a 20 point of clarification. what was the focus on

21 VO2 Max? Is that because efforts are based on 22 percentage of Max?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 77 1 DR. GRAHAM: It has to do with 2 controlling the activity. 3 DR. DAHMS: The activities are 4 based on percentage of VO2 Max, not of METS? 5 DR. GRAHAM: Well, the METS are 6 used to estimate the VO2, and we wouldn't want 7 to have -- like if an individual performed a 8 series of high level activities, we wouldn't 9 want them to exceed physiological expectations 10 with oxygen consumption. Does that explain 11 it? 12 CHAIR BRAIN: So, Milan, can you 13 maybe be more specific about which parameters 14 you have difficulty with? 15 DR. HAZUCHA: Sure, absolutely. 16 DR. GRAHAM: On the same page 3, 17 21 through 25, there are two examples given, 18 and on the first one it is not clear to me 19 what is being suggested. On the second one, 20 I can say -- It says an illustration of 21 variability in the peak levels, the COHb 22 throughout the year. Would variability in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 78 1 the daily Max be of interest? So if I can 2 have some clarity on those two examples, that 3 would be great. 4 DR. BLANC: Dr. Dahms, that was 5 your input. Can you send me clarification 6 clarifying that? 7 DR. GRAHAM: yes, that would be 8 great. 9 CHAIR BRAIN: Anything else? 10 DR. DAHMS: Well, the concern for 11 that was to see -- We had this discussion 12 among a group of us yesterday. I don't know 13 what your on and off rates are for carbon 14 monoxide, and that is what we wanted to see. 15 DR. GRAHAM: Okay. 16 DR. DAHMS: So that is why I was 17 asking for a daily kind of -- as you walk 18 somebody through different environments, how 19 the model would track that, so we could see

20 that. 21 DR. GRAHAM: Okay. 22 CHAIR BRAIN: Again, there was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 79 1 specific concern that it is very asymmetric 2 and that the loading is much faster than the 3 unloading, and would your model reflect that 4 physiologic reality. Is that right? Yes. 5 DR. DAHMS: Yes, that is correct. 6 DR. GRAHAM: And you are saying 7 not just endogenous, but with the ambient 8 exposures? Okay. 9 DR. DAHMS: Particularly ambient.

10 DR. GRAHAM: Great. 11 CHAIR BRAIN: We would find that 12 sort of reassuring, if that asymmetry were 13 reflected in the model calculations. 14 DR. BLANC: It is all for Appendix 15 C. Right? That is where this would be, up 16 here. Right? 17 DR. DAHMS: It could go anyplace, 18 as long as it is available. 19 DR. ROBERTS: Well, I would 20 suggest, if that is important, that we put a 21 sentence or two about it in the uncertainty 22 section, because that is really what we are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 80 1 talking about. Does the model have the 2 response that -- you know. So we could put 3 something there. Well, this section is -- No, 4 it can stay here. 5 CHAIR BRAIN: Anything else? 6 DR. GRAHAM: Just the final one 7 would be the last page. I'm sorry, page 4 at 8 the very bottom. it is a question about the 9 differences in the air quality that were used. 10 It is lines 39 through 43 on page 4. 11 DR. BLANC: I think that either

12 came from Dr. Dahms or from Dr. Hazucha. So 13 do you remember? 14 DR. DAHMS: It is not mine. 15 DR. HAZUCHA: It is probably mine, 16 yes. 17 DR. GRAHAM: Well, if there are 18 questions about the '95 and '97, I believe it 19 is in the text, but I can improve the clarity 20 here at least. The '95 was used for Denver, 21 and that is because it was close to just 22 meeting the current standard, and that was one

### 202-234-4433 Neal R. Gross & Co., Inc. Page 81 1 of the scenarios that we were trying to model, 2 and the '97 was used for Los Angeles. Again, 3 that is because it had fairly comprehensive 4 data and was used to reflect just meeting the

5 current standard.

6 The 2006 data were used the "as 7 is." 8 DR. BLANC: So I can change the 9 words, "it is not clear why." I have to say 10 "it should be made more clear why." 11 DR. GRAHAM: Yes, that would be 12 great. Well, I am hoping that it is clear 13 here that that is why it was done that way. 14 DR. HAZUCHA: Well, actually, in 15 the text, if I remember, indeed you said 1995 16 is for Denver and 1997 is for LA. 17 DR. GRAHAM: Right. 18 DR. HAZUCHA: But my concern was 19 why you haven't used data more recent for

20 Denver and LA. 21 DR. GRAHAM: Well, we did the 2006 22 for both cities.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 82 1 DR. MURPHY: Maybe we could 2 clarify the purpose. Sorry. 3 So our objectives were to have 4 some air quality scenarios, one which 5 reflected, quote/unquote, "current conditions" 6 or "as is," and the 2006 is intended to do

7 that. 8 Then we needed a set of scenarios 9 that reflected air quality just meeting the 10 current standard, which would be higher 11 concentrations than those today. Then we also 12 needed alternatives, which in this case fell 13 between just meeting the current standard and 14 the "as is" condition. 15 I doing them, there are a variety 16 of ways we might consider to create the air 17 quality data for those simulations. One way 18 which might be done is to roll up, if you 19 will, the current conditions using a 20 proportional or some other relationship to 21 create air concentrations that just meet the

22 standard.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 83 1 An alternative, which we employed 2 here, which we thought was appropriate 3 reflected actual conditions that had existed 4 in the past where the concentrations were near 5 the air quality standard. 6 So it is just the approach that we 7 used to create the air quality dataset which 8 reflected just meeting the current standard. 9 Then we used that same dataset, rolling it 10 down to meet the alternative standards that 11 were higher than current conditions. 12 DR. HAZUCHA: So maybe a sentence 13 or two -- a clarifying sentence or two would 14 help to understand why there is differences in 15 years. 16 CHAIR BRAIN: Can you modify that? 17 So you are simply asking them -- 18 DR. BLANC: I've got it. I've got 19 it, and I will delete the very last phrase, 20 which is about the temporal trends, because 21 once you explain it, then it is not an issue. 22 But I will say parenthetically that is why you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 84 1 did it for the processes of modeling different 2 exposure scenarios, because that is what you 3 were doing. 4 DR. GRAHAM: Absolutely. Thank 5 you. 6 CHAIR BRAIN: So I think we would 7 all like the chance to look at this a little 8 more carefully. We will now go through this 9 one more time. 10 Let's now take a break, and let's 11 give you an extra 10 minutes. So use the 12 break not only to --

13 DR. MURPHY: Excuse me. I'm 14 sorry, Dr. Brain. I didn't -- We just had a 15 question with regard to Question 1 that was 16 distributed, and I am not sure if you all 17 needed to talk about that first or not. 18 CHAIR BRAIN: Why don't we all 19 look at it, and then we can -- We will now go 20 through the document one more time, and give 21 an opportunity to EPA as well as other Panel 22 members to comment on things that are unclear

### 202-234-4433 Neal R. Gross & Co., Inc. Page 85 1 or they think fail to meet the consensus

2 standard. 3 DR. MURPHY: Thank you. 4 DR. ROBERTS: Joe, I had one 5 question. We also need to suggest to you 6 which items are important enough to put in 7 your two-page letter. Is that right? So when

8 should we do that?

9 CHAIR BRAIN: Yes. I am sort of 10 making a list. Some of them, such as 11 broadening from coronary artery disease to 12 cardiovascular disease, and the importance of 13 Epi. So those will be ones. 14 So I think I have a fairly good 15 sense of that, and again in the draft that you 16 will get in a week, it will include those 17 highlights. But again, if anybody wants -- As 18 we go around, I would very much invite people 19 saying, yes, this is something that needs to 20 be in this highlight portion for the 21 Administrator. That would be very helpful. 22 So check out of your room, if you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 86 1 haven't done that. Grab some coffee, and 2 especially look at the text. Then we will 3 just go through it quickly again. 4 Again, don't do wordsmithing, 5 grammatical problems. Yes, we would like to 6 hear from you, but do it by e-mail. Let's 7 deal with the big macroscopic issues. You 8 know, are there big issues that you have 9 trouble with, either because you disagree or 10 you think they are unclear, or omissions are 11 important as well. 12 (Whereupon, the foregoing matter

13 went off the record at 10:03 a.m. and went 14 back on the record at 10:24 a.m.) 15 MS. BARRY: Let's go ahead and 16 reassemble ourselves, so we can finish with 17 our review of our draft letters. 18 CHAIR BRAIN: So, yes, in the next 19 hour, hour and a half, our task is to make as 20 many improvements and clarifications as we 21 possibly can in the drafts to the 22 Administrator regarding these two documents.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 87 1 So let's continue, since it is 2 fresh in our mind, with the REA. Hopefully, 3 you have had time to look at parts that were 4 of particular interest to you. 5 So why don't we just sort of work 6 our way through. We have already heard from 7 the lead authors. Let's now make it available

8 to EPA staff and other members of the Panel. 9 Do you have concerns or questions about what 10 is written? 11 Again, if there are grammatical 12 errors, lack of clarity, if you can send that 13 to the topic leader and to Kyndall by e-mail,

14 that would be best. 15 So Question 1: There is a new 16 version which was distributed, should be at 17 your plate. So not what is there, but the new 18 one in a larger font. Any questions or

19 comments about that? 20 DR. MURPHY: Dr. Brain, are you 21 asking the Panel? 22 CHAIR BRAIN: Yes, as well as the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 88 1 agency. We would love to hear from you as 2 well if you have questions about that. 3 DR. MURPHY: We did have a 4 question on this one, in the middle of the 5 paragraph. I think Dr. Rajan is going to ask. 6 DR. RAJAN: Yes. I just had a 7 clarification question, and it is the sentence 8 starting on Line 9: The epidemiology provides 9 information on -- 10 CHAIR BRAIN: Are you looking at

11 the new one? 12 DR. RAJAN: Yes. It is the 13 sentence: The epidemiology provides 14 information on non-hypoxy irrelevant 15 mechanisms and chronic outcomes that cannot be 16 addressed by relying on CHb levels alone. 17 We just want a clarification 18 specifically on which epidemiological studies 19 you are referring to, as well as the chronic 20 outcomes that cannot be addressed by relying

21 on COHb levels alone. 22 DR. LADEN: Beate, are you still

### 202-234-4433 Neal R. Gross & Co., Inc. Page 89 1 here?

2 DR. RITZ: I am here. 3 DR. LADEN: Because I pulled that 4 sentence from your comment. 5 DR. RITZ: Yes. The non-hypoxy 6 irrelevant mechanisms -- that doesn't belong 7 to the epidemiology. That was actually from 8 the biological background. So that is not the 9 epidemiology. 10 DR. LADEN: Okay. 11 DR. RITZ: But the chronic 12 outcomes -- I think we considered the 13 pregnancy outcomes and some of the other 14 health outcomes more chronic than acute. 15 Right?

