### 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

+ + + + + MONDAY, MARCH 22, 2010 + + + + + The meeting convened, 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 RUSSELL DICKERSON* MILAN HAZUCHA

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

### 202-234-4433 Neal R. Gross & Co., Inc. Page 2 SCIENCE ADVISORY BOARD STAFF: KYNDALL BARRY, Designated Federal Officer ANTHONY MACIOROWSKI, Deputy Director

*Participating via telephone

### 202-234-4433 Neal R. Gross & Co., Inc. Page 3 C-O-N-T-E-N-T-S Call to Order and Opening Remarks 9 Kyndall Barry Designated Federal Official Opening Remarks 12 Dr. Anthony Maciorowski SAB Office Deputy Director Opening Remarks 12 Dr. Joe Brain Chair

Comments 16 Lydia Wegman Director, Health and Environmental Impacts Division Environmental Protection Agency Questions and Answers 22 Presentation on Risk and 26 Exposure Assessment Dr. Deidre Murphy 26

Dr. Stephen Graham 28 Public Comment 112 John Heuss 112 Air Improvement Resource, Inc. REA Charge Questions 119 Charge Question 1 119 Dr. Francine Laden 120

Dr. Arthur Penn 122

Discussion 123

### 202-234-4433 Neal R. Gross & Co., Inc. Page 4 C-O-N-T-E-N-T-S (CONTINUED)

Agency Clarification 153

Dr. Deidre Murphy 153

Panel's Response 155

Charge Question 2 163

Dr. Russell Dickerson 163

Dr. Paul Roberts 166

Agency Clarification 165

Dr. Stephen Graham 165

Charge Question 3 167

Dr. Milan Hazucha 167, 176

Dr. Stephen Thom 171

Discussion 178 Agency Clarification 172 Dr. Stephen Graham 172

Ted Johnson 172, 173

Dr. Deidre Murphy 175

### 202-234-4433 Neal R. Gross & Co., Inc. Page 5 C-O-N-T-E-N-T-S (CONTINUED) Charge Question 4 178

Dr. Milan Hazucha 178 Discussion 183 Agency Clarification 181 Dr. Stephen Graham 181, 187 Dr. Deidre Murphy 182

Ted Johnson 189, 197 Charge Question 5 205

Dr. Paul Blanc 205

Dr. Tom Dahms 207

Discussion 211 Agency Clarification 210

Dr. Stephen Graham 210 Charge Question 6 211

Dr. Paul Blanc 211

Discussion 222 Agency Clarification 214 Dr. Stephen Graham 214 Dr. Deidre Murphy 218

Ted Johnson 221

### 202-234-4433 Neal R. Gross & Co., Inc. Page 6 C-O-N-T-E-N-T-S (CONTINUED)

Charge Question 7 238

Dr. Paul Blanc 238 Discussion 243

Charge Question 8 255

Dr. Paul Roberts 255 Discussion 257 Agency Clarification 257 Dr. Stephen Graham 257

Policy Assessment 275 Dr. Deidre Murphy 275, 300, 304 Dr. Ines Pagan 278, 296, 301

Dr. Meredith Lassiter 302

Discussion 279, 306

Policy Assessment Charge Questions 328

Charge Question 1 329

Dr. Arthur Penn 329 Discussion 331

### 202-234-4433 Neal R. Gross & Co., Inc. Page 7 C-O-N-T-E-N-T-S (CONTINUED)

Charge Question 2 334

Dr. Thomas Dahms 334 Dr. Francine Laden 341 Dr. Milan Hazucha 342 Discussion 336

Charge Question 3 375 Dr. Thomas Dahms 375 Dr. Milan Hazucha 378

Discussion 376

Charge Question 4 380 Dr. Joel Kaufman 380

Dr. Stephen Thom 382

Dr. Milan Hazucha 382

Dr. Paul Blanc 384

Discussion 385

Charge Question 5 402 Dr. Thomas Dahms 402, 405 Agency Clarification 403

Discussion 406

### 202-234-4433 Neal R. Gross & Co., Inc. Page 8

C-O-N-T-E-N-T-S (CONTINUED)

Charge Question 6 420

Dr. Stephen Thom 420

Discussion 424

### 202-234-4433 Neal R. Gross & Co., Inc. Page 9 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:29 a.m.) 3 MS. BARRY: I would like to go 4 ahead and bring everyone to their seats, so we 5 can go ahead and get started with our meeting 6 today. 7 I am Kyndall Barry, the Designated 8 Federal Officer for the Clean Air Scientific 9 Advisory Committee Carbon Monoxide Review

10 Panel. 11 I would like to open this public 12 meeting with a short statement. 13 The CASAC was established under 14 the Clean Air Act as an independent scientific 15 advisory committee to provide advice, 16 information, and recommendations on the 17 scientific and technical aspects of air 18 quality criteria and the NAAQS. 19 The Carbon Monoxide Review Panel 20 is convened under the auspices of the CASAC. 21 The Panel is meeting to peer review EPA OAR's 22 Risk and Exposure Assessment for Review of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 10 1 CO Primary NAAQS Second External Review Draft, 2 and the Policy Assessment for the Review of 3 the Carbon Monoxide NAAQS First External 4 Review Draft. 5 Consistent with the requirements 6 of the Federal Advisory Committee Act, or 7 FACA, and with EPA policy, the deliberations 8 of the Panel are conducted in public at 9 meetings for which advanced public notice is 10 given. FACA also requires that, as DFO, I 11 maintain records of deliberations of the 12 Panel, make publicly available the meeting 13 summaries, and provide opportunities for 14 public comment. 15 During the public comment period 16 scheduled to begin at 9:30 today, we will hear 17 comments prepared on behalf of the Alliance of 18 Automobile Manufacturers by Mr. John Heuss. 19 The minutes of this meeting are 20 being taken to summarize discussions and 21 action items, in accordance with the 22 requirements under FACA. These minutes will

### 202-234-4433 Neal R. Gross & Co., Inc. Page 11 1 be certified by the Panel Chair, Dr. Joe 2 Brain. The Panel's draft reports on the peer 3 reviews of the REA and the PA will be 4 forwarded to the chartered CASAC for their 5 consideration and approval at a public 6 teleconference call scheduled for April 19th. 7 I would like to note that the 8 members of this Panel are in compliance with 9 the federal ethics and conflict-of-interest 10 laws that pertain to them. The SAB Staff 11 Office Director, who is the EPA Deputy Ethics 12 Official, has determined that there are no 13 conflicts of interest or appearance of lack of 14 impartiality issues for this review. 15 Therefore, waivers were not needed or 16 considered for any of the panelists. 17 Thank you for your attention and 18 participation at this meeting. 19 It is now my pleasure to introduce 20 Dr. Anthony Maciorowski, the SAB Office Deputy 21 Director, and Dr. Joe Brain, the Panel Chair, 22 for their opening remarks.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 12 1 Thank you. 2 DR. MACIOROWSKI: Thanks, Kyndall. 3 My remarks will be very short. We 4 have been here a number of times. 5 Again, I just want to thank Dr. 6 Brain and the members of the Panel for 7 undertaking this important work for the 8 Science Advisory Board and for the agency as 9 a whole. Again, thanks to Lydia and Karen and 10 all the folks from OAQPS who are here to 11 present their findings. 12 So, Dr. Brain. 13 CHAIR BRAIN: I think I can also 14 be brief. 15 Thank you for coming. 16 I think we accomplished a lot at 17 our last meeting. I received a letter from 18 the Administrator thanking us for our work. 19 I also note that, really, out of 20 our first meeting came a new format for 21 communicating to the Administrator. It used 22 to be there was this letter that was 20 pages

### 202-234-4433 Neal R. Gross & Co., Inc. Page 13 1 long. I think at discussions here we said, 2 why don't we break that into two pieces? Why 3 don't we have a one- or two-page letter to the 4 Administrator that really succinctly gives a 5 macroscopic view of the document and our 6 opinions about it, and then we'l have the 7 answers to the charge questions? 8 So, at subsequent PM meetings, the 9 format that we created has really been 10 adopted, and I think is now becoming kind of 11 standard for the way CASAC operates. I think 12 it works well. 13 So, again, that is our goal today, 14 is to produce a high-level letter about each 15 of the documents in a format that the 16 Administrator can read and understand. That 17 is followed by a consensus view of our answers 18 to the charge questions, which is, then, 19 followed by individual comments where you can 20 be as detailed and specific, and perhaps even 21 disagree, if you wish, with the consensus 22 view.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 14 1 So, I think we all sort of know 2 what we have to produce. It is a historic 3 day, isn't it? You can remember what you were 4 thinking about CO the morning after the 5 healthcare vote passed in the House. We'll 6 see how we interpret that event in the years 7 ahead. That will be really interesting. 8 So, CO, again, we were having kind 9 of an interesting conversation at breakfast 10 about some of the unusual aspects of CO. It 11 stands out as a pollutant where great progress 12 has been made. It stands out as a pollutant 13 where it is increasingly difficult, or perhaps 14 impossible, some would say, to carry out CO 15 epidemiology studies in the United States. 16 So, that creates some special problems. 17 At the same time, there are new 18 things. On the way down in the plane, the 19 latest ATS Journal -- did anyone else see 20 this? There's an article in the one that 21 arrived on my desk a few days ago, "Carbon 22 Monoxide Pollution Promotes Cardiac Remodeling

### 202-234-4433 Neal R. Gross & Co., Inc. Page 15 1 in Ventricular Arrhythmia in Healthy Rats". 2 So, it clearly has some regulatory 3 significance. Too late to include in this 4 round, but an interesting paper with some 5 interesting mechanistic data and 6 interpretations of the role of CO. 7 Then, there are other directions. 8 You know, the whole possibility that CO has 9 something to do with climate changes are some 10 new elements that we haven't really thought 11 about very much, which came up last time. 12 But thank you all for coming. I 13 don't know about you, but it is a busy time of 14 year between academia and the rhythms of 15 family life, let alone all the things we have 16 to do for this Committee and for our jobs. 17 So, let's get started. Let's now18 turn to Lydia, who will kind of bring us up19 to-date on where we are and her vision of 20 where we are in the overall process, and what 21 we have to do to complete our task and give 22 the Administrator as much direction and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 16 1 information as possible. 2 MS. WEGMAN: Thank you, Joe. 3 Welcome to everybody. Thank you 4 all for coming and for the time you have spent 5 reviewing our documents and offering us 6 comments on them, both in writing and, then, 7 today and tomorrow in person. We very much 8 appreciate the time you have all taken. I 9 know you are all very busy, as Joe says, and 10 the effort you make on our behalf, and on 11 behalf of the American public, is very much 12 appreciated. 13 I want to just go over process a 14 little bit and sort of remind you what the 15 process is for this overall review and where 16 we are in that process. 17 So, you have all seen this slide 18 before, but let's just take a quick look. You 19 have reviewed the Integrated Science 20 Assessment and commented on it. You are now 21 reviewing the Second Draft of the Risk and 22 Exposure Assessment and, also, the Draft

### 202-234-4433 Neal R. Gross & Co., Inc. Page 17 1 Policy Assessment. 2 As you all know, we are only going 3 to have one draft of the Policy Assessment 4 because of the very tight schedule we have for 5 this review. I will put the schedule up when 6 we get done with this slide. But this review 7 stage is critical, as all of the stages have

8 been. 9 Just going on now to say a little 10 bit more about this process, again, as you 11 probably remember, the Integrated Science12 Assessment is a synthesis of the policy13 relevant science and is designed to inform the14 Risk and Exposure Assessment and the evidence15 based considerations for the Policy

16 Assessment. 17 The Risk and Exposure Assessment 18 characterizes the nature, magnitude, and 19 uncertainties of the population estimates of 20 exposure, dose, and risk for the selected 21 health endpoints, and we look at recent air 22 quality conditions, the simulation of just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 18 1 meeting the current standard, which, as Joe 2 notes, is being met, and the simulation of 3 potential alternative standards under 4 consideration. So, this is designed to inform 5 the Policy Assessment and to help understand 6 the risks associated with exposure to the 7 pollutant. 8 Now we get to the role of the 9 Policy Assessment. This is a critical step 10 that helps us move forward to issuing a 11 proposal. What the Policy Assessment does is 12 link the consideration of the scientific 13 evidence and the risk and exposure-based 14 information, and presents options for 15 consideration. 16 I want to emphasize here that the 17 purpose of the Policy Assessment is to present 18 a range of options. It is to present a range 19 of options concerning the adequacy of the 20 standard and, if we think the current standard 21 is not adequate or may not be adequate, then 22 to look at consideration of alternative

### 202-234-4433 Neal R. Gross & Co., Inc. Page 19 1 standards that would be appropriate for 2 consideration. This is a pretty big issue in

3 the case of CO. 4 The purpose of this Policy 5 Assessment was to present a range of options 6 to you, one being the possibility of the 7 current standard is, indeed, adequate. But 8 the second being that the current standard is 9 not adequate. And if it is not adequate, what 10 range of options should we be considering? 11 We try to present as broad an 12 array of options as we think is appropriate, 13 in light of the evidence that is presented in 14 the Integrated Science Assessment and the 15 results of the Risk and Exposure Assessment. 16 We don't want to narrow our options too 17 drastically in this Policy Assessment because 18 our goal is to get your views on what range of 19 options is appropriate. So, we present what 20 we think is reasonable, as reasonable and as 21 broad as we can. So, I just want to make sure 22 that that is understood.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 20 1 It is not our purpose in this 2 Draft Policy Assessment to narrow our options, 3 but, again, to present as broad a range as we 4 think is reasonably supportable. We, then, 5 get your advice and, with that advice, we will 6 create a Final Policy Assessment. 7 That document will be considered 8 by the Administrator, along with your advice, 9 in deciding what to propose. I should note we 10 typically do propose a range of options, 11 especially when there is a lack of clarity as 12 to what the right path is. So, this is one 13 step along the way to a proposal. It's the 14 Administrator's judgment as to what to 15 propose. It is the quintessential science 16 policy judgment. 17 So, I just want to make sure you 18 all understand that the breadth of options in 19 the Policy Assessment is designed to allow you 20 to give us advice on whether we've got the 21 right range, whether we should narrow it, 22 whether we should broaden it, as we move

### 202-234-4433 Neal R. Gross & Co., Inc. Page 21 1 forward to give advice to the Administrator, 2 and as you give your advice to the 3 Administrator. 4 Just to go over quickly the 5 schedule, you can see here we have already, 6 thanks to your help and the work of all the 7 folks here today, completed a good deal of 8 this review, but we have some very central 9 steps to continue forward on. 10 So, we are having the review, as I 11 said, of the Second Draft Risk and Exposure 12 Assessment and the Draft Policy Assessment. 13 The Risk and Exposure Assessment will be 14 issued in its final form on May 28th. That is 15 a court-ordered deadline, so we will 16 definitely make May 28th. 17 We expect to complete the Policy 18 Assessment by early summer of this year, and 19 then move forward quite rapidly to a proposal 20 on October 28th of this year, and a final rule 21 on May 13th of 2011. So, we are moving 22 forward here on the home stretch to try to get

### 202-234-4433 Neal R. Gross & Co., Inc. Page 22 1 all these critical documents that are needed 2 for the Administrator's consideration before 3 a proposal done on time. 4 Does anyone have any questions? 5 CHAIR BRAIN: I have a question. 6 You said several times about the goal is for 7 the EPA in this policy document to give advice 8 to the Administrator and, quote, "your 9 advice", meaning us.

10 MS. WEGMAN: Yes. 11 CHAIR BRAIN: I guess I'm new 12 enough, I still don't quite understand the 13 nature of our advice. Is it to say, "Yes, 14 this is a reasonable suite of alternatives and 15 they are adequately explained?" Or, do we 16 actually have the option of saying, you know, 17 "We really like option B; it makes more sense

18 to us?" 19 Could you elaborate by what is 20 appropriate and what you expect from us in 21 terms of our advice? 22 MS. WEGMAN: Yes, I can. This is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 23 1 truly a choice that you make as the scientists 2 who are reviewing this evidence and Risk and 3 Exposure Assessment. If you feel that there 4 is one option or a very narrow range of 5 options that the Administrator should 6 consider, it is certainly your role to tell us 7 that. If you think a broader range of options 8 can be supported, or should be considered by 9 the Administrator, you should tell us that. 10 It is really your judgment, and that is what 11 is most important to us, your judgment on the 12 science and the Risk and Exposure Assessment. 13 But if you feel one or a very narrow range is 14 appropriate, you certainly can and should tell

15 us that. 16 We have presented a pretty broad 17 range of options in the Policy Assessment, 18 based on our read of the evidence and what we 19 think could be supported. If your view is 20 that the range we have presented is too broad, 21 and that some element of it is, in fact, not 22 well-supported, it is very important for us to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 24 1 know that. 2 CHAIR BRAIN: Thank you. So, it 3 sounds like the answer is it's really both of 4 those things, to comment on the suite of 5 options, but, also, if we care to, to express 6 our preference for a particular option or 7 options. Right?

8 MS. WEGMAN: Yes. That would be 9 my view. 10 I don't know, Tony, do you have 11 anything else you want to offer? 12 DR. MACIOROWSKI: No, I think 13 that's fine. I think the key here is making 14 sure that you are commenting on the scientific 15 evidence that supports it. That is kind of a 16 nuance sometimes for people who don't -- it is 17 important that the Panel puts its emphasis on 18 the science support for its decisions, 19 whatever that happens to be. 20 I only raise that because those of 21 us who work at government circles have a very 22 clear sense of what science policy and science

### 202-234-4433 Neal R. Gross & Co., Inc. Page 25 1 is, but sometimes that is not clear to a lot 2 of people. 3 But this is a science advisory 4 committee, and its role is the science support 5 for these options or this option. Within that 6 context, it is perfectly fine to go there. 7 CHAIR BRAIN: This is perhaps, 8 also, adjacent to just one other comment that 9 I will make that came up at the PM meeting 10 that was in this room about two weeks ago. 11 That was the issue of the charge questions, 12 you know, are really quite elaborate and 13 detailed. I think we all work hard on 14 providing good answers. But a few members 15 said we also need to take a step back, and the 16 existence of the charge question should not 17 prohibit us from making other comments. 18 So, we are not confined to the 19 charge questions. We do want to complete them 20 and we want to provide adequate answers, but 21 there may be other issues that are not covered 22 by the charge questions. There may be other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 26 1 advice that we want to give. This is also the 2 opportunity to do that as well, whether that 3 advice is a response to a charge question or

4 not. 5 MS. WEGMAN: Yes, that is quite 6 true, yes. 7 CHAIR BRAIN: Okay. Any other 8 questions that anyone else has for Lydia about 9 the background and the schedule? 10 (No response.) 11 It is really quite exciting. So, 12 before the year is out -- 13 MS. WEGMAN: It is. It is moving 14 forward very rapidly from our perspective 15 Again, thank you very much for 16 your time and your advice today and tomorrow. 17 I am just going to turn this over 18 now to Dr. Deidre Murphy and Dr. Stephen 19 Graham, who will make the presentation on the 20 Risk and Exposure Assessment. 21 DR. MURPHY: Okay. So, I'm just 22 going to take a couple of minutes at the top

### 202-234-4433 Neal R. Gross & Co., Inc. Page 27 1 to introduce the team, first of all, to remind 2 you all of who we are. 3 I'm Dr. Deidre Murphy. This is 4 Dr. Stephen Graham, who is the lead for the 5 Risk and Exposure Analysis. We have Dr. Ines 6 Pagan, who is the lead for the Policy 7 Assessment. You will hear more from her in 8 the afternoon. Dr. Pradeep Rajan, who is our 9 epidemiologist on the team, and Dr. Meredith 10 Lassiter, who is sitting in the back, who is 11 our eco person on the secondary standards. 12 She is the lead on that portion of the Policy 13 Assessment. Dr. Dave McKee, I'm not sure if 14 he is here, but he is a voice of experience. 15 He's been involved on numerous CO reviews in 16 the past. And you know Lydia and Dr. Karen 17 Martin, who is our group leader. 18 With the next slide, you have seen 19 these words before. Lydia took a moment to 20 discuss differences among the different 21 documents that we create as part of the 22 review.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 28 1 I will just take a moment, before 2 we launch into the details of this scientific 3 analysis that is the REA, to again delineate 4 some of the differences between the two 5 documents you have in front of you, the REA 6 being a quantitative assessment that is 7 focused on methods, key results, and 8 uncertainties associated with estimating 9 population exposure and dose for a selected 10 set of endpoints and populations. 11 The Policy Assessment, as Lydia 12 emphasized, is our staff analysis of policy 13 options that can reasonably be supported by 14 both the evidence and the quantitative 15 analyses, based on an integration and 16 interpretation of the information in the ISA 17 document and in the REA document. 18 So, with that, I am going to turn 19 it over to Dr. Graham. 20 DR. GRAHAM: Thank you, Deidre. 21 In response to the first draft 22 review, the CASAC Committee provided a number

### 202-234-4433 Neal R. Gross & Co., Inc. Page 29 1 of comments. Hopefully, we have addressed 2 those in a reasonable manner. I will go 3 through some of the modifications that we made 4 to this particular approach used in the second 5 draft here. I will provide, also, an example 6 of how we use these REA results in the context 7 of the Policy Assessment. 8 Then, I will run through some 9 results, some of which you should be familiar 10 with; they are already in the document. But 11 there were a few additional analyses that I 12 did have some time to collect the necessary 13 data and present those here. You have those 14 slides in front of you as well. 15 Those include information on the 16 COHb estimates. It includes both estimates of 17 single maximum end-of-hour COHb dose levels, 18 as well as multiple days in a year where an19 individual might experience a maximum end-of20 hour COHb level at or above a given benchmark 21 level, as well as the influence of 22 endogenous CO production on an individual's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 30 1 maximum end-of-hour COHb dose levels. 2 Then, I will go through some 3 micro-environmental contributions to exposure. 4 That is something that wasn't included in the 5 document. That is entirely new. But we will 6 include these in the final assessment when we 7 complete that in May and, of course, the 8 uncertainty characterization. 9 So, as I mentioned earlier, in 10 response to the comments that were made, we 11 did make a number of expansions, including the 12 modeling domains themselves. The same two 13 study areas were assessed, but we actually 14 included a number of additional monitors in 15 each location. By using the additional 16 monitors, we have also expanded the number of 17 persons that actually were simulated. 18 There was an increase in the 19 number of micro-environments. Originally, in 20 the first draft it was two. In this 21 assessment, we modeled eight. 22 The at-risk population was also

### 202-234-4433 Neal R. Gross & Co., Inc. Page 31 1 expanded to not only include the COHb 2 population, but also those that might be 3 undiagnosed. 4 And we included additional air 5 quality scenarios in the first draft we looked 6 at, just in the current standard as well as 7 as-is air quality. In this one, we included 8 three alternatives standards, and I will get 9 to that in a moment. 10 We also implemented the mass11 balance model for all of the indoor micro12 environments and implemented the commuting13 algorithm as well as mapping of micro14 environments, which allows for individuals to 15 experience alternative air quality 16 concentrations due to their geographic 17 location within the modeling domain. 18 As a result, this assessment 19 presents an improved representation of the20 variability in the estimated micro21 environmental concentrations as well as 22 spatial variability in the outdoor

### 202-234-4433 Neal R. Gross & Co., Inc. Page 32 1 concentrations, because we also implemented an 2 algorithm that adjusts for ambient monitoring 3 concentrations at each of the simulated 4 individual's outdoor concentrations. 5 This slide just presents an 6 overview of the approach, the general 7 approach. Again, we used APEX to simulate 8 population exposures and COHb dose levels. 9 The study areas were Denver and Los Angeles. 10 As you can see here by these11 graphs, the blocks are essentially Census12 tracked information. The population density 13 are shaded by the colors. You can see in each 14 location we have essentially captured the 15 urban core of each of these modeling domains. 16 The smaller circles are the air 17 quality radii, or shall I say the radii 18 surrounding the monitor location. Within 19 those radii is where we pulled out the Census 20 tracks for the simulated population. 21 As noted here, Denver had four 22 monitors included in its study area, and Los

### 202-234-4433 Neal R. Gross & Co., Inc. Page 33 1 Angeles had 10. I just want to note that, 2 also, CO from indoor sources was not modeled 3 in this assessment, even though we understand 4 that it is a contributor to an individual's CO 5 exposure. We are focusing on ambient 6 exposures in this assessment. 7 The simulated population, as I 8 mentioned earlier, was the individuals within 9 10 kilometers of each of these ambient monitor 10 locations within the domains. We included the 11 diagnosed and undiagnosed CHD population. 12 That is how I will refer to them, and how they 13 are referred to in the document is just the 14 CHD population. 15 The air quality scenarios, as I 16 mentioned, air quality as-is, that is 17 unadjusted 2006 air quality. We also looked 18 at concentrations just meeting the current 19 standard. In this assessment, we looked at 20 historical air quality from 1995 for Denver 21 and 1997 for Los Angeles because that is a 22 time where we actually saw concentrations that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 34 1 were either close to or very close to just 2 meeting the current standard, the current 3 eight-hour standard, which is 9 ppm or, with 4 a rounding convention, it is 9.4 ppm. 5 Three alternatives were selected 6 for the simulation. We had second-highest 7 eight-hour average, which is the form of the 8 current standard, the current eight-hour

9 standard. We looked at a lower level of 5 10 ppm, and with a rounding convention, that is

11 5.4. 12 We also looked at percentile forms 13 of the standard, one, an eight-hour percentile 14 form, and the other a one-hour percentile 15 form. It is 99th percentile. The eight-hour 16 was 5.0, and the one-hour was 8.0. So, 17 essentially, we adjust air quality to meet 18 that particular metric. Then, that was using 19 that historical air quality. So, we had 2006 20 air quality and 1995 and 1997 air quality used 21 in each of these assessments. 22 And the output, in general, were

### 202-234-4433 Neal R. Gross & Co., Inc. Page 35 1 the number and percent of individuals exposed 2 at selected levels, as well as these COHb dose

3 benchmark levels. 4 This slide presents how we make 5 this connection between the information that 6 is generated in the REA with its application 7 in the Policy Assessment. Just sort of going 8 through this quickly, for the as-is, as an 9 example, there can be a number of metrics that

10 we can extract from that. 11 So, for example, as-is air quality 12 in Denver, given an eight-hour averaging time, 13 the second-highest concentration is 3.1 ppm, 14 and the 99th percentile daily max for an 15 eight-hour is 2.8. So, we can actually 16 extract out different information using the 17 same air quality data. 18 But at the same time, we can also 19 see that, considering the actual form and the 20 averaging time for the standard, we generate 21 different exposure and dose results for the 22 air quality scenarios, but then have this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 36 1 related to the different levels within each of 2 these averaging times and forms. You will see 3 some of that later on in the Policy Assessment 4 slides, which I guess you already have a copy

5 of. 6 Is that reasonable? Okay. Are 7 there any questions about this slide? Because 8 I know it is new. 9 The whole point of it is we 10 generate these multiple air quality scenarios. 11 The results are extracted from it, and then we 12 can relate it to different levels of these 13 different standards. So, we have an idea of 14 what is happening with respect to different 15 levels of a given standard, as far as how many 16 persons might be exposed or how many persons 17 might be at or above a given COHb level. 18 Okay. This is a different 19 presentation than what was presented in the 20 document, but it is essentially based on the 21 tables, the tabular format. I have combined 22 all of the results for the five standard

### 202-234-4433 Neal R. Gross & Co., Inc. Page 37 1 scenarios. 2 Essentially, you can see on the 3 X-axis we have the maximum end-of-hour COHb 4 dose level. That is actually daily dose 5 level, the maximum end-of-hour for the day. 6 And on the Y-axis we have the percent of the 7 at-risk population, the CHD population, at or 8 above the given benchmark level. 9 As you can see, there is a 10 significant amount of variability with respect 11 to the percent of persons at a given dose 12 level, given the benchmark that is considered, 13 as well as the air quality scenario. The 14 current standard, obviously, having the 15 highest concentrations with respect to the 16 other air quality scenarios, is going to have 17 the greatest number of persons exposed at or 18 above any given level. That is given by the 19 solid line. And the other alternatives, of 20 course, since they have a lower metric or 21 target design value, they are going to have a 22 lower percent of persons at or above the given

### 202-234-4433 Neal R. Gross & Co., Inc. Page 38 1 dose levels. 2 That was Denver. This is the 3 results presented for Los Angeles, the same 4 results for all of the five air quality 5 scenarios. As you can see, for most of the 6 benchmarks, the percent of the population at 7 or above a given COHb level is pretty much 8 less than 1 percent for at least the as-is and 9 the alternative air quality scenarios. That 10 is for most of the benchmark levels, if I 11 didn't say that already. 12 CHAIR BRAIN: All the lines have a 13 clear definition, but can you say a little bit 14 more about the as-is air quality, and what is 15 that really? 16 DR. GRAHAM: Yes. As-is air 17 quality was just using the 2006 ambient data 18 for the monitors that were within each of the 19 locations as an input to the model. That was 20 unadjusted. So, that is what we refer to as 21 as-is.

22 CHAIR BRAIN: 2006 and what --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 39 1 DR. GRAHAM: Yes, it was 2006. 2 The alternative scenarios used air quality 3 that was adjusted to meet a given target, and

4 the data that were used were the 1995 for 5 Denver and the 1997 for Los Angeles. That is 6 for each of those alternatives, as well as 7 just meeting the current eight-hour standard. 8 CHAIR BRAIN: So, again, it really 9 emphasizes the extent to which we are 10 meeting/beating the current air quality

11 standards? 12 DR. GRAHAM: Right. Right. 13 Absolutely. In other words, the air quality 14 is a significant driver to a person's maximum 15 end-of-hour COHb level, yes, in the absence of 16 indoor sources. 17 Okay. The next slide has similar 18 results. But, as I mentioned earlier, we are 19 looking at the multiple occurrences. This is 20 not within a given day. 21 The output from the model, the 22 standard output is maximum end-of-hour per

### 202-234-4433 Neal R. Gross & Co., Inc. Page 40 1 day. I apologize for not having that on this 2 particular slide. 3 Because we are simulating these 4 individuals across an entire year, we are able 5 to collect the data for that entire year, so 6 there can be multiple days where an individual 7 experiences a dose level at or above the

8 selected benchmark. 9 The backdrop here for this 10 particular figure shows the data that you saw 11 earlier on those previous slides. That is, 12 how many occurrences? At least one. How many 13 times? At least one. 14 I'm sorry. The percent of persons 15 that had at least one exposure or COHb dose at 16 or above the given level, that is what is show 17 in the back here. Along this Z-axis, that is 18 where they either had more than one -- so, for 19 example, the next level is the percent of 20 persons that had at least two or more, and it 21 follow the next level would be the percent of 22 persons that had at least three or more.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 41 1 As I mentioned, or maybe I didn't, 2 this is the as-is air quality. So, you see,3 there's very few persons, considering the as4 is air quality, that experience a COHb dose 5 level at or above these selected benchmarks, 6 ranging from 1.5 to 2.0. I just want to 7 mention we only talk about the 1.5 and 2.0 8 being benchmarks, but we have data for the 9 values in between. 10 DR. BLANC: Can I just clarify?

11 DR. GRAHAM: Yes. 12 DR. BLANC: In all of these, where 13 you say, "percent of the CHD population," 14 because you actually estimated the CHD 15 population as a straight percentage of the 16 population, which wasn't modeled to be varying 17 in any kind of way, except randomly, to 18 exposure, isn't that correct? Isn't this also 19 just the percent of the population? 20 DR. GRAHAM: No. We identify in 21 the simulation, we actually do the simulation 22 for the entire modeling domain. Then, we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 42 1 identify individuals as having the disease 2 based on the disease frequency, the disease 3 prevalence rates. 4 DR. BLANC: But it is just a 5 proportion. 6 CHAIR BRAIN: Can you speak into 7 the microphone? 8 DR. BLANC: I'm sorry. 9 It is just a proportion, isn't it 10 random? You are not presuming that people 11 with CHD actually have -- or maybe I didn't 12 understand. Are you assuming, when you do 13 these percentages of the population with CHD, 14 that it varies in some way other than randomly 15 in terms of the percent of the population?

16 DR. GRAHAM: Yes. 17 DR. BLANC: What is the 18 presumption then? 19 DR. GRAHAM: We actually use both 20 age and gender statistics. So, there is a 21 different prevalence rate associated with 22 individuals between -- I don't have the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 43 1 breakout in front of me -- but it is 18 to -- 2 DR. BLANC: No, I understand that. 3 Then, what I don't understand is, then, are 4 you assuming in your modeling -- does the 5 percent -- what would be the percent of 6 people, of the whole population? Does it 7 differ much in these percentage calculations? 8 That is what I can't tell. It is not 9 transparent. 10 Let me say it a different way. If 11 you say 1.5 percent of the population with -- 12 I'm sorry. If you say that -- which is it? 13 That is the percent of the population. 14 So, if you say that .4 percent of 15 the population with CHD has two excursions or 16 more at a particular level, would the percent 17 of the population, of the whole population, be 18 much different that varies? 19 DR. MURPHY: It could be. So, let 20 me clarify the why, which is what you are 21 struggling with, if I understand correctly. 22 In the simulations, the prevalence

### 202-234-4433 Neal R. Gross & Co., Inc. Page 44 1 rate for the disease is, as Stephen mentioned, 2 broken by gender and --

3 DR. BLANC: I understand that. 4 Right. 5 DR. MURPHY: -- age, which, then, 6 is used in defining our population to be 7 simulated. Once we have defined that 8 population to be simulated by gender and age, 9 that influences various variables about those 10 people, which influences their exposures and 11 which influenced their endogenous COHb rates 12 because it influences their age and gender, 13 which can influence physiological 14 characteristics such as body weight and size 15 and which can influence their activities, 16 which can, therefore, have something to do 17 with what exposures they have, whether they 18 spend time in cars, et cetera, or indoors. 19 So, there are variables associated 20 with the defined simulated population versus 21 the general population that influence COHb 22 levels which differ.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 45 1 Now do they, is your question? I 2 think we may have analyses -- I am not sure if 3 we have pulled them together -- on a general 4 population versus the subset, which is the 5 simulated at-risk. And to know whether they 6 actually do give us a different answer, I 7 don't know the answer to that, but they could 8 because there are variables which will 9 influence their COHb. 10 DR. GRAHAM: Right. In other 11 words, the population distribution of age and 12 gender for the CHD population is going to be 13 different than the actual population that 14 resides in the defined modeling domain. 15 DR. DAHMS: But the question is, 16 is the CHAD data for the CHD population from 17 their age and gender cohorts? 18 DR. GRAHAM: Are you asking about, 19 is an individual, a CHD person different from 20 a regular person in their activities?

21 DR. DAHMS: Yes. 22 DR. GRAHAM: Well, there was an

### 202-234-4433 Neal R. Gross & Co., Inc. Page 46 1 analysis done in one of the appendices that 2 compared the data where we had information on 3 individuals that were characterized as having 4 a heart condition versus those that were 5 characterized as being normal. 6 While there were some differences 7 that were statistically significant, 8 essentially, they weren't of great practical 9 significance to suggest that there would be 10 great difference in the activity patterns of 11 those individuals. That is why we utilized, 12 as far as representing the simulated 13 population, we utilized all the CHAD data that 14 we had available to us. We felt that was 15 better than essentially using the limited, 16 extremely limited, number of diaries where we 17 had that information characterized. 18 DR. HAZUCHA: Yes. I find this 19 plot quite illustrative, but I would suggest, 20 if you can add another level for COHb, and it 21 will be 1.4 percent, simply because 9 ppm CO 22 works out in 1.4 percent COHb level. So, if

### 202-234-4433 Neal R. Gross & Co., Inc. Page 47 1 you have that level as well in the plot, it 2 will give us some comparison. 3 DR. GRAHAM: Thank you. 4 Are there any further questions? 5 Or maybe we can discuss that as we get into 6 the meat of this discussion maybe? Okay, 7 great. 8 I almost forgot we were having 9 this presentation. I was thinking for a 10 minute I was the voice of experience. How do 11 I get to achieve that? 12 Anyhow, in comparison to that 13 previous graph, remember, that was using the 14 as-is air quality. And again, if you look at 15 the back of the graph, that is essentially 16 what was presented earlier, when we showed the 17 results for all of the air quality scenarios 18 where an individual experienced at least one 19 COHb, maximum end-of-hour COHb level at or 20 above the given benchmarks. 21 So, as you come forward in the 22 plot, you can see that, with increasing number

### 202-234-4433 Neal R. Gross & Co., Inc. Page 48 1 of days where you had these occurrences at or 2 above the COHb levels, you have fewer and 3 fewer persons. Most persons, considering just 4 meeting the current standard, most persons do 5 experience -- I don't want to say "only one" 6 -- were estimated to experience one. Again, 7 like I said, fewer or more experienced two or 8 more, and so on, as the graph progresses

9 towards the front. 10 And I also want to make a note, 11 again, when we compare just meeting the 12 current standard, the results there versus the 13 results for as-is air quality, there's a 14 difference in the Y-axis here. 15 What we have here is based on the 16 data that are presented in a tabular format as 17 well in the document, but here as a graphical 18 presentation. I have constructed cumulative 19 density functions here. 20 On the Y-axis we have the 21 percentage of simulated at-risk population at 22 or above -- I'm sorry -- at the COHb level

### 202-234-4433 Neal R. Gross & Co., Inc. Page 49 1 given. This is based on bins of .25 percent 2 COHb increments, and it progresses all the way 3 up to 4.0. 4 The first dashed line is the 5 endogenous-only. We simulated the population 6 in each of the locations. So, this is Denver. 7 We simulated the entire population, as we did 8 in the presence of ambient exposure. We just 9 zeroed out the ambient concentrations. 10 So, essentially, what we end up 11 with is the maximum end-of-hour dose levels in 12 the absence of ambient concentration. So, 13 that is, it represents that as a result of the 14 endogenous CO production rate. 15 That is what is depicted here. 16 You can see the bulk of the population in this 17 first dashed line, the bulk of the population 18 experiences, I think the geometric mean was19 about .22, and this is the maximum end-of20 hour, but there are a number of persons that 21 experience higher levels, as we might expect 22 and has been shown in some of the literature.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 50 1 But in the presence of the 2 ambient, of course, since it is an additive, 3 we actually see a higher percent of persons 4 that experience maximum end-of-hour COHb dose 5 levels that are above a given dose level. 6 This first one is ambient plus 7 endogenous exposure. That is the first 8 thinner line. Then, the second line9 represents the distribution of maximum end-of10 hour COHb dose levels for persons that have, 11 for their endogenous CO production, the 12 contribution from that, as well as the 13 contribution from ambient exposure, ambient 14 that just meets the current standard. 15 The take-home message is that most 16 persons, approximately 95 percent, have that 17 maximum end-of-hour contribution from 18 endogenous of less than 1 percent, but there 19 are a number of individuals that were 20 simulated that did have some COHb contribution 21 from endogenous levels above 1 percent, and 22 that ambient exposure actually contributes a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 51 1 significant amount to individuals in 2 combination to the endogenous productions, 3 contributes to a significant amount of that 4 COHb, the maximum end-of-hour COHb level dose. 5 DR. BLANC: Can I just ask for 6 clarification --

7 DR. GRAHAM: Yes. 8 DR. BLANC: -- on the simulation 9 of the endogenous CO?

10 DR. GRAHAM: Yes. 11 DR. BLANC: At one point in the 12 document, it seemed to indicate that it was 13 simulated based on 59 individuals with 800,000 14 hours of activity. 15 DR. GRAHAM: Right. 16 DR. BLANC: Did I misunderstand

17 that? 18 DR. GRAHAM: No. This data is 19 based on a 50,000-person simulation and the 20 CHD population extracted from that. So, this 21 is the CHD population that was simulated in 22 each, the full simulated population that was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 52 1 simulated in each area for the endogenous and 2 comparable to the ambient simulation as well

3 as the current standard. 4 There was an additional analysis 5 that I will get to in a graph that follows 6 that was focused on, it was actually 92 7 individuals. Because of the way that 8 simulation was performed, I will tell you why 9 we did 92 individuals. 10 DR. BLANC: Okay. 11 DR. GRAHAM: But this is the 12 entire population. So, it is synonymous or 13 corresponds to, the endogenous one corresponds 14 to the ambient and just meeting the current

15 standard runs.

16 And these are the results for Los 17 Angeles. You can see there are negligible 18 differences between the endogenous 19 contribution as well as there are, of course, 20 differences. As we saw with the as-is air 21 quality and just meeting the current standard, 22 the Los Angeles, the results for Los Angeles

### 202-234-4433 Neal R. Gross & Co., Inc. Page 53 1 were lower than that of the Denver as far as 2 the percent of persons at or above the

3 benchmark levels.

4 DR. DAHMS: Excuse me.

5 DR. GRAHAM: Yes.

6 DR. DAHMS: Could I ask for a 7 clarification? 8 DR. GRAHAM: Certainly. 9 DR. DAHMS: The endogenous-only, 10 that is non-parametric, correct? That 11 display, is that how you would characterize 12 that? Is there a median value for that? 13 DR. GRAHAM: Well, we can 14 calculate the median, but this is, I would 15 say, non-parametric because it is binned -- 16 DR. DAHMS: Because it looks like 17 the as-is and the current get to be more 18 parametric.

19 DR. GRAHAM: I'm not sure I follow 20 the questioning, but, as I said, these are 21 based on binning between these, you know, 22 whether a person was at or above a COHb level

### 202-234-4433 Neal R. Gross & Co., Inc. Page 54 1 between zero and .25. So, the percent of the 2 total population at that given level. So, it 3 is essentially, you know -- 4 DR. DAHMS: I am just trying to 5 understand what changed the skewedness of the

6 data.

7 DR. GRAHAM: As far as that 8 between Los Angeles and Denver? 9 DR. DAHMS: No, no. They're both 10 the same. Whether it is Denver or Los 11 Angeles, they're both the -- 12 DR. GRAHAM: Oh, oh. 13 DR. DAHMS: The descriptive graphs14 look the same. It looks like the endogenous15 only has less of a tail towards the low end, 16 but then, as you add the as-is and the current 17 standard, all of a sudden, you wind up with 18 more of a symmetrical distribution. 19 DR. GRAHAM: Right. I don't know 20 if I could answer that question at this point, 21 but I can take a closer look at it. 22 DR. BLANC: You know, my guess is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 55 1 it has to do with the fact that the two are 2 randomly associated with each other. This 3 does not presume that there's any systematic 4 relationship between what your endogenous 5 level is and what your ambient air exposure 6 level is. That may tend to smooth it in this 7 way, when you add them together, and that if 8 you looked at the ambient, absent the 9 endogenous, it may look more skewed, more of 10 a tail, also. 11 I'm just guessing, but I -- 12 DR. GRAHAM: Thank you, Dr. Blanc. 13 I apologize for not recognizing that as being 14 the answer because that is, in fact, the

15 answer. 16 We shouldn't assume that there is 17 a correlation between an individual's 18 endogenous level and their ambient exposure. 19 They are not correlated. In fact, I have a 20 small discussion in the document about that. 21 Just because an individual has a high 22 endogenous rate, I mean their exposure is not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 56 1 necessarily related to that. That would be 2 the result that affects this. 3 CHAIR BRAIN: I have a qualitative 4 confusion. As I look at that, you know, 5 there's not very much difference between the 6 as-is and the current standard. And yet, in 7 an earlier graph for Los Angeles, I remember 8 these lines sort of coming down; there seemed 9 to be a rather dramatic difference between the 10 as-is and the current standard. 11 So, I am having, you know, that 12 came as a surprise, having seen that, that 13 they, then, are so close together. 14 DR. GRAHAM: Right. 15 CHAIR BRAIN: Why am I confused? 16 DR. GRAHAM: Well, I'll tell you 17 why or perhaps I can help confuse you further. 18 (Laughter.) 19 But if we look at this graph, it 20 might be deceiving in that, at the very lowest 21 benchmark that is exhibited here, we see a 22 great difference between just meeting the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 57 1 current standard -- 2 CHAIR BRAIN: Right.