16 DR. LADEN: Yes.

17 DR. RITZ: So should we use some 18 examples there?

19 DR. RAJAN: Yes. 20 DR. RITZ: I mean, you just have 21 to pull it from the ISA. 22 DR. LADEN: Yes. I mean, I can

### 202-234-4433 Neal R. Gross & Co., Inc. Page 90 1 add some examples in terms of the pregnancy 2 outcomes and also there were some with the 3 hospitalizations, I think, that was more 4 chronic. 5 DR. RITZ: Right.

6 DR. BLANC: And then for the other 7 it would be biological data then?

8 DR. LADEN: Yes. 9 DR. MURPHY: With regard to 10 chronic, it is our understanding that the ISA 11 concluded, I believe -- what is the -- 12 inadequate for chronic or -- I am trying to 13 find the right page -- and suggested for 14 developmental outcomes. 15 DR. LADEN: I think that it was 16 inadequate for the mortality, but not 17 necessarily for the chronic outcomes with 18 disease. 19 DR. MURPHY: Well, page 2-6 under 20 cardiovascular, inadequate to conclude causal 21 between relevant long term exposure and 22 cardiovascular morbidity.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 91 1 DR. BLANC: Yes. I think it will 2 help just by giving examples. I don't think 3 it is referring to cardiovascular -- I think 4 it just needs to be clarified with specific

5 outcomes. 6 DR. MURPHY: To the extent it can 7 draw directly from the ISA, since that is at 8 this point our evidence base, that would be

9 fabulous. 10 DR. LADEN: That is fine. 11 CHAIR BRAIN: So we have clarified 12 that the non-hypoxy irrelevant mechanisms does 13 not apply to the epidemiology. Since those 14 words are there, I am still a little confused 15 as to how the Panel feels about non-hypoxic 16 mechanisms in general. 17 I hear from you that you are 18 fairly enthusiastic about them and that the CO 19 may be pro-inflammatory, but I sense a lack of 20 conviction elsewhere on the Panel. Is this -- 21 is it a position that it is a possibility but 22 not a certainty?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 92 1 Clearly, in human studies -- 2 DR. BLANC: I think the issue is 3 that it is certainly a rapidly emerging area 4 of biological investigation, and I think it is 5 unequivocal at this point that CO can act as 6 a signaling factor. I don't think anybody is 7 arguing that the data are developed to the 8 point where it is going to be the basis of 9 risk modeling. 10 I think the point is, rather, that 11 it is a whole another direction of potentially 12 human health effects which are emerging and 13 which needs to be taken into account as both 14 an area of uncertainty and an area which may 15 explain currently confusing observational 16 associations. 17 CHAIR BRAIN: Is the evidence a 18 little stronger for CO as a signaling molecule 19 than as a pro-inflammatory molecule? They may 20 be related mechanisms. 21 DR. BLANC: Yes. That is true. 22 DR. THOM: That is correct.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 93 1 CHAIR BRAIN: Okay, good. That is 2 helpful. 3 DR. THOM: And just for 4 clarification, have there been epi studies 5 that would look at inflammatory related

6 outcomes? 7 CHAIR BRAIN: Probably not. 8 DR. THOM: Probably not. 9 Everything -- the focus seems to be on 10 cardiovascular disease. 11 DR. BLANC: Well, but of course, 12 there is an issue in terms of what is the role 13 of inflammation in cardiovascular disease. 14 CHAIR BRAIN: Right, but that is 15 becoming more and more convincing. 16 DR. DAHMS: But in terms of 17 relationship to stroke, any of the clotting 18 disorders -- 19 DR. BLANC: But there was data in 20 the ISA exploratory data that had to do with 21 coagulation and, obviously, the data on CVA 22 that have not yet sort of reached -- I guess

### 202-234-4433 Neal R. Gross & Co., Inc. Page 94 1 it was classified as whatever those terms 2 were, suspicious -- you know, interesting but 3 not conclusive. 4 DR. KLEINMAN: Well, I think the 5 Delfino study where they looked at 6 inflammatory biomarkers showed systemic 7 inflammation that could be related to carbon 8 monoxide, but I don't think it is at the level 9 where you can use that biomarker data for dose 10 response. 11 CHAIR BRAIN: And in the epi 12 studies, then the co-pollutant issues become 13 even more important, since PM is known to 14 trigger some pro-inflammatory responses. 15 Okay. That is all very helpful. 16 Anything about number 2? Any concerns, 17 questions? Hearing none, how about Charge 18 Questions 3, and we have an A and a B and a C, 19 and we have already talked about the bottom 20 paragraph of page 1. So we've clarified that. 21 Anything else? 22 Question 4? Since at the bottom

### 202-234-4433 Neal R. Gross & Co., Inc. Page 95 1 of page 2 I see DLCO, was there a consensus 2 and is this in there somewhere about that we 3 haven't thought deeply enough about pulmonary 4 disease as a significant susceptible group? 5 You know, people who have a lower DLCO because 6 of emphysema, because of fibrosis, to what 7 extent do they represent a group that 8 theoretically at least should be more 9 susceptible to decreases in oxygen delivery? 10 Is that something we want to say, and do we 11 say it anywhere? 12 DR. HAZUCHA: I believe we do.

13 CHAIR BRAIN: Do we?

14 DR. HAZUCHA: Yes. We have some 15 sections where the request of expansion of 16 these populations. 17 DR. DAHMS: But again, it was 18 along the lines that the pulmonary disease 19 patients did not reach the level of inclusion. 20 DR. BLANC: You know, one -- I 21 don't know if it is even a point worth making, 22 but to the extent that there is any concern

### 202-234-4433 Neal R. Gross & Co., Inc. Page 96 1 about those with chronic pulmonary diseases 2 being yet another risk group to think about, 3 even if one didn't model, one advantage of 4 expanding the at risk cardiovascular group to 5 be a cardiovascular disease more broadly 6 defined than coronary artery disease is you 7 really are going to capture many of the people 8 who you would be interested in on the basis of 9 chronic pulmonary disease, quite frankly; 10 because there will be so much overlap with 11 significant chronic obstructive pulmonary 12 disease. That is just epidemiologically the

13 case. 14 So it is just a secondary benefit 15 of looking at that more broadly defined, but 16 I don't know if that is worth saying. 17 CHAIR BRAIN: Maybe we can add a 18 -- when we are talking about the expansion 19 from coronary artery disease to cardiovascular 20 disease more generally, we can also then add 21 a sentence or two saying that adjacent to that 22 are people with diminished --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 97 1 DR. BLANC: You know, I can allude 2 to that as a secondary advantage of that 3 expansion. That would be under point 7, I 4 guess. 5 CHAIR BRAIN: And speaking of 6 susceptible populations, I think I have heard 7 the answer to this before, but why do we leave 8 out smokers? Again, when we are talking about 9 different sources of carbon monoxide and how 10 they add or interact, we don't talk about 11 smoking. Right? And why is that?

12 DR. BLANC: We don't know about 13 direct smoking, because if we do -- were 14 indoor air, nonambient sources to be included, 15 then you do capture secondhand smoke exposure.

16 CHAIR BRAIN: But what about the 17 primary smokers who start off with a higher 18 COHb? Does CO have any impact on them?

19 DR. DAHMS: The answer that I was 20 given to this 30 years ago was that they 21 choose to pollute themselves. 22 DR. KAUFMAN: But I think this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 98 1 gets back to the question I was raising 2 yesterday about whether an ambient pollution 3 is just easier to model as an increment over 4 whatever they have, because they don't 5 increase your risk. If you change from having 6 a baseline of 8 percent to having a baseline - 7 - to having 10, isn't that still bad? 8 CHAIR BRAIN: But if you come in 9 with a -- because you are a smoker and you 10 have a COHb of four or five percent, then 10 11 parts per million of CO -- 12 DR. DAHMS: You are going to be 13 exhaling and not -- you are not going to be 14 taking anything up. You are going to be 15 exhaling and not -- 16 DR. HAZUCHA: You will be actually 17 polluting air. 18 DR. DAHMS: Yes, you will be a 19 point source. 20 CHAIR BRAIN: But isn't it 21 important to clarify that, because someone 22 less thoughtful might think that smokers with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 99 1 a higher COHb are -- you know, since they are 2 at still greater risk. I guess the question 3 is why don't we address that? There are all 4 kinds of -- I mean, even obesity and 5 cardiovascular, to some extent, self-induced 6 for some people. 7 DR. DAHMS: Just point them to the 8 physiology in the Appendix, and let them 9 figure it out.

10 CHAIR BRAIN: Is there some EPA 11 tradition or something in the Clean Air Act 12 that we forget about smokers? They do seem 13 conspicuous by their absence. 14 DR. MURPHY: Well, we have -- you 15 know, as was just mentioned a moment ago, in 16 terms of our focus goal of identifying what is 17 needed for an ambient air quality standard, 18 the fact that they are creating their own 19 cloud, if you will, of higher CO means that 20 they are less impacted by the low ambient 21 concentrations that exist. However, it sounds 22 to me, what you are saying, Dr. Brain, is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 100 1 perhaps that is a useful point of 2 clarification for a reader. 3 We did in previous air quality 4 criteria recommend -- for example, in the 2000 5 criteria document, there is a section 6 describing essentially what we just discussed, 7 that smokers will have higher COHb levels, 8 that as with anyone, depending on their 9 previous exposure, that will affect whether or 10 not they are impacted by their next exposure, 11 if you will. If their previous one was quite 12 high and their subsequent is quite low, they 13 may be off-gassing and they are not affected 14 by a lower. 15 There is some discussion of that 16 in the previous AQCD which we could bring in. 17 I think there is little discussion in the 18 current ISA, but they had limited time and 19 focused more on the newer studies. But for 20 point of clarification as a backdrop, you 21 know, just like we make a point about there 22 being a variety of non-ambient sources,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 101 1 perhaps that could be brought into Chapter 2

2 of the REA. 3 CHAIR BRAIN: So is this something 4 that we would like to have in our letter as a 5 consensus view or should I just put it in my 6 own comments? What is the consensus? 7 I think no one is saying do a risk 8 analysis. We are just talking about a 9 paragraph that would explain why we are not 10 doing much with smokers, because they don't 11 represent a susceptible population, at least. 12 DR. KLEINMAN: I think it is 13 reasonable to request that a paragraph be

14 added. 15 CHAIR BRAIN: Okay. So I will 16 write such a paragraph and put that in the 17 consensus document. Thank you. 18 Okay. So anything else on pages 1 19 or 2? Anything else about Question 4? 20 How about Question 5 about the 21 modeling? 22 DR. KLEINMAN: In Question 5,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 102 1 lines 29 to 32 asking for the -- you know, 2 they say it would be more convincing if there 3 were validation. I think that is true, but 4 can we recommend any specific studies where -- 5 you know, that EPA could use to validate? I 6 can't think of any, but -- 7 DR. BLANC: I think that that is 8 why I wrote that, although in an ideal world - 9 - or my implication was in the ideal world, 10 one might want validation, because that was 11 Dr. Dahms' point, that we heard previously 12 that it is not -- there isn't a scenario by 13 which there would be, but on the other hand, 14 the previous models that they have used 15 weren't validated either, and this, for other 16 reasons, is viewed as a technical improvement 17 in the modeling from a modeling point of view, 18 and so, therefore, is still advantageous. 19 It has whatever limitations 20 previous models have. So I don't think that 21 there is anything we can recommend, because if 22 I understood the response, there is no way it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 103 1 could be done. So -- Is that correct? 2 DR. MURPHY: You were talking 3 about validating the population endogenous 4 COHb estimates?

5 CHAIR BRAIN: The CFK model. 6 DR. MURPHY: I'm sorry. 7 DR. BLANC: It is the CFK with the 8 CHAD and the APEX, and you know, I guess it 9 would be a situation where you would go out 10 and actually measure carboxyhemoglobin levels 11 and see how well the model had actually 12 predicted what you saw, and it would be people 13 that you had activity diaries and location 14 diaries. 15 I don't think it is a conceptually 16 feasible thing that one could do, and that is 17 what you said yesterday, if I understood. So 18 all I am doing is saying, okay, if this was 19 the ideal world, one would do that, but we 20 know you can't, but the model still has 21 advantages over previous models, is what you 22 said. Right?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 104 1 CHAIR BRAIN: Can you kind of 2 clarify that in what you have here? I mean, 3 it is a little opaque, the last line: This 4 approach is argued or relative to earlier -- 5 DR. BLANC: Just argue that that 6 is advantageous relative to earlier -- it has 7 to be better written. 8 CHAIR BRAIN: So maybe you can 9 rewrite that. 10 DR. BLANC: No, I will.

11 DR. HAZUCHA: There are some 12 validation 20-25 years ago by Stewart and 13 Longa when they did measure directly blood 14 COHb level and compare it to CFK estimates, 15 but those are only a couple of studies, as I 16 said, 25 years ago. 17 So there are no new studies, but I 18 believe that currently by simply using over 19 the decades CFK it was another validation 20 which sort of supposed that it is a good 21 model. There were other studies. They were 22 CFK and arterial blood to measure COHb level

### 202-234-4433 Neal R. Gross & Co., Inc. Page 105 1 and compared it to CFK estimates. 2 CHAIR BRAIN: Okay, number 6, 3 which really deals with the carboxyhemoglobin 4 estimates, which is very important. I guess 5 at the end of 6 there is some specific items, 6 and I guess the question is should some of 7 these be swept into individual comments. 8 I am talking about the top of page 9 5, or are some of them fundamental enough that 10 they need to be in this answer to the charge 11 question.

12 DR. BLANC: Those were -- I don't 13 think any of them were major. They are from 14 Milan, and I wanted to retain them here, 15 because I wasn't keeping parallel sets of 16 notes, but I can certainly make it an

17 addendum. 18 CHAIR BRAIN: Yes, I think so. 19 DR. BLANC: But you should look 20 and tell me if there is anything from the six 21 things that you think rises to the level that 22 it should be in the main response.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 106 1 DR. PENN: For lines 5 through 9, 2 in light of -- 3 CHAIR BRAIN: You are back on page

4 4? 5 DR. PENN: Page 6. 6 CHAIR BRAIN: Oh, page 6. Page 7 six? 8 DR. PENN: Well, aren't we talking

9 about number 6? 10 CHAIR BRAIN: Yes, we are talking 11 about number 6, which is on pages 3 to five. 12 DR. BLANC: So you are talking 13 about the individual items on page 5 related 14 to point 6? 15 DR. PENN: Yes, I am talking about 16 question number 6 that are on page 6, 17 actually. But if I jumped ahead, go ahead

18 then. 19 DR. BLANC: No, because page 6 is 20 a response to number 7. 21 CHAIR BRAIN: Maybe item 6 is 22 something that could be left in. Do you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 107 1 think, Paul -- I mean Item 6 of the list of 2 six at the top of page 5 could remain? 3 DR. BLANC: I would ask Milan. 4 DR. HAZUCHA: Oh, okay. Well, I 5 don't think, really, we need to have it here. 6 Those are just corrections of definitions and 7 so on, and it can be under individual 8 comments, left under individual comments. I 9 am sure that they won't be ignored by EPA, and 10 they will look at it and say, okay, it is not 11 the CO2, but it is -- 12 CHAIR BRAIN: Right. Exactly. 13 DR. BLANC: Does that also apply 14 to point 6? 15 CHAIR BRAIN: Point 6 seems a 16 little more -- 17 DR. BLANC: Joe's question related 18 to point number 6, which is a little bit more 19 detailed. Is that something you want moved to 20 the end of -- retained in the body of the 21 response? 22 DR. HAZUCHA: Oh, I see. Well,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 108 1 no. It can be under individual comments. It 2 can easily be under individual comments. 3 CHAIR BRAIN: Okay. So we will 4 seep those into Milan's individual comments. 5 Anything else about this section?

6 DR. KAUFMAN: I wrote an 7 additional paragraph that I sent to Paul. Do 8 you want me to just read it to you or how 9 would you like to address that? 10 CHAIR BRAIN: Sure. Why don't you 11 either read it or summarize it. Read it, if 12 it is not too long, please. 13 DR. KAUFMAN: It is not too long. 14 I just wrote: In an improvement over the REA 15 draft -- rather, of the PA draft itself, the 16 staff's presentation at the meeting included 17 additional analysis of the contribution of 18 ambient CO to the COHb percent levels. 19 While it was apparently 20 computationally intensive to develop, some 21 Panel members felt that this could be an 22 extremely useful avenue to further develop as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 109 1 an underpinning of the Policy Analysis. 2 Indeed, the a priori focus of the influential 3 Allred paper was on the specified increase in 4 COHb over the subject's pre-exposure or 5 filtered air exposure, not on the magnitude of 6 the COHb percent. It may well be that the 7 ambient attributable increment in COHb is the 8 most directly analogous dose for consideration 9 in assessment of risk. 10 Some Panel members considered that 11 more attention to this ambient attributable 12 increment metric in consideration of dose 13 would simplify the assessment of risk as the 14 issue of, quote, overlap with the endogenous 15 range final COHb percent would be eliminated. 16 DR. BLANC: Joel, I think that 17 actually goes beyond the view of most of the 18 panel, and I would -- I am happy to dialogue 19 with you by e-mail so that we can come to 20 wording that would be, I think, less strong or 21 would otherwise say, although this was one 22 view, we could put in the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 110 1 DR. KAUFMAN: Well, so I actually 2 think that what you said previously goes 3 beyond what most Panel members' view. 4 DR. BLANC: Well, good. That is 5 why we should have a dialogue. 6 DR. KAUFMAN: That is right. So I 7 actually think that having something that said 8 some Panel members felt this and some Panel 9 members felt that may be the appropriate way 10 to word this. 11 DR. BLANC: Well, fine. 12 CHAIR BRAIN: Okay. So we will 13 leave that to the two of you to -- 14 DR. KAUFMAN Well, maybe we should 15 have a little open discussion right now to see 16 where people on the Panel are feeling about 17 this, because Paul feels pretty strongly about 18 the multi-compartment. 19 CHAIR BRAIN: Can you give us a 20 kind of a summary of the issue? 21 DR. BLANC: I think the issue -- 22 the issue is, as I understand it, how

### 202-234-4433 Neal R. Gross & Co., Inc. Page 111 1 important is it to have an estimate of 2 ultimate levels in the human population as 3 achieved by the combined combination of 4 endogenous exposure, ambient air exposure, and 5 indoor air exposure that is not derived from 6 ambient air exposure; and is there a way to 7 present that so that simultaneously the 8 summary value is provided as well as the 9 incremental value provided, so that the 10 implications of both the incremental and the 11 combined can be interpreted? 12 I think Joel's view is that it is 13 the incremental effect, which is the 14 biologically and epidemiologically important-- 15 DR. KAUFMAN: Well, I don't think 16 biologically or epidemiologically important. 17 I think it is the increment that is ultimately 18 the crux of what needs to be done for the risk 19 assessment. That is what is going to make 20 this process work from a policy perspective. 21 DR. BLANC: And my view is that

22 one needs to look at both the total as well as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 112 1 in the increment. 2 CHAIR BRAIN: The discussion of 3 smokers was interesting, isn't it, because 4 there these levels of CO are unimportant, 5 because there is not an increment. 6 DR. BLANC: So I guess what I -- 7 the part of Joel's reason I take exception to 8 is not that -- I am not arguing that one 9 should not look at the increment. I would 10 just argue that one shouldn't look at the 11 increment only. 12 CHAIR BRAIN: So maybe we can 13 emphasize the value of each. Kyndall also 14 reminds -- 15 DR. KAUFMAN: But I think that the 16 EPA approach that they presented in their 17 slide yesterday to looking at the increment 18 models everything into account. So they have 19 modeled the increment that actually takes into 20 account the various contributions. 21 CHAIR BRAIN: Why don't we leave 22 it to the two of you to come up with language