3 DR. GRAHAM: -- but not a whole lot 4 of difference at a higher benchmark level. I 5 mean, essentially, you are less than 1 percent 6 for all of them. I mean it is just a fraction 7 of a percent for the as-is and just meeting

8 the current standard. 9 When we go to those other graphs, 10 I mean you see there, with the 1.5 percent, 11 that is where you are seeing that greatest 12 difference right here. But, of course, you 13 are not going to see much difference between 14 the distribution at the higher benchmark 15 levels. So, that is where you are seeing that 16 difference. It's the same data. 17 Okay. This is the case where, 18 because of the fact that the ambient exposure 19 isn't correlated with any individual's 20 endogenous production, we were interested in, 21 okay, well, we are calculating the maximum

22 end-of-hour COHb dose levels. How much of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 58 1 that is from an individual's endogenous 2 production rate? It is only a natural 3 question. I believe it was raised at the 4 meeting on the first draft. We said, okay, 5 well, we can actually use the model to answer 6 that question. 7 The earlier graphs, again, showed 8 the maximum end-of-hour, but it wasn't 9 necessarily the relationship between that 10 given hourly concentration. So, we performed 11 a limited simulation where 92 individuals were 12 simulated, because to generate the output, we 13 would have to actually estimate, for output, 14 every single hour for the entire year for all 15 the individuals. 16 It creates a fairly large dataset 17 that requires, again, additional analysis and 18 manipulation. So, there's time and 19 computational resources involved there. So, 20 we had to limit the population to a few 21 individuals. 22 So, we ran the model, generated

### 202-234-4433 Neal R. Gross & Co., Inc. Page 59 1 the output, the hourly output, every single 2 hour, and said, okay, well, what's the maximum 3 end-of-hour for each of these individuals, 4 just as we did in the earlier analyses. Okay. 5 Now, at that hour, where we see that maximum 6 COHb level, what is the contribution from 7 endogenous CO production? Okay. Take the 8 difference between the two. Then, we have the 9 total COHb, which is endogenous plus ambient 10 at that given hour for every single individual 11 that was simulated. 12 We've got the ambient 13 concentration or ambient contribution, as well 14 as the endogenous contribution. And that is 15 what is plotted here. 16 The total, which is on the Y-axis, 17 versus the ambient, which is on the X-axis, 18 and you can see, for most of the individuals, 19 and this is, again, 92 individuals, for most 20 of them, the relationship is fairly linear. 21 That is, the maximum end-of-hour COHb is 22 essentially driven by ambient exposure. But

### 202-234-4433 Neal R. Gross & Co., Inc. Page 60 1 for a few individuals, as you see here, they 2 have a different endogenous contribution that 3 makes up a greater portion of their total 4 maximum end-of-hour COHb level. 5 But it is as we might expect. If 6 we saw everybody that was on a straight line, 7 then we would be pretty concerned. You can 8 see, of course, that there is variability in 9 that amount of the total contribution as far 10 as the percent. 11 Are there any questions about 12 this?

13 DR. HAZUCHA: Yes. What are those 14 four outliers there? Can you identify it any 15 way? Were they from any at-risk population, 16 let's say anemics or CHD, or it's impossible 17 to do it, the ones which have higher 18 endogenous production of CO? 19 DR. GRAHAM: Right. No, there is 20 a way to do it, but I apologize for not having 21 done that at this point. But these points are 22 actual simulated individuals. There may be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 61 1 characteristics associated with why they 2 actually have that greater endogenous 3 contribution. 4 But, again, we also have to keep 5 in mind that it is just this single hour. The 6 endogenous contribution likely varies for an 7 individual across that entire simulation 8 period. We will, hopefully, have the time to 9 take a look at that and try to identify some 10 of these characteristics of what might be 11 influencing those influential or points 12 outside that regression. 13 DR. BLANC: But I think the 14 question goes to the heart of what is in your 15 predictive model for endogenous CO, which is 16 in a part of the document, but mostly the 17 appendix deals with it more, I think. It was 18 not entirely transparent, but it didn't seem 19 to me that the model actually took into 20 account disease states that would be outside 21 of a distribution, even a skewed distribution. 22 In other words, I don't think the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 62 1 model presumes a bimodal distribution with 2 subpopulations which actually had quite 3 elevated endogenous production, because, in 4 fact, your 99th percentile values were 5 considerably below 2 percent 6 carboxyhemoglobin. It was like 1 -- wasn't 7 your upper limit, your extreme limit was 1.4 8 or something or 1.8 or 1.6? I don't remember

9 the -- 10 DR. GRAHAM: Right. I think in 11 Los Angeles it might have gone up to 1.6 or

12 1.7. 13 DR. BLANC: Yes. For endogenous? 14 DR. GRAHAM: For endogenous, 15 right. 16 DR. BLANC: But that is, clearly, 17 not consistent with real population data, 18 where there are subpopulations such as people 19 with sickle cell disease. So, how does your 20 model take those conditions into account? I 21 assume it doesn't. 22 DR. GRAHAM: Right. You are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 63 1 correct in that regard. What we have for 2 endogenous production rate, I looked at some 3 of the comments, and I believe there were 4 comments and questions about one of the tables 5 there where we actually have the CO production

6 rates. 7 I haven't gone through all the 8 papers that were used there, but we know that 9 for a lot of this data there isn't a wealth of 10 data that are available. For a lot of the 11 data, the production rates may, in fact, be 12 for healthy individuals versus not as many for 13 a CHD population. It is an area that was 14 identified in the uncertainty characterization 15 of an area that we still have some improvement

16 to make. 17 If you are suggesting that there 18 are data for a CHD population that can 19 address, say, CO endogenous production rate, 20 then, by all means, we should implement that. 21 But the other thing that we need to recognize 22 is, how is that -- say there is data from a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 64 1 limited study where they measured endogenous 2 CO in 20, 100, or so persons. How 3 representative of that population, how do you 4 extrapolate that to the absolute CHD 5 population? I mean that is another 6 uncertainty that gets introduced. 7 In other words, you have it from a 8 limited study group. Is that really 9 representative of the entire CHD population? 10 So, we will have to, again, take 11 that into consideration. 12 DR. BLANC: Well, I guess we can 13 come back to this more in our discussion.

14 DR. GRAHAM: Yes. 15 DR. BLANC: But I think that the 16 first step would be making clearer the 17 presumptions of the endogenous model because 18 I think the endogenous model doesn't reflect 19 a human population. It just doesn't. It's a 20 healthy population of some sort. 21 It is not clear to me all your 22 parameters, but it is parameters which do not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 65 1 take into account that there are 2 subpopulations that we certainly know from 3 clinical literature whose endogenous CO2, I'm 4 sorry, CO rates are considerably -- 5 DR. GRAHAM: Right. 6 DR. BLANC: Like double what you 7 are saying is your upper maximum of normal. 8 So, something is wrong with the presumption. 9 It is like you are burying your head in the 10 sand. You are saying, well, we don't have 11 these data, so we are going to assume that 12 this narrow projection that we have is the 13 population, when we know that there are 14 subpopulations which don't behave in that way. 15 So, there has to be some way of taking that 16 into account in your model. 17 DR. GRAHAM: Right. And like I 18 said, if there is data available, then, if you 19 could assist us in identifying that data, it 20 could be put in the appropriate location, and 21 the simulation can be reperformed. But it 22 doesn't necessarily change the contribution of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 66 1 ambient on top of that endogenous. 2 So, in a sense, what was done 3 there can, like, for example, you are 4 suggesting that the distribution is altered 5 for endogenous. 6 DR. BLANC: Which is going to 7 shift your -- 8 DR. GRAHAM: Right, the entire -- 9 right, absolutely.

10 DR. BLANC: Yes. 11 DR. GRAHAM: So, that's fine. But 12 we would need to have that data identified. 13 CHAIR BRAIN: But I guess we do 14 know what percentage of the population has 15 sickle cell or thalassemia. I mean that is 16 what you are thinking, situations like that? 17 DR. BLANC: Yes, and I think there 18 is reason to presume that the population with 19 sickle cell is not normally distributed in Los 20 Angeles, but, in fact, lives in areas of Los 21 Angeles that probably are closer to major 22 roadways and have more ambient pollution

### 202-234-4433 Neal R. Gross & Co., Inc. Page 67 1 effects. 2 So, the distribution you show 3 here, where it is somewhat random, more or 4 less, between endogenous production and 5 ambient exposure, that presumption, in fact, 6 may not be correct in Los Angeles. 7 DR. MURPHY: Just if I could 8 clarify? So, what we would need, it seems, 9 would be prevalence rate of, for example, 10 sickle cell anemia patients among the CHD 11 population, since we are simulating the CHD 12 population here? And that's what Stephen was 13 responding to, that we would need information 14 on the CHD population and the variability of 15 the different variables influencing COHb. 16 And you all are saying, well, we 17 know something about sickle cell. And that 18 would certainly be informative, but we would 19 need that link, the representation of sickle 20 cell anemia within the CHD population, for 21 example. 22 DR. GRAHAM: Well, if that is what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 68 1 you are talking about with respect to the CHD 2 population, or is it exclusive of that CHD 3 population? Because, then, that would be a 4 different population that would be simulated. 5 What is the benchmark level of interest for 6 those individuals? Do we have health 7 information on those? 8 DR. BLANC: I think we can come 9 back to some of it, but there's certain 10 presumptions that one could make, at least in 11 terms of modeling certain scenarios. I mean 12 I think this will come back in the discussion, 13 but there's so much effort that you put into 14 simulating a whole variety of different 15 exposure characteristics, but there's very 16 little on the other side of the at-risk 17 population. That is very disconcerting. 18 DR. GRAHAM: Right. But, again, 19 if we can identify the data that we can use -- 20 DR. BLANC: But sometimes it can 21 be driven by presumptions of data, in the same 22 way that one makes other presumptions. I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 69 1 mean, if you want to be public health 2 protective, because you are making a 3 presumption. The way you do it, you are 4 making a presumption that no one has anemia in 5 the population. 6 DR. GRAHAM: Right. 7 DR. BLANC: I mean presumptions 8 that no one has anemia and is closer to a 9 freeway.

10 DR. GRAHAM: Uh-hum. 11 DR. BLANC: So, you are making 12 presumptions. 13 DR. GRAHAM: Absolutely. 14 DR. BLANC: I'm just concerned 15 that all of the presumptions that are made in16 that direction are not public health17 protective. 18 DR. GRAHAM: Right. I can agree 19 with that.

20 DR. KAUFMAN:KAUFMAN: Can I ask a 21 different question? Hello.

22 MS. BARRY: Sure. Go ahead. Is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 70 1 this Joel?

2 DR. KAUFMAN: Yes. 3 MS. BARRY: Thanks. Okay.

4 DR. KAUFMAN: Joel Kaufman. 5 I'm very pleased to see this data 6 developed that actually shows the contribution 7 of the ambient because I think, obviously, 8 that is the kernel that is missing in trying 9 to disentangle the ambient stuff.

10 I want to make sure I am 11 understanding what we are seeing in the 12 figure. Leaving aside the handful of outliers 13 on there, it appears to me -- and I want to 14 hear if I'm seeing this correctly -- that you 15 can essentially model this as a one-to-one, 16 linear, additive relationship here between the 17 ambient plus the total COHb level, whereby 18 almost all, but somewhere between .2 and .4 of 19 the total COHb can be attributed, as it were, 20 to the ambient exposure for all but a handful 21 of outliers. Am I reading this correctly? 22 DR. GRAHAM: Yes, that is correct.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 71 1 And if you looked at the earlier graph that 2 showed for the population, for most persons, 3 their maximum end-of-hour COHb level, and that 4 is not just the entire contribution -- again, 5 that is the maximum end-of-hour COHb -- is 6 about .2 to .25, I think. 7 DR. KAUFMAN: It sort of begs this 8 question that you can't model deep down into 9 the total COHb level because there's confusion 10 with that endogenous level. In actuality, if 11 you chose, instead, to do your modeling based 12 on ambient attributable COHb elevation, you 13 could do that, it seems like from this figure, 14 even though it is computationally a more 15 challenging simulation. 16 DR. GRAHAM: That is correct. 17 DR. KAUFMAN: Okay. But you have 18 chosen, as a whole, the team has chosen not to 19 go down that road, is that right? Because all 20 of the document is around total COHb, except 21 for this small number of displays. 22 DR. GRAHAM: Right. That is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 72 1 correct. That is traditionally what we had

2 done. 3 DR. KAUFMAN: Thank you.

4 DR. HAZUCHA: If I can make 5 another comment and a question as well, as I 6 am looking at it, and you will, let's say, 7 draw an additional line, it will cross the 8 Y-axis, what, approximately at .2 percent

9 COHb? 10 DR. GRAHAM: Right. 11 DR. HAZUCHA: And that intercept, 12 basically, will give you endogenous 13 production, average endogenous production 14 without any effect of ambient air. However, 15 .2, it's low, very low end of normal 16 distribution of endogenous COHb. Generally, 17 the average is about .6. So, I would expect, 18 really, that slope slightly different than 19 what one can draw from this data. 20 DR. GRAHAM: Right. I mean I 21 guess the thing we should recognize is that 22 this is based on a population simulation.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 73 1 Much of what you might be referring to is 2 based on limited studies, and I don't know the 3 number that you may be talking about, but it 4 is based on limited studies of a limited 5 number of individuals. I'm not sure of how 6 representative of the simulated population, 7 you know, as far as comparing that data versus 8 this data, I am not sure how well they 9 compare. But it is something that we should

10 take a closer look at. 11 DR. HAZUCHA: Well, just looking 12 at your distributions, for example, 13 distribution plots for endogenous COHb, the 14 mean value, mean and mode, actually, will be 15 very close, both around .5, .6 COHb level. 16 DR. GRAHAM: Right. You're 17 talking about endogenous?

18 DR. DAHMS: The mean 19 carboxyhemoglobin that he showed up here, that 20 bin is between .25 and .50. 21 DR. GRAHAM: Right. 22 DR. DAHMS: And the mean is in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 74 1 middle of that. 2 DR. GRAHAM: Right. 3 DR. DAHMS: So, the median value 4 or the mode is probably going to be around .4. 5 DR. GRAHAM: Right. 6 CHAIR BRAIN: So, you are saying 7 it is fairly consistent with the earlier graph

8 then? Or not? 9 DR. DAHMS: Yes. Well, we are 10 probably talking apples and oranges, but -- 11 DR. GRAHAM: Right, right. Keep 12 in mind, also, that earlier graph, that 13 distribution is the maximum. That would be 14 the maximum end-of-hour COHb level, rather 15 than just some average of COHb levels, 16 endogenous. 17 DR. DAHMS: But the endogenous is

18 constant. 19 DR. GRAHAM: This is for the 20 operation on an individual. 21 DR. THOM:THOM: But the population 22 is constant.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 75 1 DR. DAHMS: For whatever it is, it 2 is a constant number throughout your --

3 DR. GRAHAM: Wouldn't there be 4 variability in the population distribution of 5 endogenous contribution to COHb level? 6 DR. THOM: It is not important to 7 this discussion.

8 DR. GRAHAM: Oh. 9 DR. THOM: The issue is, it is how10 you are defining your parameter, the end-of11 hour. The point is, if one has an endogenous 12 rate of carbon monoxide production, yes, 13 there's a diurnal variability that is quite

14 narrow. 15 DR. GRAHAM: Right. 16 DR. THOM: But it doesn't matter 17 if it is 6:00 a.m. or 7:00 a.m. or 8:00 a.m. 18 The end-of-hour is sort of a trivial way of 19 defining it. It is just because it is 20 endogenous, that's all. 21 DR. GRAHAM: Okay. 22 DR. BLANC: Well, I mean maybe the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 76 1 confusion in the readers comes about, if you 2 go to Section 6.4 of the document, I guess 3 that is where you are starting in on this 4 simulation with the roughly 100 individuals. 5 DR. GRAHAM: Right. 6 DR. BLANC: So, in your simulation 7 with 100 individuals, your 50th percentile 8 endogenous CO value is .22 percent, if you go 9 to page 6-20, Section 6 --

10 DR. GRAHAM: Uh-hum. 11 DR. BLANC: So, I think the 12 question was -- 13 DR. GRAHAM: Right. 14 DR. BLANC: -- that median value 15 of .22, if that's what you got from your 16 simulation, which is consistent with your 17 intercept here, isn't that consistent with 18 other data? But that is a simulation that has 19 only 100 people in it, albeit it has lots and 20 lots of scenarios of hours, right? I mean it 21 is lots of -- 22 DR. GRAHAM: Right, 8,706.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 77 1 DR. BLANC: But the point that was 2 just made is those hours aren't going to 3 matter much for the endogenous part. They are 4 only going to matter for the other part, 5 right? 6 DR. GRAHAM: Right. Okay. 7 DR. BLANC: So, you have a very 8 seemingly tight distribution of endogenous CO 9 because what drives the variability of CO is 10 not hour-to-hour variation within person. It 11 is between-people variability, which can't be 12 captured when you use 100 people. By force, 13 you are going to have a very narrow 14 distribution of the endogenous CO.

15 DR. GRAHAM: Uh-hum. 16 DR. BLANC: So, somewhere earlier 17 on in the document, and I missed this when I 18 read it, there must be what you are assuming 19 in your population, when you did the whole 20 population simulation, what your median 21 endogenous CO value is.

22 DR. GRAHAM: Yes. As far as the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 78 1 standard output for that 50,000-person 2 simulation, that isn't a standard output from 3 the model. We wouldn't be able to generate 4 the median value or the mean value for the 5 COHb. We are just selecting at those 6 particular benchmark levels the percent of the 7 population that actually had -- 8 DR. BLANC: So, you are assigning 9 it? Or the model presumes it? 10 DR. GRAHAM: Well, we generate it, 11 but as far as output, the output is in summary 12 form for the 50,000-person simulation. So, we 13 are doing the hour, minute-by minute, an 14 individual experiences an exposure. We output 15 the hourly COHb level, but it isn't put in 16 that output file. We just summarize the data. 17 DR. BLANC: Well, do you have some 18 way of double-checking whether your model is 19 working insofar as the endogenous CO is 20 concerned in your big model, not the 96-person 21 simulation? So, that you are convinced that 22 your endogenous numbers are consistent with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 79 1 what you would expect biologically? 2 In other words, the graphs, two 3 graphs ago when you showed this thing -- 4 DR. GRAHAM: Right. 5 DR. BLANC: -- well, we should be 6 able to look at it and see what the median -- 7 what's the median on that one? Can you go 8 back two graphs? 9 So, the peak, the mode is --

10 DR. GRAHAM: .4. 11 DR. BLANC: -- .4 in that. I see. 12 Okay. So, it is probably something like .4. 13 DR. GRAHAM: But, again, this is 14 the maximum end-of-hour, not for all --15 DR. BLANC: Well, the maximum end16 of-hour for endogenous is going to be --

17 DR. GRAHAM: I've been corrected. 18 Right. 19 DR. BLANC: Right. It is going to 20 be not very, very much, right? 21 So, does that distribution, Dr. 22 Hazucha, look more like what you would expect?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 80 1 DR. HAZUCHA: Well, it would. 2 Because if you look at .2, it is on your 3 lefthand. That would be about .2. So, I 4 expect that it will be close to .4, let's say,

5 or .5. 6 CHAIR BRAIN: I just have a 7 process question. What fraction of all these 8 graphs are in the REA itself? 9 DR. GRAHAM: Most of the graphs 10 are not in the REA. These were additional 11 analyses that were performed. Some of the 12 data are based on tables that are presented in

13 the REA. 14 CHAIR BRAIN: And what is your 15 intention, that they should be folded into a

16 future --

17 DR. GRAHAM: Yes. 18 CHAIR BRAIN: Into the final? 19 DR. GRAHAM: Absolutely. 20 CHAIR BRAIN: So, these are 21 potential graphs that you are likely to add? 22 DR. GRAHAM: Absolutely.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 81 1 CHAIR BRAIN: So, this discussion 2 is fruitful and appropriate? 3 DR. GRAHAM: Yes. And I think 4 part of the reason why we included it here was 5 for that, so that you could see the data in a 6 new light, in a sense, and hopefully, you can 7 comment on it and help us present the data 8 favorably in the final document. 9 Okay, are we ready to move on? 10 I think this is a good example of 11 there's no particular charge -- well, it 12 overlaps with some specific charge questions. 13 But it seems to me the people involved in this 14 discussion should write something, you know, 15 give us your evaluation, your critique of the 16 problems and potential of these graphs, what's 17 good about them, what's bad about them, 18 because it sounds like they really would be 19 folded into the next -- 20 DR. BLANC: Well, then, let me ask 21 you a question, if that is going to be the 22 case. So, if you go back to the graph that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 82 1 adds them together, back. Yes, this one. And 2 we have a parallel one for Denver. 3 You have a table in the document 4 which was from an earlier analysis, not your 5 current analysis, but your provided analysis

6 that had been done --

7 DR. GRAHAM: The 2000 assessment?

8 DR. BLANC: The 2000 assessment. 9 In that analysis, there was a table which 10 included the contribution of indoor exposure 11 that wasn't from ambient sources. 12 DR. GRAHAM: Right. 13 DR. BLANC: How hard would it be 14 to provide in this figure what happens when 15 you finally add that in, and what the curve 16 looks like? 17 DR. GRAHAM: Well, by adding that 18 in, I mean that was -- what was done in the 19 2000 assessment, while there are similarities 20 between what was done then and now, it is not 21 necessarily something that we could just 22 easily add.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 83 1 DR. BLANC: Well, how about 2 generating your own estimate of what the 3 contribution from the indoor environment would

4 be? 5 DR. GRAHAM: Again, much like 6 making adjustments to the physiological 7 parameters that are used in updating those, we 8 would need to have updates to some of those 9 parameters that are used for the indoor source 10 model. It would be, I think, a significant 11 effort. And given the time that we have, to 12 the end of May, I think it is best to just use 13 that data that has already been generated and 14 use a quantitative approach to say, okay, 15 well, based on indoor sources, we see that 16 there is a contribution of "X". 17 DR. BLANC: Well, all right, let 18 me ask the question in a different way then. 19 Is there some way in which you could do a 20 visual display of those data that would 21 parallel, basically, what you are showing 22 here, which is a useful visualization of how

### 202-234-4433 Neal R. Gross & Co., Inc. Page 84 1 these things add together? Because that is 2 the piece that is completely lacking in the

3 current document. 4 DR. GRAHAM: Yes, that is great. 5 I think it is a good idea, but I think in the 6 2000 assessment, the endogenous, there was no 7 estimation of the endogenous contribution.

8 DR. BLANC: I understand that. 9 So, what would be the downside, bearing in 10 mind the limitations of the data, to simply 11 presuming that the values that were done for 12 the 2000 still applied as a kind of -- you 13 know, it's not any worse than that now. 14 DR. GRAHAM: Right. It is an 15 estimate. But it would have to be fully 16 characterized and qualified. 17 DR. BLANC: Well, okay, but would 18 that be possible to have some illustration

19 that would show that? 20 DR. GRAHAM: Yes, sure. 21 DR. MURPHY: Just if I understand, 22 I want to clarify if we understand. So, you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 85 1 are just suggesting we have these tables that 2 show the 2000 results? With indoor sources, 3 without indoor sources, you could present 4 those graphically? 5 DR. GRAHAM: And add to it 6 endogenous.

7 DR. MURPHY: But we don't have -- 8 DR. BLANC: Well, but do you 9 understand my frustration? There are three 10 main sources of exposure for people -- 11 DR. MURPHY: Certainly. 12 DR. BLANC: -- who are not active 13 smokers. There's endogenous. There's air 14 pollution, and there's indoor sources that 15 don't derive from the ambient air. And 16 there's nowhere in this document where all 17 three things are combined. Therefore, the 18 implication of the document is that it doesn't 19 exist. That's the implication.20 So, from a public health21 protective point of view, what we really care 22 about is, what is an actual human being's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 86 1 carboxyhemoglobin likely to be, taking their 2 real-world exposures into account? In one 3 place, you have the ambient plus the indoor, 4 but that is from 2000. Somewhere else, you 5 have the endogenous plus the ambient. But 6 nowhere are all three together. 7 But isn't that what we really care 8 about, at a certain level? 9 DR. MURPHY: Right. 10 DR. KAUFMAN: Can I say something 11 here, Paul? Joel, again here. 12 That would be one approach, I 13 agree, and the other approach, which is to 14 really focus like those human controlled 15 exposure studies that we are focused so much 16 on did, was to focus exclusively on the 17 additional impact of the ambient. Right? 18 Because that is really what the Allred study 19 is about. It is saying we have given them 20 enough CO to add 2 percent carboxyhemoglobin 21 to them. So, they are sort of ignoring what 22 it was in the beginning, but saying this is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 87 1 what it is going to be at the end. Right? 2 I mean both of those are, that is 3 very artificial, but that is what this has 4 done. But this is the first time we have seen 5 it in this REA, is this figure we have just 6 looked at, where they have subtracted the two 7 things out and modeled, actually, the ambient 8 contribution. 9 It seems like we are not seeing 10 either of the things that we need to see. One 11 is the realistic real-world view of all of the 12 components together, and where that ends up 13 somebody's COHb being, or what we have just 14 begun to see, the actual exclusive ambient 15 contribution. 16 Am I seeing something different 17 than you are, Paul? 18 DR. BLANC: No. I mean, either 19 way, you would get to the same place. The 20 problem is that, as we go forward in the day 21 and we get to the policy considerations, they 22 are driven by making the assumption that no

### 202-234-4433 Neal R. Gross & Co., Inc. Page 88 1 one has any indoor exposure. 2 DR. KAUFMAN: Right, and that they 3 don't smoke. Right? 4 DR. BLANC: Well, let's leave the 5 smoking aside for right now. But the 6 rationale, I think it is great that there is 7 attention to endogenous production, there has 8 to be, but I think it is great that there is. 9 Then, I think that the modeling is too 10 conservative, but that is almost a nuance. 11 But without the other piece, it is 12 just not realistic. I think that what was a 13 real problem is when you try to look at, well, 14 what are population distributions for 15 carboxyhemoglobin levels in non-smokers. Of 16 course, they are quite a bit higher than the 17 endogenous value. That is because, if you 18 look at the population, you are including what 19 they are getting from ambient air population, 20 and you are including what they get from 21 indoor air. 22 The data from 2000 were very

### 202-234-4433 Neal R. Gross & Co., Inc. Page 89 1 convincing that there is a hefty contribution 2 from indoor air, which, again, may not be 3 distributed randomly in relation to what you 4 get from ambient air, and probably isn't 5 distributed randomly, in fact, 6 DR. GRAHAM: Right, and when you 7 refer to indoor air, you mean in the presence 8 of indoor sources? 9 DR. BLANC: Right.

10 DR. GRAHAM: Because we are 11 modeling indoor air. 12 DR. BLANC: No, no. Yes, that's 13 right. I mean the indoor air that is not 14 coming from the outdoors, right. 15 CHAIR BRAIN: Let's figure out how 16 to proceed. I think this is a really useful 17 and important conversation. I guess my 18 question is, do these questions and answers, 19 is it embedded in the charge questions? Or do 20 we need a separate little piece? 21 It sort of sounds like we need a 22 separate piece, and it sounds like Paul and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 90 1 Tom and Milan and Joel -- because I think 2 these are potentially useful figures, and they 3 are very educational and understandable. So, 4 I think this is important. How should we deal 5 with it? Can we ask the four of you to put 6 some of this down on paper? 7 DR. HAZUCHA: Well, some of these 8 figures are really in the document, not all of 9 them. It would be maybe helpful to have 10 additional figures in the document here. 11 CHAIR BRAIN: Well, I think you 12 are saying that it is probably their intention 13 that some of these figures will be folded into

14 the next -- 15 DR. HAZUCHA: So, we can comment 16 probably, once it is in the document, we can 17 comment on the individual -- 18 CHAIR BRAIN: Well, I think now is 19 the time, now is the good time to say 20 something about it. 21 So, could we ask the four of you

22 to --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 91 1 DR. DAHMS: Are all the figures in 2 this packet that you're showing? 3 DR. GRAHAM: Right. 4 DR. DAHMS: So, we have a copy? 5 DR. GRAHAM: Uh-hum, yes. 6 DR. DAHMS: So, if we treat this 7 as an appendix to the document, we can, then, 8 make comment on it? Correct? 9 DR. MURPHY: You can make comment, 10 however you want to treat it, you can make 11 comment on these figures. Because we are 12 presenting them to you to ask for your advice 13 on these figures, with our intent of putting 14 these figures, or some variation on them, 15 based on your advice, into the final document. 16 DR. DAHMS: Okay. 17 DR. GRAHAM: Right. The intent of 18 the figures is, of course, to provide you 19 supplemental information on how the model is 20 performing and what exactly do the results 21 mean. It was in response to your comments on 22 the first draft.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 92 1 Of course, given all the 2 modifications that were done and additional 3 scenarios, and so on, that were done for this 4 analysis, there was only a limited amount of 5 time to get all of that done, and then include 6 these additional figures. So, they didn't 7 make it into that document. The intent is to 8 have them in the final document. I wanted you 9 to have them, so you can comment on them here. 10 CHAIR BRAIN: Because I think we 11 have come up with a lot of -- you know, I hear 12 issues of internal consistency. I hear issues 13 of, what about susceptible individuals, about 14 indoor air? So, I think there are a number of 15 topics. 16 Paul, perhaps can we ask you to 17 pull them together, if others give you some -- 18 DR. BLANC: Well, I think that we 19 should re-ask this question once we discuss 20 the charge questions. 21 CHAIR BRAIN: Okay. 22 DR. BLANC: Because, actually, a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 93 1 lot of my comments, although I will have to 2 correct some of them because I was really -- 3 actually, I'm still confused about how you 4 model the endogenous between the two things. 5 I think I understand better about why there 6 were 96 individuals in that. I mean I always 7 understood about that, but now I understand 8 that, in addition to that, on your big 9 simulation everybody also had some kind of not 10 simulated, or maybe simulated, CO level also, 11 based on your model of CO. So, that's why the 12 difference. 13 I mean, so those are two different 14 simulations, and I understand that better now. 15 I somehow didn't understand it, reading the

16 document. 17 DR. GRAHAM: Well, the only 18 difference is not in the actual simulation 19 that was performed. It is just the number of 20 individuals that were extracted from the model 21 and the type of data that were extracted. 22 For the limited analysis, it was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 94 1 just 100 individuals -- 2 DR. BLANC: Right. 3 DR. GRAHAM: -- or 92 individuals 4 that were randomly sampled from that 5 population. 6 DR. BLANC: Right, right. 7 DR. GRAHAM: We had to restrict it 8 to a smaller sample. 9 DR. BLANC: Right, right. 10 DR. GRAHAM: But everything that 11 was done for that simulation was the same that 12 was done in the other simulations. How we 13 estimate the endogenous contribution, how we 14 estimate the ambient, everything else was the

15 same. 16 DR. BLANC: Right. 17 CHAIR BRAIN: So, let's press on. 18 I mean I think the good news is a lot of this 19 is territory that is covered in some of the 20 charge questions. 21 Let's decide, No. 1, that we will 22 make some comment on these graphs, referring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 95 1 to this document. So, Tom and Milan and Joel, 2 and everyone else, and Stephen, who had 3 comments about this, and maybe we will ask 4 you, Paul, to pull them together. But let's 5 also do what you have suggested, is revisit it 6 and see how much of this discussion belongs in 7 a comment on these figures, and how much will 8 come up in charge questions. 9 But I think it is clear that this 10 is a potentially important part of the new 11 document that will be next and that we should 12 comment on it, because I think it has been a 13 very useful discussion. 14 Good. Are we nearing the end of 15 the discussion? Do you want to finish it up? 16 Then, we will take our public comment and get 17 going. 18 DR. GRAHAM: Yes. Right. But I 19 hate to say this is another new figure. 20 (Laughter.) 21 Again, we are interested in 22 understanding where these exposures occur.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 96 1 So, as part of the output from the model, we 2 can generate the percent of individuals where3 they experience a given exposure, what micro4 environment. 5 What I have done is taken the 6 eight micro-environments and aggregated them 7 to five. So, it would make it an easier 8 presentation. And I aggregated them based on 9 the factors that were used to estimate the 10 micro-environmental concentrations. 11 That is what is depicted here in 12 these bar graphs. They all sum to 100 percent 13 for each of the exposure concentration levels. 14 We have got inside vehicles as its 15 own, it was its own micro-environment. It 16 wasn't aggregated with others. 17 We have outdoors, low and high, 18 and indoors, low and high. Those low and high 19 categories are based on the factors that were 20 used, basically. 21 And outdoors means the person 22 experienced the concentration, the exposure

### 202-234-4433 Neal R. Gross & Co., Inc. Page 97 1 concentration, outside, and indoors means they 2 were inside some micro-environment. 3 And again, along the Y-axis we 4 have the percent of the total time that the 5 population was at or above the given exposure 6 concentrations that are listed here, 7 increasing in concentration across the X-axis. 8 For the first condition, that is 9 essentially all of the persons, the time spent10 in each of these particular micro11 environments. Of course, we tend to have this 12 spend a lot of time indoors, and that is what 13 is given by this white bar, indoors, low 14 concentration micro-environment. 15 And about 5 or so percent, inside 16 vehicles and outdoors, which is consistent 17 with this particular population. And again, 18 this is the entire simulated population, all

19 adults. 20 Then, as we go along this x-axis, 21 it is the percent of the population that 22 experienced a concentration exposure, a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 98 1 concentration, in this first instance, it is 2 at or above 3 ppm. You can see quickly a 3 distinct difference between where people 4 actually spend time in the simulation, 5 assuming that there was no exposure. 6 Most persons experienced 7 concentrations at or above 3 ppm inside 8 vehicles. This influence from inside vehicles 9 increases with increasing concentrations. 10 That is, the bulk of those high-end exposures 11 are associated with in-vehicle exposures. 12 Now there is still a small amount, 13 but relevant amount, of exposure occurring in 14 outdoor or micro-environments, both low- and 15 high-concentration micro-environments, but 16 certainly less than that of the contribution 17 from inside vehicles. 18 This is considering as-is air 19 quality. When we look at the air quality just 20 meeting the current standard in Denver, they 21 are fairly similar, but you could see that, at 22 some of the higher concentrations, you see a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 99 1 greater contribution from non-indoor sources 2 occurring inside indoor micro-environments. 3 Well, before I go, actually, were 4 there any questions about those particular 5 figures? 6 DR. DAHMS: Are any of these 7 things based on reality? 8 (Laughter.) 9 I mean the high exposures in the 10 cars, are those people that look to be 100 11 percent of the time in cars, are they sleeping 12 in their cars? What are they doing? I don't

13 understand that. 14 DR. GRAHAM: Right. Let me just 15 explain that. 16 CHAIR BRAIN: This doesn't add up

17 to 24 hours. I mean look at the -- 18 DR. GRAHAM: Right. No, no. 19 CHAIR BRAIN: It's the vertical 20 axis here. 21 DR. GRAHAM: Right. So, you have 22 a simulation. An individual experiences a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 100 1 given concentration. This is a collection of 2 that data where they experience -- we draw the 3 line in the sand, like, say, for 4 concentrations at or above 20 ppm, where did 5 they occur? Okay, well, out of the total time 6 that people had concentrations at or above 20 7 ppm, the bulk of it was associated with inside 8 vehicles. It doesn't mean that, oh, well, 9 they spent 90 percent of their time in cars. 10 No, it's 90 percent of the time that they were 11 in cars at or above 20 ppm. 12 CHAIR BRAIN: In fact, toward the 13 right, I mean the total time might add up to 14 40 minutes, not 24 hours. 15 DR. GRAHAM: Right. Right. And 16 that is probably something that should be 17 included -- 18 CHAIR BRAIN: This is only the 19 time that they are exposed above the levels. 20 DR. GRAHAM: Absolutely. 21 DR. DAHMS: Because in terms of 22 trying to understand dose, what makes sense to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 101 1 me is actual time at a concentration, and not 2 percentage of time. I guess that is where my 3 problem is. 4 DR. GRAHAM: Of course, yes. The 5 dose is going to be related to the time, the 6 duration associated with that exposure level. 7 But this is telling us, well, where are these 8 high-end exposures occurring? It is not 9 directly linked to, okay, is that linked to 10 the maximum end-of-hour COHb dose level? That 11 is not the intent of the presentation. It is 12 to show where these exposures are occurring

13 and at what level. 14 DR. BLANC: This might be more 15 informative if it also included, you know, 2 16 ppm and 1 ppm, because, basically, what you do 17 is you go from the all to these very high 18 concentrations where it is almost all blacked 19 out because it has to be, by definition, 20 dominantly from vehicular exposure. So, I 21 don't know whether you would see more of a mix 22 at the 2 ppm and 1 ppm, but it might be more

### 202-234-4433 Neal R. Gross & Co., Inc. Page 102 1 informative. I don't know. 2 CHAIR BRAIN: Yes, I mean that's 3 where most of the population is. We are 4 looking at this extreme case, and on the right 5 we are looking at, what, people with leaky 6 mufflers and things, and holes in the

7 floorboard? 8 (Laughter.) 9 DR. GRAHAM: Well, we know that on 10 road, and associated with on-road exposure 11 concentrations, inside vehicles those 12 concentrations are, of course, going to be 13 higher than ambient contribution. When we14 factor in infiltration inside indoor micro15 environments, using a mass balanced model, 16 obviously, those are going to be, in general, 17 less than the ambient exposure. So, you 18 wouldn't expect to see a large proportion of 19 the population experiencing concentrations 20 above ambient levels. When you consider as-is 21 air quality, that is why you see very few 22 people at or above 3 ppm because as-is air

### 202-234-4433 Neal R. Gross & Co., Inc. Page 103 1 quality there's very few points that are above 2 3 ppm. 3 CHAIR BRAIN: Yes, that would be 4 useful to know, what percentage because, I 5 mean, as we move right, we are dealing with 6 tiny fractions, right? 7 DR. GRAHAM: Right. Like you 8 said, this is percent of total of time at or 9 above that concentration. So, there's varying 10 minutes as you move across that X-axis, and 11 that is something that should be included as 12 far as the total minutes that the entire 13 population spent at or above those 14 concentrations. I can include that. 15 DR. HAZUCHA: Would it be possible 16 to develop such histograms for subpopulations 17 that are called CHD subpopulation? They have 18 all been indoors. They usually spend more 19 time indoors.

20 I understand that these are for 21 all individuals, including CHD. Is that

22 correct or --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 104 1 DR. GRAHAM: This is all persons. 2 I think that is the way that this data are 3 output. I think to get that data for the CHD 4 population, it would require more than we have 5 time to do -- 6 DR. HAZUCHA: Okay. 7 DR. GRAHAM: -- with the recoding

8 of the model. 9 DR. BLANC: Can you also, while 10 you are here, explain something technical 11 about the exposure scenarios? You had a 12 useful table that presented exposure levels at 13 the various, at all eight, or whatever the 14 scenarios. There were several scenarios of 15 indoor -- 16 DR. MURPHY: In the slides? 17 DR. BLANC: No, in your -- 18 DR. DICKERSON: DICKERSON: Is this 19 connection working? 20 DR. BLANC: In your document 21 somewhere, there was an explanation. I don't 22 know the page number.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 105 1 MS. BARRY: Yes. Is there someone 2 on the line who is having technical 3 difficulty? 4 DR. DICKERSON: Hi, Kyndall. This 5 is Russ. 6 MS. BARRY: Hi, Russ. 7 DR. DICKERSON: I just wanted to 8 let you know I'm here. 9 MS. BARRY: Thank you. 10 CHAIR BRAIN: Thanks, Russ. 11 In any event, we are in the middle 12 of discussing the new material and some new 13 graphs that we are looking at. We are nearing

14 the end of that. 15 DR. BLANC: Yes, 5-24, it is table 16 5-16 and has the eight scenarios of exposure, 17 and it gives the geometric mean. And then you 18 give some examples of what you include in the 19 micro-environment. 20 So, in one of the indoor 21 environments which is the sort of low indoor 22 environment, which includes healthcare

### 202-234-4433 Neal R. Gross & Co., Inc. Page 106 1 facilities and schools and churches and then 2 manufacturing facilities, and then you have 3 examples of service station and auto repair, 4 which is the highest. 5 So, in the auto repair, for 6 example, that is high because an auto repair 7 would have more ambient air pollution coming 8 into it from -- it is not treating the cars 9 that are being worked on in the auto repair 10 station as a point source? Conceptually, I 11 just want to understand conceptually since -- 12 DR. GRAHAM: Right. Yes, we can 13 go into this in greater detail later, but it 14 is based on the relationship between what is 15 measured at an ambient monitor or an outdoor 16 location, rather -- forgive me -- and what 17 occurs inside. So, it is, essentially, a 18 micro-environmental factor that is used to 19 adjust the outdoor concentration that is 20 estimated from the ambient concentration in 21 each of these micro-environments. 22 DR. BLANC: But it wouldn't be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 107 1 because an automobile was running in the 2 garage? 3 DR. GRAHAM: No, but it was based 4 on measurement data that they had 5 concentrations where they measured inside 6 these particular micro-environments, and they 7 had concentrations on the outdoor 8 concentration, and they developed this factor

9 based on that. 10 DR. BLANC: Right. But if I had a 11 heater running in the garage, that wouldn't be 12 counted because you don't count indoor sources 13 of air? You wouldn't count an indoor source? 14 I'm just trying to understand conceptually 15 because this seems to be a bit of a 16 contradiction. 17 DR. GRAHAM: Absolutely. 18 DR. BLANC: So, if it is a 19 vehicle, if it is running indoors, you would 20 count it, but if it was a heater running 21 indoors, you wouldn't count it because that is 22 not an ambient --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 108 1 DR. GRAHAM: It would be accounted 2 for if it were part of that study, and it 3 would be built into that factor. If you see 4 there's a geometric mean and a distribution, 5 that is there's variability in the 6 relationship between that concentration that 7 was measured inside versus that outside. And 8 it could be due to a particular source, 9 whether it was the motor vehicle or a heater 10 that was present. CHAIR BRAIN: Let's move 11 on and take us through the last two slides, 12 pages 17 and 18. Then, we will return to 13 these issues as needed when we get to the 14 charge questions. 15 DR. GRAHAM: Right. Thank you. 16 So, as was done in the earlier 17 assessment, we used a qualitative assessment 18 approach to characterize the uncertainty. The 19 first step, of course, was to identify sources 20 of uncertainty that may influence the exposure 21 in the dose estimates. Then, we qualitatively 22 ranked the magnitude in direction, that is,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 109 1 how much it might affect, and why would it be 2 over- or underestimating as far as the impact. 3 Would it overestimate or underestimate the 4 exposure dose? And, of course, an assessment 5 of the state of the knowledge of that data

6 that we used. 7 So, we identified 14 sources.