### 202-234-4433 Neal R. Gross & Co., Inc. Page 113 1 that you like, and again Kyndall reminds us 2 that we don't need to achieve consensus on 3 every topic. So if there are somewhat 4 divergent views or two alternatives, both of 5 which should be considered, that is fine to 6 include that. 7 It sounds like it just may not be 8 either/or. It sounds like both ways of 9 looking at it, both in absolute terms and 10 incremental terms -- they both have some

11 value. Is that -- 12 DR. BLANC: That would be my view, 13 but I don't think it is Joel's view. 14 CHAIR BRAIN: Do you want to 15 comment, Joel? I mean, are you arguing that 16 we should only address the incremental without 17 acknowledging the absolute? 18 DR. KAUFMAN: Well, I think the 19 absolute is of interest, but I think, from a 20 policy analysis -- I mean, I would appreciate 21 the perspective of the people who actually 22 practice risk assessment. Maybe that is EPA

### 202-234-4433 Neal R. Gross & Co., Inc. Page 114 1 staff, and maybe there is somebody on this 2 committee who is a risk assessment/risk 3 analysis practitioner. 4 You know, one is going to more 5 greatly inform the risk assessment. 6 CHAIR BRAIN: Would the agency 7 like to comment on this topic? 8 DR. MURPHY: Well, we created the 9 presentation we did, and actually, in the 10 document we also present the information -- 11 most of the information that was shown in 12 different form in our slides. It is in the 13 document, and we did that because we find that 14 to be a take-home message of the Allred study. 15 It has to do with the subjects 16 came in. They were given different exposures 17 to CO to achieve different increases in COHb, 18 and then in writing up the results there are 19 conclusions drawn with regard to relationships 20 between increases in COHb and various measures 21 of myocardial ischemia. 22 So in paying close attention to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 115 1 that study, both the papers themselves and the 2 discussion in the ISA, we did include that 3 section of the REA where we tried to see what 4 we could get the model to do for us in telling 5 us about the ambient contribution, because 6 that does seem to be informative. 7 In the end, what we are trying to 8 do is set air quality standards that protect 9 against ambient CO causing health effects in 10 the public. So I don't know if that is 11 useful, but so from a risk assessment 12 perspective that is certainly something we 13 often do, because our policy objective has to 14 do with the ambient piece of things. 15 DR. HAZUCHA: Well, currently both 16 absolute and increment values are important. 17 DR. BLANC: And I think, Dr. Penn, 18 you made some comments, having been familiar 19 with the study, about the dose response 20 element in it as opposed to the pure 21 incremental element. I don't know if you want 22 to reiterate some of those.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 116 1 DR. PENN: More than what I put 2 into my actual comments? 3 DR. BLANC: Well, but your 4 comments aren't in this section. So maybe you 5 just want to -- maybe my comments should 6 direct us toward your comments, which are 7 related to the policy document -- right? --

8 not to the -- 9 DR. PENN: Right, related to the 10 policy document, and that related back to the

11 ISA. 12 DR. BLANC: Well, one thing, Joe, 13 we didn't do this morning is we actually 14 didn't go back over even once yet the late 15 afternoon presentations of the initial views - 16 - initial responses to the first six charge 17 questions on the policy document. 18 CHAIR BRAIN: We are going to do 19 that next. Right. 20 DR. BLANC: So maybe that will -- 21 CHAIR BRAIN: Okay. I think we 22 have enough guidance to proceed.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 117 1 Continuing down the page, what 2 about -- let's see, we are now up to Charge 3 Question 7 on page 5. Any comments about 4 that? So again, it has some of the themes we 5 have talked about several times, such as the 6 broadening of the at risk population. 7 I suppose in here we could tuck a 8 sentence or two that extends it to pulmonary 9 disease. 10 DR. BLANC: That is where I was 11 going to put the sort of -- 12 CHAIR BRAIN: Right. I think that

13 would make sense. 14 DR. HAZUCHA: This seems to be a 15 good place, yes. 16 CHAIR BRAIN: So any suggestions? 17 Again, we will all have time to quibble about 18 particular sentences or phrases, but the big 19 picture looks familiar and consistent with 20 what we have been saying? 21 DR. DAHMS: Well, is this the 22 point where we need to define for staff what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 118 1 we mean by -- are you asking them to put all 2 heart disease patients into their at risk 3 group? 4 DR. BLANC: I hope that is what I 5 was asking. I thought I was explicit. 6 CHAIR BRAIN: Although I guess -- 7 Tom, you were saying that perhaps we need to 8 distinguish between very likely and little 9 less likely. For example, I think there is a 10 distinction between left heart failure and

11 stroke. 12 DR. BLANC: I mean, as a practical 13 matter, I was simply suggesting that they use 14 the NHIS definition, which is basically heart 15 disease, and there is a subset, which is 16 ischemic heart disease, which is what they 17 currently use, and then there is a column 18 which is all heart disease; and it is separate 19 from hypertension. It is not that, but it is

20 sort of clear. 21 DR. DAHMS: So it is not 22 cardiovascular disease. It is disease related

### 202-234-4433 Neal R. Gross & Co., Inc. Page 119 1 -- so it is the set of ICD-9 codes that relate

2 to the heart. 3 DR. BLANC: Well, it is not done 4 by the ICD-9 code, but it is a question, do 5 you have heart disease. For practical 6 matters, I think it would be the easiest and 7 most straightforward, and it would be sort of 8 an upper end estimate. 9 DR. DAHMS: And do you have any 10 idea to the extent that that increases the 11 numbers in the pool? Does it double the 12 numbers in the pool? 13 DR. BLANC It approximately 14 triples the numbers, I think. Double and a 15 half, maybe, somewhere between. I don't 16 remember. It is 28 percent instead of 11 17 percent or something like that. 18 DR. MURPHY: Right. So just to 19 clarify, if we are talking about frequency, is 20 this from the CDC publication which you are 21 referring to, the 2007 data. This is also in 22 the ISA. There is an excerpt of this table in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 120 1 the ISA. I don't have the page number, but 2 where it lists numbers of people with heart 3 disease all types, and it breaks it out, all 4 types and coronary. 5 So I believe Dr. Blanc is speaking 6 with regard to the all types column, and just 7 an eyeball on the numbers, it looks like that 8 column is approximately twice the coronary 9 column, plus or minus. 10 DR. DAHMS: And is there 11 justification for expanding it to that based 12 on the epidemiology data? 13 DR. BLANC: Yes, because that is 14 closer to the sort of all outcomes, all 15 cardiovascular outcomes, that are used. That 16 would be the closest parallel. 17 CHAIR BRAIN: Are you happy with 18 that or do you think we should make -- 19 DR. DAHMS: No, as long as there 20 is a clear link with the epi data, if that is 21 -- because it has not always been clear to me 22 that I understood how those categories were

### 202-234-4433 Neal R. Gross & Co., Inc. Page 121 1 reached in the epi studies. 2 DR. RITZ: This is Beate. The one 3 study that they are actually citing as the 4 most valid or best study under the current 5 standard is the Tolbert study, and that 6 actually has the category cardiovascular 7 disease. That includes all of the cardiac 8 diseases. So that is the epi study that 9 actually shows a relationship. 10 CHAIR BRAIN: Okay, good. That is 11 helpful. 12 DR. BLANC: And, you know, I 13 provided to them a couple of papers that will 14 allow them to show that the National Interview 15 Survey defined prevalence that they use for 16 coronary disease is supported by other 17 national survey data, the NHANES and the 18 Behavioral Risk, even though they are slightly 19 different estimates, but they are all quite 20 similar. 21 So they have that, that they can 22 cite, but I am not going to put that in my

### 202-234-4433 Neal R. Gross & Co., Inc. Page 122 1 comments with the level of detail. 2 CHAIR BRAIN: Do you want to add a 3 sentence that says that would be -- 4 DR. BLANC: Maybe that is in 5 there, and I just forgot I put it in. Okay. 6 CHAIR BRAIN: Do you want to add a 7 sentence that would say that that represents 8 sort of an upper bound risk -- upper bound 9 estimate for cardiovascular risk, but that the 10 role of CO may be more important for some 11 conditions like ventricular failure and less 12 important for pulmonary embolism or stroke or 13 something? 14 DR. BLANC: Well, pulmonary 15 embolism is not in there, and stroke is not. 16 I man, that is not subsumed in that anyway. 17 CHAIR BRAIN: Oh, good. Thank 18 you. 19 All right, the last Charge 20 Question, Number 8. Any questions about that? 21 Okay, good. 22 So the next step, to repeat

### 202-234-4433 Neal R. Gross & Co., Inc. Page 123 1 myself, is then to ask all the lead authors to 2 taken into account what they have heard and 3 their own ideas, and by the end of this week, 4 if you can send to Kyndall your updated best 5 versions.

6 Let us now turn to the other 7 document that you got, which is the Policy 8 Assessment document, the PA, and have a look

9 at that. 10 Shall we do the same thing? I 11 suppose we could zip through it twice. We 12 could first -- maybe why don't we do it one at 13 a time, but why don't we begin -- rather than 14 going through it twice, why don't we -- for 15 example, with number 1, let us first hear from

16 the lead author as to whether there are 17 unresolved issues that they need help with, 18 and then we can open it up. 19 So let's look at Charge Question 20 1. So this is Arthur. You are happy?

21 DR. PENN: I have no unresolved 22 issues. The only question is, on the second

### 202-234-4433 Neal R. Gross & Co., Inc. Page 124 1 paragraph where we specifically talk about the 2 four NAAQS basic elements, whether that 3 belongs in here or whether it belongs

4 somewhere else. 5 I incorporated what Stephen had 6 yesterday about indicators, and a couple of 7 other points that people made, but these are 8 really specific comments. Do they belong

9 here? 10 CHAIR BRAIN: Anybody want to 11 respond to that? They sound fairly specific, 12 perhaps too specific. Is there any kind of 13 overarching theme? 14 DR. PENN: Yes. I think that the 15 definitions that are given that are supposedly 16 key to all of this stuff are lousy. 17 CHAIR BRAIN: So maybe you just 18 want to say that, and sweep some of the 19 specific comments into your individual. Does

20 that make sense? 21 DR. KLEINMAN: Would it be helpful 22 to just request a table of abbreviations and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 125 1 definitions as part of the document. That 2 way, you kind of cover it. It may be in the 3 ISA somewhere, I think. 4 CHAIR BRAIN: And it would be nice 5 if you did make a general comment to give a 6 couple of examples. 7 DR. PENN: Okay, sure.

8 CHAIR BRAIN: And then the 9 complete list of problems could be swept into 10 your own comments. Anything else about Number

11 One? 12 Okay, then we move to Tom who will 13 tell us about Charge Questions 2 and 3. So 14 what about 2-A and B. Tom, we will start with 15 you. 16 DR. DAHMS: I think there is no -- 17 I don't see any unresolved issues. I don't

18 know. Most of these other comments came from 19 Milan, other than my stuff. 20 DR. HAZUCHA: Well, on the bottom 21 of the page 1, the document has the 22 epidemiologic studies, but my question is just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 126 1 a part from the previous discussion. Can they 2 -- do you think that they can present it

3 better? 4 DR. DAHMS: Well, I think that has 5 been the tenor of the whole discussion that we 6 seem to have had over the last day and a half, 7 is that -- I don't know whether we are asking 8 them to present it better, to change their 9 analysis and opinion of the epi studies based 10 on the feelings of this Panel, based on the 11 epi studies. I don't know which of those 12 things we are asking them to do. 13 We are certainly asking them to 14 put far more weight on the epi studies than 15 appears to have been put on them. Francine? 16 DR. LADEN: I just have one 17 comment. I went back and re-read parts of 18 this last night, and I really -- in reading it 19 more carefully, I felt that the epi studies 20 were actually pretty well talked about. 21 I think where I would -- in my 22 opinion, kind of where there is something

### 202-234-4433 Neal R. Gross & Co., Inc. Page 127 1 lacking is more just some more clear 2 statements about the context of the risk 3 assessment and the epidemiology studies and 4 how the epi studies can inform for public 5 policy. 6 I think that there actually was 7 some good summaries of the epi data, but I 8 think it was just that next step that was 9 missing. 10 My feeling of what is going on in 11 this committee's discussion is that, you know, 12 it is everybody here who is pretty savvy in 13 epidemiology studies isn't feeling that they 14 are given enough weight, that there is that 15 next link that needs to be made to help 16 convince people that, even though they can't - 17 - I mean, I actually feel strongly that they 18 can't really be used in the risk assessment -- 19 in the quantitative risk assessment, as you 20 have done, you know, just -- I agree with the 21 decisions that were made, but I think that 22 context is what needs to be stressed more --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 128 1 defended more, I guess, is the word. 2 CHAIR BRAIN: I guess I heard a 3 contrary view that, in fact, this broader 4 definition of cardiovascular disease could be 5 included in the risk assessment -- 6 DR. LADEN: Well, I think the one 7 way that it --

8 CHAIR BRAIN: -- and the 9 populations could be modeled -- 10 DR. LADEN: -- is doing a second - 11 - like where you have the first analysis of 12 the population at risk, but you can expand 13 that population at risk and do another 14 analysis including that, and I think that is 15 one way that it can be put into the risk 16 assessment, but not in terms of the actual 17 quantitative numbers of what the exposure is. 18 CHAIR BRAIN: Not with different 19 coefficients, right.

20 DR. LADEN: Yes. 21 DR. KLEINMAN: But I think, in 22 order to use or regroup the data, it really

### 202-234-4433 Neal R. Gross & Co., Inc. Page 129 1 requires a reanalysis of what is actually 2 published, since the authors of the 3 publication broke out the groups and did not 4 collectivize them. 5 So I think, yes, we can recommend 6 that EPA look at additional analyses of those

7 data. 8 DR. LADEN: I liked your idea of 9 the meta analysis. The question is, is that 10 really part of the charge? I'm not sure. 11 DR. BLANC: I think that, when we 12 dealt with the ISA, there were -- we 13 definitely -- Beate could probably reaffirm 14 this -- that we talked about the advantages of 15 meta analysis of the epidemiologic data. I 16 don't think it actually happened, but I think 17 that the part of the interpretative issues 18 with the epidemiology in the Policy Assessment 19 document is not that they don't acknowledge or 20 present epidemiologic data, but everything is 21 geared toward discounting it. 22 I am just saying what you said in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 130 1 a different way. The comments that I made 2 earlier about the key table which attempts to 3 undermine the epidemiologic data is not 4 convincing to me and, I think, misses the boat 5 and is used as a kind of sledge hammer, 6 inappropriately, to say let's ignore the 7 epidemiologic data, this issue about what were 8 the exposure levels in those areas. 9 For example, discounting one study 10 where the confidence interval lower limit was 11 .9999 -- that is one thing, but also 12 discounting studies which may have had some 13 excursions but where all the excursions were 14 very unlikely to be driving the observation. 15 DR. LADEN: And if you looked at 16 the ranges of the -- the interquartile ranges 17 and not the 99th percentile ranges, it is -- 18 I mean, I think there could be more weight 19 given to the fact that those studies do have 20 predominantly exposures within the range that 21 we are interested in. 22 DR. DAHMS: So, essentially, what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 131 1 we are asking staff to do is to kind of really 2 back off of the strident approach of using the 3 dose of CO as the marker, and saying that 4 there are other unknown considerations to be 5 used; or do we say that the dose of CO at very 6 low levels with the epi -- that the epi 7 studies would result in -- this is just a 8 lower end of the continuum? 9 DR. BLANC: I think what we are 10 saying is just a bit more general, that they 11 need to recalibrate their assessment of the 12 epidemiologic literature to be more in line, 13 I think, with the ISA's weighting of the 14 epidemiologic literature. 15 I think that there is some 16 confusion in the policy document between the 17 technical requirements of risk assessment that 18 require them to use the controlled human 19 exposure data in one particular way, which I 20 don't think anybody here told them not to do 21 or to back away from, and that has somehow 22 become muddied or muddled with what the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 132 1 epidemiologic literature -- the very important 2 information that the epidemiologic literature 3 is providing.

4 So that there was almost a sense 5 of sidestepping the epidemiologic literature 6 in the policy document. 7 CHAIR BRAIN: It is a nuanced 8 message. 9 DR. BLANC: So I think -- in terms 10 of nuance, I think that the wording -- it is 11 not that they didn't describe the 12 epidemiologic literature. It is not a 13 question of describing it. It is a question 14 of, as you said, interpretation. 15 CHAIR BRAIN: And how prominent it 16 is, the relative balance between those two. 17 Okay, that sounds like we have 18 some guidance there. How about Charge 19 Question 3? 20 DR. MURPHY: Dr. Brain, could we 21 make a comment on this point? 22 CHAIR BRAIN: I'm sorry?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 133 1 DR. MURPHY: Could we make a 2 comment on this point? 3 CHAIR BRAIN: Oh, please, please.

4 Yes. 5 DR. MURPHY: And it comes, I 6 believe, at page 5 and 6, one of the other 7 Charge Question comments that is in this

8 draft. 9 Perhaps it would be useful to talk 10 a minute about there were a couple of things 11 that were discussed here, and just for 12 clarification it might be useful to talk about

13 them. 14 So we certainly feel like we are 15 interpreting and giving full weight to the epi 16 studies, consistent with the ISA, in this 17 Policy Assessment and, as we talked about 18 yesterday, one thing they clearly provide is 19 this coherence with the clinical studies in 20 terms of the endpoints where we see these 21 statistically significant and the strong 22 associations.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 134 1 In terms of understanding the way 2 we have looked at things in the Policy 3 Assessment, we need to go beyond is CO causing 4 effects, and do we need a standard, to a 5 question of what should the standard be, and 6 is the current standard adequate. 7 As was mentioned previously, in 8 these epi studies -- there are two things I 9 want to speak to. In these epi studies we're 10 not measuring COHb. They are not measurements 11 of COHb. They are not measurements of total 12 personal exposure. What is done is 13 relationships between ambient concentrations

14 and outcomes. 15 So in terms of we have struggled 16 with trying to integrate the body of evidence 17 that we have that links CO to hypoxia and COHb 18 levels to measures of ischemia in the clinical 19 studies, and in the beginning of Section 20 2.2.1, I believe, through the first question, 21 goes through pages 214 to 216, and we even 22 have a figure talking about here are the two

### 202-234-4433 Neal R. Gross & Co., Inc. Page 135 1 pieces of evidence -- two types of evidence we 2 have, the clinical and the epi, and we need to 3 see how they fit together. 4 When we are lacking this internal 5 dose metric, it makes it a little more 6 difficult. So we are cognizant of the fact

7 that we don't know what the COHb levels of the 8 subjects -- or you wouldn't say subjects -- of 9 the people in the epidemiological studies, and 10 we don't know what their total exposures are. 11 So that is a handicap for us in looking at 12 that, and your views on that would be useful. 13 The other thing, though, I want to 14 mention is that we begin to do in this part of 15 the Policy Assessment with Table 2.1 and then 16 do more of in response to a latter question 17 with regard to levels where we have Tables 2.3 18 and 2.4, is say what can the epi studies tell 19 us with regard to levels of the standard. 20 Some of the interpretations of 21 this go to the issue of the form of the 22 standard. I know the Panel has reiterated

### 202-234-4433 Neal R. Gross & Co., Inc. Page 136 1 that, well, the mode, if you will -- the 2 prevalent concentrations in these epi studies 3 are quite low, but we currently do not have a 4 standard that is of the form, an annual 5 average or a multi-year average, which if you 6 were comparing to these studies, the average 7 or the median seems to be 1 to 2 ppm, 3 ppm.