8 There were a number of sources that under 9 certain conditions would exhibit bidirectional 10 influence. That is, there were certain 11 sources that could influence it up or down, as 12 far as the exposure estimates. A few were 13 identified; namely, two were identified as 14 specifically this would contribute to perhaps 15 an underestimate or an overestimate. 16 And the magnitude, of course, also 17 varied depending on the conditions associated 18 with that particular source, and the majority 19 were low, identified as having a low magnitude 20 of influence, but there were several that had 21 between low- and medium-level influence. 22 The knowledge database, we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 110 1 recognize that there is limited data that are 2 available for a lot of the data that were used 3 in the model, and, also, in performing 4 evaluations, ranging from low to medium as

5 well. 6 In conclusion, we recognize that, 7 given the time that we had to perform this, 8 that this is some of the best estimates of CO 9 exposure for the simulated population that we 10 are trying to represent here, and there were 11 a few that we identified, based on this 12 characterization, that could have potential 13 for improving the characterization. 14 Those are listed here, including 15 the spatial and temporal representation of the 16 ambient and outdoor concentrations, the use of 17 the historical data, which, again, in using 18 the historical data, there may be many 19 approaches that we could use, as I identified 20 in the earlier assessment, but it is very 21 difficult to actually predict what a future 22 hypothetical scenario might be, even though we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 111 1 can characterize it based on what we know 2 about the current situation, given current and 3 historical air quality. 4 In addition, these others, you 5 know representation of the activity pattern 6 database, and there was some discussion about 7 that in one of the appendices as far as the 8 comparability with normal, so-called normal, 9 individuals and those with CHD, and the 10 representativeness of the longitudinal profile 11 approach that we have here to string together 12 these hourly, or I'm sorry, daily diaries. 13 The micro-environmental algorithm in the input14 data that we used, as well as the earlier15 discussed physiological factors that we used 16 to represent the at-risk population. 17 So, with that, I leave it to the 18 Committee to further comment on the document 19 as well as the slides that I provided, 20 including the modifications that were made for 21 this assessment, in response to the questions 22 and comments on the earlier draft, and some of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 112 1 these additional air quality scenarios that we 2 considered, as well as the new data that were 3 presented at this meeting. 4 Thank you. 5 CHAIR BRAIN: Great. Thank you. 6 Let's now proceed to the public

7 comment. 8 MS. BARRY: Mr. Heuss, are you on 9 the line? 10 MR. HEUSS: Yes, I am. 11 MS. BARRY: Okay. We will now 12 give you your five-minute opportunity to speak 13 with the CO Panel. Your time begins now. 14 Thank you. 15 MR. HEUSS: Thank you. 16 I am John Heuss with Air 17 Improvement Resource, Incorporated. 18 The second Draft REA is a distinct 19 improvement over the first. By taking into 20 account the spatial variation in CO and 21 several micro-environments, the distribution 22 of COHb exposures is now much more realistic.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 113 1 But no comparison is provided to show the 2 substantial reduction in estimated risk. 3 EPA should include a direct 4 comparison for CASAC. For example, comparing 5 tables 6-11 and 6-12 in the second draft with 6 tables 6-22 and 6-23 in the first draft, you 7 can see that CO levels that just meet the 8 current standard, at that level, the 9 percentage of persons with maximum COHb levels 10 at or above 2 percent was reduced by over a 11 factor of ten, for example, from 6.6 percent 12 to 0.5 percent in Los Angeles. We commend EPA 13 for using more realistic assumptions. 14 In addition to the distribution of 15 maximum levels, we applaud the inclusion of 16 the data on person-days. These data are17 extremely important in evaluating the day-by18 day risk and putting it into a public health 19 perspective. For example, in LA, just meeting 20 the current standard results in only 0.002 21 percent of the person-days in the population 22 of adults with COHb levels at or above 2

### 202-234-4433 Neal R. Gross & Co., Inc. Page 114 1 percent. In fact, less than .1 percent of 2 person-days are above 1.5 percent. This 3 demonstrates that the current standard is 4 highly protective. 5 Since as-is CO concentrations are 6 now lower than the standard, the risk from 7 current ambient CO is even lower, and that is 8 documented in the REA. In addition, the 9 second draft risk estimates are quite similar 10 to the risk estimates from 2000 for Los 11 Angeles, but somewhat higher for Denver. 12 Thus, the estimates of risk for a given level 13 of ambient CO have not materially changed 14 since the standard was last reviewed. 15 However, we believe the upper tail 16 of the COHb distribution estimated for Denver 17 in the second draft is too high because one of 18 the four sites is a micro-scale site, located 19 on a traffic island at the intersection of 20 major arterial roads. In both Denver and Los 21 Angeles, we are concerned that the methodology 22 for estimating in-vehicle exposures

### 202-234-4433 Neal R. Gross & Co., Inc. Page 115 1 overestimates the actual in-vehicle 2 concentrations under adverse meteorology. 3 Since day-to-day emissions are 4 relatively constant, the wide distribution of 5 ambient CO arises due to the differences in 6 dispersion that are driven by variations in 7 meteorology. High ground-level concentrations 8 result from low wind speeds and limited 9 vertical dispersion. However, as Chock 10 documented in detail in 1977, the 11 concentration fields around roadways are also 12 influenced by the mechanical mixing and 13 turbulence generated by the traffic that 14 effectively limits the buildup of CO and other 15 pollutants under adverse ambient meteorology. 16 There is no data indicating that the 17 in-vehicle concentrations in the U.S. now 18 approach the upper end of the ranges used in 19 the model. As you just saw in slide 16, there 20 are times when the model says it is greater 21 than 60 parts per million. There is no data 22 that demonstrates this. Rather than use some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 116 1 multiplicative method, as EPA does now, we 2 think these data should be in terms of an 3 increment of mass units for in-vehicle. 4 Turning now to the Policy 5 Assessment, we agree that great weight should 6 be placed on the control studies. We urge the 7 staff to add information on the percent-days 8 of COHb from the REA to the various benchmarks 9 in tables 2.5, 2.6, and 2.7. Again, the 10 distribution of person-days of COHb is a more 11 appropriate metric to evaluate the overall 12 public health risk than just the maximum COHb 13 in the air. 14 In November of 2009, we provided 15 comments detailing reasons why the 16 epidemiology summarized in the ISA should be 17 given little weight. First, the pattern of 18 acute associations reported for CO is 19 remarkably similar to that from all the 20 criteria pollutants. 21 Second, multi-city studies report a 22 biologically-implausible wide range in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 117 1 individual-city associations from strongly 2 positive to strongly negative for each 3 pollutant. With 25 to 40 percent of the 4 associations in various multi-city studies 5 being negative, it is impossible to 6 characterize that data as consistent. 7 Third, with such stochastic 8 variation, relying on any one individual study 9 or a small cluster of studies in a given city 10 is unreliable. 11 Fourth, there is now greater 12 appreciation that model selection uncertainty, 13 publication bias, and issues of surrogacy or 14 confounding limit the interpretation of the 15 published associations as true effects. 16 The arguments in the PA for a more 17 stringent standard at one point rely on 18 cardiovascular hospital admission associations 19 reported in three Atlanta studies. In the one 20 study that reports a significant positive 21 association with CO, the authors do not 22 ascribe that to an effective CO per se, but,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 118 1 rather, raise the same issues of CO acting as 2 an indicator that are acknowledged in the PA.

3 MS. BARRY: Mr. Heuss?

4 MR. HEUSS: Yes? 5 MS. BARRY: That is five minutes. 6 MR. HEUSS: Thank you. I would just 7 indicate that, based on these considerations 8 and the improved estimates they provide for 9 COHb, we believe the current eight-hour 10 standard is protective. 11 Thank you. 12 MS. BARRY: Thank you. 13 CHAIR BRAIN: Thank you. And if you 14 do want to send us your remarks in writing, we 15 will be glad to add them to the record. 16 MR. HEUSS: Thank you.

17 CHAIR BRAIN: Let's now turn to the 18 REA charge questions. So, everyone should 19 have brought with them, this is the letter 20 dated February 24th, 2010, from Lydia Wegman 21 to Kyndall. So, this will be the sort of 22 guide, and it will also be up there as well.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 119 1 So, let's now begin with Francine, 2 who will take us through Charge Question 1.3 DR. BLANC: Can we have a five4 minute break? We have been going since 8:30.

5 It's 10:30. 6 MS. BARRY: It is scheduled for

7 10:45. 8 DR. BLANC: Well, it is scheduled 9 for 10:45? All right. 10 CHAIR BRAIN: Why don't we at least 11 get one done, and then we will take a break? 12 But if anybody needs to take an individual 13 break, feel free. 14 DR. LADEN: And from the preliminary 15 comments I have seen, this shouldn't take that 16 long. 17 Okay. So, really briefly, the 18 question was: "Does the Panel find the 19 summary of CO exposure and discussion of 20 ambient CO sources, exposure dose, health 21 effects, and risk characterization approach to 22 be technically-sound, clearly-communicated,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 120 1 and appropriately-characterized?" This is 2 about Chapter 2.3 I found this chapter very well4 organized and technically-sound. I thought 5 that EPA did appropriately characterize what 6 they did do. I thought it was also important 7 that they discussed what they did not do. I 8 thought that was well-defended. 9 In terms of there were a little 10 couple of statements in there about, you know, 11 why is it that they are focusing on COHb 12 levels as opposed to the ambient CO 13 measurements, I thought that that was 14 important to describe. And for a lay-reader 15 who is coming into this cold like, why is it 16 that all the analyses are focused on the COHb17 levels, I thought that was important and well18 done. 19 One concern I had, it is just the 20 fact that most of the Allred data is old. So, 21 there is nothing we can do about that. I just 22 wanted some statement that we are, that EPA is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 121 1 confident that the current situations can be 2 extrapolated appropriately from what was 3 observed in the past, and just acknowledgment 4 that the data is old, and that this is the 5 best that we have. I don't think it is a 6 problem. I just think it is a statement of 7 acknowledging that uncertainty. 8 I thought that the chapter was 9 clearly-communicated. Just, in general, in 10 terms of reading it, I thought there was some 11 editing that, you know, this is really minor 12 editing that needed to be done. There were 13 some very long sentences. There were a few 14 sentences where there were not complete 15 sentences. And I understand the speed of the 16 time, and I thought that just, particularly 17 when I was reading this chapter and other 18 chapters, I think there was more of it already 19 written previously, that this one just needed 20 a little bit of editing.

21 But that was all I had. 22 CHAIR BRAIN: Arthur, you also

### 202-234-4433 Neal R. Gross & Co., Inc. Page 122 1 looked at this. Any comments that you want to

2 add? 3 DR. PENN: I had, as I recall,

4 almost no comments on that. Paul had a bunch. 5 Yes, I thought, overall, that that particular 6 chapter, everything seemed to be well-done and 7 seemed technically-sound. Stylistically, 8 there were some changes that should be made, 9 but that's trivial. 10 CHAIR BRAIN: Anyone else on the 11 Panel want to response to Charge Question 1? 12 (No response.) 13 So, just to make sure we are all 14 oriented, this is -- 15 DR. RITZ: Hello this is Beate.

16 CHAIR BRAIN: Yes? 17 DR. RITZ: Yes, I would like to say 18 something. I actually thought that some of 19 the wording could really be improved with 20 respect to the non-COHb potential mechanism. 21 I totally understand and agree with the choice 22 of the REA using the COHb levels, but in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 123 1 wording of why that is happening, it puts a 2 lot of disregard onto other biologic 3 mechanisms and the Epi results. It is not 4 always very clear to me that they are really 5 addressing these are controlled studies and 6 these are the reasons why we are doing it.

7 But the reasons are because we have 8 experimental data for the short-term effects, 9 but we are really not doing a risk assessment 10 for a lot of other types of effects that could 11 be happening at other levels and through other 12 mechanisms. 13 I think there's a convolution that

14 needs to be taken care of. 15 CHAIR BRAIN: Thank you. 16 So, Francine, you are going to pull 17 this together. Is that clear you to? 18 DR. LADEN: Yes. I think it is 19 along the lines of what I was commenting 20 about, about how it is important to have that 21 discussion in there about why the reliance on 22 COHb. As far as I understand what you are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 124 1 saying, Beate, it is that it needs to be 2 clarified more and maybe expanded a little 3 bit. 4 DR. RITZ: Yes, exactly. I mean 5 right now, to me, it is not clear that a lot

6 of the sentences refer to effects that are due 7 to COHb, and that we actually also have other 8 in-human health effects that may not go 9 through the same mechanism. 10 So, we are kind of making several 11 leaps of faith that what we are doing with the 12 REA is actually addressing most of the bulk of 13 the health effects, but it might not. 14 CHAIR BRAIN: Thank you. 15 Yes, just is there anyone that is 16 missing this letter? I guess, if you need it, 17 raise your hand, and Kyndall can provide you 18 with a copy. 19 But the other thing that I want to 20 point out, which I should have done even 21 before, is the letter actually begins with a 22 detailed list of responses to our previous

### 202-234-4433 Neal R. Gross & Co., Inc. Page 125 1 comments. So, I think that is very helpful 2 and very much appreciated, and really saves us 3 a lot of time in having you summarize for us 4 what you have done. So, thank you. 5 So, we are now looking at page 1. 6 Since that went so quickly, let's, actually -- 7 yes, Milan? 8 DR. HAZUCHA: Yes, I have a couple 9 of questions --

10 CHAIR BRAIN: Please. 11 DR. HAZUCHA: -- yes, to Charge 12 Question 1. 13 The sources of endogenous carbon 14 monoxide, it is mentioned only hemoglobin as 15 source, metabolism of hemoglobin. Maybe we 16 should mention that there are other sources as 17 well. For example, medication will increase 18 endogenous production or inhalation of 19 dihalomethanes will increase endogenous CO. 20 So, I think it should be included. 21 Then, on one of the pages, and I 22 guess it is page 2-8, the users of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 1261 recreational drugs are considered to be an at2 risk population, if I read it correctly. Now, 3 certainly, they are at risk, but not from 4 ambient carbon monoxide. So, I guess that 5 needs to be clarified, if I understood it 6 correctly. Page 2-8, line 19, I believe. 7 Now, in discussion of Allred 8 studies, the results are presented as percent 9 of change. I guess it is 4.2 percent 10 decreasing time to angina. It would be really 11 very helpful for better understanding where 12 the changes are if, in addition to just 13 relative percentage changes, we also had the 14 true units, like seconds, here. So, we will 15 have the 4.2 percent is comparable, actually,

16 to 22 seconds decrease from close to 9 17 minutes. So, that way, we will get a better 18 perception of what the change is. 4.2 19 percent, it is sort of a number which is 20 difficult to compare to something. 21 In addition, I am glad to have at 22 least some comments there about time to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 127 1 angina, when it was reduced, was the 2 subsequent times to angina reduced as well? 3 What was actually the sequelae to initial 4 exposure to carbon monoxide? Was, let's say, 5 in subsequent weeks or months the change was 6 still there or was the frequency of attacks 7 increased, and so on? Maybe there are no 8 data, but if there are no data, then maybe we 9 should say so, that we really don't know 10 without a sequelae of these exposures to 11 carbon monoxide. 12 CHAIR BRAIN: So, you are asking 13 about long-term consequences of these acute -- 14 DR. HAZUCHA: Long-term, yes. 15 CHAIR BRAIN: -- exposures, like in 16 the Allred study?

17 DR. HAZUCHA: Yes. Yes. 18 CHAIR BRAIN: Then, I guess we have 19 no idea, do we? 20 DR. HAZUCHA: Well, maybe we should 21 say so, if we have no idea. 22 CHAIR BRAIN: Tom, do you want to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 128 1 comment on that? 2 DR. DAHMS: Well, this has been a 3 topic of discussion at dinner last night with 4 a bunch of us. It has gone on since these 5 studies were carried out. 6 It is a concern of mine for sure, 7 and probably a lot of us, that this is an 8 adverse health effect. I think that is pretty

9 clear. 10 CHAIR BRAIN: What do you mean by 11 "this is"? The shortening to the time of

12 onset -- 13 DR. DAHMS: The shortening of 14 anything that looks like an increase in 15 severity of disease that would logically 16 follow what would happen. Someone with 17 progressive coronary artery disease is going 18 to able to work less and less. Therefore, it 19 is, by transfer of that concept, that this

20 would be looked at as an adverse health

21 effect. 22 CHAIR BRAIN: Myocardial ischemia is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 129 1 not a good idea? 2 DR. DAHMS: Right. And increasing 3 severity of this is likewise. 4 But whether it has any consequence, 5 I look at the epidemiologic data as one way 6 and one part of the epidemiologic data is 7 getting an answer to that. If there is an 8 increase in cardiovascular admissions to the 9 hospital or ER visits, and I think that is the 10 way I interpret what is in these documents as 11 being, when they say the epidemiologic data is 12 -- I don't know whether substantiates is 13 consistent with whatever these findings. I 14 think that is, without stating it, I think 15 that was my interpretation. 16 I don't know what anybody else's 17 interpretation of those data are, but that is 18 the only way you are going to get an answer to 19 that, Milan. It is only one answer. 20 DR. HAZUCHA: Yes. Well, still, I 21 would like to see a comment that we really do 22 not have data because it will tell us for the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 130 1 future maybe some additional studies need to

2 be done. 3 CHAIR BRAIN: I guess I am still 4 unclear as to exactly what you are saying. I 5 mean, clearly, susceptibility to increased 6 levels of CO is a bad idea, and myocardial 7 ischemia is a bad idea. 8 But are you also asking whether CO 9 exposure causes a progression of the lesion? 10 Or I don't quite understand what you are 11 saying. 12 DR. HAZUCHA: What I was asking was 13 this single exposure to carbon monoxide 14 decreased time to angina -- 15 CHAIR BRAIN: right. 16 DR. HAZUCHA: -- by 22 seconds out 17 of 9 minutes. 18 CHAIR BRAIN: Right. 19 DR. HAZUCHA: Are there any 20 consequences? Let's say next time, and these 21 people have attacks, some of them -- 22 CHAIR BRAIN: Or does that suggest

### 202-234-4433 Neal R. Gross & Co., Inc. Page 131 1 that you are more susceptible to an 2 arrhythmia? 3 DR. HAZUCHA: Are they susceptible 4 to anything else? 5 CHAIR BRAIN: And I think most 6 people would say yes. 7 DR. HAZUCHA: Are they susceptible 8 to increased frequency of these attacks, and 9 so on, because of that previous exposure to 10 carbon monoxide? 11 CHAIR BRAIN: Well, when you add 12 that, then that seems to go in a different 13 direction. 14 DR. HAZUCHA: Not necessarily. 15 CHAIR BRAIN: Because it seems to me 16 you are, then, saying, does CO cause, you 17 know, heightened -- 18 DR. HAZUCHA: Yes, does CO cause an 19 increased frequency, let's say? 20 DR. DAHMS: It gets back to the 21 modeling. So, what number of exposures -- 22 let's say that 2 percent was significant in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 132 1 some way. How many of those exposures do you 2 have to have in a year's time to precipitate 3 some kind of more severe event? 4 I mean, if you are going to limit 5 your exercise performance, and you want to 6 walk to a candy dish, and you've got CO, you 7 are going to walk to the closest one rather 8 than the next one over there. That is what 9 that means, right? You are going to do less

10 work. 11 CHAIR BRAIN: But you are hinting at 12 a cumulative effect of repeated CO exposures. 13 DR. DAHMS: Well, I don't know. 14 CHAIR BRAIN: Well, I don't think we 15 have any evidence for that, do we?

16 DR. DAHMS: We don't.

17 CHAIR BRAIN: No. 18 DR. DAHMS: Milan is right; we have 19 no evidence that -- 20 CHAIR BRAIN: We are talking about 21 persistent susceptibility, but not a 22 cumulative effect.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 133 1 DR. DAHMS: And I don't know what 2 the history of this has been in terms of any 3 kind of a negative adverse health effect is 4 sufficient for the Administrator to -- 5 DR. BLANC: I mean, coming back to 6 Beate's comment on the telephone, I think this 7 is the critical flaw in emphasis, which is 8 this is the path you go down if you 9 overemphasize the controlled human exposure 10 study and put blinders onto the convincing 11 epidemiologic data. To do that, I think is a 12 big mistake. I don't want to put words in Dr. 13 Ritz's mouth, but I think that is what she was 14 trying to get at. 15 I think there is a problem -- 16 DR. RITZ: Yes, that is exactly what

17 I meant. 18 DR. BLANC: I think there is, 19 actually, a fatal flaw in Chapter 1. I think 20 it will come up in that later discussion. 21 Since Chapter 1 is kind of a summary, I don't 22 know if the way to go about it is to deal with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 134 1 it here, but it has to do, in fact, with who 2 is the population at risk. 3 Chapter 1 sets up the rest of the 4 document to narrowly define coronary artery 5 disease and disregard all other cardiac 6 disease as a susceptible population by using 7 language such as other types of cardiovascular 8 disease may also potentially contribute to 9 increased susceptible. 10 I think we went through this with

11 the ISA. We concluded that the data were 12 conclusive that there was a causative 13 relationship between CO exposure and adverse 14 health events in the population with cardiac 15 disease, more broadly defined than coronary 16 artery disease because the epidemiologic data 17 were consistent with congestive failure and 18 with more broadly-defined disease as such. 19 So, the last paragraph on 2-7 20 through the second paragraph on 2-8 I think 21 are completely off-target, and this, of 22 course, is carried through the rest of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 135 1 document, which allows the document to have a 2 fairly narrowly-defined population at risk, 3 which, then, gives them very low numbers for 4 the number of people who are overexposed in 5 all of the modeling. I think it is 6 inconsistent with the ISA, and it is why we 7 had so much emphasis and discussion on the 8 endpoints in that document. 9 So, I am not satisfied, actually, 10 with the introductory chapter, for that 11 reason. I mean I talk about it in my charge 12 question because it is where it is dealt with 13 not as an introduction, but more 14 substantively. 15 DR. DAHMS: But it was my 16 understanding that the level of causality was 17 lower, was judged to be lower, and I don't 18 remember the specific words that are used to 19 rank those levels of causality. 20 DR. BLANC: Not by us, is my 21 recollection. 22 DR. KLEINMAN: I think the document

### 202-234-4433 Neal R. Gross & Co., Inc. Page 136 1 says it is suggestive of a causal effect on 2 morbidity, which is lower than what is likely

3 to be -- 4 DR. DAHMS: Which is likely to be 5 suggestive -- 6 DR. JOHNS: Likely to be causal. 7 So, that is the second -- 8 DR. DAHMS: Likely to be causal, 9 okay. 10 DR. PENN: Yes, but if you look at 11 the actual reports dealing with congestive 12 heart failure and stroke, and we talked about 13 this in the ISA, the numbers really are better 14 than the conclusions that are drawn here. 15 They talked about two out of five represent 16 possible changes. It is really four of the 17 five studies that they talked about. 18 In my writeup, I had another 19 extended thing on it. If you look at, for 20 congestive heart failure, stroke, and for 21 coronary artery disease, I think it was 22 figures 5.2 through 5.4 in the ISA, the x-axis

### 202-234-4433 Neal R. Gross & Co., Inc. Page 137 1 changed dramatically. So, that for coronary 2 artery disease, where I think there were 31 3 studies that were listed, 27 of them showed 4 relative risk increases of less. The relative 5 risk went from 1 to 1.04; whereas, for 6 congestive heart failure and for stroke, they 7 went up over 1.75. In one case, they went up

8 to almost to 3. 9 So, the sense that you get from 10 looking at the data is that things weren't 11 balanced equally. So, if all of the data were 12 presented for each of the three sets, if for 13 the three sets of data all of the graphs were 14 presented with the same axes, I think you 15 would see that the epidemiology data really 16 speak very strongly to the fact that there are 17 causal relationships between CO exposure and 18 stroke, and ischemic stroke, and CO exposure 19 and congestive heart failure, that tend to be 20 really minimized in this writeup. 21 DR. KLEINMAN: But I think the point 22 that they make in the document is that there

### 202-234-4433 Neal R. Gross & Co., Inc. Page 138 1 are other factors that make it more difficult 2 to pinpoint CO. There are other confounding 3 things, other things that are associated with 4 CO that make it difficult to use the 5 epidemiology to have a dose/response 6 relationship. Therefore, the controlled human 7 exposure work, where all you have is CO, they 8 have a nice, clean dose response curve that 9 they, then, apply to their models. 10 So, I think we have to separate the 11 concept of the short-term exposures being used 12 as a way or a tool to develop a dose/response 13 relationship that we can, then, use to set a 14 standard, as opposed to the epidemiology, 15 which gives very good evidence that there is 16 something going on that is associated with CO, 17 but can you really put the number, you know,

18 the CO number that would be related to that 19 effect? That may be more difficult. But I20 think that it is clear that there is a long21 term consequence of chronic CO exposure, based 22 on the epidemiology.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 139 1 CHAIR BRAIN: So, I think this is 2 really important. I think it is clear from 3 our discussion of the ISA that everybody 4 wanted to broaden the definition of 5 susceptibility beyond angina, and that all 6 these other underlying cardiovascular 7 conditions were really important. 8 I guess this now really becomes more 9 critical when we move to the REA, where we 10 want to make some quantitative risk 11 assessments, which are all saying, is that 12 concern and the data that generates that 13 concern, good enough that it should really be 14 part of the REA? 15 What's your summary sort of, 16 Francine? Is it included adequately in 17 this -- 18 DR. LADEN: I think that the way 19 Michael put it is really important. I mean 20 I'm not trying to discount the epidemiology at 21 all. I think it is very crucial to show the 22 importance of doing this, and trying to figure

### 202-234-4433 Neal R. Gross & Co., Inc. Page 140 1 out what the risks are for the susceptible 2 populations, but I think there's a lot of 3 limitations for what we can do with the 4 epidemiology in figuring out a number to use 5 in the Risk Assessment because of the 6 confounders and the interpollutant 7 concentrations. 8 What I just want to say is that I 9 think that, given all that, I'm not saying it 10 is impossible, but the decision was made to

11 use the COHb data and the controlled 12 experiments to use for the REA. So, I think 13 expanding the discussion of that decision, and 14 of what the epidemiology can mean in terms of 15 putting it in context and the importance of 16 the chronic exposures, and what is in 17 persistence, it shouldn't be ignored, but I 18 don't think -- so, I think that those 19 limitations need to be acknowledged, but I 20 think that it still makes sense what it was

21 that was done. 22 CHAIR BRAIN: I guess I am also

### 202-234-4433 Neal R. Gross & Co., Inc. Page 141 1 hearing that this topic, this concern, really 2 ought to achieve its full flower in the Policy 3 Assessment, right? 4 DR. BLANC: But, Joe, the Policy 5 Assessment is driven by the tables which show 6 how many people are being exposed. And in 7 fact, to define the population at risk more 8 broadly has nothing to do with whether or not 9 they used the ppm exposure response data from 10 the human exposures. 11 What it has to do with is, how do 12 you define population at risk? Everybody 13 agrees that the data from the human exposure 14 is convincing, that there's a physiologic 15 response. Because the experiment was done in 16 patients with ischemic heart disease with an 17 ischemia outcome is one thing, but to say that 18 that has no bearance at all or no connection 19 to epidemiologic data, which convincingly 20 shows that you see the effect not only in 21 people with narrowly-defined ischemic heart 22 disease, but, also, with hospitalizations and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 1421 morbidity in other more broadly-defined at2 risk cardiovascular disease is not to, then, 3 say, but there must be some different 4 biological mechanism. 5 I think it is the presumption, the 6 public health protective reasonable 7 presumption is that it is a continuum, and the 8 word "continuum" was used in the document. 9 So, the question is, what is the -- 10 it has nothing to do really with -- no one 11 here is suggesting throw out the 12 carboxyhemoglobin-driven exposure methods that 13 are used. The only question is, what is your 14 number that you are going to use for the 15 percent of the population which is at risk? 16 I am going to come back to this in 17 my own comments, but they spent all of this 18 energy on very sophisticated modeling, which 19 is great in terms of exposure, and then, take 20 very simplistic, very crude, and very, I 21 think, overly-narrowly-defined scenarios for 22 what the population at risk is.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 143 1 Now you can do more than one 2 scenario, the same way that they say, what is 3 it at the current standard? What would it be 4 "as is?" What is it with the 99th percentile? 5 There are easy ways of doing the estimates 6 that they do of how many people are exposed. 7 Under one presumption, let's presume we define 8 it narrowly as coronary artery disease only, 9 and let's use National Health Interview Survey 10 self-report as the way we derive that, versus 11 more broadly-defined cardiac disease. That is 12 all I am saying. 13 CHAIR BRAIN: I think that makes a 14 lot of sense, right, and particularly in terms 15 of the pathogenesis. I mean, if you are 16 talking congestive heart failure or 17 susceptibility to arrhythmia, I mean there's 18 no reason not to think that the same 19 mechanisms of oxygen delivery apply -- I mean 20 stroke is maybe a different matter. I don't 21 quite see the same link of susceptibility to

22 stroke.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 144 1 DR. BLANC: Dr. Ritz, are you still 2 on the phone?

3 DR. RITZ: Yes. 4 DR. BLANC: I mean, maybe, since 5 you were a secondary on this charge question, 6 and I certainly wasn't, I mean, if you think 7 this is consistent with what you were trying 8 to say, maybe you could -- 9 DR. RITZ: It is consistent with 10 part of what I was saying. It is consistent 11 with, well, we are using certain models in 12 chambers studies of diseases because that is 13 ethical to do and possible. We are not 14 looking at other types of diseases because it 15 is just not possible. We are not going to put 16 pregnant women into those chambers, right? 17 So, I think that gets lost in that 18 document. I think the non-COHb-related 19 mechanisms are what has more recently been 20 discussed in the newer literature. That comes 21 back to Francine Laden's comment that all of 22 the COHb literature is fairly old. But that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 145 1 is okay because it is valid, certainly. 2 But we have some things that maybe 3 there's actually additional biological 4 mechanisms to be taken care of. Maybe the 5 COHb threshold or levels that we are dealing 6 with are also not very accurate. We are just 7 guessing that that's the relevant number that 8 we should use for a risk assessment. 9 So, we are making a lot of 10 assumptions that do not include either a 11 larger susceptible population or maybe even a 12 lower threshold for biologic mechanisms that

13 are not related to COHb. 14 DR. KLEINMAN: I guess when we come 15 to the Policy Assessment, I think a lot more 16 is said about those factors because that 17 really provides the rationale for the 18 alternative standards that are brought up. 19 DR. RITZ: I agree. 20 DR. KLEINMAN: So, there may be some 21 way of taking some of the information, 22 especially the way it has been interpreted in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 146 1 the policy analysis, and moving some of that 2 or duplicating some of that in the Risk 3 Assessment as a defined paragraph or something 4 that would give it a little bit more structure 5 and attend to this. 6 CHAIR BRAIN: Okay. Well, I think 7 this is going to come up repeatedly. I think 8 we are going to return to this first chapter. 9 It seems to me this is also kind of at the 10 level where our view on this topic belongs in 11 the two-page letter to the Administrator. 12 So, why don't we move on, unless 13 anybody has a specific comment? 14 Milan, you have something you want

15 to -- 16 DR. HAZUCHA: Yes, I have a specific 17 comment, actually. Many of you found, we 18 already saw this Special Report No. 17 19 published in January, 400 pages, by a special20 panel of experts. It is entitled, "Traffic21 Related Air Pollution: a Critical Reading of 22 the Literature on Emissions, Exposure, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 147 1 Health Effects". 2 What is surprising in this document 3 is that carbon monoxide is considered simply 4 as a surrogate for traffic-related air 5 pollution, primarily for PM. Basically, there 6 is barely any discussion on the health effects 7 of carbon monoxide. 8 I am sort of inclined to believe, 9 and I recall the data from epidemiologic 10 studies, ISA, which we discussed earlier, that 11 the concentrations of carbon monoxide which 12 are presented in these studies will, 13 essentially, result in normal, almost normal 14 range of carboxyhemoglobin levels in blood. 15 So, it appears like that, indeed, 16 carbon monoxide here is more like a surrogate 17 for other pollutants than actually the 18 effective agent itself. 19 CHAIR BRAIN: So, how does that -- 20 so, you are accepting the conclusions of this 21 HEI summary? And you are saying -- or how 22 does that affect what we say about the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 148 1 DR. HAZUCHA: Basically, yes, that 2 carbon monoxide, despite the data presented 3 that there is an increased risk associated 4 with carbon monoxide, that probably just 5 reflects sort of a different pollutant, most 6 likely PM or other pollutants and nitrogen 7 dioxide or a combination of those, but not 8 necessarily just carbon monoxide itself 9 because it acts as a surrogate. 10 DR. BLANC: But the epidemiologic 11 literature argued against that because the ISA 12 takes into quite heavy consideration the 13 studies which adjusted for co-pollutants and 14 didn't adjust for co-pollutants. So, in fact, 15 the data were surprisingly convincing, 16 adjusting or taking into account the measured 17 co-pollutants and arguing against that 18 interpretation. In fact, studies which did 19 not measure co-pollutants were basically 20 thrown out of the mix or taken out of the mix. 21 CHAIR BRAIN: I guess the other 22 comment, Milan, is you are really discussing

### 202-234-4433 Neal R. Gross & Co., Inc. Page 149 1 in that report, the study discusses the as-is 2 levels. You know, what are the current levels 3 of CO? But the report we are talking about is 4 focusing on the CO standard and what do we

5 know about health effects at that level and 6 around it. Just because we are now way below 7 that doesn't mitigate our responsibility for 8 trying to make an accurate assessment of what 9 might be happening at the CO standard, right, 10 and alternative standards? 11 DR. HAZUCHA: Yes, we certainly 12 should consider it, but, as I said, I am more 13 suspect, after reading this report here, I am 14 more suspect that it is not the effect of CO; 15 it is the effect of other pollutants which we

16 see.

17 CHAIR BRAIN: But most of those 18 studies are at lower levels of CO than the

19 current standard.

20 DR. HAZUCHA: Yes.

21 CHAIR BRAIN: Tom? 22 DR. DAHMS: Some guidance from Dr.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 150 1 Ritz, we have talked about asking to have 2 additional numbers of at-risk people from 3 cardiovascular disease. Would you add 4 pregnant women to the at-risk pool? 5 CHAIR BRAIN: Or their fetuses? 6 DR. RITZ: What's the question? 7 DR. DAHMS: Well, we are trying to 8 figure out, I am trying to figure out, if you 9 were going to ask the EPA to increase the 10 number of people potentially at risk for CO 11 exposure, would you add fetuses to that list? 12 DR. RITZ: Yes, I would. 13 CHAIR BRAIN: Okay. I think, why 14 don't we take a break? Russell, you will be 15 here after the break? You are available? You 16 are the lead discussant for the next charge 17 question. 18 DR. DICKERSON: Okay. Did I 19 successfully unmute? 20 CHAIR BRAIN: Yes. Yes, thank you. 21 Yes, we heard you. 22 So, it is now about almost five of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 151 1 11:00. Let's return at 10 after 11:00, and we 2 will begin with Charge Question 2. 3 Kyndall has a comment. What? 4 MS. BARRY: My watch shows 10:50. 5 CHAIR BRAIN: Well, somewhere in

6 between. 7 MS. BARRY: Okay. So 10 minutes?

8 CHAIR BRAIN: Yes. Let's be back 9 between five and ten after, and we will resume 10 with Russell. 11 (Whereupon, the foregoing matter

12 went off the record at 10:52 a.m. and went 13 back on the record at 11:08 a.m.) 14 CHAIR BRAIN: So, let's reconvene. 15 Hi, Russell. Are you there? 16 DR. DICKERSON: I am. Can you hear

17 me? 18 CHAIR BRAIN: Oh, good. 19 Before we turn to you, we are going 20 to do one other thing first. That is simply 21 to turn to the agency representatives and ask 22 them for feedback or for points that they want

### 202-234-4433 Neal R. Gross & Co., Inc. Page 152 1 clarified. 2 I think we are all a little confused 3 and hope that clarity will emerge as we deal 4 with some of these issues, as we march

5 forward. 6 But, please, tell us other comments 7 or questions that you might have. 8 DR. MURPHY: Sure, sure. I think we 9 all together are finding clarity. 10 But what we wanted to just touch on 11 in terms a clarifying question and comment is, 12 with regard to some of the discussion here, I 13 think the panel is doing some things which we 14 had to do as well, tease out how we use the 15 different types of evidence that are available 16 to us in this review, and how those puzzle 17 pieces can be fit together to be considered in 18 considering a review of the standard. 19 In terms of the REA, as we talked 20 about earlier, that is a piece where we do a 21 quantitative analysis based on the evidence 22 that allows us to do a quantitative analysis.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 153 1 Then, we bring that into the Policy Assessment 2 to meet up with all the other types of 3 evidence that doesn't fit so well into the 4 quantitative analysis, and try to consider all 5 of that together in the policy assessment. 6 With regard to the quantitative 7 assessment, which is some of the discussion 8 here talked about in Chapter 2 giving a little 9 more discussion to some of the evidence in 10 terms of broadly characterizing what it can 11 tell us, but some of the rest of the 12 discussion had to do with identifying a 13 population to be simulated in the REA. 14 What we had selected for simulation 15 was the CHD population, based on the fact that 16 the clinical studies showing COHb response 17 relationships was focused on individuals with 18 coronary heart disease and the responses that 19 they got at the different COHb levels. 20 There seemed to be some discussion 21 here about considering a larger or additional 22 populations. We just wanted to understand how

### 202-234-4433 Neal R. Gross & Co., Inc. Page 154 1 we might do that, given that the quantitative 2 relationships that we have are for coronary 3 heart disease patients, and what we are 4 looking at in the quantitative analysis here 5 is relating our simulated COHb to potential 6 health benchmarks drawn from those studies. 7 So, we would be interested in the

8 Panel's comments on that.

9 CHAIR BRAIN: Paul? 10 DR. BLANC: I think the answer is 11 straightforward. I think that, in the same 12 way that the actual experimental study was 13 done with people defined with coronary artery 14 disease in a very specific, narrow way, and, 15 obviously, you haven't limited yourself in 16 terms of estimating the population at risk to 17 be simply defined literally that way because 18 you couldn't. I think in the same way, at 19 least some model should be estimated where you 20 simply extrapolate the parallel risk, whatever 21 the risk is for ischemic heart disease. In 22 fact, that risk can be applied at the same

### 202-234-4433 Neal R. Gross & Co., Inc. Page 155 1 level to cardiac disease more broadly defined. 2 So, the proportion of the population 3 who are at risk, you have all the same 4 assumptions, but you define not as 13 percent 5 of the population based on the NHIS definition 6 of self-reported coronary artery disease, but 7 you take a broader proportion of the 8 population who have cardiac disease broadly 9 defined. If you want to use the other NHIS 10 column, which is, as you know, coronary artery 11 disease, all cardiac disease, you could use 12 that as your upper-end limit. 13 But there is no biological reason to 14 presume, which is what you are doing, that 15 because the Allred experiment was done in 16 coronary artery disease, that, in fact, the

17 same adverse health effects at the same levels 18 wouldn't occur in the more broadly-defined 19 population because the epidemiologic data 20 support expanding that effect. Biologically, 21 it makes sense. Epidemiologically, the data 22 are convincing.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 156 1 DR. MURPHY: Well, the strongest 2 data among the epidemiological data was for 3 the ischemic heart disease. 4 DR. BLANC: No, that is not correct. 5 That is not the strongest data. I think that 6 was a mischaracterization. 7 In fact, it depends on what you 8 define as strong. That was the point I think 9 Dr. Penn was trying to make. If you are 10 talking about relative risk, maybe that wasn't 11 the strongest effect. It is just that you had 12 more studies that you could -- in fact, I even 13 don't know if consistency is the right word; 14 you could say that one was more consistent

15 than the other. 16 So, no, I don't think --

17 CHAIR BRAIN: But I hear Paul also 18 saying, even if that data was lacking, why not 19 simply say, why not give those caveats? You 20 know, there's not adequate epidemiology. But 21 if we broaden the category of cardiovascular 22 disease to include X, Y, and Z, then this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 157 1 number may be four times greater. 2 DR. MURPHY: So, what we need to 3 understand is, is the Panel suggesting that 4 ischemia would result as similar COHb levels 5 for a population that goes beyond the coronary 6 heart disease patients? That is what this 7 presumption, so to speak, would be doing, 8 applying the dose/response relationships that 9 we have from the coronary heart disease 10 patients. 11 What we tried to do is, rather, 12 focus in the REA on the population for which 13 we had those dose/response relationships, and 14 then, in the Policy Assessment, recognize that 15 there's a larger population potentially at 16 risk, which we very clearly provide sizes 17 estimates for that larger population, as Dr. 18 Blanc has suggested, to raise that as 19 something which is an important consideration 20 for the Policy Assessment because we have a21 variety of populations with oxygen22 availability issues with potential

### 202-234-4433 Neal R. Gross & Co., Inc. Page 158 1 susceptibility to the increased CO. So, that 2 is the way we have covered this, if you will, 3 in the review. 4 But I am interested in the question 5 on my first, which is, do we expect to see 6 ischemia? 7 CHAIR BRAIN: I guess, in part, you 8 are dealing with a fear that some people that 9 have that, if it is missing in the REA, it is 10 not going to appear in the PA. I guess you 11 are saying that is not true.

12 DR. MURPHY: It's not true. 13 CHAIR BRAIN: So, I guess that is 14 one of the issues for CASAC, is: do you want 15 to add that concern about other populations in 16 the REA, or are you content with it? 17 DR. BLANC: I'm not content, and I 18 think it is a different question. I think Dr. 19 Ritz's point about pregnant women, where we 20 don't actually know the mechanism, and I think 21 that would be a very big leap to say it is 22 going to be a mechanism of ischemia. So,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 159 1 therefore, I think that is an example of 2 something where you would talk about it in a 3 different context. 4 But in terms of your modeling, in 5 fact, I think the presumption would have to be 6 that, in fact, the mechanism would be ischemia 7 or ischemic-related in those people with, for 8 example, congestive heart failure. 9 I think that is why I wouldn't 10 include the cerebrovascular accident group 11 because I think, then, you are getting, yet, 12 one more step, and the epidemiologic data are 13 slightly less robust. But I think when you 14 are talking about hospital admissions as the 15 endpoint convincingly, and the epidemiological 16 issues are for the population with congestive 17 failure, it ultimately is ischemia or 18 downstream from ischemia, one way or the 19 other. I think that is a reasonable 20 assumption for one model. 21 Am I saying you shouldn't model your 22 narrower at-risk population? No, I'm just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 160 1 saying, in the same way that you have a 2 scenario, okay, here is if the standard were 3 at the maximum, here is at the standard "as 4 is" the number of people, I want to see if you 5 had a more realistic number of people with 6 cardiac disease as a susceptible population, 7 what is your input? Yes, I do think it is a 8 reasonable extrapolation from the controlled 9 human exposure data that you have. 10 I really do think that you are in a 11 situation where we are saying A equals B, and 12 B clearly equals C; then, we should have some 13 model which assumes that A equals C. It is 14 just a critical piece that is missing. 15 It is not the same as saying, okay, 16 also, model for pregnant people or model for 17 some of these other things, where, yes, that 18 should be discussed as something that we are 19 not modeling at all or not including, but it 20 is still an important thing to think about. 21 DR. PENN: I think you will have to 22 at least have some language change because

### 202-234-4433 Neal R. Gross & Co., Inc. Page 161 1 there is some place -- I think it is in the PA 2 -- that says very clearly that the most 3 susceptible population are people with 4 coronary artery disease. Maybe it would be 5 easier at some level to say the clinical 6 studies clearly indicate that the coronary 7 artery disease population is very susceptible 8 to these changes in ambient CO. However, the 9 epidemiologic data strongly suggests that 10 there are other groups that are at least as 11 susceptible, if not more so, to CO exposures.

12 But the blanket statement that the 13 coronary artery disease is the most 14 susceptible is really unfair because those are 15 the only people where there has been a 16 clinical study. So, you can't make the 17 extension to -- 18 CHAIR BRAIN: And, in fact, the 19 people who really meet the Allred criteria are 20 increasingly rare because people with 21 reproducible angina are treated, right? I 22 mean the subjects they studied have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 162 1 reproducible angina, and they are getting hard 2 to find. 3 DR. DAHMS: But I still think for a 4 lot of people, all of the people stayed on 5 their medications. 6 CHAIR BRAIN: Yes, but now they are 7 more likely to have stents or coronary -- I 8 think this is not finished, but I think we 9 should move on and let's see what develops 10 with the charge questions. 11 I think we also need to look and see 12 what we find in the Policy Assessment, but I 13 think it is a big, you know, it is the 14 elephant in the room for the whole Panel that

15 we have. 16 So, let's hear from Russell. 17 Russell, you're still there? Tell us about 18 Charge Question 2. 19 DR. DICKERSON: Okay. Charge 20 Question 2 concerns air quality 21 considerations, Chapter 3 and 5. I think Paul 22 Roberts has some comments, too.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 163 1 The question is: Does the Panel 2 find the consideration of current ambient 3 carbon monoxide monitoring data, et cetera, et 4 cetera, approximately characterized? 5 I think the broad answer to that is, 6 yes, we are looking at a big improvement in 7 air quality considerations in Chapters 3 and 8 5. Measurements were poor, but are getting 9 better. This is adequately handled. 10 The NCOR assemblage of monitoring 11 sites is not characterized. That is an 12 important improvement that EPA put in to

13 adhere. 14 There are still too few quality 15 measurements. I think they are extrapolated 16 to exposure as best as can be done, given 17 their limitations. So, what more can you do? 18 One thing that may be missing is 19 that there is substantial evidence in the 20 reviewed literature that the emissions 21 estimates from emissions models such as Mobile 22 6 may be in substantial error by as much as a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 164 1 factor of two. This limits the usefulness of 2 chemical transport models for exposure

3 assessment. 4 Those questions about the emissions 5 models need to be addressed before bottom-up 6 chemical transport models can become more 7 useful on a scale too fine to monitor. 8 That, basically, is all I have to 9 say on the REA. 10 CHAIR BRAIN: Thank you.

11 Paul? 12 Yes, first, a quick question or 13 response from the agency. 14 DR. GRAHAM: I just want to comment 15 briefly on the comment on emissions. While I 16 don't disagree that there needs to be 17 improvement in emissions estimates, in this 18 assessment we didn't use any sort of air 19 quality modeling that would require emissions 20 estimates to estimate the concentrations. All 21 the concentrations that we used were based on 22 ambient monitor measurements.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 165 1 DR. DICKERSON: Yes, but that is the 2 point, that, in fact, the ambient measurements 3 are substantially more accurate than the 4 emission. That is not a particularly good 5 situation. 6 It is worthy of comment. I'm not 7 saying that it doesn't detract from your 8 calculations of exposure assessment, but it is 9 a tool that could be used, should be used, and

10 at the moment can't be used.

11 CHAIR BRAIN: Paul? 12 DR. ROBERTS: Yes, I have fairly 13 brief comments here. 14 I agree with Russ in that Chapter 3 15 especially has a better description of what is 16 going on. You know, it does describe the poor 17 representation near roadway concentrations 18 with these particular monitors. I think that 19 is really good because none of these, even 20 though, as was mentioned, one of them is a 21 micro-scale monitor, it really doesn't 22 represent near roadway. So, that is all good,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 166 1 and I think those are improvements. 2 So, I think I will let that stand. 3 I think this chapter is good. 4 CHAIR BRAIN: Anyone else want to 5 comment on Charge Question 2 or any other 6 questions or comments from the EPA? 7 (No response.) 8 Okay. Let's now turn to Charge 9 Questions 3 and 4, and Milan will lead us 10 through that. 11 Does it make sense to deal with 3 12 and then 4? Or how would you want to parse 13 your comments, Milan? 14 DR. HAZUCHA: Yes, we can start with 15 Charge Question 3 and then, once we are 16 finished with that, we can go with Charge 17 Question 4. 18 CHAIR BRAIN: Very good. 19 DR. HAZUCHA: Anyhow, some of the 20 questions and comments were already discussed 21 briefly from Charge Question 2. 22 Because for this Charge Question 3,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 167 1 we have actually three chapters, and they all 2 deal in one way or another with APEX modeling. 3 Unfortunately, I do not have all the 4 comments here. I just got some comments from 5 Tom, but Beate and Joel, they will have to

6 comment themselves. 7 Generally, the chapters accurately 8 reflect the currently-available information.9 They are clearly communicated. They are well10 organized, appropriately-balanced, and so on. 11 However, after this praise, there is always 12 however. We would like to make some comments 13 to include on some section or clarify some of 14 the sections. 15 I found a bulleted list of modified 16 or expanded sections very helpful, actually, 17 because, then you know exactly what was 18 changed, particularly the major changes. 19 Similarly, the flowcharts showing the input 20 points and flow data was helpful as well. 21 Now the subquestion A deals with 22 number of monitors. It may be actually quite

### 202-234-4433 Neal R. Gross & Co., Inc. Page 168 1 helpful to have for exposure assessment more 2 monitors. I am not sure because this is not 3 discussed in comparison to previous REA, where 4 there were fewer monitors than we have now in

5 the second draft. 6 There is a number in each, whether 7 it is Denver or LA, we have a number of air 8 districts, methodological zones, and for LA 9 study areas as well, where there is a 10 considerable overlap. For exposure, it is 11 dealt with algorithms, and so on, for 12 adjustments. 13 But what about other input besides 14 exposure data input? For example, how you 15 dealt with input with individuals, where you 16 have overlapping areas? And particularly for 17 LA, where practically the two areas are almost 18 90 percent overlapped, have you simply 19 evaluated first one area and then the second 20 area, or somehow merged both areas together, 21 ultimately? How was it dealt with? That is

22 unclear from the document.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 169 1 Also, then, the section dealing with 2 some of the APEX modules, the demographic 3 variables I believe should include 4 socioeconomic status and race. It is 5 particularly important for a COHb module, 6 where race may have an impact, like for 7 example, blacks, it is well-known that they 8 have lower concentration of hemoglobin than 9 whites, and it will affect COHb levels. Or, 10 for example, for individuals with diseases 11 like COPD, diffusion will be substantially 12 lower in healthy individuals. And it doesn't 13 come up clear from the description here how 14 that was handled in the APEX model. 15 I found the tables, and we already 16 discussed briefly some of the tables and some 17 of the parts, very valuable, actually, very 18 elucidating. Because you can really see 19 clearly how, when the concentration changes or 20 the percentage of individuals, to what degree 21 they will be affected. 22 The plots and tabulation of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 170 1 endogenous COHb, and again, we discussed it 2 considerably, was also very helpful. So, if 3 we have now additional plots as an appendix, 4 then that will be really great. 5 Those are basically my comments for 6 Sub-Charge Question A. I guess Thom has a

7 comment or two.

8 DR. THOM: Me? 9 DR. HAZUCHA: Yes. Right here. 10 DR. THOM: Okay. So, my only, it is 11 a question. Perhaps it is because I don't 12 understand a lot of the modeling issues. 13 But discussed in the REA was the 14 fact that, with the APEX modeling, because of 15 the sensitivity of the monitors, and the fact 16 that they re-zero themselves, there is a 17 drift. And the model can't, and I don't 18 understand why, take a zero or a negative 19 number into consideration. I can understand 20 a negative number, but zero would seem to make

21 sense. 22 But, nonetheless, according to the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 171 1 REA, it says that for your modeling 2 calculations, because of the zeroes and the 3 negative numbers, you added .5 parts per 4 million to all of the measurements in order to 5 come up with your estimates. Or did I not 6 understand what was written in the REA? 7 DR. GRAHAM: Yes, I'm not sure what 8 you are referring to because my understanding 9 -- well, I don't want to say my understanding; 10 I did generate the air quality data. 11 Substituting for missing values where there 12 weren't any hourly measurements, and if there 13 were -- I don't believe there were too many 14 negative values, but I don't think .5 was

15 added to -- 16 MR. JOHNSON: I think that might 17 have been a different part of the assessment, 18 when we were calibrating one of the 19 algorithms, and we needed to adjust some of 20 the data. But I think the actual monitoring 21 data that was used, we did not add .5 to it. 22 DR. ROBERTS: It is on page 4-22 of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 172 1 the REA. 2 DR. THOM: I'm sorry, what page,

3 Steve? 4 DR. ROBERTS: Page 4-22. 5 DR. GRAHAM: Before we go any 6 further, this is Ted Johnson with TRJ 7 Environmental. He provided substantial 8 technical expertise in the APEX modeling. 9 MR. JOHNSON: And the part that you 10 are talking about was the development of an 11 algorithm that was used to take the values 12 that were measured at monitors and estimate 13 what the concentrations were at outdoor 14 locations near various micro-environments. It 15 was an analysis done back in 2000. 16 This was used to calibrate an 17 algorithm, but the monitoring data which is 18 used as the input for Denver and Los Angeles, 19 we just used the data that came from the 20 monitor, and we occasionally filled in missing 21 values, but we did not add .5 to the 22 concentrations.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 173 1 DR. THOM: So, what is being spoken 2 about on this page? 3 MR. JOHNSON: When we have a monitor 4 value, we have a separate algorithm which 5 takes the value at the monitor and uses that 6 to estimate what an outdoor concentration 7 would be outside, say, somebody's home. That 8 particular algorithm is a probabilistic 9 algorithm. The statistical analysis that 10 developed that algorithm required that we get 11 rid of negative values. 12 DR. THOM: So, you are telling me 13 that that's not what is being used today?14 MR. JOHNSON: Well, there's a two15 stage process going on. We start with the 16 fixed-site monitors in the city. That tells 17 us what the concentrations are at the monitor 18 locations. We, then, have a process which 19 takes those concentrations and converts them 20 to concentrations that are outside various 21 micro-environments, like schools, for 22 instance.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 174 1 That transfer equation is based on 2 the analysis of data. To analyze that data, 3 to come up with that equation, required that 4 we not use negative values. 5 DR. GRAHAM: So, it is essentially 6 using that to derive a relationship. Then, 7 that relationship is used for the air quality 8 that was input into the current assessment. 9 DR. ROBERTS: Using real data, not 10 the adjusted --

11 MR. JOHNSON: These are real

12 numbers. 13 DR. GRAHAM: Right. 14 DR. THOM: So, why is it in the REA?

15 DR. GRAHAM: Because that was used 16 to derive the actual relationship, the factors 17 that are used for estimating the outdoor 18 concentrations and the micro-environmental 19 concentrations in this assessment. 20 MR. JOHNSON: The relationship had 21 to be based on an analysis of data. This is 22 telling you the data that was used for that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 175 1 relationship. Okay? 2 DR. THOM: No, but okay. 3 DR. MURPHY: Let me try, as someone 4 a little further away. Maybe I could be 5 closer to what your confusion is. 6 CHAIR BRAIN: Well, I think we 7 understand the confusion. I think we just 8 want the document changed, so that it explains 9 -- SO it is less confusing. 10 DR. MURPHY: We could certainly try 11 to address that in the document, if you would 12 like to move on. 13 CHAIR BRAIN: Milan, why don't you 14 polish off a, b, and c? Then, we will also 15 move on to others. Joel and Beate may have 16 something to say -- 17 DR. HAZUCHA: Okay, sure.

18 CHAIR BRAIN: -- rather than 19 breaking it up too much. But, yes, why don't 20 you complete? 21 DR. HAZUCHA: Okay, very good. 22 For b, it is micro-environments,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 176 1 yes, they are micro-environments. Initially, 2 in the 2000 document there were 15 3 environments, micro-environments, considered. 4 Now in REA 1, there were two, and now it is 5 expanded to eight. 6 I would like to see somewhere sort 7 of a statement or two. It doesn't make really 8 a difference whether you use fifteen or two or 9 eight, or it is just simply an easily-changed 10 number and it doesn't have any impact on the 11 APEX modeling. Why, for example, how eight is 12 better than two, or these two represented 13 those fifteen reduced to indoor and outdoor. 14 So, that is one of the comments I have for b. 15 Certainly, I believe that, if you16 have actually more of these micro17 environments, it probably will enhance the 18 decisionmaking, ensure the estimates, and then 19 decisionmaking. 20 I found the key observations 21 actually in every chapter very helpful because 22 it, basically, summarizes what was done and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 177 1 what happened. They reflect, indeed, truly 2 what was discussed in those sections. 3 So, those are comments for b. And, 4 for c, since it was really these questions are 5 rather narrow questions, indeed, I consider 6 the selection of most bonds appropriate for 7 indoor estimation. 8 CHAIR BRAIN: Sounds good. 9 Joel, are you with us? Dr. Kaufman? 10 DR. KAUFMAN: Yes, I'm here. 11 CHAIR BRAIN: Oh, good, yes. Do you

12 want to comment on -- 13 DR. KAUFMAN: I actually have no 14 additional comments on Question 3. 15 CHAIR BRAIN: Okay. Beate, how 16 about you? 17 (No response.) 18 DR. THOM: Nothing further. 19 CHAIR BRAIN: Steve, nothing else? 20 Okay. 21 Why don't you proceed to Charge 22 Question 4, Milan?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 178 1 DR. HAZUCHA: Okay. Well, for the 2 Charge Question 4, again, the same goes as for3 Charge Question 3, that it is really well4 written. However, again, the APEX model, it 5 is certainly better than the older versions 6 because it is shown much better some of the 7 inputs. 8 I am still unclear, since, as we9 discussed so many times about this Coburn10 Foster-Kane equation on the COHb models, why, 11 for example, in the document it is mentioned 12 Bruce and Bruce module, which is really simple 13 enough. I still haven't seen anywhere even in 14 this document an attempt made to explore other 15 predictive COHb models. 16 Probably, just again, one or two 17 sentences: yes, we tried it, and it doesn't 18 add anything to CFKE, which is not a robust 19 equation, well-validated and used over 20 decades. But Bruce and Bruce, and others, 21 they all claim, oh, our model is much better 22 than CFKE. So, if they claim it is much

### 202-234-4433 Neal R. Gross & Co., Inc. Page 179 1 better, there must be something to it. They, 2 of course, go through details, why it is

3 better than CFKE. 4 So, it might and it might not be 5 true, but it might be worth it to examine it 6 again. You might have done it, but I don't 7 see anything about it over here. 8 Now, regardless of the mathematical 9 model used for COHb prediction, one of the 10 modules which is very sensitive, of course, is 11 the COHb module and the input estimates to the 12 module. I already mentioned hemoglobin, for 13 example, or diffusion capacity. There are 14 data, there are predictive formula, for 15 example, for diffusion capacity which can be 16 used. So, you have a range of data that are 17 depending on age, for example, and gender. 18 For others, that is true, like, for 19 example, capillary concentration of CO2. 20 Unfortunately, we do not have data, so we 21 cannot do anything about it. But if you can, 22 it will really add to the model to make it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 180 1 more better-tuned. 2 In Appendix A, you actually agree 3 and say the current physiology data file is 4 obsolete, and it may even have incorrect data 5 for some variables. So, my question is, are 6 you going to overhaul this physiologic model, 7 and when are you going to overhaul it? 8 DR. GRAHAM: Well, if I can respond, 9 I guess I will first talk about the model 10 itself, the CFKE versus Bruce and Bruce, and 11 maybe other models that individuals may have 12 suggested are improved. 13 The ISA states that, I think in a 14 conclusion statement, based on the evaluations 15 and comparisons that were done by several 16 authors, that the CFK model is the most 17 widely-used as well as the most validated 18 model to date. To actually incorporate 19 additional algorithms or what other 20 researchers might suggest in recent 21 investigations, that would require significant 22 model development activities, something that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 181 1 we certainly don't have available to us on the 2 short-term, but it doesn't not necessarily 3 mean that on a longer-term plan regarding CO 4 and estimating COHb dose levels, that it is 5 something that could be undertaken in the6 future, but that would certainly be a long7 term plan. 8 DR. HAZUCHA: And the physiology

9 module? 10 DR. MURPHY: Yes, I'm sorry. I'm 11 not sure if you looked at Appendix B, but 12 there is a table in Appendix B that makes 13 clear -- it is titled, B-2, which begins on 14 B-11, Principal Parameters Included in the 15 Profile. It talks about how they were 16 estimated. 17 For example, if I am following 18 correctly what your comment was on diffusion 19 rate, you talked about an equation. There is 20 an equation used by the model to estimate 21 diffusion rate. That is described on B-13. 22 So, gender, age, and height specific.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 182 1 DR. HAZUCHA: Well, that's what I 2 got, but what about diseases, for example, 3 coronary heart disease, for which we may not 4 have data, but we certainly have for COPD 5 patients data? 6 Yes, I read all what you said. It 7 is adjusted, but for COPD, for example, I 8 don't see any comment there to that effect. 9 DR. MURPHY: And obviously, if our 10 focus was the COPD population, then that would 11 be more of an issue than for the CHD 12 population. Presumably, you are talking about 13 the subset of the CHD population that may have 14 COPD, that perhaps we are missing that in our 15 characterization. That certainly would be 16 something to describe any uncertainty to the 17 extent we are missing that.

18 CHAIR BRAIN: But to take a common 19 problem that people with COPD or emphysema or 20 fibrosis have, you know, they have a 21 diminished diffusing capacity. So, to what 22 extent is that in the model, if you have a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 183 1 lower-than-normal DLCO? Again, we have some 2 data on what fraction of the population have 3 problems in oxygen diffusing across the 4 air/blood barrier. Is that part of it? 5 DR. GRAHAM: Right, and, of course, 6 as you stated, that may be extremely limited 7 as far as its utility currently in the model. 8 But if CASAC has recommendations or can 9 identify particular studies that have that 10 type of data that we could use as an input, 11 that would certainly be helpful. 12 CHAIR BRAIN: So, it is not 13 currently part, people with diminished 14 diffusing capacity, that is not currently a 15 susceptible population that is considered in

16 the model. 17 DR. GRAHAM: Right. 18 CHAIR BRAIN: Is that right? Yes.

19 DR. HAZUCHA: What about race and 20 socioeconomic status? Is that in the model? 21 Because I'm not sure. I might have missed 22 something, but I don't see that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 184 1 DR. GRAHAM: We could have that as 2 an output, based on the U.S. Census data, 3 because that is where we are deriving the data 4 to formulate this simulated population. But 5 what you are suggesting is, do we also have 6 the physiological variables to represent those 7 populations? We don't have that input data in 8 the model currently. But if you can identify 9 particular studies that might have that 10 information, then that would be helpful. 11 CHAIR BRAIN: Okay, let's move on to 12 other discussants.

13 DR. DAHMS: I have one 14 clarification. 15 CHAIR BRAIN: Yes, Tom? 16 DR. DAHMS: In that table B-2, when 17 you talk about ventilation rate, are you 18 talking about alveolar ventilation rate? 19 DR. THOM: Which page? 20 DR. DAHMS: B-2, page B-11, you list 21 algorithms. In the appendix.

22 CHAIR BRAIN: It's alveolar

### 202-234-4433 Neal R. Gross & Co., Inc. Page 185 1 ventilation, not minute ventilation, not total 2 ventilation?

3 MR. JOHNSON: No. 4 CHAIR BRAIN: Dr. Kaufman, do you 5 have anything to add in relation to Question

6 4? Dr. Kaufman? 7 DR. KAUFMAN: I don't have anything

8 to add. 9 CHAIR BRAIN: Okay. Dr. Ritz, are 10 you there? 11 DR. RITZ: Yes, I'm here. 12 CHAIR BRAIN: Oh, good, yes. Do you 13 have any comments, actually, on Charge 14 Questions 3 or 4? 15 DR. RITZ: Yes, actually, I have a 16 general comment, which refers to taking care 17 of the spatial heterogeneity issue. I just 18 want to remind everybody, we have already 19 discussed it earlier, that we really do not 20 measure spatial heterogeneity by using these 21 ambient monitors correctly. We are all aware 22 of it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 186 1 So, the APEX model, actually, makes 2 a lot of assumptions about now addressing 3 spatial heterogeneity, when it really isn't by 4 using more monitoring data, that it is not 5 really representative of the high-exposure 6 scenarios that we know near freeways and on 7 freeways, et cetera, et cetera. 8 DR. GRAHAM: Can I just comment? 9 DR. RITZ: So, the question was, 10 does it adequately reflect safer 11 heterogeneity? I don't think so. 12 CHAIR BRAIN: So, the EPA has a 13 response for you. Then, we will come back and 14 see if you have other comments. 15 Yes, we will hear from staff. 16 DR. GRAHAM: Yes. Well, actually, 17 there are a number of adjustments that are 18 made for estimating outdoor concentrations for 19 the individuals that are simulated, in 20 addition to not just the outdoor 21 concentrations, but the micro-environmental 22 concentrations have adjustments associated

### 202-234-4433 Neal R. Gross & Co., Inc. Page 187 1 with them. 2 Like, for example, in one of the 3 tables, table 4-5, it contains a listing of 4 all the factors that are used to address, or 5 shall I say, to apply to the outdoor ambient 6 concentration that is estimated, and they are 7 a distribution. It is not just a single 8 number that is used. 9 So, for example, the in-vehicle, the 10 geometric mean was approximately 3, and that 11 value ranged from about 1.5 to upwards to 6. 12 So, in other words, while an individual was 13 inside a motor vehicle, they could experience 14 concentrations as high as six times the 15 ambient -- I'm sorry -- the outdoor 16 concentration, but, on average, the geometric 17 mean of that would be three times that. So,18 we are adjusting for high-concentration micro19 environments. 20 DR. RITZ: Well, yes, I am very 21 aware of that table and your adjustment 22 factor. But when you use a monitoring station

### 202-234-4433 Neal R. Gross & Co., Inc. Page 188 1 that is not reflective really of -- well, it 2 has a very low background measure. Some of 3 them are actually below the detection limits. 4 Any factor you are adding doesn't really add 5 anything. Do you see what I'm saying? 6 As soon as you get close to the 7 detection limit, this may not work at all. I 8 don't know how many monitors had that kind of 9 situation. 10 MR. JOHNSON: This is Ted Johnson.11 In addition to the micro12 environments, we also have another factor 13 which adjusts the monitor values up and down. 14 That factor also was based on a study of 15 spatial variation of actual outdoor 16 concentrations versus the concentrations 17 measured at nearby monitors. 18 So, it will also produce values that 19 are both higher and lower than the fixed-site 20 monitors that we are using. So, I think that, 21 plus the micro-environmental multipliers, 22 provides actually a very high degree of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 189 1 variability.

2 We have also taken the overall model 3 that does all these calculations, and we have 4 compared it to a personal monitoring study 5 that was done in Denver, Colorado, where we 6 had a thousand people carrying personal 7 monitors around. We got a good, we got 8 similar characteristics, spatial 9 characteristics, from what the model was 10 producing to what was actually measured by 11 these personal monitors. So, in a sense, that 12 was a partial validation of this approach. 13 Yes, this was done in the past. 14 DR. ROBERTS: I had a question here. 15 I don't see a lot in your numbers that the 16 adjustments can be higher than the monitor 17 site. All I see is the lower-than.18 MR. JOHNSON: Well, the micro19 environment, the geometric means, which would 20 be a middle point in the multiplier, 21 distribution multipliers, most of those values 22 are greater than one.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 190 1 DR. ROBERTS: Okay. Yes, I 2 understand on 4-5 that is the case. I thought3 you were mentioning that like the Wilson4 Colome had higher-than, and I think it only 5 has lower-than, unless maybe I misunderstood 6 your comment. 7 MR. JOHNSON: Well, there's actually 8 a distribution of multipliers. It may be that 9 more of them are lower, but there are still 10 some multipliers that are greater than one in 11 the distribution. 12 CHAIR BRAIN: Back to Dr. Ritz, any 13 other comments you want to make? 14 DR. RITZ: Yes, I still don't 15 understand how measurements near the detection 16 limit or under the detection limit at the 17 monitors would give you any results. Do you 18 replace it with a detection limit? Or what 19 did you do there? 20 DR. GRAHAM: Are you referring to 21 the ambient concentration, as to whether or 22 not zero estimates were replaced with some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 191 1 sort of detection limit? 2 DR. RITZ: Right. 3 MR. JOHNSON: Is your point that, if 4 a monitor measured zero, that with all these 5 multipliers, we would still get zero because 6 they would all be multiplying an initial value

7 of zero? 8 CHAIR BRAIN: I don't think it was a 9 point. It was a question. What do you do 10 with zero? How are they handled. 11 DR. GRAHAM: Zero was retained as 12 zero. If it were reported as a level below 13 the detection limit, then that data were used 14 "as is." 15 CHAIR BRAIN: Which could be a zero, 16 or it is the detection limit? 17 DR. GRAHAM: If a zero was reported, 18 it was used a zero. Yes, it was used as zero. 19 DR. MURPHY: Just to clarify, there 20 are reported values below the detection limit. 21 So, often, in the data you will have a 22 reported value that it just happens to fall

### 202-234-4433 Neal R. Gross & Co., Inc. Page 192 1 below the method detection calculated by that 2 lab. But the reported value would have been 3 used, as well as zeroes, I think is what they 4 are saying. 5 CHAIR BRAIN: Does that answer your 6 question, Dr. Ritz?

7 DR. RITZ: Yes. 8 CHAIR BRAIN: Okay. Anything else 9 that you want to add to Questions 3 and 4? 10 DR. RITZ: No, that's it. 11 CHAIR BRAIN: Okay. Before turning 12 to Dr. Thom, Paul, you had a question? 13 DR. ROBERTS: Well, on the new 14 detection limit, I am concerned about that a 15 little bit when -- and I don't know the exact 16 details on these monitors, but some agencies 17 with older monitors only report whole 18 increment ppm concentrations. So, they might 19 only report zero or one, for example. I am 20 not sure how that is used. 21 But if you look at the distributions 22 of the data, like on 3-3, figures 3-3 and 3-2,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 193 1 et cetera, which are on pages 3-9 and 3-10, it 2 doesn't look like there's a significant amount 3 of data down at the zero level. So, 4 hopefully, the question Dr. Ritz is asking is 5 not too important, I think. 6 DR. GRAHAM: Right, and I was going 7 to point to that as well as some of the data 8 that are in tabular format, that 9 concentrations that are, say, at or below a 10 so-called detection limit of approximately 1 11 ppm aren't necessarily highly prevalent, but 12 they are not necessarily the most important 13 driver to maximum end-of-hour COHb level. 14 Most of those are going to be driven by the 15 upper percentiles of the distribution of the 16 air quality data, most, if not all. 17 CHAIR BRAIN: Dr. Thom, anything 18 else you want to add? 19 DR. THOM: I have nothing else.

20 DR. ROBERTS: I have some. 21 CHAIR BRAIN: Yes, anything else on 22 Question 4?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 194 1 DR. ROBERTS: Well, a few of my 2 questions may be on 5, comments may be on 3 Charge Question 5, too. I think it is a 4 little together. 5 But I do think the expansion of the 6 modeling domain with more monitors, the7 spatial distribution, the more micro8 environments, all of that does have a really 9 positive effect at the end I'm concerned 10 about, which is the near-roadway exposure 11 part. 12 I think those are really positive 13 improvements here in this version of the REA 14 versus the second. Even with the limitation 15 that Dr. Ritz talks about with adding the more 16 monitors, the spatial coverage from that 17 doesn't produce the better representation of18 the near-roadway, but I think the micro19 environmental addition does do that. I think 20 those are real positives here. 21 But I do have a question or a 22 comment. There's one part I don't understand,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 195 1 and I have put it in my written comments. 2 There's a couple of equations, 4-11 and 4-22, 3 which are essentially the same equation, 4 basically reduce the ambient concentration to 5 other outdoor locations. Okay? 6 And I don't really see the 7 justification for this power of .621. I think 8 that is pretty weak. In one place, it says, 9 well, that is the way to make pNEM and APEX 10 agree. I don't see any physical rationale

11 there. 12 In another place, it talks about the 13 Wilson-Colome work as sort of confirming that. 14 The problem I have with that is that I'm 15 pretty sure that most of that work was homes 16 and not near roadway or other kinds of 17 locations. 18 In the end, to me, what is 19 bothersome is that the kinds of factors, in 20 particular, for the high exposure part, the 21 near-roadway/in-vehicle kinds of factors that 22 are in table 4-5 should represent from a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 1961 monitor to this exposure location, micro2 environment, but, in fact, that monitor is 3 being reduced almost by a factor of two in 4 some cases by this .621 factor. I don't 5 really understand. That sort of defeats the 6 purpose of having -- you know these multiple 7 predictors of factors have been developed with 8 the real ambient data and not some reduced 9 ambient data. 10 So, maybe you guys can point out 11 where I am missing something. 12 MR. JOHNSON: This equation was 13 developed by fitting data to the Colome study.

14 The .621 factor was not added as an 15 afterthought. It actually improved the fit of

16 the model to the data. 17 The fit was done by statisticians 18 with ICF, and I assisted with the analysis. 19 But besides the exponential value of .621, 20 these various terms had their own 21 distributions. It is the product of all these 22 terms together which determines what the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 197 1 multiplier is, not just the .621 factor. 2 When you look at the distribution of 3 the product of all these terms, including the 4 one with the .621 factor, you do get a 5 distribution of multipliers which is 6 consistent with the relationships that were 7 found in the Colome study between outdoor 8 locations and fixed-site monitor 9 concentrations. 10 Also, the Colome study, though it 11 was mostly residential, included many 12 residential areas that were close to roadways. 13 So, it is a diversity of different outdoor 14 locations. 15 The extra exposure that you would 16 get if you were walking down a sidewalk or17 something is reflected with the micro18 environment factor. You could think of this 19 as providing more of the distribution of a 20 more general ambient outdoor location. Then, 21 the micro-environment factor would provide an 22 extra degree of exposure if you were next to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 198 1 a roadway. 2 The main reason for having this type 3 of equation in the model is it provides for 4 all the micro-environments an estimate of what 5 the outdoor concentration is. For the indoor 6 micro-environments, it gives us an outdoor 7 concentration that the mass balance model can

8 work on. 9 For outdoor locations, it gives us a 10 value that you could consider a proximity 11 factor would be added to. The proximity 12 factor would be the fact that somebody is 13 staying right next to a roadway, which would 14 increase their exposure more. 15 It is not a perfect solution, but it 16 does have the advantage of providing a very 17 good fit to one of the most extensive datasets 18 of data representing a wide variety of 19 locations, all of which were paired with 20 nearby fixed-site monitor concentrations. 21 That type of study is actually very rare in 22 the literature.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 199 1 Also, this equation and everything 2 was developed for the 2000 pNEM CO analysis. 3 This long discussion that is in the REA is 4 explaining the fact that we are still using 5 the same relationship, but in order to make it 6 work with APEX, we have to implement it in a 7 slightly different way. This is an 8 explanation of the changes in the 9 implementation, but the mathematical 10 characteristics of the equation are still the 11 same as they were in the 2000 pNEM assessment. 12 The .621 is not something that was added after

13 the fact. 14 DR. ROBERTS: Well, I understand 15 what you are saying, but the net result, 16 though, is that, yes, the table 4-5 has 17 distributions. By the way, I think that is a 18 big improvement, too, if I didn't mention it 19 earlier, over the earlier REA. The 20 distributions are good.21 But take the top end of the in22 vehicle, for instance, the factor of six. The

### 202-234-4433 Neal R. Gross & Co., Inc. Page 200 1 factor actually is only three because of this 2 .621. That does not agree with the ambient 3 data that was in the ISA, as far as I

4 understand. 5 I mean I haven't gone back and 6 looked at Wilson and Colome, but, as I 7 remember when that study was being done, we,8 as a community, were not focused on near9 roadway. I didn't really remember that a 10 significant number of those were near-roadway 11 homes. I don't think they were, but I could 12 be wrong. I just don't remember. But we, as 13 a community, certainly weren't focused on 14 that. So, that comparison is sort of weak, 15 from my view, as justification of this. 16 But the net result, from my view, if 17 I calculate what the ratio-to-ambient is for 18 these higher-exposure micro-environments, it 19 is a factor of two less than this because of 20 that factor. That is not what the literature 21 says on those ratios. That is not what the 22 ISA said.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 201 1 MR. JOHNSON: Well, we are getting 2 concentrations from APEX that are greater than 3 30 parts per million. In fact, I believe they 4 go as high as 40 for the current standard. 5 Are you suggesting that they should 6 be much higher than that? 7 DR. ROBERTS: Well, I didn't do 8 exact concentrations. All I was doing was 9 ratios based on outdoor concentration to the 10 .621 factor times these ratios. Okay? That 11 net ratio is only three, instead of six. My 12 reading of the ISA literature was that that 13 number was five and six, not three. Even 14 though 30 seems pretty high, it seems 15 reasonable, but that is not what this factor 16 would say. 17 DR. GRAHAM: Right, and I think we 18 need to think about it from a practical 19 consideration. As Ted pointed out, we are 20 estimating concentrations, say, inside 21 vehicles because that is largely the driver of 22 the higher concentrations. We are estimating

### 202-234-4433 Neal R. Gross & Co., Inc. Page 202 1 concentrations as high as 30 or 40 ppm, which 2 is a reasonable estimation, given air quality 3 just meeting the current standard. 4 We have to recognize that the data 5 that are reported in a lot of these studies, 6 they provide some relationship between the 7 concentration and the vehicle versus the 8 ambient monitor. We are also not provided, 9 well, what was that concentration? Was it a 10 low concentration at the ambient monitor or 11 was it a high concentration at the ambient 12 monitor? 13 Because a lot of times we will see 14 there's a relationship between the two; that 15 is, you will have smaller ratios between high16 concentration, ambient concentrations and in17 vehicle versus the opposite of that is that, 18 from a very low concentration, you will have 19 a high ratio because of concentrations that 20 are measured at the in-vehicle site. 21 So, this, in effect, adjusts for 22 that. That is, we won't apply high ratios to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 203 1 high concentrations because, then, the next 2 thing you know, there will be individuals that 3 have exposures that are outside of what has 4 been observed previously. 5 DR. ROBERTS: Right. Well, the 6 distribution I think helps take care of that. 7 I think that is good. Okay. 8 CHAIR BRAIN: Okay. Are we ready to 9 move on to Charge Questions 5 and 7? So,

10 let's hear from -- 11 DR. BLANC: Can I just ask --

12 CHAIR BRAIN: Yes. 13 DR. BLANC: After hearing all of 14 that, so it is still a doubt that you have 15 that the system that was used may selectively 16 or systematically underestimate near-roadway 17 exposure? Because that, for a different 18 reason, was Dr. Ritz's concern, but for a 19 completely different reason. 20 DR. ROBERTS: Right, yes. 21 CHAIR BRAIN: So, that concern 22 persists?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 204 1 DR. BLANC: So, I think that when, 2 at a minimum, when we come back to whoever is 3 doing the chapter with the estimates of 4 uncertainty and direction of estimation, that 5 needs to be emphasized there, if it is not 6 already reflected. 7 CHAIR BRAIN: That sounds like a 8 good summary comment. 9 Okay. Yes, why don't we turn to 10 you, Paul, and also to Francine and Tom Dahms' 11 questions to 7? 12 DR. BLANC: So, 5, 6, and 7, so it 13 is a big hunk of a thing. Can we do it one at 14 a time? 15 CHAIR BRAIN: How would you like to? 16 What is the most appropriate way? Do any of 17 the three fit together? 18 DR. BLANC: Well, I mean I would 19 just do 5, and have everybody do their spiel. 20 Is that okay? 21 CHAIR BRAIN: Okay. 22 DR. BLANC: Because 5 overlaps a lot

### 202-234-4433 Neal R. Gross & Co., Inc. Page 205 1 with what we have just been talking about.

2 CHAIR BRAIN: Yes. 3 DR. BLANC: As I understood it, it 4 was really talking, again, about the modeling 5 approach and was it technically sound. 6 Again, I think it comes back to the 7 comments that were already made that the model 8 certainly has increased its number of inputs 9 and has been, in that sense, extremely 10 responsive to the feedback that was given at 11 the first review, and especially because there 12 was a lot of hesitancy, I think, because of 13 the person-hours of work that it would take to 14 do these changes. I think it was extremely 15 responsive. 16 I think that the challenge is really 17 the technical nature of the modeling and how 18 can you communicate that in ways which are 19 interpretable to non-modelers. If I had some 20 solution to that, I would give it to you. 21 But, as you can see, I mean I just 22 heard a 15-minute discussion, and at the end

### 202-234-4433 Neal R. Gross & Co., Inc. Page 206 1 of it I wasn't sure whether Paul's question 2 had been answered or not. You may feel you 3 did answer it, but he still doesn't feel that 4 you did -- not answer it, but, you know, allay 5 his concern. 6 So, that is my answer to No. 5. 7 Yes, I think it is within the limitations of 8 being able to explain that it certainly seems 9 that they have used a lot more data to drive 10 it. 11 CHAIR BRAIN: Tom, do you want to 12 chime in? 13 DR. DAHMS: My concern is with 14 scratching for some sort of validation in the 15 model, no matter how weak, how limp, how 16 brief, whatever. Because, over the years, 17 things get changed. 18 I am familiar with how much 19 validation went into the CFK thing over the 20 past 30 years, but I'm still looking for some 21 way of showing that, because, basically, my 22 concern is, if we are using the dose metric of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 207 1 COHb, how reliable is the model? Is the 2 distribution of values too great, so we wind 3 up overestimating the number of people at 4 risk? 5 So, I kept scratching around for 6 some kind of way of validating this thing 7 where people have actually measured blood 8 levels of COHb. You know, it is just the 9 unease, the real uncertainty of the values 10 generated by the model. 11 You know, we have heard a lot about 12 that all morning. I think that everybody is 13 anxious about that. I don't know how to 14 alleviate those concerns. 15 I know it is trivial, but I thought 16 that maybe where you have all the coronary 17 artery disease patients in Sheps, Kleinman and 18 Allred, you have exposure data from pretty 19 well-calibrated monitors, even though the 20 levels are higher than what you've got, than 21 what you're using here, is there a way of 22 plugging it in to see if the numbers even are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 208 1 in the ballpark? 2 What's the range of data that you 3 get out of these people with coronary artery 4 disease? I don't know if there has been any 5 attempts to use this whole APEX model. I mean 6 you've even got an activity pattern for these 7 people and ages, and everything else, pretty 8 well laid out. 9 I don't know. Has anybody ever 10 attempted to do this? 11 CHAIR BRAIN: So, you are talking 12 about real measurements of COHb in people

13 when -- 14 DR. DAHMS: Yes, to validate. 15 CHAIR BRAIN: -- you have both 16 exposure and blood values?

17 DR. DAHMS: Yes. 18 CHAIR BRAIN: And there's little of 19 that or none of it is here?

20 DR. DAHMS: No. And I understand 21 what the modeling is, that the range of values 22 you are getting are for thousands of people

### 202-234-4433 Neal R. Gross & Co., Inc. Page 209 1 over an entire year. So the splay is going to 2 be much greater than what you get. 3 DR. GRAHAM: Right. I agree that 4 there can always be more evaluation that5 improves our confidence or reduces our so6 called uncertainty about what's being 7 generated. 8 In earlier NAAQS reviews, we have 9 done some -- and again, we have to look at it

10 as we don't have the end-of-hour COHb levels 11 for the population. It just doesn't exist. 12 So, I don't even want to call it a gold 13 standard, but that would be some way where we 14 could evaluate the model performance with some

15 measured data. 16 But we do have pieces. One of the 17 pieces is, yes, the CFK module. We know that 18 that has been extensively evaluated, as well 19 as validated, based on real measurement data. 20 We know that there is, again, other 21 pollutants that APEX has been used to model, 22 and those have been compared to personal

### 202-234-4433 Neal R. Gross & Co., Inc. Page 210 1 exposure or measurement data for ozone and, 2 recently, for nitrogen dioxide. 3 The model is generating reasonable 4 estimates of individuals' exposures. We know 5 that CFK module is estimating dose reasonably. 6 Therefore, we can feel a little bit better 7 about the estimates, in the absence of the 8 actual measurement data that, yes, it is 9 likely that we are estimating COHb dose levels 10 reasonably. 11 But, again, more can be done to try 12 to evaluate these pieces that exist in the 13 model. I will include additional discussion 14 about what has been done in the past. 15 CHAIR BRAIN: Francine, anything you 16 want to say about Question 5? 17 DR. LADEN: I don't have anything to 18 add. I think we covered it. 19 CHAIR BRAIN: Good. In fact, Tom, 20 it sounds like a lot of what you had to say 21 deals with Question 6. So, back to Paul. 22 DR. BLANC: So, as opposed to my

### 202-234-4433 Neal R. Gross & Co., Inc. Page 211 1 sort of generic models that are for the 2 previous question, here is where I start to 3 have a lot of issues. I alluded to many of 4 them this morning in the questions that I was 5 asking. 6 So, as I tried to take a step back 7 and think about it, there are four 8 contributors to somebody's carboxyhemoglobin 9 level in general. One we are not going to 10 deal with at all, which would be active 11 smoking. A second is endogenous production. 12 A third is indoor point sources that are 13 independent of outdoor ambient pollution 14 coming indoors. And the fourth is ambient 15 pollution. 16 So, I had to step back and think 17 about that because that really confuses the 18 picture when you start thinking about what is 19 the carboxyhemoglobin distribution in a normal 20 population, in a normal, non-smoking 21 population. Because, obviously, in a normal, 22 non-smoking population, it comes from three of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 212 1 those four because they are not active 2 cigarette smokers. 3 So, that is not actually said 4 explicitly in the document. I don't know 5 whether it would help solve confusion or not, 6 but it was helpful for me to think it through. 7 Because the document insofar as the 8 indoor contribution is focused on the outdoor 9 contribution to the indoor contribution, it 10 gets confusing. It might be helpful, again, 11 for you in some of your exposure scenarios to 12 be explicit about what would be contributing 13 to the indoor from the outdoor, as you are 14 saying, because I don't think you actually are 15 consistent. 16 Because an automobile that is 17 running in a garage isn't exactly an ambient 18 source, but that is why your garages come out 19 having higher levels. But your manufacturing 20 facilities, which are the same as churches and 21 hospitals, obviously, there's no possible 22 scenario that there is a forklift in any of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 213 1 those manufacturing facilities, let alone a 2 manufacturing process that would produce CO 3 some other way. 4 Now, if it produces CO some other 5 way, it wouldn't be consistent with your 6 definition. But I don't see why a forklift is 7 different than an automobile, just as an 8 example. It may have to do with the sample on 9 which you drew those. 10 But in Chapter 6, well into the 11 chapter, suddenly, you start talking about 12 internal sources of carbon monoxide and 13 carboxyhemoglobin, using the 2000 data. 14 So, first of all, I have a question. 15 Is the word internal, as it is used there, 16 meant to be only indoor, non-ambient, or does 17 it mean indoor, non-ambient plus endogenous? 18 As it was used in the 2000 report, what was 19 that? Was that just indoor, non-ambient? 20 DR. GRAHAM: I think what's referred 21 to in Chapter 6, when it says, internal, I 22 think they are talking about the indoor

### 202-234-4433 Neal R. Gross & Co., Inc. Page 214 1 sources that were modeled.

2 DR. BLANC: Internal sources? 3 DR. GRAHAM: Right, yes. So, it was 4 gas stoves and -- 5 DR. BLANC: So, it was not 6 endogenous? Not endogenous, internal, but

7 not -- 8 DR. GRAHAM: Yes, yes, and I 9 apologize for that language. 10 DR. BLANC: Okay. I would 11 definitely go back and clean up that language. 12 DR. GRAHAM: I think that is how 13 they termed it back then, and maybe that is 14 why it was called -- 15 DR. BLANC: So, I would rename it 16 for your document, please.

17 DR. GRAHAM: Yes. Yes. 18 DR. BLANC: And say indoor, not 19 ambient. 20 DR. GRAHAM: Right. 21 DR. MURPHY: It is just additional 22 indoor.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 215 1 DR. BLANC: Additional to the 2 ambient to the indoor. 3 So, you can see why --

4 DR. GRAHAM: Yes. 5 DR. BLANC: Okay. So, your data, 6 though, are very convincing that this is an 7 important driver to somebody's 8 carboxyhemoglobin level, which is why, in 9 part, when I think one of the reviewers said, 10 well, wait a second, if we look at the 11 baseline pre-exposure data in Allred, they 12 have carboxyhemoglobin levels that are above 13 what you are saying people's carboxyhemoglobin 14 levels are from endogenous production. 15 But, of course, that is because 16 those people's levels aren't just endogenous; 17 they are also from their own airborne and 18 their own indoor air exposure, wherever they 19 are coming from. 20 And it is clear from what you show 21 that, when you add this indoor air pollution, 22 that 5 percent of the population hits a 3

### 202-234-4433 Neal R. Gross & Co., Inc. Page 216 1 percent carboxyhemoglobin level, and 2 percent 2 hits a 4 percent, roughly, slightly higher and 3 lower. Yet, then, that is sort of completely

4 abandoned. 5 That is why I said earlier today 6 that I think it would be critical to see the 7 curve of what happens when you add all three 8 together. Because you have one presentation 9 which is the indoor plus the outdoor, and you 10 have one which is the endogenous plus the 11 outdoor, but you don't have anywhere all

12 three. 13 Although your stated rationale -- 14 and I forget where it was in the document -- 15 is, well, you know, this is about ambient 16 pollution, we can't control by our standard 17 indoor air pollution, but you can't control by 18 your standard endogenous production, either, 19 but you do take it into account. 20 I wonder if there isn't some other 21 standard process that you have gone through 22 where the issue of multiple sources of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 217 1 exposure have to be dealt with as explicitly. 2 For example, the last time you redid an 3 ambient lead standard, didn't you have to take 4 into account sources of lead that weren't from 5 ambient air pollution? 6 DR. MURPHY: Yes. Yes, I worked on

7 that standard. 8 And, yes, the reason we did was 9 because of the non-linear relationship in the 10 blood biokinetic modeling. So, that we 11 needed to pull together all of the exposure, 12 and then take back out to figure out how much 13 was ambient. Because in setting the standard, 14 we focused on the amount of air-related blood 15 lead that was contributed by the air, be it 16 multiple pathways of exposure, but, still, the 17 focus in lead was on the ambient air-related 18 lead, although we did in the assessment need 19 to consider all the different sources because 20 we had a non-linear relationship going on in

21 the blood lead model that was used. 22 There was a comment made this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 218 1 morning which I thought was useful. What we 2 are looking for here is a link back to the 3 Allred data. Obviously, they had an 4 experimental exposure that upped their COHb. 5 So, it is that change that saw the response 6 that we saw in that study. So, that is sort 7 of a parallel to what we are looking at here 8 in terms of the ambient concentration. 9 DR. BLANC: But, in order to do 10 that, if the issue is biologically -- you are 11 taking an approach where, in your tabular 12 presentations, you are saying how many people 13 are pushed over 2 percent carboxyhemoglobin 14 and how many people are pushed over 3 percent. 15 Well, if the issue is being pushed 16 up to that level, then you have to think about 17 where people are starting from. You have done 18 that appropriately because you think about the 19 endogenous level. So, clearly, you are going 20 in that direction. 21 By the same logic, it also matters 22 what people's contribution from their indoor

### 202-234-4433 Neal R. Gross & Co., Inc. Page 219 1 air is because they are going to be pushed 2 even higher. So, in fact, the percent of the 3 at-risk population which reaches 3 percent for 4 carboxyhemoglobin isn't what you are 5 estimating it is. It is going to be higher 6 because those people don't just have their 7 endogenous production; they have their indoor 8 exposure as well. 9 DR. MURPHY: But it seems to me it 10 would depend on the relationship between the 11 ambient contribution and the indoor 12 contribution. In some ways, the ambient may 13 not really change a person's COHb if they have 14 a larger indoor contribution to their COHb. 15 DR. BLANC: Well, I don't see why 16 that would be true, and that wasn't what your 17 estimation from the 2000 data showed. You 18 added them together linearly. You wouldn't 19 assume that you would have less of a response 20 to ambient superimposed carbon monoxide 21 because you have already been exposed 22 internally.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 220 1 DR. MURPHY: It would depend on the 2 magnitude of the indoor contributions, and 3 that is an uncertainty we have in this

4 assessment; that's true.