8 The current form of the standard 9 is this not to be exceeded. So looking at any 10 distribution of air quality, the upper tail of 11 that distribution will be higher. When we set 12 the standard with a form of not to be 13 exceeded, we recognize that that will bring 14 the distribution of air quality down. 15 So that is why, when we are 16 thinking of the question of level of the 17 standard, it is important to think about what 18 form are we talking about for which we want to 19 identify the level of the standard. 20 So that is why, in this table, we 21 not only have, in Table 2.1 I am now talking 22 about, the bulk of the table is just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 137 1 reiterating descriptive information about the 2 standards, which is in the ISA, the far right 3 most columns provide what we call design 4 values, which is the statistic for the air 5 quality in those areas that would be compared

6 to the standard. 7 So that allows us to say during 8 these studies were these areas in attainment 9 or would there be controls being put in place 10 through different implementation plans, for 11 example, which is what the standard is 12 intended to achieve. 13 When we do that, we end up saying, 14 well, while all of these studies are hugely 15 useful to us in drawing connections between CO 16 and health effects, when we get to this other 17 issue of choosing a level for the standard, we 18 need to think in terms of all the elements of 19 the standard, one of them -- and think in 20 terms of form that goes with the level, and 21 the current form is second max, which is what 22 is shown in this table.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 138 1 So then, clearly, we are not 2 suggesting that the -- I mean, we can't take 3 apart these studies and get more out of them 4 than what is in them. So we don't know what 5 people's exposures were. We don't know what 6 people's COHb levels were. So we don't know, 7 you know, in terms of the people that went to 8 the hospital, but we can say whether or not 9 they were in areas where the standard was 10 exceeded, which is informative to us in terms 11 of our objective in identifying ambient 12 concentrations of CO, which we need to protect 13 against. 14 So maybe I am rambling a bit, but 15 I am just hopeful that you all have tried to 16 get at what we were trying to convey, and can 17 give us advice on what we were trying to 18 convey. If we did it not well, at least you

19 can tell us that. 20 DR. PENN: Could I make just a 21 comment on this? I appreciate the fact that 22 you guys do recognize -- you realize -- You

### 202-234-4433 Neal R. Gross & Co., Inc. Page 139 1 are making a good balance here, and you 2 recognize our concerns, and you have told us 3 your concerns. But part of the stuff that 4 Paul pointed out yesterday is the way this 5 stuff reads, and the Policy Assessment is 6 really apparently a major document that is 7 going to come out of this. 8 So you have all of the ISA, and 9 that is the Scientific Assessment, and all of 10 these data that we talked about for the epi 11 stuff is in there; and the focus -- the way it 12 reads is that the focus now is away from that, 13 and this is the point that Paul brought up 14 yesterday, and I think it just reads -- to an 15 objective reader, it reads that there is this 16 bias that is underlying all of this. 17 So maybe my suggestion that there 18 be a meta analysis of the epi data would 19 really be worthwhile here. 20 CHAIR BRAIN: I think we need to - 21 - this has all been very helpful, and I think 22 we can take this into account. I guess the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 140 1 only quick comment that I would make is it 2 seems to me you are holding carbon monoxide to 3 a standard that is higher than what we have 4 used for other criteria pollutants. 5 You are saying, you know, we don't 6 have -- for the epi, we don't have COHb, we 7 don't have an internal dose metric. I mean, 8 that is true, but we don't have that for PM2.5 9 or NOx or SOx either. 10 The existence of COHb is a really 11 pleasant, convenient biomarker, but in 12 general, for all kinds of environmental 13 threats, maybe with the exception of lead or 14 something like that, you know, we don't have 15 biomarkers for air pollution studies. 16 I think now we need -- we only 17 have about a half an hour left. So I think 18 everyone feels they have gotten good input 19 from the agency and from people around the 20 table. Tom, anything else that we need to say 21 about Questions 2 or 3?

22 DR. DAHMS: No.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 141 1 CHAIR BRAIN: We all set? 2 DR. HAZUCHA: Charge Question 3, 3 if I may have a comment here -- it will be 4 very, very difficult, not only for EPA but 5 certainly, even for us to link subsidiary 6 mechanisms to standards. 7 Now here oxygen in these studies - 8 - Yes, there are studies, but it is very 9 difficult yet to have enough information to 10 link it to exogenous levels of CO, and then 11 the statement that endogenous levels of CO 12 that could be altered by exogenous exposure -- 13 again, I am not sure that there is any 14 evidence that you can do that, that you can 15 simply change by exogenous exposure -- change 16 endogenous levels. 17 There are studies, for example, on 18 effects of carbon monoxide on brain, and you 19 have clearly vasodilation. Yet heme 20 oxygenase, for example, in brain wasn't 21 affected at all, although clearly, you had 22 local effects by vasodilation.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 142 1 So there is still, I guess -- this 2 evidence is still emerging, and I am not sure 3 whether we are in a position to say too much 4 about it. 5 CHAIR BRAIN: Is there agreement 6 with that? 7 DR. DAHMS: Well, what I wanted 8 was some acknowledgment that -- you know, 9 there is no acknowledgment that I can see -- 10 and Steve may be more sensitive to this, but 11 I didn't see it and, Milan, that sentence -- 12 there are some grammatical mistakes in there - 13 - that regional increases in endogenous levels 14 of CO or COHb that could be altered by 15 exogenous exposure. 16 CHAIR BRAIN: I guess I am a 17 little concerned about lumping -- you know, 18 you are mentioning two areas, the 19 epidemiologic studies and the heme oxygenase 20 studies. To me, I think those are quite 21 different. The epi has greater -- 22 DR. DAHMS: Well, yes, I am still

### 202-234-4433 Neal R. Gross & Co., Inc. Page 143 1 scratching to try and find some mechanism for 2 the -- you know, there is no postulated 3 mechanistic point. Maybe there doesn't need 4 to be one. If there doesn't need to be one, 5 then let's just strike it and go on. 6 CHAIR BRAIN: I don't understand, 7 because don't we have reduced oxygen delivery 8 as a common mechanism for the epi studies of 9 other cardiovascular conditions? 10 DR. DAHMS: No, we talked about 11 the internal dose metric, and how do you 12 postulate some kind of an internal dose metric 13 that is consistent between the controlled 14 human exposure data and the epi data? How do 15 you get there? Is there -- 16 CHAIR BRAIN: That is a luxury we 17 don't have with any other criteria pollutants. 18 DR. DAHMS: Okay. Then let's not 19 worry about it, delete this, and go on. 20 CHAIR BRAIN: No, no. I guess I 21 just have a problem with sort of making epi 22 studies and heme oxygenase studies sort of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 144 1 sounding as if they were of equivalent 2 importance in the validity. 3 DR. DAHMS; No, no. That was not 4 the intent. 5 CHAIR BRAIN: So I think that is 6 one thing that I would suggest clarifying.

7 DR. DAHMS: Sure. 8 CHAIR BRAIN: I think the heme 9 oxygenase area is interesting, but very 10 contradictory, and it is unclear. 11 DR. DAHMS: I was thinking in 12 mechanistic terms and not -- 13 CHAIR BRAIN: Well, then somewhere

14 we need to be clear about are there non15 hypoxia mechanisms such as signaling or heme 16 oxygenase or -- but that is sort of at a 17 different level. 18 Other comments about Question 3? 19 Then that gets us to Question 4. Joel, are 20 there things you -- any concerns that you have 21 in terms of Question 4 where you need advice 22 or you sense lack of consensus?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 145 1 DR. KAUFMAN: I tried to bound 2 what I thought were some contrasting opinions 3 that were both in written comments and that I 4 heard during the discussion yesterday. I 5 guess I would appreciate people reading it 6 through and advising me if I haven't reflected 7 the Panel's opinion as well as I should have. 8 I also have the specific comments 9 at the end. I guess earlier in one of the 10 Charge Questions, we decided that maybe they 11 don't -- minor things like this don't belong, 12 but I don't know. I will defer to your 13 judgment on that. 14 DR. BLANC: Joel, those are the

15 bullets at the end?

16 DR. KAUFMAN: Yes. 17 CHAIR BRAIN: Any opinions? Are 18 these broad issues that should be part of the 19 answer to the Charge Question? Are they more 20 specific? 21 DR. DAHMS: I think they should go 22 into the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 146 1 CHAIR BRAIN: They should go what?

2 DR. DAHMS: Come out of here and 3 go into the specific comment. 4 CHAIR BRAIN: Is that a consensus, 5 that they are specific enough they can be put 6 into Joel's specific comments? 7 DR. DAHMS: Well, Joel, take 8 another look at the last bullet, because that 9 seems more general, and maybe you want that -- 10 DR. KAUFMAN: Yes. I think the 11 last one is fairly substantive. Probably 12 could be a stand-alone paragraph up above. 13 CHAIR BRAIN: But not the first 14 two. DR. BLANC: I also think 15 it is excellent that you remind about the 16 discussion of the one percent threshold, 17 because I don't think that appears anywhere 18 else, and it is good not to lose track of

19 that. 20 CHAIR BRAIN: Okay, any other 21 discussion of Question 4? I think it reads 22 well. So that looks good. Thank you. Thank

### 202-234-4433 Neal R. Gross & Co., Inc. Page 147 1 you, Joel. 2 DR. KAUFMAN: All right.

3 CHAIR BRAIN: Let's move on to 4 Charge Question 5, and this brings us back to

5 Tom Dahms. 6 DR. DAHMS: Well, again, there was 7 -- you know, I started adding everything into 8 this, and some of it, obviously, needs to come 9 out and to be put into specific comments. 10 The first -- well, the second 11 paragraph under Exposure Risk Based 12 Considerations. Again, I was still struggling 13 with trying to figure out how to deal with the 14 dose metric with the epi studies, and so this 15 is -- 16 CHAIR BRAIN: Sounds like a 17 combination of some specific suggestions, but 18 then still an overarching concern that -- 19 DR. DAHMS: So maybe we need to 20 edit it out of there. 21 CHAIR BRAIN: Right. Maybe we can 22 divide it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 148 1 DR. DAHMS: And leave the concern. 2 DR. PENN: Well, the next three 3 paragraphs after that were mine. Do you want 4 me to just put that into my own personal 5 comments, on page 5, the first three 6 paragraphs? 7 CHAIR BRAIN: Well, there is sort 8 of the big issue of the Allred studies and how 9 they are to be interpreted and used. 10 DR. PENN: That is more general, 11 but the next two -- well, the next paragraph, 12 certainly, deals with specific stuff. 13 CHAIR BRAIN: Yes. So we will 14 leave that to the two of you to extract some 15 parts while leaving the broad macroscopic 16 judgments there. I mean, I think again the 17 last paragraph is important, the concern about 18 CO as a surrogate. So that sounds like it 19 should stay. 20 Other questions, comments, about 21 the answer to Charge Question 5? 22 DR. PENN: Is there going to be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 149 1 one place where you bring together all the 2 uncertainty issues, because some of them could 3 have fit in Question 2. Some could be in 5. 4 Some could be, I think, in 7. So when you 5 write the letter, are you going to just put it 6 altogether in one place? 7 CHAIR BRAIN: I confess, I didn't 8 have uncertainty as one of my current four or 9 five most important topics, but let's have a 10 look, and maybe -- does it rise to that level? 11 I didn't see it quite at the importance as 12 some of the other concerns and advice that we