5 DR. BLANC: Yes. 6 CHAIR BRAIN: So, if it is higher 7 indoors and you go outdoors, then it will go 8 down, not up, right? 9 DR. BLANC: Yes. Yes, but, overall, 10 your value will be higher, right? And since 11 you showed in your model that for most people 12 90 percent of their exposure is coming from 13 their times indoors, right? 14 DR. MURPHY: Right. 15 DR. BLANC: Well, I mean in the all 16 column. People spend most of their time -- 17 MR. JOHNSON: But it is unlikely 18 that you have a really high ambient exposure 19 indoors. So, the really high COHb would 20 probably not be affected. 21 Another point here is these numbers 22 are for 2000. Some of these indoor sources

### 202-234-4433 Neal R. Gross & Co., Inc. Page 221 1 have actually come down since then. That 2 doesn't mean we should ignore them, but the 3 effect will probably be less than what is

4 shown. 5 DR. BLANC: Well, okay, it will be 6 less, but I think it is going to add overall 7 a part per million to everybody, which means 8 that the percentage of people, if you 9 estimate, however you do the at-risk 10 population, the number of people who exceed 11 each threshold would be substantively more, 12 substantially more. 13 DR. MURPHY: Their total exposure is 14 not necessarily from ambient, that's right. 15 DR. BLANC: That's right, but that's 16 what matters, is who gets pushed over because 17 of the ambient up into this higher category 18 biologically and clinically and 19 epidemiologically. 20 DR. KAUFMAN: Paul, this is Joel 21 again. 22 I guess I don't read the Allred data

### 202-234-4433 Neal R. Gross & Co., Inc. Page 222 1 that way. I mean I read that data as being 2 increments up having an effect, not reaching 3 a certain COHb concentration being important. 4 It is important, obviously, but that is not 5 the way that data is laid out. 6 DR. BLANC: Well, it is a linear 7 response, in fact. So, I would disagree with 8 your interpretation. In fact, those data 9 suggested that there is a linear dose 10 response, and the higher you go, the worse 11 your effect is. 12 CHAIR BRAIN: Tom, do you want to 13 comment on that? You are one of the key

14 authors. 15 DR. DAHMS: You are probably both 16 right. 17 Because the way in which the 18 analysis was done was to compare the decrement 19 from a pre- and post-test versus one with two 20 different levels of exposure in that study. 21 So, in that sense, it is incremental. 22 However, when you do the analysis of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 223 1 a dose response, you do get a clear dose 2 response curve that suggests that it is

3 related to the absolute level of the 4 increment. So, it is linear, yes. 5 DR. KAUFMAN: I mean I put my weight 6 on the incremented being what is informative 7 and also would be extremely informative to 8 see, as the actual outcome in the modeling in 9 the REA and the Policy Assessment because this 10 was a clinical trial that was designed in a 11 way to increase people a certain amount. So, 12 that is really the inference that is designed 13 to be taken out of that study. 14 I always think, when you analyze 15 that kind of data, your first approach should 16 be to take what was the design element of the 17 study, sort of just as you would in a clinical 18 trial, with an intent-to-treat kind of thing, 19 rather than trying to model it in a different 20 way post-hoc. 21 So, that is why, for me, I mean I 22 wasn't on the group to answer Question 6, but,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 224 1 to me, the piece that I liked seeing this 2 morning, and that I think needs to be pulled 3 out even more and emphasized as this process 4 moves forward, and it doesn't sound like we 5 are going to have another crack at it, is 6 really to develop the part where we talk about 7 attributable to ambient exposure, rather than 8 so much on the endpoint of what is the total 9 carboxyhemoglobin level. 10 Because people come in with all 11 kinds of background levels from all kinds of 12 reasons, as we have been discussing, including 13 smoking. If you are adding some amount of 14 carboxyhemoglobin on top of whatever their 15 background is, I think there is reason to 16 believe, from what we have heard, that it 17 pushes them further. That is what has been 18 informed by the study that we are really 19 basing the whole risk assessment on. 20 DR. BLANC: Well, but, Joel, I think 21 that completely ignores the epidemiological 22 literature. If we only had Allred and no

### 202-234-4433 Neal R. Gross & Co., Inc. Page 225 1 epidemiological literature, I might be 2 inclined to -- but I don't think that that is 3 a public health protective interpretation of

4 the Allred data. 5 DR. KAUFMAN: I disagree. I think 6 the way that I am interpreting it is 7 completely public health protective and 8 provides public health protection across the 9 entire range of background carboxyhemoglobin 10 level that people come in, rather than 11 discounting people who come in with high 12 levels, which I think your approach does. 13 Further, I think the epidemiological 14 data is actually surprisingly weak, for the 15 reasons that are discussed extremely well, I 16 thought, in the Policy Assessment and the REA. 17 So, I think where we are right now, 18 we may be better off in five years, but where 19 we are right now is, unfortunately, this 20 process is appropriately based on the Allred 21 study. That is where we are going to have to 22 be. I think public health protection says

### 202-234-4433 Neal R. Gross & Co., Inc. Page 226 1 that you start with wherever somebody's 2 carboxyhemoglobin level is and talk about the 3 increment and trying to reduce the amount of 4 increment caused by the ambient contribution 5 to their carboxyhemoglobin level. 6 That is where I think this piece 7 actually needs to be firmed-up. And they have 8 taken initial steps towards that, but haven't 9 gone far enough yet. 10 CHAIR BRAIN: Francine, while Paul 11 is thinking about that, do you want to add 12 anything to Charge Question 6? 13 DR. LADEN: I don't have anything to 14 add to that, except I would actually agree 15 with what Joel has just said. I think that 16 the increment is what is really important here 17 and what we have got the data to be able to

18 look at. 19 DR. BLANC: But if that were true, 20 then we wouldn't be talking about an at-risk 21 population. You would say the population is 22 the entire population that is exposed, Joel.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 227 1 So, I don't think you can have your cake and 2 eat it, too. 3 If we are going to say only people 4 with coronary disease are at risk, then, in 5 fact, those are the people that are being 6 thrown over a threshold. If you are saying 7 everybody is at risk, then, the epidemiologic 8 data don't suggest that. 9 So, you haven't convinced me. Maybe 10 it is partly the language that we are using is 11 we are talking apples and oranges. I don't

12 know. 13 But, to me, why I am harping on the 14 indoor air pollution is because, if you are 15 going to make a calculation with the added 16 increment of ambient pollution, how many 17 people have now gone into the danger zone 18 because they are using a cutoff of, for better 19 or for worse, 2 parts per million, then I 20 think it is reasonable to think about. 21 Because your argument would say, then, cut out 22 the endogenous production, too, and forget

### 202-234-4433 Neal R. Gross & Co., Inc. Page 228 1 about that. 2 For the second half of my comments 3 on the CO, I would just reiterate what I said 4 this morning, which is that the model isn't so 5 transparent of how the endogenous was done. 6 But from what I can understand from it, it 7 doesn't include parameters that presume 8 outlying subpopulations.

9 We are told that there aren't 10 numeric ways of really doing that, but it 11 comes back more to the question of when you, 12 then, go back and see, are the numbers that 13 are being generated here reasonable, we know 14 that there have to be people by endogenous 15 production who are higher than the maximum 16 numbers that are coming out here. So, that is 17 a little tricky. 18 I do think that, whatever you stick 19 with, it could be more transparent. In the 20 appendix is where that stuff is supposed to 21 be, but you can't actually tell -- from the 22 appendix, there is a reference list, but you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 229 1 can't tell, and it says somewhere something 2 like eight different studies were used to 3 inform. But there is no way of knowing which 4 eight those were. 5 DR. GRAHAM: Yes, they are 6 summarized in the table. 7 DR. BLANC: Yes, but the table is

8 not labeled.

9 DR. GRAHAM: B-3. 10 CHAIR BRAIN: Okay. Anything else 11 on Question 6? We sort of wandered around 12 into multiple issues. 13 DR. DAHMS: Well, I've got 14 something.

15 CHAIR BRAIN: Yes. 16 DR. DAHMS: My concern with the 17 endogenous levels, now in the past I went 18 looking for this through all the documents 19 from '79 on, trying to find a description of 20 baseline levels of carboxyhemoglobin. Now one 21 of the issues that you bring up with the 22 endogenous rates not having an influence on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 230 1 anything doesn't make any physiologic sense to 2 me. That is what I am really having a hard 3 time with. 4 Because if we are all exhaling 2 5 parts per million, that means we have to have 6 a gradient of 2 parts per million to get rid 7 of what we are producing every minute of every 8 day. If you add one part per million 9 inspired, that means you've got to raise your 10 expired to 3 parts per million to get rid of 11 our endogenous production. So, it is just 12 going to keep raising it up. 13 So, I'm really having a hard time 14 understanding why the endogenous rate does not 15 influence the eventual dose of 16 carboxyhemoglobin, which is related to the 17 parts per million of carbon monoxide. 18 It gets back to exactly what Paul is 19 talking about. If you have got 3 parts per 20 million in your kitchen and you need three to 21 get rid of your endogenous, you are going to 22 wind up with 5 parts per million being

### 202-234-4433 Neal R. Gross & Co., Inc. Page 231 1 exhaled. 2 CHAIR BRAIN: So, the alveolar PCO 3 will be higher, and so the carboxyhemoglobin 4 will be higher.

5 DR. DAHMS: Correct. And I can't 6 figure out why that is not the case. 7 DR. HAZUCHA: Well, let me comment 8 here. It is true and maybe not so true. 9 The COHb level depends on the 10 maximum level of carbon monoxide you inhale. 11 If you have in the environment 5 ppm, and your 12 COHb production is 2 ppm, you will be taking 13 in carbon monoxide. If you are in absolutely 14 pure air, you will be exhaling carbon 15 monoxide. 16 If you are outside and there is 5 17 ppm exposure, and you came from inside where 18 there was 9 ppm, you will be exhaling carbon 19 monoxide outside. If it is reverse, we have 20 a higher concentration outside and lower 21 concentration indoors, then probably you will 22 be taking in. If there is carbon monoxide

### 202-234-4433 Neal R. Gross & Co., Inc. Page 232 1 seeping inside indoors, then you will be 2 taking up carbon monoxide. 3 So, it is not additive effect. It 4 is not 2 ppm and 5 ppm, and so on. It is the 5 highest concentration which you are inhaling 6 which will be driving carbon monoxide level. 7 CHAIR BRAIN: I mean what I find 8 helpful about that, Milan, is it is sort of 9 the steady-state. Once you have equilibrated 10 with this 3 parts per million --

11 DR. HAZUCHA: Yes. 12 CHAIR BRAIN: -- then there is no 13 additional. 14 DR. HAZUCHA: There is no minimum 15 exchange. 16 CHAIR BRAIN: You don't have to get 17 rid of it anymore. You have reached that new 18 equilibrium level. Now you simply -- 19 DR. DAHMS: But, then, you reach 20 maximum levels in your body, and that doesn't 21 happen. Your endogenous rate continues. You 22 can't stop it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 233 1 CHAIR BRAIN: You are now no longer 2 taking up the 3 ppm of CO. You are 3 exhaling -- 4 DR. DAHMS: You've got to maintain 5 that gradient to get rid of -- 6 CHAIR BRAIN: But, then, you have to 7 add the 2. You are adding your own 2 ppm to

8 that. 9 DR. DAHMS: Yes. You are raising 10 your own body burden. 11 DR. HAZUCHA: You will be increasing 12 body burden, but you won't be adding. You 13 will have, indeed, steady production, let's 14 say, of endogenous carbon monoxide. And it 15 will be always produced, but if the outside 16 level is higher, you will be constantly taking 17 in until it is reached -- 18 DR. DAHMS: But we will be masking

19 that. 20 DR. HAZUCHA: Yes, you will be 21 masking that. 22 DR. DAHMS: No, you will never reach

### 202-234-4433 Neal R. Gross & Co., Inc. Page 234 1 an equilibrium because you are always going to 2 get rid of it. 3 CHAIR BRAIN: But now you are 4 equilibrating at this new level of five 5 instead of two. 6 DR. BLANC: So, just a final 7 question because I actually hadn't -- it is 8 helpful to see the table B-3. I guess it 9 wasn't right where the other statement was 10 made. But what are the units in this table? 11 DR. GRAHAM: Yes, I know. I 12 apologize for that not being there. It's mLs 13 per hour. If you look in table B-2, that 14 actually has the -- it is on page -- oh, I'm 15 sorry -- B-14. That confirms that and 16 provides the distributions of the endogenous 17 CO production rate that were used for males 18 and females, and females for -- stratified by

19 two. 20 DR. BLANC: So, these would be the 21 number of subjects?

22 DR. GRAHAM: Yes.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 235 1 DR. BLANC: Each of these? Does 2 that mean you probably could explain, label

3 the table -- 4 DR. GRAHAM: Right. And again, I 5 apologize. And of course, none of the 6 subjects are identified as far as females and 7 males. I will try to get that in there as

8 well.

9 CHAIR BRAIN: Let's break for lunch. 10 We will return and do 7. 11 I guess just a final question. I 12 found this exchange with Milan and Tom 13 helpful. Is that consistent with what the 14 document is saying or does something need to 15 be altered to reflect your understanding?

16 DR. DAHMS: It's a concern.

17 CHAIR BRAIN: Yes. 18 DR. DAHMS: This goes back to the 19 concern about the validity of the modeling, 20 and it is an uncertainty. I don't know that 21 it can be resolved. But somehow, when we get 22 to those uncertainties, we have to flesh it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 236 1 out a little bit. 2 CHAIR BRAIN: Well, maybe you can 3 confer. I mean I guess it is not quite clear 4 to me what we are telling the EPA, given your 5 understanding of the situation. But maybe we 6 can start with that when we come back. 7 Let's break for lunch, and we will 8 reconvene at 1:30. Maybe a few extra minutes. 9 So, we will break for lunch and we will

10 reconvene at 1:30. 11 (Whereupon, the foregoing matter 12 went off the record for lunch at 12:36 p.m. 13 and went back on the record at 1:30 p.m.)

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### 202-234-4433 Neal R. Gross & Co., Inc. Page 237 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 1:30 p.m. 3 MS. BARRY: Okay. It is straight-up 4 1:30. I would like us to go ahead and

5 reconvene. 6 CHAIR BRAIN: All right, I think we 7 are now up to Charge Question 7. So, we will 8 turn back to Paul to get us started on that. 9 DR. BLANC: Okay. Let's see, 10 Question 7 is the one that really addresses, 11 as I interpreted it, addresses the issue of, 12 what's the population at risk? Because that 13 has to do with the public health implications, 14 from my point of view, all other things being 15 equal. 16 Just to briefly reiterate, I think 17 that they are to be commended on the effort 18 that went into all of the parameters on 19 modeling exposure. You know, even if there 20 are suggestions on how they could bring into 21 that the estimate of indoor non-ambient source 22 exposure, and even if perhaps the distribution

### 202-234-4433 Neal R. Gross & Co., Inc. Page 238 1 isn't wide enough on the endogenous component, 2 and even if there are some questions about the 3 near-roadway, some degree of potential 4 systematic underestimation of near-roadway 5 exposure, but I think all of that is kind of 6 dwarfed by this issue of who the population at 7 risk is. 8 It is not that I would suggest that 9 there be no estimation, roughly, using the 10 approach that they did of one definition of 11 the population at risk for adverse cardiac 12 events being persons believed to have coronary 13 artery disease narrowly-defined. I appreciate 14 the effort, also, of trying to estimate 15 undiagnosed coronary artery disease. But I 16 think that there needs to also be an upper-end 17 estimate provided in parallel, which is 18 exposure to people with cardiac disease 19 defined more broadly. 20 I think in terms of the estimates 21 that are there, probably the document would 22 help itself by pointing out that, although

### 202-234-4433 Neal R. Gross & Co., Inc. Page 239 1 estimates based not on a National Health 2 Interview Survey, but based on the National 3 Behavioral Risk estimate survey, and based on 4 the NHANES, are slightly different, they are 5 not outrageously different, just for 6 consistency's point of view. 7 I think that this ratio that they 8 derive from the heart disease facts and 9 figures from the brochure of the American 10 Heart Association is probably a weak source 11 for an estimate of undiagnosed ischaemic heart 12 disease, unless that document itself provides 13 some coherent source of that estimate. 14 So, that would be another -- 15 because, obviously, if it is double the amount 16 and not 40 percent more, it would change it 17 considerably. The problem with that number, 18 also, is I think anybody looking at it would 19 presume that the proportion is different for 20 women than for men, as women are recognized to 21 be underdiagnosed and undertreated for heart 22 disease. So, on face value, whatever the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 240 1 number is, there should be a sex differential. 2 So, those are my main comments in 3 terms of Question No. 7. 4 CHAIR BRAIN: Okay. Tom? 5 DR. BLANC: Just to put a number by 6 it, by the way, I mean the National Health 7 Interview Survey number is approximately three 8 times as large, if you say heart disease 9 generally. I think that is about the range. 10 It is quite a bit larger. 11 CHAIR BRAIN: So, one possibility is 12 not to substitute that larger number, but to 13 add it and say, if you would also include

14 these other --

15 DR. BLANC: Yes. I mean the same 16 way that you model, if we are just at the 17 standard, if we are at the 99th percent, so I 18 think it is worth seeing, what are we talking 19 about, if we are not talking about this 20 definition of disease? And I think that the 21 biological plausibility is there. 22 CHAIR BRAIN: All right. Tom?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 241 1 DR. GRAHAM: May I just ask a 2 question? Just so I'm clear on this, I think 3 you referred to NHIS, which is where we 4 derived the original dataset. You are 5 suggesting there's additional information on 6 coronary disease as a whole? 7 DR. BLANC: Well, you took the 8 coronary disease column, and then there's all 9 heart disease. 10 DR. GRAHAM: Right. All heart 11 disease. I'm sorry. 12 DR. BLANC: Yes, right there. 13 DR. GRAHAM: Right. 14 DR. BLANC: If you could be 15 consistent -- 16 DR. GRAHAM: Right, and use the same 17 approach that we did to stratify it by age and 18 gender. 19 DR. BLANC: Yes, yes. 20 DR. GRAHAM: Okay.

21 CHAIR BRAIN: Tom? 22 DR. DAHMS: I have just one concern.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 242 1 I may have missed it someplace in the text of 2 this. But the number of people, person-hours, 3 everything else at risk, has been listed for 4 LA and Denver in detail. How are we to 5 connect this to the whole country, because you 6 are using whole country data for heart 7 disease? So, I was having trouble going to 8 the whole U.S. population when you take the 9 number of people with coronary artery disease, 10 or however you want to define it for the whole 11 country. I don't know how to go from the 12 exposure data from these two cities to the 13 whole country. How do we do that? 14 DR. GRAHAM: Right, and that is an 15 important question. I mean these two case 16 studies represent two specific locations in 17 the United States. As you can see by the 18 results, we have two different sets of results 19 that are different. Or shall I say I said 20 that already? 21 How that relates to other locations, 22 in the past what we have done, like for NO2,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 243 1 we had information on what may be influencing 2 these concentrations, and then, comparing that 3 within these locations to other select 4 locations across the United States to get a 5 feel for, well, where does Los Angeles fit 6 with respect to air quality data? Where does 7 Los Angeles fit with respect to time spent 8 inside vehicles, since we see that that is 9 important in determining high-end exposures? 10 So, that type of information could be included 11 in this final discussion, as far as the 12 representation of these two locations. 13 DR. BLANC: I think he was asking, 14 rather, did you, beyond an age/gender 15 adjustment, were there other adjustments for 16 region of the United States or for race in 17 terms of heart disease? 18 I thought that is what you were 19 asking. 20 DR. DAHMS: I was really trying

21 to -- 22 DR. BLANC: You just did a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 244 1 gender/age adjustment, but not adjusting on -- 2 you assumed the national rates were -- 3 DR. MURPHY: Yes, just to clarify, 4 is that what you were asking? It sounded 5 different. 6 I mean there are two things. One, 7 we took the national estimates of prevalence 8 of the disease that we had stratified by 9 gender and age, and then applied that to the 10 two study populations. 11 But you seem to be asking a question 12 from the other perspective, of taking the 13 results from the two study areas and saying, 14 what do they mean with regard to the rest of 15 the country? That is what we -- 16 DR. DAHMS: That was the question I 17 was really asking. How in the world do we 18 apply this? Because it is not the Denver/LA 19 EPA. It is the U.S. EPA. 20 DR. MURPHY: Right, and what Stephen 21 said is, well, they provide us information, 22 and we need to, then, look at that and put

### 202-234-4433 Neal R. Gross & Co., Inc. Page 245 1 them in context, to the extent we can. It is 2 not unusual for the different pollutants we do 3 different things. It is unusual for us to do 4 a national risk assessment. Usually, we do 5 case study risk assessments for different 6 areas where we have the best data, for 7 example, or we have a particular interest. 8 Then, we try to look at those 9 results and put them in the context of other 10 information we have nationally to help inform 11 the Administrator's decisions about what 12 significance they are going to ascribe to

13 those data. 14 In this case, for example, the 15 differences that we see between the study 16 areas, that will be important to consider as 17 well, how prevalent are such differences in 18 other cities across the country. 19 DR. DAHMS: I guess it just gets to 20 the whole idea, and I don't know whose task it 21 is in this whole chain of command to decide 22 what's an acceptable number of people to be at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 246 1 risk. Is that totally the Administrator's 2 decision? When do we get anxious about there 3 being too many people, too many days at risk 4 in the country? 5 DR. MURPHY: Right, and that is what 6 Lydia was referring to this morning, is 7 clearly a public health policy-based judgment. 8 That is a judgment made by the Administrator 9 in deciding in the end on what the standard 10 ought to be. There are a lot of things that 11 need to be weighed. 12 Our job, in terms of writing the 13 assessment, the staff's job in terms of 14 writing what used to be the staff paper, and 15 is now the Policy Assessment, is to try to 16 pull together all the appropriate options that 17 are reasonably supported by the scientific 18 data and the analyses that we have done, and 19 that could be described to the Administrator, 20 so that they can understand what the weights 21 are scientifically behind the information that 22 we have, and they can understand what the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 247 1 science policy judgments are that need to be 2 made. Then, there will need to be decisions

3 made. 4 We do it with every standard that we 5 set. Lead was mentioned earlier. Lead had 6 its own host of public health policy decisions 7 to be made in terms of IQ results, et cetera. 8 So, it is something that the agency 9 struggles with. It is, in the end, the 10 Administrator's decision. But, as Lydia 11 mentioned, it is also an area where we are 12 interested in the Panel's views in terms of 13 how well we have characterized what the 14 evidence and the science support in terms of 15 the range of public policy options. 16 CHAIR BRAIN: Thank you. Tom, other

17 comments?

18 DR. DAHMS: No. 19 CHAIR BRAIN: Francine? 20 DR. ROBERTS: I just had an 21 observation there. Would it help -- and I 22 didn't see this -- would it help to actually

### 202-234-4433 Neal R. Gross & Co., Inc. Page 248 1 translate the numbers of people from LA and 2 Denver to a national, to have a national table 3 somehow that says this results in X number of 4 people in different exposure or COHb 5 categories? 6 Because that is part of it. I guess 7 it is percentage.

8 DR. DAHMS: But we don't have 9 exposure data for the rest of the cities.

10 DR. ROBERTS: No. You have to 11 explain that you are using this to represent

12 the rest and how well that does. 13 CHAIR BRAIN: But they don't 14 represent very well the rest of the country. 15 Francine? 16 DR. LADEN: Okay I don't really 17 have very much to add. I just wanted to say 18 that, I mean, I think this is an interesting 19 challenge because the CO levels have decreased 20 so significantly over what the standards are, 21 and how to express that, you know, what the 22 public health risk is, I think is important.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 249 1 It is, obviously, very important, and I think 2 an interesting challenge. 3 In terms of just a little comment 4 that Paul had brought up about the undiagnosed 5 rates between males and females, I had 6 mentioned that in my response to Question 5. 7 I think that is an important question. I 8 don't think we can assume that they are the

9 same. 10 It seemed like those rates, the 11 undiagnosed rates, were from 1990. I am not 12 sure that they would still, if we really think 13 that they are the same now. So, just how does 14 that relate to what today's reality is, I

15 don't know. 16 CHAIR BRAIN: Yes, it is an 17 interesting question. To what extent do we 18 address and summarize where we are today? And 19 what are the current levels? I suppose the 20 decision is more about the standard and what 21 we will expect as different alternatives to

22 the standard.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 250 1 DR. ROBERTS: The standard would be 2 easier to meet if -- 3 DR. LADEN: Exactly. It should be 4 easier. 5 DR. BLANC: Can I just ask one 6 follow-up question just to clarify? 7 I think it is the case that the 8 activity diary data that went into the 9 modeling was area-specific. 10 DR. GRAHAM: No, and the answer, the 11 reason for that is, of course, there is a 12 limited number of diaries that are used. I 13 mean the maximum is about 35,000. That 14 includes individuals of all ages. We reduce 15 that automatically by just simulating all 16 adults 18 and over. So, there's a smaller 17 number of diaries that are available.18 Not all the diaries have location19 specific information. You will find that with 20 a lot of these diaries, that there may be some 21 lapses in the data provided for age or gender. 22 So, there's a limited number of diaries that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 251 1 can be used. 2 So, if we were to use, say, diaries 3 that came specifically from, say, California, 4 we would have an extremely limited pool of 5 data available to do this simulation for the 6 entire population. So, it may not necessarily 7 be representative, based on those limited 8 diaries. 9 However, we know that there are 10 activities that people perform in locations 11 that they visit that are influenced by certain 12 attributes like temperature. That is actually 13 used as a variable to sample for. 14 So, we know that in, say, Los 15 Angeles the maximum or the mean temperature 16 was 55. Well, then, we draw from diaries that 17 actually have a temperature that corresponds 18 to, say, between 50 and 60, so that we can 19 reproduce the activities that people might 20 perform, given the general temperature, which 21 is more of an influential variable likely 22 than, say, a specific location. So, in a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 252 1 sense, the diary simulation for the population 2 in each area is representative but not from by 3 that person. 4 DR. BLANC: Right. 5 DR. GRAHAM: We also stratify by 6 other variables like, say, day of week. We 7 know that our activities during the week as 8 adults are generally driven by our workplaces 9 and time spent indoors. But on the weekends, 10 it might be something different. So, we 11 stratify the diaries that way.

12 DR. BLANC: The reason I asked the 13 question is because you made the comment that 14 is quite correct that exposure is -- and you 15 showed us day to that effect, too -- that 16 exposure is driven by commuting time, and 17 commuting time in Los Angeles is certainly on 18 the higher end. I don't know the Denver 19 patterns as well. 20 DR. GRAHAM: Right. Well, in one of 21 the appendices there is a comparison of the 22 CHAD as a whole for the population age 18 and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 253 1 above, I think stratified by various age 2 groups. In there, we compare that 3 distribution of drive times, in-vehicle drive 4 times, with that that we have got from the -- 5 it's Appendix E. We compare that with the 6 distributions obtained from the Census as far 7 as time spent and the percent of vehicles 8 spent -- I'm sorry -- the percent of -- 9 DR. BLANC: Nationally or for the 10 two locations? 11 DR. GRAHAM: For the two locations, 12 Denver County and Los Angeles County. 13 DR. BLANC: And did it come out 14 okay? 15 DR. GRAHAM: Yes, they looked very 16 comparable. I mean, of course, there is going 17 to be some locations or shall I say some 18 differences in some of the time for some of 19 them, but if you look at the numbers, they are 20 very comparable. 21 CHAIR BRAIN: All right. Any other

22 comments on 7?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 254 1 Let's go on, then, to the last 2 Charge question. That's Number 8, and Paul 3 Roberts will lead us on that. 4 DR. ROBERTS: So, this has to do 5 with the views of the Panel on the adequacy of 6 the assessment of uncertainty and variability, 7 and how they have been identified and what 8 their implications are, and to what extent it 9 is adequately described. So, this is the same 10 approach that was in the previous draft table 11 with qualitative low, medium, and high in 12 direction. 13 I think this is pretty good. I 14 still repeat my comments from the previous 15 one, which I would much rather see some 16 sensitivity runs on the ones of most concern. 17 I realize the time schedule, but I still think 18 that is a better approach in general. 19 I guess I am still getting used to 20 this new system, but I would still like, even 21 though I guess it has been said that the 22 summary of this is in the PA, I would still

### 202-234-4433 Neal R. Gross & Co., Inc. Page 255 1 like some summary in here of what this means 2 in this document before someone goes on to 3 read the Policy Assessment. But maybe that is 4 just me. 5 I guess, let's see, one other -- I 6 think, in general, the improvements from the 7 first draft to the second draft have, like in 8 terms of the micro-environments, for example, 9 et cetera, those have reduced the impact of 10 those parameters on the overall results, and 11 that is reflected here. I think that is good. 12 You know, there are still some 13 uncertainties here. I think the significant 14 improvements, though, have resulted in better 15 representing the tail of the distribution that16 we are most concerned about, again, the near17 roadway and in-vehicle exposures. So, I think 18 that is good. 19 I could quibble about a couple of 20 small words, but I can put those in my 21 detailed comments. I am talking mainly about, 22 I guess, it is the first 10 or so here.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 256 1 Others can comment on the last three or four

2 that are more related to the rest of the 3 panel's comments. 4 CHAIR BRAIN: Thank you. 5 Joel, Dr. Kaufman, are you with us?

6 DR. KAUFMAN: I am. 7 CHAIR BRAIN: Oh, thank you.

8 DR. KAUFMAN: But I don't have 9 anything to add here. 10 CHAIR BRAIN: Okay. Very good. 11 Anyone else want to comment on Charge Question 12 8? Milan? 13 DR. HAZUCHA: I have, actually, two 14 questions. 15 One is the activity pattern is over 16 30 years old. Nowadays, our activity pattern, 17 we are much more sedentary. We spend more 18 time in vehicles. 19 Is there any way that you can update 20 the activity pattern? 21 DR. GRAHAM: Well, I think there is 22 a table, if somebody could help me out here as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 257 1 far as the activity patterns that were used. 2 I think it is in Chapter 5. 3 Some of the data actually do come 4 from more recent studies that were conducted 5 internally, as well as I think some external 6 studies funded by the EPA, and includes a 7 number -- I think we have increased that 8 dataset that we originally used back in 2000, 9 we have increased it by 15,000 person-days. 10 While your comments are reasonable 11 in suggesting that persons' activities have 12 changed over time, we may spend more time 13 indoors or it is possible that we are more 14 sedentary, as you suggest. But there's no way 15 for us to actually compare, say, data now to 16 the prior data that were available because of 17 a lot of the differences in the surveys18 themselves. There may be different micro19 environments that were identified or missing 20 information regarding activities performed or 21 different descriptions of activities. 22 So, in a sense, if you were to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 258 1 compare a given parameter, like, say, time 2 spent outdoors with the more recent data to 3 the earlier data of time spent outdoors, you 4 might end up with a significant effect, but it 5 is more related to the study rather than the 6 actual differences in persons' behaviors. So, 7 it is a very difficult thing for us to 8 actually -- if there were significant or 9 statistically-significant effects, is it 10 because of that or is it because we are doing 11 a better job of characterizing where people 12 are and what they are doing?

13 But there are recent data. 14 DR. HAZUCHA: Yes, okay. 15 The other question which I have is, 16 this APEX model has built in internal, what I 17 would call, consistency checks between input 18 variables. Like, for example, and I guess we 19 already discussed it briefly in the morning, 20 if you, for example, select in the model 21 somebody with CHD, and then there is randomly 22 assigned an activity level. That individual

### 202-234-4433 Neal R. Gross & Co., Inc. Page 259 1 may not, for example, perform beyond a 2 moderate level. He or she may have 3 difficulties even with upper level of a 4 moderate exercise level. 5 So, are there any internal checks 6 that, if you select a CHD patient, heavy 7 exercise is out? Or if you select some other 8 patient or other individual, something else is

9 out?

10 DR. GRAHAM: But for the CHD 11 population, that is not something that we 12 would correct for at this time. Right now, 13 what we have is an algorithm that directly 14 applies to what is called excess post-oxygen 15 consumption that is over a period of time, 16 like you suggest. No, I'm sorry. Let me talk 17 about something else. 18 It is the METS distribution, right. 19 There is actually a control on the METS 20 distribution itself that, again, a person 21 couldn't necessarily keep performing activity 22 after activity at a strenuous level. So, we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 260 1 do have an algorithm that controls for that. 2 But, again, that is based on the general 3 population. It isn't necessarily driven for 4 the CHD population.

5 CHAIR BRAIN: Other comments about 6 this charge question or any other one? 7 DR. BLANC: Well, I have a question

8 for Paul. 9 We had talked earlier about the 10 systematic possible effect of underestimating 11 near-road exposure. So, where on the grid of 12 this table of uncertainty on exposure and dose 13 estimates would that be? And is the direction 14 of the influence of uncertainty appropriately 15 characterized? 16 DR. ROBERTS: You know, I guess it 17 is the micro-environmental algorithm and input 18 data. It is a medium-medium. 19 DR. BLANC: So, it's not under 20 spatial temporal representation? 21 DR. ROBERTS: Well, I don't know. I 22 wouldn't put it there. I guess I would put it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 261 1 under how the algorithm is actually working. 2 I don't know. I had trouble figuring that out 3 earlier. 4 DR. BLANC: And is that the one that 5 says, direction unknown?

6 DR. ROBERTS: Yes. 7 DR. BLANC: But, basically, I think 8 it needs to be made clear that if the 9 direction is, in fact, not unknown, but more 10 likely to be underestimation, at least in 11 terms of that issue, it should be stated, if 12 I understood the critique correctly. 13 DR. ROBERTS: If that is the right 14 category. Maybe somebody else can tell me

15 where -- I'm not sure where else that comes. 16 DR. BLANC: Because one thing I 17 would say is that, at least in the current 18 formulation where it says, CHD prevalence, I 19 would say that the direction is probably -- 20 well, first of all, the magnitude of the 21 uncertainty is high because it is a major 22 final driver in the number of people exposed.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 262 1 I think that our knowledge base 2 uncertainty isn't medium. It is probably low. 3 It is just how you use the data. Let us say 4 we have epidemiologic data on prevalence. It 5 just depends on what you are defining as 6 disease. 7 And the direction is that the more 8 narrowly you define disease, the more likely 9 you are to underestimate the population at 10 risk. 11 I wouldn't agree with the 12 characterization of the uncertainty issues as

13 stated here. 14 DR. GRAHAM: I just want to comment 15 on the in-vehicle micro-environment, as far as 16 the exposure concentrations being over- or 17 underestimated. I do have some discussion 18 about that, not about the over- or 19 underestimation, but there was a limited 20 comparison that I could do to literature data 21 that were available. It is on page 6-5. 22 This has to do with the scenario

### 202-234-4433 Neal R. Gross & Co., Inc. Page 263 1 where we estimated people's exposure with just 2 meeting the current air quality, that 3 particular scenario, and again, which used the 4 1995 data. At that same time, not that same 5 exact time, but I think it was 1997, where6 they collected some measurements for in7 vehicle concentrations. Those are presented

8 there as well. 9 You can see that our upper end is 10 actually above that which was measured in this 11 particular study. I think they measured less 12 than 10 for a two-hour average concentration, 13 which, of course, is different from the 14 averaging that we are reporting here for 15 hourly concentrations. 16 But it gives you a feel or a sense 17 of where we are with respect to hour 18 estimation. We have concentrations maximums 19 going upwards to, I think it is 30 or, yes, 20 upwards to 60 ppm. 21 Then, there was this other study 22 available as well -- where they actually had

### 202-234-4433 Neal R. Gross & Co., Inc. Page 264 1 more individuals, a greater number of 2 commuters where they estimated in-vehicle 3 exposures. Those went upwards to 46, I think, 4 yes, 46 ppm. 5 So, again, I know it is a limited 6 comparison, but it should give you some 7 perspective on the relationship between our 8 upper end and some of the upper ends that have 9 been reported in the literature. 10 CHAIR BRAIN: All right. Any other 11 comments from the agency or from anyone else 12 on the panel on the REA? 13 (No response.) 14 CHAIR BRAIN: Well, let me just very 15 quickly sort of tell you where we are going 16 and how we are going to get there. Again, 17 this is a familiar process. It is what we did 18 the last time as well. 19 So, we are hoping, more than hoping, 20 we are expecting that the topic leaders for 21 each of the charge questions will put together 22 what they feel is a reasonable consensus

### 202-234-4433 Neal R. Gross & Co., Inc. Page 265 1 statement. So, again, your job is to put 2 together something that really sort of almost 3 everyone can sign on. If there are more 4 detailed comments, put them in your own 5 individual comments. If you feel they are 6 really idiosyncratic and not widely shared, 7 then, again, put them in your own individual

8 comments. 9 What we are going to do is, if you 10 send those to Kyndall probably anytime until 11 nine o'clock or something like that, she will 12 put them together after the charge questions, 13 and we will have a first draft of our letter 14 to the Administrator. 15 She will print that out, and we will 16 look at it tomorrow, which I think is really 17 important because there is some difference of 18 agreement and there's some tough problems that 19 it wasn't exactly clear how we were going to 20 frame our answer. But if we can put together 21 our best shot, then tomorrow morning we will 22 find some time to look at that, and not to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 266 1 wordsmith it, but really for everyone to say, 2 yes, this is generally what I can sign my name

3 to. 4 It will also be an opportunity for 5 the agency to look at it and say this doesn't 6 make sense; I don't understand where you are 7 going with this. So, tomorrow is really an 8 ideal time to get some feedback on the general 9 direction of those comments. 10 Then, you will have an extra couple 11 of days -- maybe we will announce that 12 tomorrow, but probably through the end of this 13 week or something -- to improve those. Then, 14 next week we will go to work and do some 15 additional wordsmithing and try to make it 16 more coherent and integrated and see if 17 there's any conflicts between one question 18 saying one thing and another question saying 19 something else. 20 We will, then, send that to you for 21 you to look at and give you a little time to 22 look at. Then, when we have done our best

### 202-234-4433 Neal R. Gross & Co., Inc. Page 267 1 collectively, then we will send it on to the 2 CASAC Committee, and there will be a 3 teleconference, which you already know about, 4 April 19th. 5 So, yes, in fact, working backwards, 6 in order to have a legal teleconference on 7 April 19th, it needs to be posted, what, a 8 week before that? Something like that. Plus, 9 we want to give CASAC time to look at it, 10 which I think is particularly important since 11 CASAC is not adequately represented or is not 12 widely represented at this meeting. 13 So, then, CASAC will look at it. 14 They will make a few more edits. Then, it 15 will go off to the Administrator. So, that is 16 the general process. 17 The other thing, as you are 18 preparing your best draft for tomorrow, if you 19 think there are things that should be part of 20 this two-page highlights letter to the 21 Administrator, let us know. I will be looking 22 at that, and I've got a few notes already of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 268 1 things that I think are big issues that we 2 want to bring simply to her. 3 DR. BLANC: I'm sorry, Joe, now I am 4 confused. You are saying there are going to 5 be three documents, a highlights letter, 6 bullets, and then our own detailed comments? 7 CHAIR BRAIN: Yes. So, the first8 letter is a two max, you know, about a two9 page letter to the Administrator saying 10 general comments. We like it. We don't like 11 it. Here's some big problems you need to 12 really think about or major comments. 13 Then, that is followed by the first 14 attachment would, then, be the Panel consensus 15 on the answers to all the charge questions, as 16 well as other major topics. Again, we don't 17 need to be confined by the charge questions. 18 For example, it came up this morning 19 that we have some comments on the new graphs 20 that were presented to us. So, if that 21 doesn't intersect adequately with a charge 22 question, that can be a completely new topic.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 269 1 Or you may have some other comment that you 2 think came up. So, we need not be constricted 3 by that. 4 But, yes, so there is the two-page 5 letter. Then, comes Attachment A. Well, 6 then, there's the members of the Panel. Then, 7 comes the Attachment A, which are the answers 8 to all the charge questions with an adequate 9 amount of detail. That is usually 10-15 pages 10 or something. Then, comes everybody's 11 individual comments. 12 MS. BARRY: Did that answer your 13 question? 14 DR. BLANC: Yes, I just didn't 15 remember that last part as being what happened 16 last time. 17 CHAIR BRAIN: Yes. And you should 18 have, on the website are the letters that went 19 forward from the Committee last time. 20 DR. BLANC: I just remember the 21 integrated comments. I don't remember a bunch 22 of additional comments.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 270 1 MS. BARRY: The members always have 2 an opportunity following the meetings to 3 revise your individual review comments. So, 4 you will have an opportunity. We always 5 append any revised comments to the letter 6 because a lot of times the agency has 7 requested specific references that have been 8 discussed. So, that is generally an 9 opportunity for you all to identify other 10 references that may be useful. 11 So, we have the cover letter. We 12 have the consensus responses to the charge. 13 Then, there's always opportunity for a 14 compendium of individual review comments to 15 also be attached to make this final report 16 that goes to the Administrator.

17 CHAIR BRAIN: In the case of the 18 REA, you might find it useful to look at the 19 final document that did go from CASAC to the 20 Administrator, which was our report, because, 21 again, it will remind you of some of the 22 issues that we addressed last time. One of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 271 1 the questions is, were all those concerns 2 addressed as best as they could or not? But 3 that will also sort of let you see what the 4 final document looked like. That is available 5 on the website. 6 Or, if you need a hard copy -- in 7 fact, is it trivial for you to send that as an 8 attachment to everybody? 9 MS. BARRY: The previous letter?