13 have. 14 Charge Question 6, Dr. Thom. 15 DR. THOM: Well, Paul and I have 16 spoken, and there is a couple of things that 17 I need to change, specifically regarding Table 18 2.1, just a correction, that it is four 19 studies where the standard was exceeded in the 20 eight-hour 9 parts per million. But 21 basically, the gist remains the same in terms 22 of stronger use -- consideration of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 150 1 epidemiologic data. 2 I have added a sentence from, 3 basically from what Paul had said earlier 4 today, that with regard to the studies in 5 Table 2.1, even those where the standard was 6 exceeded, it is unlikely that the positive 7 association between ambient CO and health 8 effects were related to the brief intervals

9 when the CO levels exceeded the current 10 standards. That is to say, there is still 11 valid information in the epidemiologic data. 12 So that has been changed a little 13 bit. The only other item is basically the 14 last three lines on page 6, 43 to 46, which, 15 I believe, is I don't understand what the 99th 16 percentile standard is. 17 My understanding was that -- from 18 our discussion yesterday, was that that was 19 basically a moving target based upon actual 20 data, but Paul thinks that I've got that 21 wrong. So probably those three lines need to 22 be deleted, but I confess, I don't understand

### 202-234-4433 Neal R. Gross & Co., Inc. Page 151 1 the 99th percentile component of a statistic. 2 DR. BLANC: Do you remember that 3 discussion yesterday, back and forth, and I 4 think what I heard them say, you know, 5 whatever we set the limit to, then one option 6 is to talk about the 99th percentile in that 7 range, but 99th percentile isn't a moving 8 target. So it wouldn't be a standard that 9 would shift every year, depending on what your

10 actual observed levels were. 11 DR. MURPHY: Right. The standard 12 would not shift. Which lines, though, Dr. 13 Thom? I just want to make sure I was 14 following you. Which lines on the page? 15 DR. THOM: The last three lines on 16 page 6. I wrote that based upon what our 17 discussion was yesterday. I had the sense 18 that, if the 99th percentile standard was 19 used, essentially it would drop by near 50 20 percent the acceptable eight-hour -- well, 21 whatever standard you use, it would drop. 22 DR. MURPHY: No, and I am

### 202-234-4433 Neal R. Gross & Co., Inc. Page 152 1 confused. I just want to -- to be able to be 2 clear, it would help me to understand why do 3 you think 50 percent, so I understand where 4 the confusion is? 5 DR. THOM: The ambient levels are 6 now in the range of -- whatever, 5 to 6 parts 7 per million or lower. 8 DR. MURPHY: It depends on your 9 statistic. On average? As a 99th percentile? 10 DR. THOM: So I think with regard 11 to this document, I am going to just delete 12 those three lines. But fundamentally, the 13 issue comes down to I don't understand what 14 the 99th percentile standard means. 15 DR. MURPHY: All right. So it 16 goes to form, and this may -- I am struggling

17 to make sure I follow where the areas of 18 confusion are, and I am wondering if some of 19 the confusion about the tables of epi studies 20 relates to this, because one of the metrics 21 for describing air quality for the epi 22 studies, I believe, is a range of 99th

### 202-234-4433 Neal R. Gross & Co., Inc. Page 153 1 percentile values in one of the columns; but 2 that is simply the 99th percentile value of 3 whatever that number is across the monitors in 4 the study. 5 Now in terms of the form of a 6 standard, we do -- as was mentioned earlier, 7 if we have five monitors in an area and one 8 exceeds the standard in the form of the 9 standard, then that area does not meet the 10 standard, and things happen.

11 So the forms of the standard could

12 be a not to be exceeded value. In the case of 13 lead, that is what it is. You cannot exceed 14 a three-month rolling average of .15 ppm lead 15 in total particles in the air at any of the 16 monitors. That is lead. 17 For CO, we say you can exceed only 18 once at any monitor the standard of 9 ppm. If 19 we were to go to a different form, we 20 mentioned you can have -- and these are -- and 21 that is in terms of an eight-hour average. 22 We have other standards which have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 154 1 annual average standards. Clearly, the 2 averaging time will affect the level, and also 3 the form, the statistical form, will affect

4 the level. 5 So these things together, how we 6 measure the pollutant, what averaging time we 7 think is important for the pollutant in 8 ambient air, and what statistical form would 9 be appropriate to best protect public health 10 with an adequate margin of safety; and that 11 consideration goes a bit beyond just looking 12 at something that might be compared to a 13 simple toxicological study design. 14 It considers -- when we implement 15 a standard, we need to make judgments about an 16 area which trigger different control actions. 17 We don't want to make that lightly. We don't 18 want to decide someplace is out of compliance, 19 trigger some control actions, and the next 20 year have to change our mind and back off and 21 rethink the whole thing. 22 So that is a consideration we call

### 202-234-4433 Neal R. Gross & Co., Inc. Page 155 1 stability, which we want to have -- we want a 2 form to be stable in that way, so that we 3 don't have area coming in and out. So that is 4 why here we have considered a more stable form 5 than a second maximum or a to be exceeded only 6 once a year might be a 99th percentile, 7 because that is not as extreme a value in your

8 dataset. 9 So that when you judge have you 10 met the standard, if your standard is a 99th 11 percentile value at 8.4 or some number -- make 12 a number -- say it is at 8.4, then you look at 13 your dataset, and you will say what is the 14 99th percentile in that dataset for that 15 monitor. Is it above that level? If it is 16 above that level, you have not met the 17 standard. If it is at or below that level, 18 you -- 19 CHAIR BRAIN: I think we need to 20 get back to Charge Question 6. 21 DR. MURPHY: Oh, sorry.

22 CHAIR BRAIN: Are we clear?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 156 1 DR. THOM: I said that I am taking 2 it out. But the point -- I would like to make 3 the one point, though, that what allows -- the 4 99th percentile allows one percent excedences, 5 which would be three days a year instead of 6 one day a year, so at the same level. 7 So the level of the standard is 8 nine. 9 CHAIR BRAIN: Right. 10 DR. THOM; But now if you move to 11 a 99th percentile, then you could have three 12 excedences a year. That would be bad. So my 13 only point is it would drop it. 14 DR. KLEINMAN: So if you go to the 15 more stable form, then probably we would want 16 to suggest a lower standard.

17 DR. THOM; Yes. 18 CHAIR BRAIN: So it is not 19 relevant. You are just going to delete that

20 sentence.

21 DR. THOM: Yes. 22 CHAIR BRAIN: Clearly, the form

### 202-234-4433 Neal R. Gross & Co., Inc. Page 157 1 has profound implications. All right, let's 2 go on to 7, which again we talked about this 3 morning. We've got about 10-15 minutes to 4 finish up here. Mike, I guess you have 5 already talked about this today.

6 DR. KLEINMAN: Yes. 7 CHAIR BRAIN: Is there anything 8 you want us to focus on? 9 DR. KLEINMAN: Well, based on the 10 discussion this morning, I am going to add -- 11 I would like to add a paragraph that says, 12 based on the analysis of the epidemiological 13 studies presented in the PA, there is a 14 consensus in the Panel that the current 15 standards may not adequately protect public 16 health with a reasonable margin of safety and, 17 therefore, revisions that result in reducing 18 the standards should be considered. 19 CHAIR BRAIN: I think that is 20 really important. 21 DR. HAZUCHA: With one abstention.

22 CHAIR BRAIN: Let that be shown.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 158 1 If you even want to add a sentence as to why 2 you abstained, we could include that. 3 DR. HAZUCHA: Because I just feel 4 there isn't enough scientific evidence for 5 changing the standard. 6 CHAIR BRAIN: Fine. Good. 7 Anything else in regard to Charge Question 7? 8 Then Mike also was responsible for number 8. 9 Anything about Charge Question 8?

10 DR. KLEINMAN: Let me see. So 11 just to reiterate -- yes, I made four 12 suggestions, recommendations for additional 13 considerations. 14 The first one I made was the 15 question about how many locations might go out 16 of compliance, and in retrospect I don't think 17 that is appropriate for this letter. So I am 18 going to delete that. 19 CHAIR BRAIN: Okay. 20 DR. KLEINMAN: Any other guidance

21 for me on what else we should do? 22 DR. BLANC: I don't think,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 159 1 actually, you need it here to reiterate what 2 they said about what the range of policy 3 options are, necessarily. 4 CHAIR BRAIN: Unless you want to

5 comment on -- 6 DR. BLANC: Well, for CASAC? 7 DR. KLEINMAN: Maybe what I will 8 do is I will just put in a sentence relating 9 the level and form, saying that if the 10 recommendation is to go to a different form,

11 then the level of the standard should be 12 appropriately modified so that we don't lose 13 protection. 14 CHAIR BRAIN: Well, I think some 15 sense of the excellent lesson that you gave us 16 on the importance of the form and how that 17 really affects how many excedences there are 18 and how stringent the standard really is 19 depends not just on the level but very much on 20 the form -- so I think -- because you said to 21 educate CASAC and give CASAC a chance to 22 comment on that, if they wish, is a good idea.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 160 1 DR. KLEINMAN: Okay. 2 CHAIR BRAIN: I'm sorry, what? So 3 we don't have before us 9, 10 and 11, but we 4 talked about that. Paul, is there anything 5 else you want to bring to our attention?