10 CHAIR BRAIN: Yes. 11 MS. BARRY: No, that's easy. 12 CHAIR BRAIN: So, why don't you send 13 out the previous letter for the REA? That 14 will both serve as a draft as well as some 15 context and background for this letter. 16 Again, one would hope that the two letters are

17 somewhat coherent. 18 So, does that all make sense? So, 19 give it your best shot. 20 Yes, we are now going to make as 21 much progress as we can with the Policy 22 Assessment. We will do the same to the extent

### 202-234-4433 Neal R. Gross & Co., Inc. Page 272 1 that topic leaders can produce a consensus 2 report, even though we won't complete the 3 discussion today. Again, we can ask Kyndall 4 to pull those together, and at the end of our 5 meeting tomorrow we can at least look at the 6 answers to the charge questions that we have 7 addressed today. 8 Again, the major question is for you 9 to all have a chance to say, yes, that is my 10 recollection of our discussion; that 11 represents a consensus statement. Or, if 12 there is something that still needs to be 13 resolved, this will be an ideal time to 14 resolve it. 15 Then, Kyndall, there is also dinner 16 is going to be at 7:30 with people leaving at 17 7:15, and the destination is --

18 MS. BARRY: We'll work on that. If 19 you guys are not opposed to trying some 20 Mexican food -- notice the air quotes -- if 21 there are any objections, let me know and we 22 will pick somewhere else.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 273 1 CHAIR BRAIN: So, the plan for 2 those, do they need to let you know if they

3 are able to come or not? 4 MS. BARRY: Well, I have got a hint. 5 CHAIR BRAIN: Okay. So, meet in the 6 lobby at 7:15, dinner at 7:30, back at 9:00 or 7 9:30 or something probably. 8 So, any other questions about that? 9 We are surprisingly on time. As is true, some 10 areas took longer than anticipated, but, 11 fortunately, that was compensated by others 12 that were less complicated. 13 So, let's now turn to the next step 14 in the process. So, after the ISA comes the 15 REA. Then, comes the PA. So, we are getting 16 closer to a real decision. So, let's hear all 17 about the PA. You will hear a little bit more 18 about the philosophy and how it will be used 19 by the Administrator. Then, we will hear 20 about the document itself. Then, we will move 21 to the charge questions. 22 So, we will turn it over to EPA

### 202-234-4433 Neal R. Gross & Co., Inc. Page 274 1 staff. 2 DR. MURPHY: Sure. While he is 3 getting the slides up, I will remind you all 4 of the team. We have changed faces here at 5 the table. Again, Deidre Murphy here as the 6 team lead, and we have Dr. Inez Pagan, who is 7 the lead on the Policy Assessment document, 8 particularly for the health aspects. Then, we 9 have Dr. Meredith Lassiter, who is the lead on 10 the secondary standard, the ecological 11 aspects, and Dr. Pradeep Rajan, who is the 12 epidemiologist on the team. 13 So, the team we just introduced. 14 The overview, we are going to go through the 15 Policy Assessment, touching on the purpose and 16 description, as we did this morning as well. 17 Then, just reminding you all on what's in the 18 document in terms of the considerations raised 19 for primary standards and consideration of the 20 secondary standard, and then, briefly, an 21 overview of the subject areas for the CASAC 22 charge.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 275 1 Just a reminder, as we did this 2 morning of the role of the Policy Assessment 3 and the purpose, it is a staff analysis of key 4 science policy issues. It is created to 5 facilitate the Administrator's judgment and 6 review of the CO NAAQS, so that we create this 7 document, and then we go into briefings with 8 the Administrator to help identify what should 9 go into the proposal notice, as Lydia 10 mentioned this morning. 11 This is the step preceding 12 development of a proposal notice. So, this 13 document is intended to interpret and 14 integrate information from both the ISA and 15 the REA. As we said before, often, we have a 16 lot of evidence presented in the integrated 17 science assessment, some of which will be used 18 to design and frame the quantitative analysis 19 that is in the REA document, and some of which 20 doesn't quite fit into that box, if you will, 21 but it comes back into the conversation, comes 22 back into our consideration in this document.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 276 1 So, that we try to consider all of 2 the evidence and any of the quantitative 3 analyses that we have performed. So, by 4 default, then the Policy Assessment will 5 include consideration of ISA evidence and our 6 quality analyses perhaps that are beyond the 7 focus of the quantitative REA. 8 Also, as was mentioned this morning, 9 the document facilitates our getting your 10 advice on the adequacy of the current 11 standards and on any appropriate alternative 12 standards. That, also, Lydia tried to explain 13 this morning. 14 As I mentioned, this precedes the 15 rulemaking phase, which, as you will recall, 16 we have a court-ordered date for a proposal 17 notice to go out in October of this year. So, 18 we are keeping to a very rapid pace. 19 With that, I will turn it over to 20 Dr. Pagan to continue on. 21 DR. PAGAN: So, we have a very brief 22 presentation.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 277 1 In the Policy Assessment, we have 2 framed our discussions around policy-relevant 3 questions with regard to the adequacy of the 4 current standard and the alternative 5 standards. The overarching question with 6 regard to the adequacy of the current standard 7 addresses whether the current available8 scientific evidence and exposure and risk9 based information, as reflected in the ISA and 10 in the Risk and Exposure Assessment, supports 11 or calls into question the adequacy of 12 protection afforded by the current CO

13 standards. 14 With regard to the alternative 15 standards, that same information is used to 16 support consideration of alternative standards 17 to the current CO, and the focus would be to 18 provide increased protection to ambient CO 19 exposures. 20 The discussions included that the 21 evidence-based considerations indicate since 22 the last review that ischemia-related effects

### 202-234-4433 Neal R. Gross & Co., Inc. Page 278 1 is the most sensitive endpoint. Hypoxia due 2 to increases in COHb levels is the best 3 characterized mechanism of CO-induced effects. 4 Cardiovascular diseases and other 5 diseases that have limited oxygen availability 6 are potential susceptibilities. 7 DR. BLANC: And what does, 8 potential, mean to you? 9 (Laughter.)

10 DR. PAGAN: Well -- 11 DR. BLANC: Don't you see potential 12 as an extremely weak adjective in that

13 sentence? 14 DR. PAGAN: At their potential, we 15 can speculate on -- 16 DR. BLANC: But it is not 17 speculation. Didn't the ISA have a very 18 different take on that? 19 DR. MURPHY: No, the ISA had a very 20 similar take on it. It used the words, 21 potentially susceptible. We drew from the ISA 22 in the language that we used in the Policy

### 202-234-4433 Neal R. Gross & Co., Inc. Page 279 1 Assessment, and it used the words, potentially 2 susceptible. 3 DR. PAGAN: I think we have 4 characterized what the ISA has put together, 5 was summarized on this. 6 And as we were discussing before, 7 the coronary artery disease continues to be 8 the best characterized susceptibility. 9 Clinical studies and estimates of 10 COHb levels associated with ambient CO 11 exposure play a key role in our conclusions on 12 ambient CO levels associated with health

13 effects. 14 Since the last review, we have an 15 expanded epidemiological database and 16 specifically very strong in supporting 17 ischemic outcomes, and it is in coherence with 18 the clinical evidence. 19 Previously, we still have some of 20 the identified uncertainties from previous 21 reviews remaining. Those are the key, most 22 important, the clinical significance of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 280 1 ischemia-related changes that are observed at 2 the lowest levels tested in the controlled 3 human exposure studies; the CO and the COHb 4 levels at which potentially-susceptible 5 populations may be affected and the exact 6 nature of those effects. Of course, the 7 expanded body of epi data includes its own set 8 of uncertainties. 9 CHAIR BRAIN: I just have one 10 question. On that first, the word ischemia or 11 ischemia-related or ischemic outcomes appears 12 three times. I mean, aren't we really talking 13 about diminished oxygen delivery? And, yes, 14 when you have ischemia, that sort of sets the 15 stage for further decreases in oxygen delivery 16 being important. 17 But, I mean, in none of these 18 situations -- I mean ischemia is not an 19 outcome. We don't measure ischemia. So, I 20 think hypoxemia is a much better word 21 throughout. 22 Tom agrees, yes?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 281 1 DR. PAGAN: Yes, and the 2 epidemiological database has been 3 characterized as ischemic or ischemia-related 4 outcomes in the ISA, but -- 5 CHAIR BRAIN: Well, maybe we need to 6 go back. I find it misleading. Am I the only

7 one? No.

8 Yes? 9 DR. THOM: If it is in your 10 epidemiologic data, it is the wrong word. 11 CHAIR BRAIN: Yes, it is really 12 hypoxemia or hypoxic-related effects.

13 DR. THOM: Yes. 14 CHAIR BRAIN: It is lack of oxygen 15 delivery. I mean in no case, nobody is 16 measuring changes in blood flow. 17 DR. MURPHY: If I could just make 18 sure we understand the point, in terms of the 19 outcomes in the epi database, it is IHD, 20 ischemic heart disease, is the outcome that -- 21 CHAIR BRAIN: It is not the outcome. 22 It is the susceptible population.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 282 1 DR. MURPHY: In the epidemiological 2 study? 3 DR. BLANC: Yes, I can see the 4 problem here. No, you're quite correct, in 5 the epidemiologic literature what the 6 endpoints are are hospital admissions for 7 ischemic heart disease or acute MI. 8 CHAIR BRAIN: Okay. 9 DR. BLANC: Or due to compensation 10 of CHF. So, I think the wording problem is 11 mixing up probable mechanism with what the 12 endpoints are. Of course, the endpoint in the 13 main study that is used for the dose response 14 is EKG changes which are consistent with 15 ischemia, but it is not hypoxemia. The 16 carboxyhemoglobin level is the exposure side, 17 but the endpoint -- it is both in a sense. 18 So, you know, I see why the problem 19 is arising, but it is partly because in some 20 sense this is cast too narrowly and in others 21 maybe too broadly. But I don't see an easy 22 solution to it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 283 1 CHAIR BRAIN: Well, maybe in the 2 very first bullet, if we changed it to 3 cardiovascular-related effects encompass the 4 most sensitive endpoints. 5 DR. BLANC: I certainly support

6 that. 7 CHAIR BRAIN: Right. 8 DR. BLANC: But that is part of the 9 whole problem. I am trying, while I am doing 10 this, to look through because I think, again, 11 the way this is constructed, it discounts 12 everything else except for the narrowly-cast 13 Allred endpoint. I think that fails to 14 integrate the epidemiologic literature with 15 biological controlled exposure literature, and 16 I think that is a major shortcoming, the major 17 shortcoming of this document. 18 I just think there is no way around 19 that. I think back-peddling and saying, well, 20 and there is also the possibility that it 21 might, on the other hand, have some 22 relationship to other cardiovascular

### 202-234-4433 Neal R. Gross & Co., Inc. Page 284 1 endpoints, that is not what the epi literature 2 said. And even if they used the word 3 potential, they didn't use it in the same 4 implication that it has in the bullets here. 5 DR. MURPHY: If I could just clarify 6 the bullets for a minute, to make sure we are 7 all on the same page, I appreciate your

8 comments. 9 The first large set of bullets is 10 with regard to evidence available since the 11 last review and how it continues to indicate 12 things. So, things that were true or 13 concluded at the time of the last review, 14 whether or not the current evidence still 15 relates or supports that. Ischemia-related 16 effects may not be the appropriate phrase. We 17 certainly recognize that point. 18 We recognize here that hypoxia is 19 identified as the best characterized 20 mechanism. The current ISA continues to 21 support that. 22 In terms of susceptibilities, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 285 1 current ISA continues to support that 2 cardiovascular and other diseases with reduced 3 oxygen availability are the key potential 4 susceptibilities and that CHD continues to be 5 the best characterized one, predominantly 6 because we do have the controlled studies on

7 that.8 Then, lastly, under this as a sub9 bullet, that the clinical studies, and in 10 combination with estimates of COHb levels 11 associated with ambient, continue to play a 12 key role in helping us draw conclusions on 13 ambient CO levels that might be associated 14 with health effects. 15 Then, moving on to the next large 16 bullet, since the last review, what has 17 changed, one thing that has changed is we have 18 an expanded epidemiological database 19 supporting ischemic outcomes, and that that 20 database is coherent with the clinical 21 studies. That fits together very well. That 22 was discussed this morning, I believe, in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 286 1 various Panel members' comments. 2 Then, lastly, we just go through 3 some of the previously-identified 4 uncertainties which still remain. Some of 5 them have been reviewed. Some still remain. 6 And then, along with the epi 7 evidence, we have its own complications for 8 interpretation. 9 CHAIR BRAIN: But I still have 10 problems with that third bullet from the 11 bottom, you know, ischemia-related changes 12 observed at low doses of CO. I mean they are 13 not -- well, maybe they are related to 14 ischemia, but it seems to me they are more 15 related to oxygen delivery. Ischemia sort of 16 sets the stage for their susceptibility. 17 DR. PAGAN: The clinical studies are 18 described as myocardial ischemia indicators, 19 which are the reduced time to onset of angina 20 or reduced time to onset of the ECG ST 21 segment. 22 CHAIR BRAIN: Well, ischemia is one

### 202-234-4433 Neal R. Gross & Co., Inc. Page 287 1 contributor, but it is not the only one. No 2 one thinks, do they, that CO is affecting 3 arterial diameter and affecting blood supply 4 to the myocardium? No, I haven't heard that 5 theory. Or is that a theory? 6 DR. THOM: There's some data, but it 7 is not a lot. It is not worth going into,

8 Joe. 9 DR. DAHMS: And it's not when you 10 get diseased vessels that can't dilate. So, 11 the whole point is that it is a combination of

12 factors. 13 CHAIR BRAIN: Right. 14 DR. DAHMS: It is not just that you 15 are going to get a relative ischemia. 16 CHAIR BRAIN: Right. 17 DR. DAHMS: You are also going to 18 get -- 19 CHAIR BRAIN: The consequences of 20 ischemia are augmented by CO. We are not 21 claiming that CO causes -- 22 DR. DAHMS: Otherwise, if you don't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 288 1 use reduced oxygen delivery, then you have to 2 talk about relative ischemia and reduced 3 oxygen supply. 4 CHAIR BRAIN: So, it is okay as it 5 is? Or what --

6 DR. DAHMS: No.

7 CHAIR BRAIN: No? 8 DR. DAHMS: I think it ought to be 9 changed, but -- 10 DR. PAGAN: Do you have any 11 suggestions? 12 CHAIR BRAIN: Clinical significance 13 of CO aggravating ischemia, or something like

14 that. Isn't that what we are -- or 15 interacting with ischemia? 16 DR. MURPHY: Your point being that 17 the CO is not causing the ischemia; it is 18 exacerbating it? 19 CHAIR BRAIN: Yes, and in no case 20 are you measuring ischemia. You are measuring 21 angina or -- 22 DR. PENN: Why not CO-aggravated

### 202-234-4433 Neal R. Gross & Co., Inc. Page 289 1 changes?

2 CHAIR BRAIN: Yes. 3 DR. KAUFMAN: I guess I would 4 interpret ST segment changes as ischemia, not 5 just hypoxemia. 6 CHAIR BRAIN: Say that again?

7 DR. KAUFMAN: If I remember 8 correctly, one of the outcomes in the studies 9 is ST segment changes, which is a measure of 10 ischemia, not just hypoxemia. 11 DR. DAHMS: But in the controlled 12 studies, it is both. 13 DR. KLEINMAN: Well, what we have is 14 a chemical hypoxia, chemically-induced 15 hypoxia, that leads to reduced supply of 16 oxygen to the heart, which is ischemia.

17 CHAIR BRAIN: No. 18 DR. KLEINMAN: Isn't it? 19 CHAIR BRAIN: Which is angina. 20 DR. KLEINMAN: Well, angina is a 21 system of ischemia. 22 DR. KAUFMAN: Depression is,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 290 1 although some might quibble, is considered a 2 sine qua non of ischemia, and as opposed to ST 3 segment elevation, which is infarction. So, 4 if that is what is observed as an outcome in 5 a study, then that is ischemia. 6 DR. DAHMS: Yes, but carbon monoxide 7 enhanced that, brought it on sooner, and 8 therefore, there's an underlying ischemia when 9 you are undergoing exercise that is enhanced 10 by the carbon monoxide. 11 So, you are trying to convey all the 12 things in a few words, and it may not be 13 possible. 14 DR. KAUFMAN: Well, I mean, you 15 know, if you follow the concentration/response 16 relationship, we know that at rest a person 17 can have a myocardial infarction with 18 underlying ischemia as a result of just carbon 19 monoxide exposure. It happens all the time. 20 Carbon monoxide does that. 21 So, the question is, does it also -- 22 I don't think it is a big stretch to say at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 291 1 the lower concentrations ischemia is also an 2 outcome, not just a bystander, I guess. 3 CHAIR BRAIN: But if we take what 4 you said, do you really think that CO acts for 5 any of these outcomes by reducing blood flow 6 to the myocardium? That if you monitored 7 blood flow through the coronary vessels with 8 microspheres or -- 9 DR. KAUFMAN: Well, the ischemia 10 does not require a decrease in blood flow. It 11 requires decreased oxygen delivery to the 12 myocardium to decrease -- 13 CHAIR BRAIN: That is not the Latin 14 root of the word. Ischemia has to -- 15 DR. KAUFMAN: But that is the way it 16 is used -- 17 CHAIR BRAIN: That may be true. 18 DR. KAUFMAN: I mean if you read a 19 cardiology textbook, they don't talk about the 20 Latin roots; they talk about -- 21 CHAIR BRAIN: No, but ischemia 22 implies a particular mechanism.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 292 1 DR. KAUFMAN: Cardio ischemia, that 2 is what it is. 3 CHAIR BRAIN: You know, there's 4 hyperaemia, unusually high blood flow, and 5 then there's -- you know, it is relating to 6 blood flow, and we are talking about something 7 more complex, where blood flow is a critical 8 component and often the major cause, but it is 9 a different -- 10 DR. BLANC: So, Joe, can I just try 11 to cut through this knot?

12 CHAIR BRAIN: Yes. 13 DR. BLANC: As I understand it, 14 where you are really taking exception is in 15 the use of ischemic outcomes more than 16 anywhere else in the bullet that says ischemic

17 outcomes. 18 CHAIR BRAIN: Outcomes usually 19 associated with ischemia or something like

20 that. 21 DR. BLANC: Well, I think really, to 22 be consistent with the ISA, what that phrase

### 202-234-4433 Neal R. Gross & Co., Inc. Page 293 1 there should be is adverse cardiovascular 2 outcomes because that is what, since the last 3 review, the epidemiologic database supporting 4 adverse cardiovascular outcomes has expanded 5 and is coherent with the clinical evidence. 6 That is what the section summarizes, the 7 summary comments on the section there say. 8 So, that would, I think, solve it for 9 everybody. 10 DR. HAZUCHA: Well, they refer to 11 controlled human exposure studies. I believe 12 that it is reference to Allred studies. Right 13 here, and they repeat it again and again, it 14 is myocardial ischemia. Myocardial ischemia, 15 these findings show that myocardial ischemia, 16 and so on, as measured by ECG changes and 17 angina, and so on. 18 So, repeated as you go through the 19 document, it is myocardial ischemia. 20 DR. BLANC: I'm not talking about 21 Allred here. I'm talking about -- 22 DR. HAZUCHA: So, we are talking

### 202-234-4433 Neal R. Gross & Co., Inc. Page 294 1 about what study? 2 DR. BLANC: About the epidemiologic 3 database. Their sentence, Since the last 4 review, epidemiological database supporting 5 ischemic outcomes is expanded. It's really 6 the epidemiological database supporting 7 adverse cardiovascular outcome is expanded, 8 because that is what we reviewed and that is 9 what the summary comments are on.

10 CHAIR BRAIN: It seems to me that 11 kills two birds with one stone. It both 12 enlarges it a little bit and it clarifies the 13 messy language. Then, in detail, you can 14 parse it. 15 DR. BLANC: And the final sentence 16 of that whole section is, A causal 17 relationship is likely to exist between 18 relevant short-term exposures to CO and 19 cardiovascular morbidity. 20 So, you should be able to live with 21 that, with adverse cardiovascular. 22 DR. MURPHY: Hopefully, you all will

### 202-234-4433 Neal R. Gross & Co., Inc. Page 295 1 give the same focus to the words in the 2 document as our slide. And we may have said 3 it better in the document. 4 CHAIR BRAIN: Okay, yes, let's press 5 on. I think this has been helpful. Please. 6 DR. PAGAN: Okay. So, you have 7 heard this morning on the risk, a lot about 8 the risk-based considerations. 9 The current and the potential 10 alternative lower standards provided by this 11 analysis have differing maximum COHb levels on 12 the simulated at-risk populations. 13 For the scenario of just meeting the 14 eight-hour controlling standards, less than 15 four percent of either of the study 16 populations would experience maximum COHb 17 levels at or above two percent. On the other 18 hand, more than 80 percent of both of the 19 study populations are estimated to have 20 maximum COHb levels below 1.5 percent.21 Just meeting the alternative eight22 hour standard of approximately three ppm would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 296 1 result in more than 99 percent of both study 2 populations with maximum COHb levels below 1.5 3 percent. 4 Similar to the evidence-based 5 information, with regards to the risk-based 6 considerations, some uncertainties previously 7 identified have been reduced and some still 8 remain. 9 Public health implications of the 10 exposure and dose estimate will be affected by 11 our interpretation of the clinical 12 significance of the responses observed at the 13 lowest COHb levels in the controlled studies, 14 the clinical studies. That is the weight that 15 we give to the different benchmarks and 16 judgments regarding the potential significance 17 of those estimated COHb levels, what would 18 that signify for other potentially-susceptible 19 populations? 20 So, here, in making interpretations 21 with regards to the current and alternative 22 standards, we integrate the information, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 297 1 evidence and the exposure risk information, as 2 it relates to the level and form of a 3 standard. On top of that, we overlay some 4 public health policy considerations. 5 For the eight-hour standards, those 6 would be, as we had said before, the nature 7 and severity of the effects that we are 8 considering. What are the appropriate COHb 9 benchmarks to focus on? And what is an 10 adequate margin of safety for the at-risk 11 population? 12 And those same considerations would 13 apply for the one-hour standard, in addition 14 to the peak levels that this one-hour standard 15 is protecting against, and how frequently we 16 would have peaks of CO, ambient CO. 17 So, this integration is illustrated 18 in this graph. On the X-axis, we have the 19 level for the second-highest eight-hour 20 average, which is the current form, and on the21 Y-axis we have the percentage simulated at22 risk population. We have highlighted on the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 298 1 X-axis where the current standard lays, which 2 is 9.4 ppm. 3 This is all related to specific 4 benchmarks. We have highlighted three 5 benchmarks here: the 1.5, which is labeled in 6 black; two percent COHb, labeled in green, and 7 2.5 COHb, labeled in orange. The solid 8 symbols represent the LA area, and the open 9 symbols represent Denver. 10 As you can see, more than 90 11 percent, with all of these benchmarks, except 12 for the one in Denver, the black open in 13 Denver, more than 90 percent of the population 14 would experience maximum COHb levels below

15 these benchmarks. 16 And this is a slide, the same 17 graphical presentation. However, we present 18 here on the X-axis, this is the level for the 19 99 percentile daily max eight-hour average, 20 which this is an alternative form than the 21 eight-hour second max -- 22 DR. MURPHY: I was just going to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 299 1 take a moment to make sure you all understood 2 these slides because these figures are not in 3 the document, similar to some of the figures 4 we saw this morning that Dr. Graham presented. 5 This is just another way to present the data 6 that are in the tables in the Policy 7 Assessment. This is just presenting them 8 graphically. 9 So, I wanted to make sure, if there 10 were any questions, you could ask them and we 11 could make sure you understood. 12 It is just showing -- using how you 13 can look at these data. Dr. Graham mentioned 14 this morning that the five scenarios that were 15 run actually give you information about a lot 16 of different combinations of averaging time, 17 form, and level, which might go to a potential 18 alternative standard. 19 This just illustrates different ways 20 you can look at it for two different forms for 21 the standard, with the level varying across 22 the bottom. Both of these figures are with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 300 1 regard to the eight-hour standard. 2 DR. PAGAN: Any questions with 3 regards to those figures? 4 So, in summary, the adequacy of the 5 current standards may or may not be just 6 adequate, depending on judgments regarding the 7 nature and the severity of the effects that we 8 are considering at the lowest COHb levels 9 tested, the weight that we place on the 10 different benchmarks, the weight that we place 11 on the epidemiological studies, and an 12 adequate margin of safety for the at-risk 13 population. 14 With regards to the alternative 15 standards, for the eight-hour standard it may 16 be appropriate to consider a range from nine 17 to three ppm with the lower end depending on 18 the same judgments as above. In conjunction 19 with considering revising the level, it may be 20 appropriate to consider an alternative form, 21 such as the 99th percentile or fourth highest 22 daily max, average across three years.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 301 1 And for the one-hour standard, it 2 would be appropriate to consider a range of 3 policy options that include retaining, 4 revising, or revoking. This would be 5 depending on the role that this standard has 6 relative to the eight-hour standard. 7 DR. MURPHY: So, now we are just 8 going to switch to Dr. Lassiter for the 9 secondary standards slide. 10 DR. LASSITER: All right. To 11 address our overarching question in regards to12 the secondary standards, does the currently13 available information provide support for 14 considering the establishment of a secondary 15 standard for CO? We considered both the 16 climate effects and the non-climate effects of 17 CO, including effects on vegetation and 18 ecosystems.19 So, there is no evidence of pseudo20 effects on non-climate-related endpoints. For 21 the effects of CO on climate, there are both 22 indirect and direct effects. The direct

### 202-234-4433 Neal R. Gross & Co., Inc. Page 302 1 effects are weak and highly variable. The 2 primary effects of CO on climate are the 3 indirect effects, which is mediated through 4 methane and through ozone formation. 5 So, we found there's insufficient 6 information at this time to interpret how 7 these ambient levels of CO, which are 8 spatially variable and localized, and depend 9 on the other atmospheric chemistry, the 10 atmospheric chemistry in local areas. So, 11 there's not enough information right now to 12 assess how these differences would affect 13 climate changes at the local and regional

14 level. 15 DR. MURPHY: And the last slide is 16 just providing an overview of the areas of the 17 charge for the CASAC review on these Panels. 18 The questions cover the background with regard 19 to our characterization of the air quality 20 information. We have questions with regard to 21 the organization. This is one of the first 22 Policy Assessments. We previously had staff

### 202-234-4433 Neal R. Gross & Co., Inc. Page 303 1 papers, and, then, for one, I guess just one 2 review or two, we had an Advanced Notice of 3 Proposed Rulemaking. Now we have a Policy

4 Assessment. 5 So, we have a question with regard 6 to the organization, have we teed-up the 7 policy-relevant questions appropriately, 8 provided the appropriate level of detail in 9 discussing them? 10 Then, specifically, with regard to 11 the primary standards, we discussed the issue 12 of adequacy of protection provided by the 13 current standards and tried to bring forward 14 what are thought to be the appropriate 15 considerations that inform that question. 16 That goes at characterization and integration 17 of the health effects evidence, including 18 differences from the last review; 19 characterization of the quantitative exposure 20 dose estimates, as well as important 21 uncertainties, particularly those significant 22 to drawing conclusions regarding adequacy of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 304 1 the standard. 2 We ask about your reviews on the 3 considerations that we have brought forward to 4 inform our initial conclusions, and, more 5 broadly, as we described this morning, we are 6 interested in the Panel views on the adequacy

7 of the current standards and the extent to 8 which the current document is consistent with

9 them. 10 Then, with regard to potential 11 alternative standards, we ask with regard to, 12 have we teed-up the appropriate considerations 13 that inform a characterization of the options 14 that are appropriate for the Administrator to 15 consider and that are well-supported by the 16 information? Have we provided the rationale 17 to justify the range of policy options 18 presented? And again, more broadly, what are 19 the Panel views on the range of alternatives 20 that are appropriate to consider? 21 Then, lastly, with regard to 22 consideration of the secondary standard, we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 305 1 ask questions regarding our characterization 2 of the current evidence, including 3 specifically the climate-related effects of

4 CO. 5 CHAIR BRAIN: Thank you. 6 Yes, a question? 7 DR. DAHMS: I would just like to 8 clarify something and admit my total 9 ignorance. When you go back to the 10 alternative standards, you talk about picking 11 the fourth highest. Could you inform me of 12 the statistical basis of the rationale for 13 picking that number? 14 DR. MURPHY: Right. So, the current 15 form of the standard, the standard is 9 ppm, 16 not to be exceeded more than once per year, 17 and the rounding convention is such that it is 18 one figure. So, a 9.4 as a second maximum in 19 the year meets the current standard. So, that 20 is what we call a design value. 21 DR. DAHMS: So, you can exceed the 9 22 once and be in compliance?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 306 1 DR. MURPHY: Yes. 2 DR. DAHMS: And the second time 3 you're out of compliance? 4 DR. MURPHY: Right. So, if we have 5 an area where the second highest eight-hour 6 average CO concentration is above 9.4, then we 7 have an area that is out of attainment and 8 controls need to be brought to bear, a state 9 implementation plan developed, et cetera. 10 DR. DAHMS: And so, when you are 11 talking about the fourth, then you are talking 12 about going to the fourth incident? 13 DR. MURPHY: Right. And really, in 14 more recent standards that we have developed, 15 we tend to move away from the more16 deterministic not-to-be-exceeded or to-be17 exceeded-only-once. It is a less-stable form 18 of the standard to use because you may end 19 with areas that go in and out of attainment, 20 just because of meteorological differences 21 year to year. 22 So, in terms of implementing the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 307 1 standard, you want to put a control program in 2 place and keep people in that control program 3 longer-term. So, more recently, we tend to

4 use forms of the standard that are more 5 stable, we would say, such as 98th or 99th 6 percentile daily maximum, averaged over the 7 last three years. So, the 99th percentile, 8 when you have hourly measurements over a year, 9 will correspond to the fourth highest value. 10 So, often, it is a question of, do 11 we want to call the form the 99th percentile 12 or is it more easily understood by the public 13 to call it the fourth highest value? So, that 14 is why, in the discussion in the document, we 15 say one or the other, so people understand 16 they are the same, when you have a full 17 dataset of hourly values, and the decision on 18 which it will be will be up to the 19 Administrator. Some of what is taken into 20 account is what is more easily understood. 21 But in terms of the form, that type 22 of form, which is a more stable form, is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 308 1 thought to be a better form in terms of 2 stability for control programs, which is 3 really what we are after in the end. 4 DR. DAHMS: So, that is not so much 5 an acute public health warning thing as it is 6 an attainment issue, right? 7 DR. MURPHY: Well, we set the 8 standard to keep the air quality where we want 9 it to be. So, there are different ways to do

10 that.

11 I am not sure how to answer the 12 question because there is not a clear answer 13 really. But one thing I would mention is you 14 can see that there's a correspondence between 15 an air quality dataset that has a second 16 maximum and a fourth maximum. So, when you 17 look at those different X-axes for the two 18 figures, you can see the same data plotted 19 there; they will just be shifted down for the 20 fourth highest because it will correspond to

21 a lower level. 22 That is perhaps a little off your

### 202-234-4433 Neal R. Gross & Co., Inc. Page 309 1 question, but -- 2 DR. DAHMS: Well, no, I'm just 3 thinking about the practicality of living in 4 LA and when it is really a bad day for health 5 for people with cardiovascular disease. Now, 6 let's see, this is the fourth time, so it's 7 bad, but the first time that it hits 9, it's

8 not so bad? 9 DR. MURPHY: Now you are talking in 10 terms of the public communication about, you 11 know, people's behaviors.

12 DR. DAHMS: Sure. 13 CHAIR BRAIN: And she is talking 14 about long-term planning. 15 DR. DAHMS: Oh, I know. That is 16 what I am talking about, attainment versus 17 public health. 18 CHAIR BRAIN: Right, which are 19 different. 20 DR. MURPHY: Communication. And 21 that is certainly a good point, and we have, 22 obviously, the agency has a whole program with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 310 1 the air quality indicator, the AQI, the Air 2 Quality Index, where we try to inform people. 3 For example, on ozone, when we have high ozone 4 days, what are the populations that need to 5 take action? And we do that when the days are 6 just below the standard.

7 Now we haven't talked at all about 8 an Air Quality Index for CO. That would be a 9 whole other conversation. But the things you 10 are raising are things that would be pertinent 11 to that conversation. 12 DR. BLANC: So, can I clarify? 13 There's a difference a little bit in the slide 14 I guess before this one. I'm not sure. And 15 the document, the draft document, seems to say 16 unequivocally, that whatever it may be, the 17 standard should at least be as tough as it is 18 currently. I thought on the slide it sort of 19 said, well, the policy considerations are it 20 could be as restrictive as it is or it could 21 be less restrictive or it could be more 22 restrictive.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 311 1 But you have already, your 2 recommendation, at a minimum in the draft, is 3 that it should at least be what it is 4 currently, right? 5 DR. MURPHY: Right. We have not 6 recommended that it should be relaxed. 7 DR. BLANC: But in that slide I was 8 confused by it because of the way it was 9 worded. I might have just read it too 10 quickly. 11 DR. MURPHY: Oh, you mean the phrase 12 "may or may not be judged adequate"?

13 DR. BLANC: Yes. 14 DR. MURPHY: The point being, if it 15 is not judged adequate, it needs to be more 16 stringent. That would be the way we would 17 view that phrase. 18 DR. BLANC: Oh, I see. Okay. 19 DR. MURPHY: Yes, yes. So, it may 20 be adequate; it may not need to be more 21 stringent, which is why our range that we say 22 is appropriate --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 312 1 DR. BLANC: Okay.

2 DR. MURPHY: -- extends to that

3 value. 4 DR. BLANC: Okay.

5 DR. MURPHY: Yes. 6 DR. BLANC: But the opposite is 7 true? At a minimum, you are saying it has to 8 be, what you are saying here is what you are 9 saying there? It is just worded differently? 10 Okay. 11 DR. ROBERTS: Joe, I have one 12 question.

13 CHAIR BRAIN: Yes. 14 DR. ROBERTS: It seemed a little 15 off-base, but maybe not. In considering 16 alternative standards, can you tell us what 17 the thought process was for the NO2 near 18 roadway, in particular? I mean you haven't 19 mentioned anything like that here. The 20 alternative standards you have suggested are 21 all of the same -- well, not exactly the same 22 form, but the same approach, rather than

### 202-234-4433 Neal R. Gross & Co., Inc. Page 313 1 that's a completely different approach to 2 trying to address the tail of this 3 distribution? Is that something that could be 4 considered here or should? Or how is that not 5 been thought about? 6 DR. MURPHY: I'm not completely 7 familiar with the NO2 review issues. I do 8 know that they did consider different forms, 9 and going from a more deterministic to a 10 percentile-based form. Some of the 11 considerations that are raised in the policy 12 chapter of the NO2 REA are consistent with the 13 ones we raised here in terms of judgments you 14 might make on selection of a form, that there 15 is greater stability in going to a 99th 16 percentile or a 98th. I can't remember which 17 they ended up going to, 99th or 98th. 18 DR. ROBERTS: Yes, 98. But that is 19 a near-roadway, I mean there's a near-roadway

20 standard now.

21 DR. MURPHY: Yes. Yes. 22 DR. ROBERTS: That is the part I am

### 202-234-4433 Neal R. Gross & Co., Inc. Page 314 1 asking about really, not the form. Doesn't 2 that address the same kind of thing as we have 3 here, which is here's a tail that is driven by 4 the highest exposures? 5 DR. MURPHY: Well, I think one 6 difference is the dataset. My understanding 7 is they do not have monitors near roads; 8 whereas, CO monitors, while they are not all 9 near roads, many of them are because that is 10 the focus for CO, the main, the source for CO, 11 if you will. The main source is roadways. 12 So, in designing the monitoring 13 network, the first push was to put them near 14 roads. Now we currently don't have as many 15 near roads as we would like. 16 But in NO2, I thought they did not 17 have the near-roadway monitors per se. 18 DR. ROBERTS: Right. 19 DR. MURPHY: So, they ended up in a 20 different world for their -- 21 DR. ROBERTS: Right, there are none. 22 But, in hindsight now, I would judge that the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 315 1 CO network isn't much better. Okay? I mean 2 the new monitoring approach for NO2 is 50 3 meters, and none of these CO monitors -- you 4 know, there's one micro-site on the sidewalk 5 in Las Vegas and a couple of others like that 6 for CO, and that's it. So, the network isn't 7 really any better. 8 DR. MURPHY: Right. And one point 9 you are raising is that, as part of the 10 proposal notice, as we go forward, we will 11 consider all aspects of the standard. One 12 aspect of the standard is the design for the 13 monitoring network. 14 So, I suspect that in developing the 15 proposal our monitoring group will be looking 16 closely at the existing network and how it 17 needs to be tweaked because it has been a 18 while since we did a review of the CO 19 standard. And therefore, those monitors are 20 not any more where they perhaps would be most 21 appropriate to be. 22 My understanding in talking to some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 316 1 of the monitoring group is that they are 2 looking to how they are doing the design of 3 the network for NOx and thinking maybe there's 4 some similarities that could be done for 5 reemphasizing the network for CO in similar 6 ways. That goes to monitor placement, but 7 that is another aspect of the proposal that 8 will go forward. It doesn't affect the 9 standard per se in terms of quantitatively, 10 but it affects how we monitor for the

11 standard. 12 DR. ROBERTS: Now, I agree, I have 13 heard from the staff the idea that they are 14 going to put out an NO2 network with the idea 15 that they might add CO or other pollutants to

16 that same network. 17 But it seems to me for this Panel, 18 our consideration is, should we consider a 19 near-road standard, form of the standard? I 20 don't know. That is what I am asking about 21 because you haven't brought it up at all. 22 Yet, it seems, like NO2, it could protect

### 202-234-4433 Neal R. Gross & Co., Inc. Page 317 1 against the -- but am I way off? I don't

2 know. 3 DR. MURPHY: So, are you suggesting 4 that there be two types of standards? I mean 5 we were suggesting there be a standard which 6 protects all ambient air, be it near-road or 7 not-near-road, and that we need, of course, to 8 place monitors to appropriately judge 9 attainment of that standard. 10 But I am not sure I am seeing what 11 you are thinking -- 12 DR. ROBERTS: Right. Well, I guess 13 I am saying we could, I guess, I am wondering 14 whether we should be considering this. We 15 could pick a near-roadway standard to protect 16 against this distribution or we could pick a 17 more stringent, you know, sort of everywhere 18 standard. In either case, we are trying to 19 address the same part of the distribution, 20 which is those people who spend time commuting 21 or near roadways. Couldn't there be both 22 considered?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 318 1 DR. MURPHY: Part of my handicap is 2 I don't understand exactly why the NO2 3 standard was constructed the way it was. 4 In this review, it certainly makes 5 sense, what's being considered, in terms of a 6 standard that would apply wherever there is 7 ambient air. I mean that is a usual way to do 8 it. There were nuances to the data, the 9 evidence associated with NO2, that led them to 10 what they have ultimately decided on, but I 11 don't know that all those nuances apply in the 12 CO situation. They haven't been raised

13 before. 14 DR. ROBERTS: You're probably right,15 in that the recent epi studies have done near16 roadway mapping and imply that NO2 is having 17 more effect in that, and that is not done

18 here. But I don't see that the fundamental 19 logic really should be different. I don't

20 know. 21 Do other people have this concern? 22 DR. PENN: Well, for the PM, have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 319 1 they talked about near-roadway mapping also? 2 Because there have certainly been recent 3 studies with PM trying to associate PM 4 exposure with increased admissions for asthma 5 for kids and for things like that from a 6 couple of places.

7 CHAIR BRAIN: There was some 8 discussion like that, but it never bore fruit 9 in terms of affecting the possible standards.

10 Tom? 11 DR. DAHMS: Yes, I have a question. 12 If you go to the 99th percentile and 13 levels keep dropping, that means the standard 14 keeps dropping. 15 DR. MURPHY: No, no, no, no, no. 16 Sorry. No. 17 In judging attainment with the 18 standard, you would take the 99th percentile 19 of a year's worth of data at a particular 20 site. You wouldn't change the standard. The 21 standard would be whatever the number is. If 22 it remains 9, it will be 9. Then, you look at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 320 1 your dataset over the year and say, did you 2 exceed 9, or how many times? 3 DR. DAHMS: Oh, okay. 4 DR. MURPHY: Or what is the 5 distribution and what is the 99th percentile? 6 DR. THOM: But just because ambient 7 CO concentrations are dropping, by switching 8 to the 99th percentile, in effect, you would 9 be making the national standard substantially 10 lower than 9 parts per million for eight-hour 11 exposure. Right? 12 DR. MURPHY: Well, yes. That is why 13 I think we teed it up in the conclusion 14 section, that we would consider a change to 15 the form, if there was to be considered a 16 change to the standard. If we were going to 17 retain the current standard, we wouldn't just 18 change the form. 19 But you're right, there's a 20 relationship between levels. The level is 21 different for a different form, obviously. 22 That is actually what those two figures were

### 202-234-4433 Neal R. Gross & Co., Inc. Page 321 1 intended to -- one thing they illustrate is 2 that you move the curves along the X-axis 3 because you are changing the level for that

4 form. 5 DR. THOM: Okay. 6 And then, to Paul, I guess I am 7 confused, maybe because I am just ignorant. 8 But carbon monoxide is equally as poisonous or 9 injurious to a person, whether they are on a 10 roadway or in a house. I guess I don't get 11 the logic of why you would have a standard 12 next to the road versus someplace else. 13 DR. ROBERTS: Well, I'm not sure I 14 know, Steve. Okay? But I was trying to 15 figure, if you look at some of the plots we 16 were shown this morning that were new, 95 17 percent of the exposures at the high 18 concentration are driven by the near-roadway. 19 CHAIR BRAIN: So, why doesn't that 20 affect where you put the monitors? 21 DR. ROBERTS: Right, and I guess we 22 are ignoring in-home other sources. Okay? If

### 202-234-4433 Neal R. Gross & Co., Inc. Page 322 1 we weren't ignoring that, then, yes, the 2 question is completely different. 3 But if those figures are showing 4 almost all the exposure at the levels above 5 the current standard, well, at the individual

6 hours that are above the current standard -- 7 I mean they accumulate to be less-than -- our 8 near-roadway, then should we be focusing on 9 near-roadway? That is sort of what I am 10 asking. 11 CHAIR BRAIN: And if so, how do we 12 focus? I mean, is it by modeling, by 13 monitors?

14 DR. ROBERTS: Yes. 15 CHAIR BRAIN: I mean you could have 16 modeling that would emphasize those higher

17 levels. 18 DR. ROBERTS: And you know, one of 19 the uncertainties in the exposure modeling is 20 taking this central site, which doesn't 21 represent those high concentrations, and 22 translating it over, because that is where the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 323 1 big exposures are. 2 So, I am asking, should we be 3 considering something else? I don't know. Is 4 it we can ask about a network that is more 5 focused on the highest exposure locations, but 6 not change the standard? 7 DR. MURPHY: Yes, I'm not sure what 8 you gain by -- you're suggesting there be a 9 different type of standard, and I'm struggling 10 to understand what you would gain by that than 11 what we have teed-up here, which is just 12 whether or not the current standard is 13 appropriate or needs to be lower. But it 14 would be applied to all ambient air, 15 regardless of where that is. 16 Obviously, the network needs to be 17 appropriate. With every review of every 18 standard, we look again at the network and 19 say, how's the network doing in terms of is it 20 monitoring in places with a likelihood of 21 exceeding the standard? That is the judgment? 22 That is what the network of monitors should be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 324 1 doing? 2 To the extent it is not doing that, 3 it needs to be revamped. That is part of what 4 the review helps us do, is focus again on, 5 how's that network doing? Does it need to be 6 revamped? 7 And my understanding, based on 8 talking to the monitoring group, is that they 9 are already starting to look at that to see if 10 there is tightening to the distribution of 11 monitors to make sure they are appropriately 12 placed to find any exceedances that there 13 might be. That is their objective, the 14 monitors. 15 DR. ROBERTS: That's good. Maybe 16 that is the direction. Because, certainly, 17 well, I know agencies don't want to move their 18 monitors to a place that will measure a higher 19 concentration. Okay? So, there is a 20 reluctance to even consider that. 21 DR. MURPHY: That is why we have 22 regulations that require it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 325 1 DR. ROBERTS: Yes. 2 CHAIR BRAIN: And, Paul, it would be 3 good if you made that clear in your 4 recommendations, even if it was a separate 5 part. You know, we talked about that before. 6 Say something about the adequacy of the 7 network, what would an ideal network look 8 like. That would really capture your

9 concerns. 10 DR. ROBERTS: Yes, I think so. 11 CHAIR BRAIN: I think that is 12 important. 13 DR. GRAHAM: Dr. Brain, I just 14 wanted to add one thing. The current exposure 15 assessment, just as a reminder, that is linked 16 to the existing monitoring network that is in 17 those locations. So, if you are going to 18 control at the monitor, then that has going to 19 be linked to the exposures and the dose, and

20 so on. 21 CHAIR BRAIN: Okay, thank you. That 22 got us started on a lot of key issues.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 326 1 So, everyone should have a copy of 2 the letter from Lydia Wegman dated March 2nd. 3 So, that includes the charge questions that we 4 will now be dealing with. So, if you don't 5 have a copy, ask Kyndall. 6 And looking at the schedule, we are 7 a little bit past the break. So, maybe we 8 should take a break for 15 minutes and return 9 a little before quarter after 3:00. We will, 10 then, begin with Arthur, who will get us 11 started on Charge Question 1. Okay? 12 So, let's take a break and let's 13 reconvene a little bit before 3:15. 14 (Whereupon, the foregoing matter 15 went off the record at 2:57 p.m. and went back 16 on the record at 3:14 p.m.) 17 CHAIR BRAIN: It would be very 18 helpful if those of you who have new comments 19 or haven't sent your comments for the REA, if 20 you could send them to the topic leader, the 21 person whose name is underlined, that would be 22 very helpful.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 327 1 And if you need to, when we adjourn 2 this afternoon, it is often helpful for people 3 to meet. So, if you are unclear about what 4 the consensus is or some point of 5 clarification, don't hesitate to get together. 6 But if everyone who wants to update their 7 comments, revise it, with an eye toward what 8 the consensus should be, please send that 9 along by email. 10 So, let's now with begin Charge 11 Question 1. Arthur is going to started on 12 this. 13 DR. PENN: I found this one pretty 14 easy. Apparently, a couple of other comments 15 I have seen also thought it was pretty easy. 16 I have just one exception. 17 A brief chapter, I thought they did 18 a very good job, a limited number of pages, 19 good introduction and background for this 20 Policy Assessment, a brief review going back 21 to the Clean Air Act and establishment of the 22 air quality standards and margins of safety

### 202-234-4433 Neal R. Gross & Co., Inc. Page 328 1 and reviews and new monitors and low dose 2 levels and the NCOR network, and all that

3 stuff. 4 I thought in 12 pages everything was 5 summarized pretty well. I went through a 6 couple of the references, and they seemed like 7 they are very descriptive. 8 The one item that I take issue with 9 is on page 1-1. I think it could benefit from 10 some clarification and possibly a change of 11 location. 12 On lines 22 through 25, on page 1-1, 13 it emphasizes that the focus of the Policy 14 Assessment is on four basic elements of the 15 air quality standards: indicator, averaging 16 time, form, and level. None of those items is 17 explicitly defined in the first 46 pages of 18 the Policy Assessment. 19 Indicator and averaging time are 20 both noted on page 2-47, and they are clearly 21 defined. Level, I had a real problem with, 22 despite the footnote on page 1-1. I couldn't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 329 1 begin to figure out what it meant. 2 When I went back last night after 3 watching all the basketball games and the 4 votes and everything, I found, I think it was, 5 page 2-52, there was a table that was 6 presented this morning that showed that form 7 could be the 99th percentile, but it could 8 also be the second or third exceedance, or I 9 forget what the other characterization was. 10 But the explanation for form on page 11 1-1 and the footnote is, to me, inadequate 12 because it says, it defines the air quality 13 statistic without saying what it is. That is 14 to be compared to the level of the standard. 15 So, I thought that that was not really 16 descriptive. 17 Concentration-based form without 18 explaining what form is, also, is apparently 19 an area of focus, and that is not defined. It 20 is clear on another page that form sometimes 21 equals percentile. 22 So, my question is, could all of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 330 1 those four things be explained as a footnote 2 of page 1-1? So, that everybody can, then, 3 follow that through, and maybe that they can 4 be explained a little bit more clearly. 5 CHAIR BRAIN: Yes, I guess I also, 6 early on, would like to point out, it seems to 7 me that there's sort of no charge question 8 that deals with the overall sort of size and 9 scope of the Policy Assessment. But I would 10 like to hear at some point, perhaps at the 11 end, you know, thinking of its destination and 12 how it will be used by the Administrator, is 13 it too short, too long? What is your sort of 14 overall assessment of too documented, not 15 documented enough, sort of some of those 16 general overarching questions?

17 Dr. Thom? 18 DR. THOM: I have nothing to add to 19 what Arthur said. 20 CHAIR BRAIN: Okay. Anybody else 21 want to talk about it? 22 DR. THOM: Is Larry on?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 331 1 CHAIR BRAIN: I think Larry is not 2 on the phone, wasn't able to join us today. 3 Okay. Any questions or comments 4 from the agency? 5 (No response.)

6 No? 7 DR. PENN: Could I just ask, where 8 does the term "form" come from? Because it 9 seems to be so out of keeping with all the 10 other labels and titles, and things like that. 11 I mean, is it percentile? Why don't you say 12 percentile? 13 DR. MURPHY: Oh, no, because it 14 doesn't have to be percentile. 15 DR. PENN: But what is it? You look 16 at all these statistics and you say, well, 17 what is that statistic, and you say, well,

18 that's the form. 19 DR. MURPHY: It depends on the 20 standard. So, for example, I don't mean to be 21 facile in answer. But, for example, for lead, 22 it is a not-to-be-exceeded form. In the case

### 202-234-4433 Neal R. Gross & Co., Inc. Page 332 1 of CO, it is may be exceeded once. That is 2 the form. In the case of PM, it is 98th 3 percentile. In the case of NOx, I believe it 4 is 98th percentile now. It was something 5 different previously. 6 So, the form is a statistic. It is 7 a statistic that we look at our air quality 8 dataset, we apply the averaging time, and then 9 we derive that statistic and compare it to

10 that level of the standard. 11 DR. PENN: And I think that should 12 be said. 13 DR. MURPHY: We need to say it more 14 clearly for you, yes, definitely. 15 CHAIR BRAIN: Thank you. Yes, that 16 was helpful. 17 All right, number 2, I guess 2 and 18 3. I don't know, how do you want to handle 19 those, Tom, do both at once or one at a time? 20 What works for you? 21 DR. DAHMS: One at a time. 22 CHAIR BRAIN: One at a time, okay,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 333 1 number 2. 2 DR. DAHMS: All right, everyone can 3 read what's up on the screen. A lot of what 4 I am going to say you have heard before, you 5 have heard earlier today. 6 Basically, I think it lays things 7 out fairly well, but the biggest thing is not 8 dealing with the epidemiology data. To me, 9 they are rather crucial for explaining -- you 10 know, this falls under 8. "Does the Panel 11 find the questions posed appropriately reflect 12 the policy-relevant questions in this review?" 13 Without the epidemiology data 14 supporting the controlled human exposure data, 15 I would just strongly state it to be the fact 16 that it presents a real problem to me. 17 When you get into the details about 18 raising some of the concerns about the 19 controlled human subject stuff, especially the 20 Allred study, the ST segment information is 21 pulled out of there and questioned. You have 22 to understand the design of that study is that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 334 1 in all these studies, if you look at time to 2 angina, that is a subjective endpoint. 3 You are asking the patient to tell 4 you when their angina came on, and that can be 5 pretty variable. One person may have a little 6 bit of angina, but not really raise their hand 7 until it is severe enough that they would 8 stop. That is a very subjective endpoint. 9 So, only in concert with that, you 10 have the ST segment change that confirmed that 11 time to angina. So, to pull them apart is not 12 really legitimate, from looking at those 13 studies. 14 There is a statement on that where 15 the ST segment, the interpretation of the ST 16 segment changes is a matter of concern or 17 there's various opinions about what that 18 means. That means, to me, that you are trying 19 to pull that out, and that is the way it read. 20 So, that needs to be fixed. Otherwise, you 21 have to have ST segment changes have to be 22 valid; otherwise, how could you ever determine

### 202-234-4433 Neal R. Gross & Co., Inc. Page 335 1 silent ischemia? So, that was on page 2-32, 2 I think that all that was going on.

3 CHAIR BRAIN: And there's an 4 extensive literature showing ST segment 5 depression does correlate with increased 6 susceptibility to arrhythmias and all kinds of 7 things. 8 DR. DAHMS: Yes. Then, part of the 9 problem you run into, I think, with putting 10 the epidemiology data in is all we have talked 11 about this morning, is, then, what mechanism 12 do you propose? Is it, as Paul brought up 13 earlier, a continuum of the reduce in oxygen 14 availability? That is one possibility, that 15 you get very low levels of exposure and you 16 just have a much higher N, so you are going to

17 see the effect. 18 But it gets back to this whole -- 19 again, I think there must have been some 20 statements in there that, you know, well, it 21 is consistent. I can give you the written, in 22 here, the citations where you state in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 336 1 document that CO effects are without 2 threshold. There's, I don't know, half a 3 dozen of them in this section alone. 4 If you accept that, then there's got 5 to be some verbalization, a description of how 6 you assume the epidemiologic effects are 7 occurring. There has to be some mechanism 8 brought forward, you know. I suggested 9 another way of approaching this, but it seems 10 to be talking about partial pressure of CO is 11 just introducing something that is too foreign 12 to this document at this point. I mean it has 13 not come up in the REA or anywhere else before 14 this. So, to introduce it now is probably too

15 late. 16 We talked earlier on about the 17 uncertainties with dealing with CO exposure 18 because of not knowing what the real 19 relationships are between CO exposure in20 people with coronary artery disease and long21 term prognosis. It's got to be an 22 uncertainty.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 337 1 But it gets back to this very first 2 point of, what is an acceptable risk? I guess 3 all of us have to come up with our own opinion 4 of this. Because if we don't have some, 5 there's no guidance given in this document. 6 There is probably no guidance given in any EPA 7 document as to what an acceptable risk is, 8 right? It is up to every one of the Panel 9 members to decide what is an acceptable risk. 10 If the current risk is too great, then we 11 would push for a lower standard. 12 Is that how this whole process 13 functions through CASAC? Is that what it is,

14 Joe?

15 CHAIR BRAIN: What -- 16 DR. DAHMS: So, in other words, you 17 know, we all have our own internal standard of 18 what an acceptable risk is. 19 CHAIR BRAIN: Right. 20 DR. DAHMS: So, if we feel the 21 numbers are showing that the risk too high, 22 then we have to push for a lower standard,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 338 1 justify a lower standard. 2 So, is it a consensus of this group, 3 written, I mean either in writing or just by 4 action, that we make those decisions? 5 CHAIR BRAIN: I think that is what 6 we are looking for, is, yes, we should give 7 advice as to whether we think it is acceptable 8 or not. That opinion will, then, be passed on 9 to the Administrator. 10 MS. BARRY: The CASAC will make a 11 recommendation.

12 CHAIR BRAIN: We don't set the

13 standard.

14 MS. BARRY: Based on the state of 15 the science, the agency can decide what level 16 is acceptable for protection, but your job, as 17 independent scientists, is to just speak to 18 the evidence, and perhaps if there is a range 19 that is more acceptable or more protective, 20 that can be done in this venue. 21 DR. MURPHY: Right. And another 22 way, I would add, to think about it is, I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 339 1 mean, we would suggest you look at the 2 considerations that we teed-up and think 3 about, did we hit the appropriate 4 considerations or did we miss some? Or did we 5 characterize some inappropriately? And have 6 we recognized there seemed to be a variety of 7 public health policy judgments that need to be 8 made in drawing a conclusion as well, in terms 9 of the adequacy of the standard? Have we 10 characterized them appropriately? Is there 11 any science that would inform these public12 health policy judgments that hasn't been teed13 up that needs to be? That sort of thing, I 14 think, is another way to look at it. 15 But, as Kyndall is saying, it is 16 tied to the science. What is well-supported 17 by the evidence and the quantitative analyses

18 that we have? 19 CHAIR BRAIN: Okay. 20 DR. DAHMS: That's all I have to say 21 on Charge Question 2. 22 CHAIR BRAIN: So, then, we have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 340 1 Milan and Francine. Do you want to add? 2 DR. HAZUCHA: Do you want to go 3 first? 4 DR. LADEN: I don't really have that 5 much to add. I think the questions were 6 appropriate. I liked the questions. I 7 thought they were a good way of organizing the 8 discussion. 9 And I thought that the level of 10 detail, when I first read it was appropriate, 11 although based on the discussions that we have 12 had today, I think that it is important to 13 increase the effort to integrate the 14 epidemiologic studies more in terms of their 15 strengths and limitations, in terms of 16 answering these questions. I don't think it 17 is necessarily that they are going to change 18 much, but that there are limitations to 19 integrating the epi more than has already been

20 done. 21 And also, the considerations of the 22 susceptible populations, I do think some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 341 1 expansion of that discussion I would

2 recommend. 3 CHAIR BRAIN: Milan? 4 DR. HAZUCHA: Yes. Actually, 5 compared to the old staff papers, I very much 6 like the approach of posing questions. But 7 one question which I thought -- we are already 8 discussed it -- which should have been posed 9 is about non-traffic sources of carbon 10 monoxide like indoor air. I believe that 11 should have been discussed here, sort of 12 potential interference, and so on, which I 13 wasn't able to find, particularly, for 14 example, for individuals with CVD, they stay 15 more indoors than venture outdoors, and so on. 16 The general response to Question 2, 17 I guess it provides sufficient details, and so 18 on. So, I am fine with that. 19 DR. MURPHY: Can I just ask a 20 question of clarification? Your point with 21 regard to more discussion of non-traffic 22 sources of CO is with regard to interpretation

### 202-234-4433 Neal R. Gross & Co., Inc. Page 342 1 of the epidemiological studies? Is that how 2 you -- 3 DR. HAZUCHA: No, no. For example, 4 even acute exposures, if you have, for 5 example, individuals staying at home for a 6 longer period of time, and their level may be 7 elevated, for example, during wintertime, how 8 it may impact, for example, the relationship 9 between outdoor ambient concentration and 10 indoor CO concentration. So, what impact it 11 will have on actual COHb levels? Will it 12 override the actual standard or will it be

13 below standard? 14 DR. MURPHY: The non-ambient CO?

15 DR. HAZUCHA: Yes. 16 DR. MURPHY: Of course, the standard 17 is for ambient CO. 18 DR. HAZUCHA: Yes, I know. 19 DR. BLANC: But, for example, your 20 figures, if I understand correctly, your 21 figures that you showed where you have various 22 scenarios of proportion of people that would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 343 1 be -- now that included, that took into 2 account what the modeling said about their 3 endogenous carboxyhemoglobin, is that correct? 4 DR. MURPHY: You're talking about 5 the figures in the last set of slides?

6 DR. BLANC: Yes.

7 DR. MURPHY: Yes. 8 DR. BLANC: Right? 9 DR. MURPHY: That is from the REA. 10 DR. BLANC: Right, but it doesn't 11 take into account their indoor non-ambient?

12 DR. MURPHY: Because the REA does 13 not have indoor sources modeled, yes. 14 DR. BLANC: Well, but that's right. 15 So, you see how things become circular and 16 feed on themselves. It is the same 17 limitation. It's, well, wait, I can't do that

18 because I don't have that from the REA; the 19 REA doesn't do it because somewhere else it 20 says not, you know. 21 So, the graph is misleading because, 22 if you just look at the graph and say, okay,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 344 1 this is what you're modeling people's levels 2 would be, but the graph should at least say 3 somewhere very clearly, "By the way, this 4 doesn't actually estimate what somebody's real 5 value would be because it would be, on 6 average, 2 percent higher than this."

7 DR. MURPHY: It doesn't have the 8 indoor sources contributing, that's true. 9 DR. BLANC: Right. I think the text 10 that you are talking about is something that 11 says we know from estimates -- in fact, it is 12 modeled; it is just modeled from the 2000 data 13 on what people's average indoor contribution 14 is, right? 15 DR. MURPHY: Is that what you're 16 getting at, though? 17 DR. HAZUCHA: Yes, yes. 18 DR. MURPHY: Okay. Thank you. I 19 didn't follow it. Thank you. 20 CHAIR BRAIN: Okay. On to Question 21 3, back to Tom.

22 DR. THOM: Joe?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 345 1 CHAIR BRAIN: Yes? 2 DR. THOM: I guess I need, if I may, 3 just to add something on Question 2, because 4 I ended up writing a modest amount about this 5 in the next two questions. 6 I guess I am going to disagree with 7 some of the things that have been said here 8 today with regard to the Policy Assessment. 9 Maybe it is just it is written for a 10 politician. But I found it a very convoluted 11 way of presenting information as a general

12 statement. 13 So, in my writeup, there's a lot of 14 specifics on particular issues. But let me 15 just say that, as a general statement, I 16 understood why you constructed it to pose a 17 question and, then, to attempt to respond to 18 that question. But I had to read it several 19 times before I realized that some of your 20 questions are never answered. I give you, the 21 details are written up in my little thing that 22 I submitted.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 346 1 So, personally, I don't think that 2 that approach serves you very well because, 3 specifically, some questions have no answer in 4 the Policy Assessment. Then, many of your 5 conclusions are basically the standard could 6 be changed or not. That is the conclusion. 7 It's like we could have said that before we 8 started the first ISA. So, I was disappointed 9 that there was not more in the document from 10 what was said in the REA or the ISA in terms 11 of some of the risk assessments. 12 And one could come with a conclusion 13 to say the data are insufficient to warrant a 14 change in standard. I think that is a 15 legitimate thing to say. 16 But there was no conclusion. It was 17 we could change it or not. 18 DR. MURPHY: Well, as Lydia 19 described this morning, that is an acceptable 20 conclusion because, as the staff, we are not 21 making the decision on a standard. We are 22 identifying what are the appropriate policy

### 202-234-4433 Neal R. Gross & Co., Inc. Page 347 1 options that are supported, reasonably 2 supported, by the information that should be 3 taken to the Administrator for their 4 consideration. 5 To the extent that you all think 6 that we have gotten too broad a range, then 7 you all need to speak to that, and in your 8 comments let us know that you think the 9 evidence doesn't support such a broad range of 10 policy options and it should be narrowed. 11 That would be quite useful information for us. 12 DR. THOM: So, this was to be just a 13 strawman to be torn apart? 14 DR. MURPHY: No, not per se, 15 although you're welcome to do that.

16 17 It is intended to describe the 18 options that are well-supported by the 19 available evidence and the quantitative 20 analyses, and recognize that we have 21 identified what weight you might put on 22 different public health judgments and how that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 348 1 weight would give you a different answer. 2 This is true for all of our 3 standards, that there could have been a 4 conclusion that we thought the current 5 standard was adequate; there was no evidence 6 to suggest that we should conclude it was not 7 adequate. But the staff felt that, based on 8 all of the information we had, depending on 9 the weight you put on some of those pieces of 10 information, it might be appropriate to judge 11 it's not adequate. 12 So, we thought it was appropriate to 13 say, well, depending on the weight you put on 14 these things, what you put on the epi, what 15 you put on different benchmarks, what you put 16 on clinical significance, you might draw one 17 conclusion or another. The weight that you 18 put there is not, there's no black-and-white 19 answer to that. Some of that has a science 20 aspect to it, but some of it is more a public 21 health judgment aspect to it. 22 And it's not up to the staff to say

### 202-234-4433 Neal R. Gross & Co., Inc. Page 349 1 what the standard should be. It is up to the 2 staff to describe well what the evidence and 3 the quantitative analyses can support well. 4 We are asking you all to tell us if we have 5 done that well or not or if you have a 6 different conclusion. 7 DR. BLANC: Can you put this in 8 context? How frequently when you get to this 9 stage of policy are you in the position of 10 saying, well, you could leave the standard the 11 way it is; on the other hand, you could modify 12 the standard? Is that a typical scenario? 13 DR. MURPHY: It is not unusual. I 14 don't know how typical it is, but it is not

15 unusual. 16 DR. BLANC: But it has precedent? 17 DR. MURPHY: Oh, definitely. 18 DR. BLANC: You've done it that way

19 before? 20 And a related question: my 21 interpretation of the document was that last 22 time you did this process for carbon monoxide

### 202-234-4433 Neal R. Gross & Co., Inc. Page 350 1 the position was more unequivocal that it 2 should stay the way it was? 3 DR. MURPHY: We're struggling to 4 recall. The staff paper would have been the 5 '92 staff paper, and I think it probably said 6 it was appropriate to consider retaining the 7 standard, and perhaps did not tee-up 8 alternatives at that point. 9 Now we have an expanded set of 10 evidence, and we have drawn a different 11 conclusion at this point. 12 DR. BLANC: Okay. That's helpful.

13 Thanks. 14 CHAIR BRAIN: So, it is kind of left 15 to you as to how prescriptive you want to be 16 in suggesting retaining the standard or you 17 can give a few hints or more than a few hints, 18 if you care to, but -- 19 DR. MURPHY: It is determined by the 20 evidence and the analyses and what they tell 21 us. The previous review, the '92 staff paper 22 had an exposure assessment that was done in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 351 1 one city. I believe it was Denver. It did 2 not have the expanded recent epidemiological 3 studies. 4 So, there are various things that 5 are now available that have made us look a 6 little more broadly at the issue and say, 7 well, depending on how much weight you give on 8 the epi studies that may be performed in areas 9 where the standard is attained, et cetera, you 10 might draw different conclusions. We have 11 teed that up for this draft assessment as our 12 initial conclusions. We are looking for how 13 well that flies with you all in terms of 14 describing what is supported by the evidence. 15 DR. PENN: So, if we don't make 16 absolute recommendations to either keep the 17 standard the same or to, let's say, lower the 18 standard, then there's going to be a couple of 19 letters that get sent to Lisa Jackson, and, 20 then, she is going to sit there and she's 21 going to make a determination based on what is 22 sitting in here now that says you could raise

### 202-234-4433 Neal R. Gross & Co., Inc. Page 352 1 it or not? Then, somebody is going to ask 2 her, when she goes to sit in front of 3 Congress, "What do you recommend, raising or 4 lowering it?" She's not going to say, "Well, 5 you could raise it or not." 6 DR. MURPHY: No, she will make a 7 decision. But, as Lydia said this morning, it 8 is ususal for our proposals to have a range of 9 policy options. When we go to proposal, we 10 may say, you know, there will be language in 11 there about the Administrator -- I can't 12 remember the phrasing -- something like 13 preliminarily or tentatively judges the 14 standard to be adequate or not. Or they might 15 say judges that the level for the standard 16 should be at least as protective as the 17 current standard, and it may be appropriate to 18 consider a range of alternatives that range 19 below the current standard down to "X", and we 20 are soliciting comment on the rationale that 21 we might give to one option or another. 22 This is a public process. So, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 353 1 Administrator would intend to identify the 2 appropriate range, supported by the science, 3 and clearly articulate the rationale for 4 different conclusions that might be drawn and 5 how the evidence supports that, and how public 6 health policies come into conclusions with 7 regard to that. 8 So, that, then, we receive comment 9 on that whole suite, on not just any numbers 10 and forms, but on the rationale that is used. 11 So, people can say, "That's an inappropriate12 rationale for a standard" or "That's not well13 supported by the science." They can say 14 whatever they need to. 15 Then, we consider all the public 16 comment and go back to the Administrator, tee 17 it all up, and they decide what's the 18 appropriate conclusion. 19 CHAIR BRAIN: And we can be part of 20 that process, if we care to say whatever --

21 DR. MURPHY: You have a front-row 22 seat in that process.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 354 1 CHAIR BRAIN: Right. 2 DR. BLANC: Do you view Charge 3 Question 6, which we haven't gotten to, as the 4 charge question which directly asks us whether 5 or not we think the current standard is 6 adequate? 7 DR. MURPHY: One thing I should 8 mention is in the slides, you will recall when 9 I went through the topic areas for the 10 standard, I emphasized that we were interested 11 in the Panel views on whether or not they 12 consider the current standard to be adequate 13 and the range of appropriate potential 14 alternatives to be considered. 15 One reason I was trying to emphasize 16 it in the slides is we neglected to clearly 17 say that in the charge questions that came to 18 you, but we are quite interested, obviously, 19 as Lydia said this morning, in your views on 20 the adequacy of the current standard, the 21 range of alternatives that might be 22 appropriate to consider.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 355 1 CHAIR BRAIN: And it certainly 2 sounds like Charge Question 11 kind of invites 3 us, "What are the Panel's views regarding the 4 appropriateness of staff's initial conclusions 5 related to considering a secondary" -- no, I 6 guess that's just a secondary standard. 7 DR. MURPHY: Yes. We did it more 8 clearly on the secondary. We didn't do it -- 9 CHAIR BRAIN: Right. No. 7.

10 But we should make sure that we 11 discuss and see whether there's consensus, 12 right? 13 DR. BLANC: You know, it might be 14 slightly out of arithmetic order, but I have 15 to say that the answer to that question will 16 taint every other answer to the charge 17 questions to an extent -- color, not taint, 18 inform. 19 (Laughter.) 20 CHAIR BRAIN: Taint is tainted? 21 DR. BLANC: Yes. Or am I wrong

22 about that?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 356 1 CHAIR BRAIN: Let's take a few 2 minutes. Some preliminary feelings as to the 3 adequacy of the current standard? 4 DR. ROBERTS: Could I ask a question 5 of EPA that is sort of, at least in my mind,

6 relevant to that?

7 If the current standard were to be 8 retained, and the levels are so low, does that 9 allow agencies to unrestrict and pollute back 10 up to the level of the standard? I mean I 11 know that is a loaded question, but it sort of 12 addresses what our conclusions might be in 13 this overall answer. 14 CHAIR BRAIN: So, you are saying, is 15 that an invitation to pollute? 16 DR. ROBERTS: Well, yes. I mean I 17 am asking conceptually, is it, yes. 18 DR. MURPHY: I wouldn't answer you 19 directly, but say to you that our job is to 20 judge the adequacy of the current standard, 21 not necessarily to judge the adequacy of the 22 current air quality.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 357 1 DR. ROBERTS: Right. That is sort 2 of what I meant, yes. 3 DR. MURPHY: We are interested in 4 having a standard that is appropriately 5 protective of public health. 6 DR. ROBERTS: Right. So, we as a 7 Committee, shouldn't just say, well, the 8 concentrations are so low it doesn't matter 9 what the standard is set at; they're low? 10 CHAIR BRAIN: Right. 11 DR. ROBERTS: We actually --

12 CHAIR BRAIN: The standards matter. 13 DR. ROBERTS: We actually need to 14 say it the way you just did. If those levels 15 are where they should be, the ambient levels,

16 then the standard should be lower. 17 CHAIR BRAIN: If that is warranted. 18 DR. ROBERTS: Yes, if the science 19 warrants it. 20 DR. MACIOROWSKI: Can I just jump in

21 here for a second? 22 This gets in that really kind of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 358 1 fuzzy area. This is fascinating topic in a 2 lot of ways. 3 (Laughter.) 4 If you have an ideological position 5 that it should be this, based on your personal 6 opinion, we don't care to hear it in this 7 forum because this is the Clear Air Scientific 8 Advisory Committee. So, the advice here, 9 actually, should be based in science, and you 10 are providing a scientific set of advice and 11 opinions to the Administrator. 12 I need to say that because, had 13 prior to your being seated on this Panel, had 14 you written all kinds of letters on behalf of 15 this advocacy group or this industry group -- 16 or I'm just making this up -- you would not be 17 allowed to serve because you would have had a 18 preconceived notion of what that science 19 should say. In our ethics screening, we would 20 sort of -- so, there's always this kind of 21 tension between keeping the scientific advice 22 primarily scientific.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 359 1 Now, having said all of that, a lot 2 of this depends on how it is couched. And I 3 am going to sort of relate this back to how we 4 do an ethics review. 5 Dr. So-and-So from University X has 6 a paper that says, "Based on the science, I 7 have looked at a risk assessment scenario, and 8 this range of values is more or less 9 scientifically-validated and should be 10 protective." 11 That is different than sort of 12 saying, coming together with a letter -- and 13 this is really a whole different topic. We 14 just had a range of academics who had a very 15 strong policy position on what the agency 16 should do on something not related to air at 17 all. Because they have a preconceived notion 18 specifically on the issue coming before the 19 Science Advisory Board, that would be 20 construed as a perception of a lack of 21 impartiality, and we would basically recuse 22 them from service.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 360 1 So, as a science advisory board, you 2 guys are sort of in that area where it is fine 3 to have a scientific opinion. It is based on 4 your research. It is based on data. It is 5 based on information available to you. 6 Once you start to cross that line 7 into advocating for a particular position, as 8 long as it is based on science, you can do 9 whatever you want. It is when it starts to 10 sort of say, "Well, it should just be more 11 protective because...." or "It should be less 12 stringent because....", where it becomes, say 13 -- I hate to use the word "factions", but God 14 knows we have them, in terms of what it is. 15 So, I just kind of wanted to clarify 16 that point in terms of the focus here ought to 17 be on we reviewed the science; the science 18 supports this. The science does support this. 19 You know, there's a range in here, and of that 20 range -- this became a big issue several years 21 back -- is there a valid range of scientific 22 interpretations around that range?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 361 1 And say -- I'm making this up again 2 -- somebody sort of says, "Hey, the 3 Administrator says we're going to consider 1 4 to 10," and you start saying, "No, no, it 5 should be 3 to 7," based on the data. Those 6 kinds of things are perfectly fine for you to

7 do. 8 And actually, in past years we have 9 actually tried our best to move away from this 10 as best we can. CASAC used to sort of approve 11 the standard, but it is an advisory body, not 12 an approving body. So, in sort of how federal 13 advisory committees, and so on, are set up, 14 and how they kind of play out, the advice that 15 you provide the Administrator is taken 16 seriously. It is taken seriously by OAQPS. 17 It is taken seriously by ORD. But it is 18 advisory. The Administrator is free to make 19 decisions based on other information that may 20 not be scientific in a specific case. 21 I don't know if that helps or not, 22 but I thought this is always a little bit of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 362 1 a -- here's another example: if you were a 2 scientific FACA, you were a representative 3 FACA, you would be representing a 4 constituency, and then we would be more than 5 happy to have your opinion on that 6 constituency on a representative FACA, but 7 this is not that kind of federal advisory 8 committee. It is a scientific advisory 9 committee. 10 So, this is always kind of an issue 11 that gets a little strange at times to talk 12 about and interpret, but, hopefully, that 13 helps. If you have any questions, I will try 14 my best to answer them. 15 CHAIR BRAIN: No, I think that helps 16 a lot. So, given the necessity of basing your 17 opinions on science and on the evidence, does 18 anybody want to talk briefly about whether 19 they feel the current standard is adequate or 20 whether the evidence suggests something 21 different, something lower, or a different 22 format, form?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 363 1 Mike? 2 DR. KLEINMAN: I just wanted to 3 frame it because I had responsibility for 4 Question No. 7.

5 CHAIR BRAIN: Uh-hum. 6 DR. KLEINMAN: So, the bottom line

7 was the staff recommends -- I want to read 8 this, so I get it right -- "The data provides 9 support for retaining or revising the current 10 eight-hour standard." 11 I think, overall, when we come down 12 to it, the Panel will agree with that sort of 13 at the bare minimum. But, with the 14 epidemiological evidence providing data that 15 shows that at the current exposure levels, 16 which are below the actual level of the 17 standard, health effects are accruing, and 18 therefore, the evidence might be leaning in 19 the direction of suggesting a revision 20 downward of the existing standard. 21 CHAIR BRAIN: So, is that an 22 emerging consensus of the evidence suggests,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 364 1 for heaven's sakes, don't think about a higher 2 standard; don't make it lax, and if anything, 3 it should be heading downward a little bit? 4 DR. THOM: I think it is given to 5 say that we would never support raising the 6 number beyond 9. 7 Mike, I agree 100 percent with what 8 you said. My only quandary is you say, okay, 9 fine. So, one might consider dropping the

10 level down. 11 But, in the opening slides, there 12 were a couple of them that had 9 to 3 parts 13 per million, for example. And I thought, 14 well, 3, that sounds good to me. But there 15 are no data to make a statement that 3 is a 16 good mark to use for a standard, at least that 17 I'm aware of. So, I think there is a problem 18 with putting a number. 19 DR. KLEINMAN: This is what I think 20 where that range comes from. Using the 21 benchmarks of 1.5 percent carboxyhemoglobin 22 and 1.8 and 2, you can generate, using the CFK

### 202-234-4433 Neal R. Gross & Co., Inc. Page 365 1 equations, what exposures would do, and then, 2 using the risk model, come up with what 3 percent of the population would exceed those

4 benchmarks. 5 So, they picked that range to 6 protect various numbers or various percentages 7 of the population ranging from 99.9 percent to 8 whatever it was. I think 95 percent was what

9 the lower was. 10 DR. THOM: But, once again, that is 11 the coronary artery disease. I mean those 12 data were generated -- 13 DR. KLEINMAN: And they are using

14 them as a benchmark. 15 DR. THOM: That is sort of a -- 16 okay. 17 DR. KLEINMAN: Right. 18 DR. THOM: For better or for worse, 19 that's what it was. 20 DR. KLEINMAN: Yes. So, that is 21 where the range came from. So, they could 22 recommend or we could recommend a range based

### 202-234-4433 Neal R. Gross & Co., Inc. Page 366 1 on just coronary artery disease, couched in 2 the terms that this would not necessarily 3 protect everybody who is susceptible. There 4 is this whole other block of susceptible 5 individuals that seem to be showing effects, 6 based on the epidemiology at substantially

7 below that. 8 DR. THOM: Right. It is 9 substantially less than 3 parts per million.

10 DR. KLEINMAN: What? 11 DR. THOM: At less than 3 parts per 12 million. 13 DR. KLEINMAN: At less than 3 parts 14 per million, but -- 15 DR. MURPHY: Can I interject just a 16 minute? 17 This is great conversation, and I 18 hate to interject. 19 DR. KLEINMAN: That's okay. 20 DR. MURPHY: But there's one thing I 21 just want to make sure you all read in terms 22 of how we describe some of the considerations

### 202-234-4433 Neal R. Gross & Co., Inc. Page 367 1 here. 2 And when we walked through the 3 question on levels with health effects, and we 4 talked a bit about the epidemiological data, 5 and we made a point of looking closely at the 6 study areas, where we had epidemiological 7 studies, and identified whether or not the 8 current standard was attained or exceeded. We 9 found that in many, most of those studies, the 10 current standard was not met during some 11 period of that study. 12 So, while the common concentrations 13 to which people may have been exposed were 14 below the standard, the standard was not met. 15 So, to us, those studies are actually less 16 useful in answering the question of at what 17 level below the current standard might there

18 be effects. 19 So, we tried to sift through the 20 studies and say, which studies actually were 21 performed in areas and during time periods

22 when the standard was exceeded? When we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 368 1 focused on some of the key health outcomes 2 that the ISA focused on, we came to just a 3 couple of study areas, most prominently the 4 Atlanta study area, where we had three 5 studies, but all in the Atlanta area, and one 6 of which was statistically-significant. 7 So, when we walk through saying, 8 okay, if we are going to give weight to the 9 epi, it comes down to that, and that's what 10 might lead us toward -- and in that study 11 area, I believe the second highest eight-hour 12 average concentration was about 4.9 ppm. So, 13 presumably, you would want a value below that, 14 if that study is telling you that you have 15 effects when a potential standard of 4.9 was 16 attained. 17 So, just to help you understand some 18 of the logic that we constructed to identify 19 the rationale that might support different 20 alternatives for the standard, that's one view 21 of the epi study. We needed to take into 22 account, was the current standard met or not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 369 1 in these study areas? Because, conceivably, 2 the outcomes we saw could have been driven by 3 exposures associated with levels above the 4 standard, since they did exist during those 5 studies. 6 So, hopefully, that is useful to 7 you. That is described in the document. 8 CHAIR BRAIN: All right. So, I 9 think this is a discussion well-started, not 10 completed yet. Why don't we go back to Charge 11 Question 3? 12 DR. BLANC: Well, can I just add 13 something?

14 CHAIR BRAIN: Yes. 15 DR. BLANC: I think that it would be 16 sufficient for us to address whether the body 17 of the scientific evidence weights in favor of 18 a more restrictive standard without committing 19 ourselves to a body of evidence recommendation

20 of what that standard can be. 21 I don't think that we should be 22 prevented from saying the direction that we go

### 202-234-4433 Neal R. Gross & Co., Inc. Page 370 1 just because we can't go beyond that. Because 2 I think the reason that we can't is because we 3 weren't provided the data to scientifically 4 assess because, in fact, some of the things 5 that have been pointed out just aren't in the

6 document. 7 But I think we have a preponderance 8 or a body of evidence which weights more in 9 favor of a more restrictive standard than in 10 favor of keeping the standard as it is. I 11 think that we should make that clear. 12 I think that there are a number of 13 issues that would be marshaled, scientific 14 issues, that would support that conclusion, 15 many of which have been brought up around the 16 table already today. 17 But, to summarize some of them, most 18 saliently, the population at risk is probably 19 larger than has been estimated, that there 20 were some sources in the exposure estimation 21 that might tend to underestimate effect, 22 including, as we heard, near-roadside exposure

### 202-234-4433 Neal R. Gross & Co., Inc. Page 371 1 and the tail of endogenous production in 2 certain subsets. 3 And finally, the observation that 4 there aren't good data that allow them to 5 combine modeling of indoor non-ambient sources 6 with the ambient and the endogenous together, 7 meaning that the numbers of people that exceed 8 certain levels of exposure are going to be far 9 larger in number and in proportion than the 10 tabular estimates show. 11 So, when I look at all of those 12 scientific issues combined, that certainly 13 weights in favor of not remaining with the 14 status quo. 15 CHAIR BRAIN: I suspect your summary 16 of a movement toward lowering the standard 17 will probably be shared. But why don't we 18 return to it and see whether we want to -- 19 DR. DAHMS: I have a question of

20 Paul. 21 Do you think that the ISA should 22 have been couched in different terms, so that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 372 1 the information was more readily available 2 with the idea, with some view, some analysis 3 of the studies that were included relative to

4 these -- 5 DR. BLANC: Oh, relative to the last 6 point that was made, whether some of the 7 studies -- what proportion and to what extent 8 the epidemiologic studies met or didn't meet 9 the 9 ppm current standard? I mean this is 10 the first we have sort of heard that argument. 11 So, it is hard for me to say. Absent the 12 information, I really can't -- 13 CHAIR BRAIN: There is still time in 14 the policy document. It seems to me the 15 policy document can do that. Out of all the 16 information in the ISA, here are the ones that 17 we think are particularly important because --

18 DR. MURPHY: In table -- 19 DR. BLANC: No, no, I'm talking 20 about in the ISA. 21 DR. MURPHY: Oh, but it is in the 22 policy document.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 373 1 DR. BLANC: Yes, yes. I'm not 2 saying you didn't put it there. 3 CHAIR BRAIN: And maybe that is just 4 the right place for it. 5 DR. PAGAN: The ISA presents the 6 author's averaging, just an averaging time 7 that actually dilutes the time periods of the 8 study. So, it is a low level. 9 DR. BLANC: Well, some of the data 10 are from outside the United States as well 11 that are quite germane. But, nonetheless, 12 that is the epidemiologic data is pretty 13 convincing that there is an effect. It is 14 more relevant to me to what the population at 15 risk is rather than this specific question, 16 which is why I didn't really focus on it as

17 much. 18 CHAIR BRAIN: This is a really 19 important point and it needs to be front and 20 center. This sounds like something that will 21 be in the two-page letter in one form or

22 another.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 374 1 So, let's return to exactly what we 2 want to say a little later. Let's continue 3 with Q/A No. 3. So, back to you Tom. 4 DR. DAHMS: Charge Question 3?

5 CHAIR BRAIN: Yes. 6 DR. DAHMS: All right. 7 CHAIR BRAIN: Which is about links 8 with the ISA, which we have been talking

9 about. 10 DR. DAHMS: Yes. The one major 11 issue I had with this was that, the one major

12 concern that I had was that all of the work 13 that was done for the documents in the late 14 1990s just sat, waiting for this study on 15 altitude and extreme conditions. I don't 16 recall any reference to that document. It may 17 have been referred to. It may be in a 18 bibliography, but there is no description of 19 the outcome of that and how that should impact 20 our view of the Denver data. 21 Does the Denver data, does that 22 altitude of 4800, 5200 feet make any

### 202-234-4433 Neal R. Gross & Co., Inc. Page 375 1 difference in the way we should view Denver 2 versus LA, based on -- who did this study, the 3 NRC, National Research, who did that study on 4 altitude and -- 5 DR. MURPHY: Yes, it is the NRC. It 6 is the NRC. 7 DR. DAHMS: Okay, but, you know, 8 there's no discussion of that in here. Given 9 the fact that there is an indefensible delay, 10 I think that is why the courts got kind of 11 snippy with us, that we needed, you know, 12 there needs to be some information in here 13 about that study. Was it found to be just a 14 delay? Was there no guidance from that study

15 at all? 16 DR. MURPHY: Yes, we can certainly 17 provide more description of the study. It is 18 mostly an air quality analysis. It talks 19 about controls, I believe, also. I don't 20 think it gets at what you are thinking it 21 might get at. But we can certainly augment 22 our document to describe more completely

### 202-234-4433 Neal R. Gross & Co., Inc. Page 376 1 what's in that. 2 DR. DAHMS: I mean, because based on 3 what was shown here, that the numbers of 4 people at risk in Denver are greater than 5 those in LA, right? 6 DR. MURPHY: And that has to do with 7 the distribution, the air quality distribution 8 for the study area in Denver. 9 DR. DAHMS: But it has nothing to do 10 with the physiologic parameters in APEX for 11 people being at altitude? 12 DR. GRAHAM: I think there's one 13 adjustment. I don't have it in front of me, 14 but not all the variables adjusted for 15 altitude. 16 DR. MURPHY: He's saying there's one 17 variable that may have an influence on 18 altitude that would be included in the 19 analysis, but it is unlikely that is a large 20 driver behind the results that we are seeing 21 here. It is just the air quality 22 distributions, more likely.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 377 1 DR. GRAHAM: Right. 2 DR. DAHMS: And that's all, the only 3 comments I had on Charge Question 3. 4 CHAIR BRAIN: Milan? Francine? 5 DR. HAZUCHA: As I already mentioned 6 in the REA, I would like to see here as well, 7 when there is a discussion of all the studies, 8 to give the changes in real units. It doesn't 9 have to be, you know, a big description of the 10 results, but simply state that 4.2 percent 11 translates into 22 seconds from approximately 12 9 minutes. 13 I would like to also see maybe at 14 least to give the reader some guidance15 because, most likely, the readers will be non16 scientists, and basically say, well, do we 17 know anything about the long-term effects of 18 such shortened time to angina here? Is the 19 frequency of angina because of those one or 20 two times a year exposures to carbon monoxide 21 when the COHb level may reach 2 percent? Will 22 it impact in any way on frequency, on future

### 202-234-4433 Neal R. Gross & Co., Inc. Page 378 1 frequency of angina, and so on, or the 2 severity of angina? 3 And if we don't have data, then we 4 will say, well, we would like to address it,

5 but we do not have data. 6 And then, I have other minor 7 comments which I am listing here. 8 CHAIR BRAIN: Francine? 9 DR. LADEN: I don't really have 10 anything to add. 11 CHAIR BRAIN: Okay. Anybody else 12 want to say anything about Charge Question 3? 13 (No response.) 14 All right. Let's now move on to 15 Charge Question 4. Dr. Kaufman, are you out 16 there and ready to take us through this 17 question?

18 DR. KAUFMAN: I'm here. 19 So, Charge Question 4 relates to 20 Section 2.22. This is whether the 21 quantitative analysis of exposure and dose 22 reflects what is in the REA. Part A, it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 379 1 doesn't reflect what is in the REA. I think 2 that my comments would be not whether it 3 reflects what's in the REA, but whether what 4 is in the REA is what we want to have 5 reflected finally. 6 I think it does accurately reflect 7 what is in the Draft REA that we have been 8 looking at and is the version that we have 9 now. The questions that were raised this10 morning about whether sort of both the micro11 environmental question about what's the 12 quantitative analysis of the carboxyhemoglobin 13 levels versus the approach that I think I 14 would advocate, which is to try to further go 15 down this road of understanding the 16 attributable increase, increment of 17 carboxyhemoglobin due to ambient 18 contributions. 19 I think it would make it a cleaner 20 analysis of exposure and dose because you 21 would no longer have the sort of clouding at 22 the bottom end by the endogenous levels and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 380 1 the other background sources of the exposure 2 to indoor sources, and so forth.