6 DR. ROBERTS: I don't even need 7 anything else. I have a version. I thought 8 I sent it to you last night, but I don't know 9 what happened to it. So it's fine. I can 10 make sure Kyndall gets it. 11 CHAIR BRAIN: Okay. You have his 12 version? 13 DR. ROBERTS: I had a couple of 14 minor additions. 15 CHAIR BRAIN: Okay. So I guess an 16 additional question is: Are there items on 17 the Policy Assessment -- in addition to the 18 answers to the Charge Questions, we have 19 already mentioned a couple of topics that we 20 want to include, but again are there any other 21 themes or comments that don't tuck into the 22 answers to the Charge Questions?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 161 1 DR. PENN: How does staff look at 2 our individual comments versus these summary

3 comments? 4 CHAIR BRAIN: Can you respond? 5 DR. MURPHY: Certainly, certainly. 6 They are quite helpful to us, clearly. So we 7 certainly read them. We consider them. it is 8 useful. Often, they will note things that 9 haven't come up at the meeting, and it is 10 something for us to think about. So we 11 certainly pay attention. 12 CHAIR BRAIN: Yes, it is 13 interesting, because the individual comments 14 are really of two types. Some are 15 wordsmithing and requests for clarity that 16 everybody would endorse, and so they really 17 are consensus view. But then there are also 18 some that are perhaps more idiosyncratic or 19 forward looking that are kind of inappropriate 20 for a consensus report, but I guess we kind of 21 leave it up to you to sort out those two 22 flavors. There may be more.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 162 1 DR. KLEINMAN: Joe, I would like 2 to recommend that we put a sentence in the 3 letter complimenting EPA staff on this first 4 draft of the Policy document as being very 5 well put together, very cogent, and very 6 comprehensive. 7 CHAIR BRAIN: I will include that 8 in my letter. Any other sort of overall

9 comments? 10 DR. ROBERTS: Well, I think we 11 should also -- you know, they made a lot of 12 changes to the REA based on our comments from 13 last time. I think that was really great. 14 You know, the time and everything was a 15 difficult element, I am sure, to overcome. 16 CHAIR BRAIN: So there's general 17 enthusiasm and gratitude for really both 18 documents, the improvements in the REA and the 19 first draft of the PA. 20 DR. BLANC: And, Joe, if you are 21 going to do that, I think in the same sentence 22 you might also say that, even though we didn't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 163 1 discuss the final ISA, that it was also 2 responsive to our input and was quite useful 3 in the discussions. You saw we kept referring 4 back to it. 5 CHAIR BRAIN: And that could go in

6 the REA letter. 7 DR. ROBERTS: So, Joe, I guess I 8 have a question. The PA is not going to be -- 9 it is just going to be revised once, and we 10 won't see it except the final version, and 11 that is after our meeting, our phone call in 12 April? 13 MS. BARRY: Even though there is 14 not a -- there may not be a specific charge 15 from EPA to comment on the final Policy 16 Assessment, it is within CASAC's purview to 17 provide any comments that you have on the 18 final document. 19 As we have heard, you know, you 20 guys are very comfortable with the ISA. That 21 is excellent to know. When the EPA is 22 finalized in May, if you all take a look at it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 164 1 and have some concerns, we could -- it is 2 within the Chair's decision to say, you know, 3 we probably need to have a meeting and talk 4 about where there is still some need for 5 improvement before there is a proposal of any 6 policy. 7 CHAIR BRAIN: Or even the quote 8 final ISA, if CASAC really wanted to make some 9 comment about it -- you know, we still 10 disagree -- even though it is final, we can 11 still make a comment.

12 MS. BARRY: Yes. 13 CHAIR BRAIN: Not that anyone has 14 suggested that that is necessary. We have a 15 lot of latitude. In fact, I think that comes 16 to the top. As we have mentioned before, we 17 shouldn't be too focused, too constrained by 18 the Charge Questions. We may have other 19 issues we want to bring up. 20 DR. BLANC: But one piece of 21 feedback in terms of the Charge Questions is 22 that a couple of us around the table have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 165 1 responded, and I think it resonated, 2 certainly, with me, even though I didn't make 3 the comment, that there is overlap to such an 4 extent in some of the Charge Questions that it 5 makes it difficult for us as we are trying to 6 respond to them. 7 So always be sensitive to -- you 8 are so close to the document, but what is it 9 going to look like for us trying to answer 10 five versus six when they are very 11 interrelated, and also a Charge Question 12 related to a summary chapter that is first 13 puts a reviewer in a really difficult spot, 14 because they have to read the minds of 15 everybody else who is going to respond to the 16 other Charge Questions, which are going to 17 influence -- 18 If Charge Question Number 1 is 19 what did you think about the summary chapter - 20 - right? -- but we haven't heard the input 21 from everybody else, or the introductory. 22 CHAIR BRAIN: And I guess that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 166 1 brings up another opportunity which we really 2 didn't have this time, as I understand it. It 3 is appropriate for CASAC to, in fact, have a 4 discussion about the Charge Questions. This 5 time, we were very constrained by time. We 6 really didn't have time to do that, but in a 7 perfect world, CASAC would have a look at 8 those Charge Questions and might say, you 9 know, we really don't understand these. 10 Again, EPA has the final authority for the 11 Charge Questions, but we could have a 12 conversation about that to try to improve 13 their clarity. 14 DR. MURPHY: Certainly, this 15 schedule is just extremely tight, and it has 16 made things hard. 17 CHAIR BRAIN: And I think, given 18 that, let me conclude by just thanking 19 everyone. Thanks to EPA staff for your 20 presentation, and I think there is consensus 21 that the REA is really dramatically improved 22 and very responsive to our suggestions, and we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 167 1 appreciate the clear responses. 2 I think, you know, again we had 3 this discussion of no comment on our input and 4 too much comment and track changes, and I 5 think we have really reached some happy medium 6 where the level of detail of what has changed 7 is helpful and just right, sort of the 8 Goldilocks phenomenon, not too much, not too 9 little. Again, I think there is a lot of 10 enthusiasm for the Policy document. 11 DR. MURPHY: If I could just take 12 a minute. We certainly appreciate the time 13 and the enthusiasm that the Panel brings to 14 this project. It is difficult. It is tight 15 timelines, and we are asking you to review 16 documents in a very quick turnaround, and we 17 certainly appreciate your time on this. Thank 18 you. 19 CHAIR BRAIN: Yes, and I realize 20 this has -- you didn't have as much time 21 either to plan your travel or your comments, 22 but I think, in spite of those constraints,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 168 1 this was remarkably successful. 2 I look forward to hearing from you 3 all or from most of you by the end of the 4 week, and to joining the conference. You will 5 have another opportunity to look at the draft.

6 So thanks so much. 7 MS. BARRY: Okay, and thank you, 8 everyone for all of your hard work. Thank you 9 for, really, a very productive meeting. This 10 concludes the meeting of the CASAC Carbon 11 Monoxide Panel. Thank you. 12 (Whereupon, the foregoing matter 13 went off the record at 11:51 a.m.)

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A abbreviations 124:22 ABC 1:11 ability 70:20 able 9:6 152:1 absence4:13 99:13 absolute 113:9,17 113:19 115:16 absolutely 18:17

45:14 54:21 72:21 77:15 84:4 abstained 158:2 abstention 157:21 accept 67:2 acceptable 151:20 account92:13 112:18,20 123:2 139:22 accrue 15:17 accruing 10:3 accurate 50:19 achieve 113:2 114:17 137:12 achieved 111:3 acknowledge 129:19 acknowledges

51:20 acknowledging 113:17 acknowledgment 142:8,9 acquire46:5 act24:4 92:5 99:11 actions 154:16,19 activities 77:3,8 activity 77:2 103:13 actual 27:21 30:19

72:19 83:3 116:2 128:16 150:19 151:10 acute 11:15 89:14 add 17:2 25:16

33:4 39:5 50:14 90:1 96:17,20 97:10 122:2,6 157:10,11 158:1 added 66:20 101:14 150:2 addendum 64:5 105:17 adding 147:7 addition 19:17

52:13 64:19 160:17 additional 7:3 13:17 60:1 65:17 68:16,18,22 108:7 108:17 129:6 158:12 160:16 additionally 32:7 additions 160:14 address 26:13 99:3 108:9 113:16 addressed 88:16,20 adequacy 5:5,14 adequate 21:22

63:13 134:6 154:10 adequately 16:11 16:18 157:15 adjacent96:21 adjusting72:7 Administrator 13:5 27:11 85:21 86:22 advantage 96:3

97:2 advantageous 102:18 104:6 advantages 103:21 129:14 advice 24:15 25:6

66:2 138:17 144:21 149:12 advise 17:16 advising 145:6 ADVISORY 1:3

2:10 affect 100:9 154:2 154:3 African 19:2 afternoon 116:15 agencies 33:8 agency 1:1 88:1 114:6 140:19 AGENDA 3:5 agent7:19 44:5 aggressive 60:19 ago 26:12 97:20

99:15 104:12,16 agree 10:12 40:16

42:22 127:20 agreed 50:3 agreeing 51:17 agreement 16:22 142:5 ahead 86:15 106:17 106:17 air 1:3 5:20 21:7

24:4 29:12,14 30:5 31:16 46:16 52:17 72:4,15 74:7 80:9 82:4,9 82:16,21 83:5,7 97:14 98:17 99:11 99:17 100:3 109:5 111:4,5,6 115:8 136:10,14 137:4 140:15 152:21 153:15 154:8 alert21:12 algorithm 72:19 algorithms 76:11 allow 50:16 51:12 121:14 allows 137:7 156:3 156:4 Allred 109:3 114:14 148:8 allude 97:1 altered 141:12 142:14 alternative 5:6

83:1,10 Alternatively 11:20 alternatives 16:5 16:10 82:12 113:4 altogether 149:6 ambient5:22 21:7 29:12,14 30:5 31:16 37:15 68:6 69:1,7 72:4 79:7,9 98:2 99:17,20 108:18 109:7,11 111:4,6 115:5,9 115:14 134:13 138:11 150:7 152:5 154:8 ambiguous 9:21 American 19:2 analogous 109:8 analyses 8:3 129:6 analysis 5:5 8:19 14:8 34:20 37:4 72:3 101:8 108:17 109:1 113:20 114:3 126:9 128:11,14 129:9 129:15 139:18 157:12 and/or 63:18 anecdotes 21:14 Angeles 81:2 animal45:18,19 Ann 14:21,22 annual 136:4 154:1 answer29:8 36:13

46:6 57:14 58:11 97:7,19 105:10 145:19 148:21 165:9 answers 71:2 160:18,22 ANTHONY 2:14 anticipated 75:9 anybody 36:7 44:1

49:8 85:17 92:6 124:10 131:20 anyplace79:17 anyway 122:16 apart 138:3 APEX 103:8 apparent7:21 apparently 18:1 108:19 139:6 appear75:3 appears 6:9 44:8 126:15 146:17 Appendix 66:12

76:4,5 79:14 99:8 applied 15:13 27:4 apply 91:13 107:13 appreciate 113:20 138:21 145:5 167:1,12,17 approach 10:16

36:16 62:15 83:6 104:4 112:16 131:2 approaches 8:4 10:20 43:18 appropriate 36:15

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