3 But I know there's others on the 4 Committee who don't see it this way. But that 5 was mine, my thoughts. 6 Then, the question, does the Panel 7 find the presentation to be technically-sound,8 clearly-communicated, and appropriately9 balanced? I thought that the discussion was 10 quite lucid, cogent, and I thought it was

11 well-done. 12 So, those are my comments. I did 13 have, there were some written comments 14 submitted by Dr. Thom, I think, and then Milan 15 also had some comments which were on the first 16 part, coming from a slightly different place. 17 I think he should probably state them. 18 So, that was all I had. 19 DR. THOM: My comments were mostly, 20 again, the stylist stuff. So, the details are 21 there. It is more to do with the language 22 used. I just didn't think it was terribly

### 202-234-4433 Neal R. Gross & Co., Inc. Page 381 1 focused. 2 DR. HAZUCHA: Again, as I commented 3 on the REA, I would like to see the APEX more 4 shown, particularly the COHb module. As I 5 mentioned, hemoglobin levels and effective 6 rates, for example, may be, if possible. The 7 CO is another variable. The rest I have 8 really problems because there are some 9 clinical data, but not enough really to 10 incorporate it in the model. 11 But, initially, SES, because there 12 are low-income groups there which were located 13 close to traffic areas, high-traffic areas, 14 they would be more affected than high-income 15 groups. 16 So, if it is possible to turn out 17 APEX, taking into consideration these other 18 factors and inputs, that would be desirable. 19 DR. MURPHY: As I think we discussed 20 this morning --

21 DR. HAZUCHA: Yes. 22 DR. MURPHY: -- it is a question of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 382 1 having the data to support that in terms of 2 the distribution of different SES groups or 3 different races within the simulated 4 population, which in this case was CHD. It is 5 just, if you've got the data and can point us 6 to the studies, that would be something to 7 consider, although I'm not sure timing-wise if 8 that could be worked into the model, given its 9 current design. 10 DR. BLANC: So, Joel, you don't have 11 my written comments, I think, because they 12 were distributed in hard copy. 13 So, I agree that the issue is not 14 whether the policy document reflects the REA, 15 but, really, whether we want it to reflect the 16 REA. Without trying to make the agency crazy 17 by hearing two diametrically-opposed views, I 18 think the solution to it is to present the

19 data that allows the reader to construct the 20 cumulative exposure or to look at the 21 incremental exposure, so that the data are 22 there for all three, the endogenous, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 383 1 ambient contribution, and the indoor air 2 contribution. 3 And I actually think that is 4 probably more important for the policy 5 document even than the REA, although it is 6 hard for the policy document to present new 7 data that haven't come out of either the ISA 8 or the REA. So, that is more a technical 9 issue. 10 But I think that would be a way of 11 solving both of our concerns, would be to have 12 the three pieces there separately and 13 additively, so that one could see, depending 14 on what your assumptions were, what data you

15 have. 16 CHAIR BRAIN: Anyone else on Charge 17 Question 4? Yes, Tom?

18 DR. DAHMS: Yes. I was concerned 19 that the other studies besides Allred dealing 20 with the controlled exposures were not given 21 any space in this section. So, it looks kind 22 of imbalanced to me to focus absolutely

### 202-234-4433 Neal R. Gross & Co., Inc. Page 384 1 everything on the Allred study. 2 Then, there are a couple of minor 3 things. One that has just irritated me all 4 the way through this, and it is the lack of 5 understanding by whoever is writing this about 6 the fact that carbon monoxide binds to reduced 7 hemoglobin. That was stated in the ISA. It 8 was stated in the REA. Now it shows up again 9 here. That is just not correct. 10 I know where it comes from. It 11 shows up in Appendix B of the REA on page B-5 12 where there is a fiddle with the equation, 13 saying that in order to make the math work, 14 they've got to assume that carbon monoxide 15 binds to reduced hemoglobin. Then, that got 16 carried through all the text, which presents, 17 you know, something that's just absolutely not 18 true, because carbon monoxide, relative to 19 infinity, carbon monoxide pumps oxygen off all 20 the time. 21 All right, the next thing that 22 bothers me, on page 2-9, line 1, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 385 1 statement, "or increased cardiac output" makes 2 absolutely no sense, but that has also been 3 carried through. It is also definitely not 4 clear to the reader what is meant. 5 The preceding sentence is discussing 6 cardiovascular disease in the context of 7 coronary artery disease. The reason I bring 8 it up, the normal compensatory mechanism in 9 healthy people is the increased blood flow 10 through vasodilatation, not vasodilatation and 11 increased cardiac output. 12 So, the current verbiage does not 13 make sense and needs to be changed to 14 something like an increased blood flow. Then, 15 that makes the earlier discussion --

16 CHAIR BRAIN: You mean local blood 17 flow, not -- 18 DR. DAHMS: Yes, local flow, not 19 massive, not the whole cardiac output, because 20 the diseased heart has enough trouble 21 producing increases in cardiac output. 22 So, those are just whining issues

### 202-234-4433 Neal R. Gross & Co., Inc. Page 386 1 that have been aggravating, as a reader, all 2 the way through this. 3 DR. BLANC: Dr. Dahms, could I ask a 4 clarification? When you said that you felt 5 the policy document didn't address the 6 epidemiologic literature sufficiently, you 7 meant the epidemiologic literature in terms of 8 adverse cardiovascular outcomes? Or what 9 aspect of the non-cardiac other health 10 effects -- where is that coming from? 11 DR. DAHMS: In my statement just 12 before this?

13 DR. BLANC: Yes. 14 DR. DAHMS: No, I was talking about 15 the Kleinman study, the Sheps study, the other

16 controlled human -- 17 DR. BLANC: Oh, the other controlled 18 human studies? Okay.

19 DR. DAHMS: Yes. 20 DR. BLANC: Do you feel that both 21 the cardiovascular epidemiologic literature 22 and, then, the literature or the discussion of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 387 1 other health effects, and potentially other 2 at-risk groups, is sufficient in the policy? 3 DR. DAHMS: No, and that is what I 4 said in my response to Charge Question 2, that 5 I think that that really needs to be

6 addressed. 7 DR. BLANC: For both pieces then? 8 DR. DAHMS: Both pieces. 9 DR. BLANC: Okay. 10 DR. DAHMS: Because, otherwise, it 11 looks like you are kind of hanging out the 12 whole thing to dry on the Allred study. That 13 is the appearance that it gives. That may not 14 have been the intent, but that is the 15 appearance that it gives. And it is 16 disconcerting to all of us, I think. 17 CHAIR BRAIN: When you say, "epi", 18 you are both talking bout more controlled 19 human exposures as well as genuine, more 20 traditional epi? You mean both of those

21 should be -- 22 DR. DAHMS: No, I'm talking about,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 388 1 when you talk about the controlled human 2 subjects studies --

3 CHAIR BRAIN: There's more than

4 Allred?

5 DR. DAHMS: -- there's more than

6 Allred. 7 CHAIR BRAIN: Right. 8 DR. DAHMS: And when you are talking 9 about cardiovascular disease, there is 10 epidemiology and the controlled. 11 CHAIR BRAIN: Right. 12 DR. BLANC: And then, when you talk 13 about the other effects, there's just whatever 14 there is on the other effects. Some of it is 15 animal studies. Some of it is --

16 DR. DAHMS: Well -- 17 DR. BLANC: I mean you are talking 18 about the issues of, what about in pregnancy, 19 what does it mean? What about in these 20 others? Yes, okay.

21 DR. MURPHY: If I could ask -- now 22 I'm a little confused. I meant to ask Dr.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 389 1 Dahms what you meant when you made your 2 overview comments with regard to lack of 3 emphasis or discussion of the epi. Because it 4 wasn't clear to me what you were looking for 5 exactly, what you felt was missing. 6 We did discuss the epi in going 7 after different questions. We tried to talk 8 about troubles that we have in integrating the 9 epi with the clinical, because, of course, we 10 have no COHb measurements in the epi. We have 11 no personal exposure measurements with the 12 epi. 13 So, what is it that you are thinking 14 isn't here that needs -- 15 DR. DAHMS: But you have no COHb 16 measurements in all of the modeling. You have 17 estimates. 18 DR. MURPHY: Sure. Yes, and it 19 is -- 20 DR. DAHMS: So, you must have 21 estimates or the epidemiologists could equally 22 come up with estimates if they had access to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 390 1 the APEX model. 2 DR. MURPHY: They don't have 3 estimates of exposure. Their estimate or 4 surrogate for an exposure estimate is the 5 ambient monitor concentration. The epi 6 studies look at those relationships, the 7 ambient monitor concentration to the different 8 types of outcomes. They don't have in those 9 studies any presentation of what were those 10 people who had the various health outcomes 11 exposed to, in terms of their total cumulative 12 exposure to CO, and they certainly don't have

13 the COHb measurements. 14 We try to discuss that in this 15 document in terms of a challenge that we face 16 in integrating the epi studies with what we 17 know so strongly about CO from the wealth of 18 evidence over the years and from some of the 19 clinical controlled studies. 20 DR. BLANC: Well, but you actually 21 have very little positive to say about the 22 epidemiologic literature and lots and lots and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 391 1 lots to say about its limitations. So, again, 2 I don't know what you intended, but the net 3 result is to discount the epidemiological -- 4 DR. PENN: But could I just add 5 something to that, sort of as an outsider to 6 this group? 7 In trying to read this from the 8 perspective of a reasonably intelligent 9 person, reading it but not being involved with 10 all this stuff, the ISA is loaded with epi 11 data. There's also clearly mention of the 12 Allred studies and the Kleinman and the Sheps 13 studies. 14 But, as you go through the document 15 we looked at this morning, and then go through 16 the Policy Assessment, Paul is completely 17 right, it really reads like, yes, we've got 18 this epi stuff over there, but here's the 19 reason why it's no good, and here's the reason 20 why it's no good. So, we're going to all talk 21 about coronary artery disease. That is the 22 message that really comes across.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 392 1 I have comments on it for Question 5 2 that would probably fit with Question 2, just 3 pointing out what I think are real 4 inconsistencies in the way EPA has read the 5 information that you've already collected and 6 given to us that is in the ISA. It just seems 7 like the ultimate response in the PA is

8 unbalanced. 9 DR. MURPHY: And that is appropriate 10 for you to tell us, but one thing to keep in 11 mind, of course, the ISA is looking at the 12 most recently-available information. Of 13 course, that is dominated by the epi. We 14 haven't had more recent clinical studies. 15 Whereas, on the Policy Assessment, 16 what we are trying to say is, what evidence do 17 we have that is going to inform our judgment

18 of the standard? We have to look across all 19 the types of evidence we have. More recently, 20 we have a wealth of new epi, and we try to 21 bring that to bear, but we have this 22 longstanding clinical dataset. We have our

### 202-234-4433 Neal R. Gross & Co., Inc. Page 393 1 knowledge that goes over years and years in 2 terms of how CO operates mechanistically, some 3 of the ways that we know it to operate, some 4 of what we've got new information indicating 5 potentially additional mechanisms, and putting 6 it all together. 7 So, it is not the intent that the 8 Policy Assessment should match or reflect the 9 different amounts of pages, if you will, given 10 to one type of study or another that the ISA 11 has. No, it should look at the evidence and 12 say, what does that evidence, how do we look 13 at all that evidence and have it inform our 14 decisionmaking in terms of the standard? 15 We struggle with the epi because, as 16 I point out, the largest number of these 17 studies were conducted at times when they are 18 exceeding the current standards. So, when we 19 are faced with this question of, is the 20 current standard adequate, and if not, what 21 might be potential alternatives, more 22 important to us is any epidemiological studies

### 202-234-4433 Neal R. Gross & Co., Inc. Page 394 1 that might be conducted in areas that have met 2 the standard. So, that limits us a bit. 3 Then, we recognize things that the 4 ISA says and that folks on the Panel have said 5 in terms of limitations, uncertainties 6 associated with drawing conclusions from epi. 7 CHAIR BRAIN: That seems like a 8 classic problem in environmental health, to 9 have the bulk or a lot of studies above the 10 standard, where you, then, have the challenge 11 of trying to extrapolate to or beneath the

12 standard. 13 DR. MURPHY: But it certainly tells

14 us -- 15 CHAIR BRAIN: I mean I think we are 16 talking about nuance, aren't we? I mean we 17 are really in the main talking about a little 18 more emphasis on those other studies. 19 DR. MURPHY: Yes, and I think the 20 ISA tells, what they are using those studies 21 to tell us is that CO is likely causally 22 related to these outcomes. Those studies, at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 395 1 whatever concentration they are conducted at, 2 inform that understanding. And we try to 3 reflect those statements as well in the Policy 4 Assessment, but we have to, then, go out at 5 another layer down and say, okay, at these 6 lower concentrations, what do we know about 7 whether or not CO is harmful and causing harm 8 in the exposed population? 9 CHAIR BRAIN: But, again, we really 10 haven't heard any evidence that suggests that 11 it is highly non-linear or there's a threshold 12 or something. I think we are mainly operating 13 with reduced oxygen delivery is bad, even if 14 it is small; it is less bad, but it is still

15 bad. 16 So, I guess I find myself less 17 troubled by epi studies that may, in part,

18 exceed the current CO standard. I don't see 19 that as quite as much of a problem as you have 20 suggested. 21 DR. BLANC: I mean listen to your 22 first sentence that talks about epidemiology.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 396 1 "In considering the epidemiologic studies in 2 the case of CO, we recognize that there is a 3 coherence between the available clinical and 4 epidemiologic evidence with regard to the 5 health effects of CO in the cardiovascular 6 system (primarily for ischemic-related 7 events)." 8 So, already, you are narrowing it 9 that it is mostly ischemic. We would argue 10 that some of the data for congestive failure 11 is as convincing and a larger relative risk. 12 You are saying that we recognize 13 that there is a coherence. Well, your ISA 14 said that it supports causality; it is not jut 15 coherence. Coherence is one component of a 16 causal relationship. In fact, it met causal 17 criteria on a bunch of different criteria. 18 I am just saying how it reads, not 19 what your intent was. I can't read your mind. 20 Then, the very next sentence is, "As 21 noted above, however, we also recognize 22 several gaps between the two lines of evidence

### 202-234-4433 Neal R. Gross & Co., Inc. Page 397 1 which complicate their integration, 2 particularly with regard to ambient exposures 3 and ambient concentrations associated with

4 health effects concern." 5 I think what we are trying to say 6 is, you know, give the epidemiology a couple 7 of more pluses before you start. Because, to 8 the even non-causal reader, it comes off as a 9 complete discounting or as much of a 10 discounting as you can get away with of the 11 epidemiologic literature. Now that may not be 12 your intent, but that is how it comes across. 13 DR. PENN: And the idea is not to 14 diss the studies from 20 years ago because, I 15 mean, Mike and Tom individually have said, 16 when I just talked to them today, could you 17 repeat these experiments today, if you wanted 18 to? And the answer is almost surely not, for 19 reasons of cost and all kinds of other things. 20 So, these are one-time studies which 21 all happened to occur within about two years 22 of each other and that are never going to get

### 202-234-4433 Neal R. Gross & Co., Inc. Page 398 1 repeated. So, we are not dissing those 2 studies at all. It is just that, in addition 3 to those studies, which point to the clear 4 interaction of high CO exposures and the 5 cardiovascular sequelae to those, you have all 6 of these other instances that you guys have 7 presented to us. 8 In one case, there were 31 studies. 9 In one case, there were 27 studies. There are 10 a whole bunch of them in figures 5-2 through 11 5-4 that really talk about other stuff that is 12 related in not necessarily a one-to-one way, 13 but in a very clear way to the results that 14 were reported in 1989 and 1991. 15 So, at least the two of us, and I 16 suspect a lot of people around this table, 17 feel there should be more emphasis on that 18 because, in reality, the kind of data you are 19 going to get in the future are going to be epi 20 data. You are not going to get controlled 21 clinical studies. 22 So, there's sort of, I think,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 399 1 considerable strength to the information 2 presented in the ISA that would support an 3 argument for the health effects of the CO 4 exposure that doesn't really come through from

5 the PA. 6 DR. HAZUCHA: I hear repeatedly that 7 there is no threshold, and I guess it is 8 coming from all that study where the 9 regression line was extended over and across

10 to zero. 11 The threshold is your endogenous 12 production. So, that is your threshold. You 13 cannot go below that. And endogenous 14 production will be always above zero. 15 DR. KLEINMAN: Going back to the 16 epi, I just want to point out that we 17 shouldn't feel bad about it. We are using 18 almost entirely the epi data for PM standards, 19 and primarily because the clinical studies 20 with particles were relatively robust. You 21 couldn't find health effects in a controlled 22 exposure study at anywhere near the levels

### 202-234-4433 Neal R. Gross & Co., Inc. Page 400 1 that we are seeing in epidemiology for PM. 2 I don't think the CO studies are any 3 worse than the studies of particulates. I 4 think there are a lot more of those. 5 So, I don't think the epi should be 6 discounted just on the basis that we don't 7 have a good metric for the dose, when we are 8 using the ambient exposure data. 9 CHAIR BRAIN: Okay, very useful. 10 Anything else in regard to this 11 charge question? Anything more about Charge 12 Question 4? 13 (No response.) 14 We're doing very well. I would like 15 to suggest that we go on to one more charge 16 question to give us enough time tomorrow to

17 look at the draft letter and the draft PA 18 responses. We will look at both of those to 19 see whether we have really succeeded in 20 putting on paper a consensus. 21 So, Tom has told me that he is ready 22 to proceed with Charge Question 5. Then,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 401 1 Arthur may chime in as well. 2 DR. DAHMS: Given the discussion we 3 have had today, I think I've got to go back 4 and review the uncertainties in that chapter 5 for sure, to make sure that they are all dealt 6 with sufficient robustness, because we have 7 certainly raised more uncertainties. But, on 8 the first blush, it seemed like they were 9 dealt with appropriately; they were all 10 brought up. 11 One other issue I had, which was 12 dealing with this ST segment change on the 13 current review of page 2-32, line 25 to 28, 14 about the ST segment indicators, where they 15 were pulled apart, in my view, and it was 16 referred back to ISA page 48, with the 17 uncertainty about the meaning of ST segment 18 changes. 19 It says page 48. I assumed this to 20 be 5-48 in the ISA. And there is no line 21 reference because, in reading that entire 22 page, there's no indication that the ST

### 202-234-4433 Neal R. Gross & Co., Inc. Page 402 1 segment on anything I can read on that page is 2 brought into question. So, that raised real 3 alarm bells with me that somebody is not being 4 careful with what they are documenting. 5 DR. MURPHY: Would you like us to 6 clarify?

7 DR. DAHMS: Sure. 8 DR. MURPHY: It is the first full 9 paragraph on page 5. You're right, it should 10 be 5-48. The sentence is while the exact 11 physiological significance of the observed ST 12 segment changes among individuals with CAD is 13 unclear, while recognizing that the depression 14 is an indicator of myocardial ischemia. 15 The point is not to question or to 16 say it is unclear what ST segment depression 17 means. It is to say the ST segment response 18 that was observed in the clinical studies is 19 decreased time to seeing the ST segment 20 change, being on the order of 3 to 5 percent. 21 What is the physiological significance of that 22 is unclear.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 403 1 DR. DAHMS: It needs to be stated 2 that way. 3 DR. MURPHY: More clearly, you're 4 right. 5 DR. DAHMS: That is certainly -- a 6 poor choice of words. That is also a reason 7 for the level of uncertainty in using, as 8 Milan has pointed out, and we have all pointed 9 out, of using one of the concerns about 10 pointing out what are very small changes in 11 time to angina and time to ST segment changes. 12 The next thing I had was back to 13 this same old thing we have been talking about 14 all along, which was, how do you interpret the 15 epidemiologic data? Is it either part of the 16 continuum going down to everything from 17 endogenous baseline above or is there some 18 extraneous effect of something we don't 19 understand that is being looked at in the 20 epidemiologic data? 21 You know, the whole thing deals with 22 throwing out the request of this Panel to look

### 202-234-4433 Neal R. Gross & Co., Inc. Page 404 1 at the numbers of people who might be exposed 2 at 1 percent carboxyhemoglobin, which is what 3 we voted on last time, and the decision was 4 made to not do that or to discount that data 5 and not show it because of the supposed 6 overlap between that and the baseline 7 endogenous numbers. 8 I still have concern that the model 9 is giving too big of a splay to the endogenous 10 carboxyhemoglobin levels. It leads to my 11 uncertainty in the model of overestimating the 12 exposure because of that. But that gets 13 mitigated dramatically because of my concern, 14 my other concern that was raised earlier today 15 by Paul and others that we are really 16 underestimating the number of people exposed 17 because we are just looking at people with 18 coronary artery disease, and not everyone

19 else. 20 DR. MURPHY: Can I ask a question? 21 We are interested in understanding, when you 22 all are saying, we would like to rerun, if

### 202-234-4433 Neal R. Gross & Co., Inc. Page 405 1 there's time, or whatever, or in some way get 2 estimates from our exposure analysis for a 3 larger simulated population that might not 4 just be limited to an estimated population 5 with coronary artery disease, diagnosed and 6 undiagnosed, but expanded larger to other 7 heart disease. 8 When we go forward into the Policy 9 Assessment, the outputs of the REA that are10 there are in terms of percentage of that at11 risk population. It is not in terms of 12 numbers of people. 13 In the writeup in the Policy 14 Assessment, we go on to talk about the much 15 larger size of the larger cardiovascular 16 disease population as being an important 17 consideration in interpreting those results

18 from the REA. 19 So, we are struggling a little bit 20 to understand what you all think is missing so 21 much from that. I mean, obviously, the REA 22 could have used a different population if you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 406 1 all would say that the data presume that those 2 benchmarks are appropriate for that, but in 3 the Policy Assessment we are saying that we 4 are concerned about the full cardiovascular 5 disease population, and that is a large 6 population, much larger than that which is 7 simulated. We don't put actual numbers from 8 the simulation into the Policy Assessment, 9 only the percentages. 10 So, I am just curious about it. 11 DR. DAHMS: Well, yes, I struggle 12 with what you are going to put in that bin 13 based on what we know about disease states and 14 the whole mechanism, the linchpin mechanism, 15 of denying or providing insufficient oxygen to 16 a tissue. What disease states exacerbate 17 cardiovascular disease? I mean there are 18 various types of cardiovascular disease that 19 are not due to, I mean, well, heart disease 20 that are not due to inability of vessels to 21 dilate, at least as I understand it. 22 I mean you could have, I guess, a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 407 1 severely -- Paul, you can help with this. But 2 it would seem to me you would have a massively 3 infarcted heart leading to heart failure, that 4 the rest of the heart is not necessarily full 5 of rigid coronary vascular disease. I don't 6 know. Could they still dilate? 7 I don't know. In other words, I am 8 looking for the two-hit thing that you've got, 9 rigid vessels that can't dilate and you're 10 taking away oxygen. To me, you've got to have 11 two hits to get an effect, from what we know, 12 physiologically know.

13 All the work that Steve has been 14 doing and others looking at tissue effects of 15 carbon monoxide, that brings on a whole 16 different thing. Most of them are at much 17 higher levels than we are dealing with. 18 But I am trying to figure out what 19 in the world to put in that bin. 20 DR. BLANC: I mean I think that what 21 you say may be literally true, but I don't 22 think that directly answers your question.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 408 1 But I think that what you say may be literally 2 true, but since in the text, for example, you 3 say, you know, Draft REA, Section 6.2, and it 4 refers back, and it is all integrated, it may 5 be true that you may not put real numbers; you 6 may just use percentages. But since the other 7 document does have real numbers, the 8 collective interpretation is to downplay it. 9 So, it is true, literally, that, 10 yes, you talked about percentages without 11 putting the actual numbers. So, you could 12 leave it the way you have it if the REA 13 changes and includes the bigger numbers. 14 But I will point out, though, that 15 you do go back and forth. So, that at one 16 point, you have a series of tables which 17 present everything. It would be tables 2-6 18 and 2-7 that present everything as the number 19 of people below.

20 DR. MURPHY: Percent. 21 DR. BLANC: So, everything is 99.9

22 and 99.8 or 99 --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 409 1 DR. MURPHY: Percent. 2 DR. BLANC: Yes. Yes, percent. 3 That is sort of a related thing, but that does 4 have an inherent spin in it. 5 I think it is hard for the reader to 6 look and appreciate the difference between 7 99.8 and 99.9. It makes everything look 8 fairly trivial. But since you are talking 9 about .4 percent and .2 percent of thousands 10 and thousands of people, it is still not 11 trivial in numbers, when you tie it back into

12 the REA. 13 So, in terms of percents, what you 14 say is correct, but, then, the REA at that 15 point has to change because you are referring 16 back to it anyway. I would actually say, to 17 be consistent, you probably would want to 18 change around 2-6 and 2-7, not to talk about 19 the percent who are below the level, but the 20 percent that are above the level, just to be 21 consistent with how you have done it 22 everywhere else in the document.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 410 1 DR. MURPHY: Right. And just to 2 clarify why those two tables are done that 3 way, it is because now we are looking at 4 alternative standards and facing the question 5 of what should the standard do. Of course, 6 the standard, we don't want a standard to have 7 a certain number of people with an effect. We 8 want to protect a large group of people from

9 an effect. 10 So, the presentation here is, what 11 amount of that population do we want to focus 12 on in identifying the appropriate margin of 13 safety, so that we have an adequate margin of 14 safety for the population? 15 DR. BLANC: It is just hard for the 16 reader to hone in on what you may want to make 17 as the critical point. That's all. 18 DR. MURPHY: Right. And it is not

19 unusual for the REA to be focused on a more 20 specific endpoint than we are considered with 21 in the Policy Assessment because we bring in 22 the additional evidence from the ISA and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 411 1 elsewhere, and have a broader view, which adds 2 weight to what we pull from the ISA, or the

3 REA. 4 So, we are certainly not limited to 5 what is in the REA. That is the whole point 6 of the Policy Assessment. It delves into the 7 ISA to say, well, how do we need to view what 8 we get from the REA? We need to view it in 9 the light of these uncertainties, which makes 10 us give additional weight to some things that 11 we can't quantitatively. 12 CHAIR BRAIN: Any more discussion? 13 DR. PENN: I do. I have something. 14 CHAIR BRAIN: Yes, please. 15 DR. PENN: I don't know who is going 16 to be charged with writing up about the epi 17 data that we have been talking about, but I 18 just had a couple of things to add to that. 19 There were a couple of statements 20 that I thought were not entirely correct. 21 Page 2-27, lines 8 through 10, the document 22 states -- and we have heard this statement

### 202-234-4433 Neal R. Gross & Co., Inc. Page 412 1 before -- we did not include studies of 2 association with congestive heart failure for 3 which evidence is less clear. And it seems 4 you noted five studies in a footnote at the 5 bottom of that page, and four out of five 6 showed increased hospital admissions for 7 congestive heart failure that was associated 8 in terms of the CO. 9 On page 2-14, lines 16 through 19, 10 it says there are only small or no 11 associations between hospital admissions and 12 stroke. But if you go back to the ISA, 13 figures 5-2, 5-3, and 5-4, you see that there 14 are clear associations with congestive heart 15 failure and with stroke. And in at least two 16 of those studies, where the relative risk was 17 raised, and I think it was with the congestive 18 heart failure, but I'm not sure, in at least 19 two of those studies there were large 20 increases in relative risk where the 24-hour 21 average ambient CO levels were about .8 ppm. 22 So, that is right at the level that we are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 413 1 talking about. 2 I mean we had talked about having 1 3 ppm as a cutoff. We recommended that in the 4 ISA, and you guys responded as to why you 5 didn't recommend going down to that level. 6 But here are two pretty good-sized 7 epi studies where they are talking about 8 effects at .8 ppm. So, somehow those have to 9 be, I think they should be recognized. 10 Then, there was one other issue that 11 we talked about a little bit this morning that 12 came up to me with an issue of uncertainty, 13 whether CO is a surrogate or whether its 14 effects at low concentrations can be untangled 15 from those of co-pollutants. My comment was 16 that, while there may be administrative 17 reasons for focusing on these distinctions, it 18 is not clear that there is a scientific 19 justification that is as strong. 20 Both carbon monoxide and organic 21 particles in ambient air are largely products 22 of incomplete combustion. In the real world

### 202-234-4433 Neal R. Gross & Co., Inc. Page 414 1 and in most laboratory situations, where you 2 generate particles, especially from organic 3 particles, it is going to be difficult to 4 generate and, therefore, to breathe organic 5 picks without any volatiles, including CO. 6 So, there may actually be CO effects 7 at low levels when they are associated with 8 these particles. This is another issue. So, 9 I am not sure that talking about it just as a 10 surrogate or just as an absolute pollutant on 11 its own or a health risk on its own includes 12 all the possibilities. 13 DR. MURPHY: Can I just ask? I am 14 confused by your emphasis on the .8 ppm. What 15 are you -- 16 DR. PENN: I have to go back to the 17 ISA. Figure either 5-2 or 5-4, and there was 18 an associated table. I have the disk

19 somewhere. 20 Paul, do you have the -- 21 DR. MURPHY: No, but I understand 22 what you're saying, but it is .8 as a 24-hour

### 202-234-4433 Neal R. Gross & Co., Inc. Page 415 1 average --

2 DR. PENN: Yes. 3 DR. MURPHY: -- which, of course, I 4 mean, it -- 5 DR. PENN: I mean that is what was 6 reported. I mean they didn't say that at 11 7 o'clock there was 7 ppm and at 23 hours it was 8 .2 ppm. I mean the only data that we can look 9 at are the data that are presented in this 10 thing. So, they talked about a 24-hour -- 11 DR. MURPHY: Right, and the 12 additional thing that we have done in the 13 Policy Assessment is look at the air monitors 14 that we have in those study areas -- 15 DR. PENN: Okay. 16 DR. MURPHY: -- to see, in terms of 17 the metric for the form of the standard, that 18 statistic, were those areas in attainment at

19 the current standard or not? We can look at 20 it that way. 21 DR. PENN: Okay. 22 DR. MURPHY: So, in table 2-1, that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 416 1 is done in the far right two columns. So, to 2 the extent those studies are in that table, 3 they would be shown there. 4 But, Doug, were you going to speak 5 to the issue of the epidemiological -- 6 DR. JOHNS: Actually, this is figure 7 5-3 in the ISA showing the associations 8 between stroke and CO. It is really not very 9 impressive. I mean the effect estimates are 10 right at about, relative risk is right at 11 about 1. Some are negative; some are 12 positive. 13 The .8 that you are referring to is 14 the standardization looking at .75 ppm 15 increase in eight-hour average. Is that where 16 you -- 17 DR. PENN: Can I borrow your copy? 18 DR. JOHNS: So, this is on page

19 5-30. 20 DR. PENN: Okay. Yes. I mean part 21 of my original thing this morning is that, if 22 you look at figure, let's see, at 5-2, which

### 202-234-4433 Neal R. Gross & Co., Inc. Page 417 1 is on page 5-27, the relative risk X-axis goes 2 from 1 to 1.4, but all the values are below 3 1.2. So, it looks like you've got a boatload 4 of major effects, when really the relative 5 risk for 27 out of the 31 is below 1.05. 6 If you go to the one on 5-30, yes, a 7 bunch of them are right around, either just 8 below or just above 1. But if you had a scale 9 of 1 to 1.4, then you might see that they 10 actually look more magnified than they do in 11 this particular one. And you still have six 12 that have a relative risk of about 1.4 or 1.3 13 up to 2.8. So, yes, it is six out of nineteen 14 studies, but there's an imbalance in the way 15 that the data are presented in figures 5-2, 16 5-3, and 5-4. 17 So, if you standardized all of them 18 to have the same X-axis, then you would be 19 able to compare the data slightly more easily. 20 I mean, if you want to say, hey, look, 13 out 21 of 19 studies show barely a change, that is 22 one way. If you say six out of nineteen

### 202-234-4433 Neal R. Gross & Co., Inc. Page 418 1 studies show a real change, that is another 2 way. So, it depends on, you know, how you 3 want to cut this. 4 CHAIR BRAIN: Okay. Any other 5 comments about Charge Question 5 or any other 6 responses or requests for clarification from 7 the agency? 8 (No response.) 9 We have a choice. We could recess 10 or we could do one more charge question to 11 make sure we have plenty of time tomorrow 12 morning to look at the draft documents and to

13 have lunch. 14 Dr. Thom, are you in the mood to do 15 one more? Or do you want to postpone? What 16 is the consensus? 17 DR. THOM: I collected everyone else 18 -- well, there's only one other person's 19 comments. I just saw it today. 20 Sure, I can do mine. 21 CHAIR BRAIN: Let's do it, then. 22 DR. THOM: But, then, the other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 419 1 people can still -- 2 CHAIR BRAIN: Then, we will be in 3 great shape for tomorrow. 4 DR. THOM: All right. 5 CHAIR BRAIN: We'll do Charge 6 Question 6. 7 DR. THOM: So, Charge Question 6 is 8 asking whether the document has integrated 9 health effects from the Final ISA and risk 10 exposure information from the Second Draft REA 11 as it relates to reaching conclusions about 12 the adequacy of the current standard and 13 potential alternative standards for 14 consideration. 15 Does the Panel view the integration 16 to be technically sound, et cetera? Second, 17 does the document appropriately characterize

18 the results of the Draft REA? 19 So, what I had submitted as 20 comments, again, you have posed it as 21 questions. In fact, in this section you did 22 answer the questions.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 420 1 There are some things that I found 2 at least troubling. Section 2.3.1, you state 3 the indicator for carbon monoxide is carbon 4 monoxide. That seems a little unnecessary to

5 me. 6 (Laughter.) 7 But, then, you fail to mention -- 8 and I don't say this is something to be 9 stressed, but in the ISA, Chapter 3, there is 10 an extended discussion about carbon monoxide 11 as an ozone precursor and the localized 12 chemical interdependency of carbon monoxide, 13 methane, and NOx. 14 To say that there are some 15 alternative products that might in the future, 16 with future work, offer some surrogates is a 17 statement, but to carry that over from the ISA 18 into the Policy Assessment, that may have to 19 do with my own ignorance as to whether or not 20 the Policy Assessment should be so broad or 21 not. I just raise that as a question. 22 Section 2.3.2 said to consider

### 202-234-4433 Neal R. Gross & Co., Inc. Page 421 1 alternatives to the current averaging times of 2 one- and eight-hour exposures. Then, a 3 question is posed, do health effects 4 assessments provide support for considering 5 different exposure times? 6 You come close to saying that you 7 should retain the one- and eight-hour 8 averaging times in this particular segment of 9 the Policy Assessment, but, then, elsewhere, 10 later on, you sort of back away from that. 11 You go on in ensuing paragraphs and 12 sections to discuss use of the 99th percentile13 concentration base form and the exceeding14 once-per-year form. You sort of recapitulate 15 a lot of what is in the REA, which is 16 perfectly fine. 17 My trouble with this is that you 18 raise these questions, but, then, well, you 19 have already said that you viewed this as more 20 or less posing the options, rather than 21 providing the conclusion. But, see, for me, 22 the options were there before we started the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 422 1 first ISA revision, which was you could change 2 it or not. 3 Just in closing, I guess, my view 4 would be that the 99th percentile statistic 5 offers a more conservative regulation of 6 environmental carbon monoxide than using a 7 fixed value of 9 parts per million for an 8 eight-hour average. And therefore, it would 9 be more protective for the public health. 10 That is about covering my comments. 11 DR. MURPHY: Can I ask a clarifying 12 question? We were confused by, what part of 13 the ISA, Chapter 3, are you pointing to with 14 regard to discussion? 15 DR. THOM: Okay. 16 DR. MURPHY: So, that is an ambient 17 air quality? We were a little confused by

18 that. 19 DR. THOM: Well, in Chapter 3 of the 20 ISA they talk about -- 21 DR. MURPHY: What section? 22 DR. THOM: Well, I don't know. I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 423 1 don't have it written down here. 2 DR. MURPHY: Oh, sorry. 3 DR. THOM: So, read Chapter 3, and 4 it will be there. 5 DR. MURPHY: But it has to do with 6 air concentrations of CO and how other 7 chemicals -- 8 DR. THOM: CO may be a reflector of 9 some other pollutants. That's all. 10 Okay. Where my concern was, 11 actually, it started with the statement that 12 the indicator for carbon monoxide is carbon 13 monoxide. That was like, well, duh? 14 DR. MURPHY: Right. And maybe if I 15 could just clarify, that was a comment earlier 16 that we didn't carefully describe or explain 17 the four elements of the standard. Indicator 18 is one of the elements of a standard. For CO, 19 it is kind of a duh kind of indicator. CO is 20 what we measure. CO is the indicator. But, 21 for other pollutants, it is more complex.

22 DR. THOM: Sure.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 424 1 DR. MURPHY: For example, for lead, 2 the indicator is lead in total suspended 3 particles. Now there are a variety of 4 alternatives we could have made the indicator. 5 It could have been in PM10. It could have

6 been -- 7 DR. THOM: So, for me, that is my 8 ignorance. It is written there because that 9 is part of how the EPA needs to couch -- 10 DR. MURPHY: Right. 11 DR. THOM: -- their decisions. 12 DR. MURPHY: Right. 13 DR. THOM: Okay, fine.

14 DR. MURPHY: But we need to be more 15 clear, so you understand why it is there, 16 obviously. 17 DR. THOM: Okay. 18 CHAIR BRAIN: Or an introductory 19 sentence. There are these classic four 20 parameters, and here's the first one. 21 Paul, you have some additions? 22 DR. BLANC: They really relate -- I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 425 1 interpreted this question as a bit more 2 related to our discussion Question 7. They 3 are pretty integrated in a sense, aren't they? 4 What would you describe as the nuance of the 5 difference between what you are asking in this 6 charge question and what you are asking in 7 Question 7? 8 DR. MURPHY: So, Question 7 has to 9 do with the considerations. When Dr. Thom10 said, well, it was obvious to him at the get11 go what the -- these are my words, not yours, 12 obviously -- what the alternatives were, we

13 need to make a clear record here as to not 14 just what the alternatives are in terms of a 15 decision on the standard, but what is the 16 scientifically supported rationale for any of 17 these alternatives, and only present those 18 that are scientifically supported. 19 So, while because you are quite 20 familiar with all the evidence, it might have 21 been obvious to you, it would not be obvious 22 to the others who are not so familiar with the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 426 1 science. 2 So, what we are asking for here in 3 Question 7 is, have we discussed the 4 appropriate things to consider about the 5 evidence, the consideration with regard to the 6 evidence and with regard to the exposure dose 7 estimates, with regard to drawing a conclusion 8 on the current and potential alternative

9 standards? 10 In terms of 6, we are asking the 11 question of, have we integrated all of this 12 information together and described it in a way 13 that is technically sound, clearly 14 communicated, and appropriately characterized? 15 And does it appropriately characterize the 16 results, also, of the REA, including their 17 significance? 18 Part of that might be 6b. Another 19 way to look at 6b is, did we take the results 20 of the REA, which was focused on the coronary 21 heart disease population, for which we had a 22 clinical study which gave us an exposure, a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 427 1 concentration response function for that 2 population, did we take that focused 3 quantitative analysis and did we describe it 4 in a broad enough or appropriate enough way 5 that the larger body of evidence supports? 6 In other words, we should not look 7 just narrowly at the REA. That is really not 8 -- I am suggesting this might be a way to 9 think about it. Should we not look just -- 10 our conclusion was we should not look narrowly 11 at the REA and have that be the only thing 12 which drove any standards decision. 13 Of course, our whole process is set 14 up to look at the ISA and the evidence that we 15 have over the years, and to have that inform 16 our interpretation of the REA. Together, we 17 look at the information. We recognize the REA 18 will inherently be narrower than the full bulk 19 of the evidence. 20 So, I am kind of rambling at this 21 point. Sorry, I think it is late for me. 22 DR. THOM: So, what you have just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 428 1 said, what you were trying to get at with 2 these questions, I guess I didn't understand 3 at all. But I would say that the Policy 4 Assessment doesn't even begin to address what 5 you just said you were after. 6 And the reason I say that is because 7 you are establishing your perspective 8 regarding coronary artery disease ST segment 9 depression with a particular carboxyhemoglobin 10 level. So, the current standard, the data 11 would not support changing or diminishing the 12 current standard based upon the rigid EKG 13 changes that the literature has documented. 14 However, if you take the broader -- 15 which this is recapitulation again -- of all 16 the epidemiology data, where there is clear 17 inference that the standard as it exists today 18 is probably not stringent enough, that is to 19 say, there is a risk of cardiac 20 decompensation, whether you want to call it 21 congestive heart failure, a progression of 22 cardiac decompensation associated with carbon

### 202-234-4433 Neal R. Gross & Co., Inc. Page 429 1 monoxide levels substantially lower than 9 2 parts per million for eight hours, then the 3 point would be that your Policy Assessment 4 falls short of adequately describing the data 5 as it has already been presented in the ISA

6 and the REA. 7 DR. MURPHY: Right. And this is one 8 thing I alluded to earlier. I am going to 9 forget the words you used, because that is 10 what I was reacting to. 11 You are saying the epidemiological 12 studies clearly show effects at levels below 13 the current standard. But we would say look 14 at those studies because most of those studies 15 were conducted in areas during time periods

16 when the current standard was exceeded.

17 DR. THOM: Those data are not 18 available to the literature. 19 DR. MURPHY: We looked at the study 20 areas as described in studies. 21 DR. THOM: Okay. 22 DR. MURPHY: This is in our document.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 430 1 DR. THOM: Okay. I'm not arguing, 2 but that's not available to us. 3 DR. MURPHY: It is. It is in the

4 document. 5 DR. THOM: Now it is. 6 DR. MURPHY: That's what we tried to 7 describe for you. It is in the document that 8 you all have been reviewing. So, we recognize 9 it is not in the ISA, and we are all moving at 10 breakneck speed here. But when we get the 11 information over in the Policy Office, what 12 matters to us is, well, wait a minute, were 13 those studies, was the standard exceeded? 14 And if they are exceeded, that still 15 speaks to this larger issue that everyone 16 thinks is so important, which is, of course, 17 we see this cogency, this coherence, between 18 the epidemiological studies and the clinical 19 studies. We are seeing the types of outcomes 20 that you might expect, based on what we know 21 from the clinical studies. They show that 22 quite well.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 431 1 But when we look at it and say, 2 well, what do they tell us about the current 3 standard, we also say, well, look at those 4 study areas and let's look at what the air 5 quality was in those studies. Actually, 6 during some of the studies, they were 7 exceeding the standard. So, it could still be 8 showing us that coherency and that cogency, 9 but it is at levels that were above the

10 current standard. 11 So, if we want to ask the question 12 and say, what do these studies tell us about 13 meeting the current standard and being below 14 the current standard, and any potential 15 effects there, we need to look at what studies 16 have we got where we met the standard. Then, 17 it limits what we do look at. 18 DR. BLANC: But, then, there were 19 still studies that did. 20 DR. MURPHY: There are some, yes. 21 DR. BLANC: Right. 22 DR. MURPHY: And we identified them,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 432 1 and that is what we say when we talk about -- 2 DR. BLANC: Right. 3 DR. MURPHY: -- the alternative 4 standards. When we say a range of standards, 5 well, if you look at the epi studies that 6 we've got, well, that might lead to some of 7 the lower end of the range of studies. 8 DR. BLANC: Right. 9 DR. MURPHY: If you would put weight 10 on those epi studies, recognizing 11 uncertainties, recognizing limitations that 12 this Panel has, for example, raised on those 13 studies. 14 DR. BLANC: So, one thing you would 15 like feedback on, for example, is our response 16 to the analysis that appears only in the 17 policy document in terms of ambient levels in 18 the studies that occurred in America, because 19 you don't actually talk about the ambient 20 levels, I suppose, on the studies from Taiwan 21 and other places? So, you are limiting it to 22 the U.S. studies.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 433 1 DR. MURPHY: We don't have air 2 quality data for those. 3 DR. BLANC: Right. So, you are 4 asking, you know, is the cup half empty or 5 half full, for example. You would like 6 feedback from us on, given those limitations, 7 how do we interpret the policy implications of 8 the epidemiologic literature, right? I mean 9 that is what you are saying. 10 DR. MURPHY: Well, I think this is 11 part of Question 7, which is what do you think 12 regarding our discussion of considerations 13 relating to the adequacy of the current and 14 alternative -- because the considerations, as 15 we raised them here, are, well, when we look 16 at the epi, we say it is very strong in terms 17 of this cogency and coherence. It gives us 18 our likely causal relationship. 19 It seems to be that many of these 20 studies, though, are when we exceeded the 21 standard. So, that means it is good we've got 22 a standard, and this is a good standard to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 434 1 have. But do we need it to be lower? Let's 2 look again. 3 DR. BLANC: And so, you would like 4 feedback from us, again, to repeat, on whether 5 or not our view of that would be, yes, some of 6 these studies are from times when the levels 7 were exceeded, but some weren't? And 8 therefore, the bulk of the scientific evidence 9 would weigh towards a more conservative 10 standard. That is the feedback you want from

11 us? 12 Do we view it that way or do we view 13 it, well, so many of them were with the 14 standard exceeded that we have to actually not 15 bring to bear the epidemiologic evidence at 16 all? It is not relevant because too many of

17 them were above the standard? 18 I mean that is our purview, is what 19 you are saying, right? We should tell you our 20 scientific interpretation of that evidence, in 21 light of those potential limitations? 22 DR. MURPHY: Right. And the Panel

### 202-234-4433 Neal R. Gross & Co., Inc. Page 435 1 did provide comment to us with regard to the 2 epi studies. On the ISA, there was a bullet 3 which I think we cite at a place or two within 4 the Policy Assessment in terms of the 5 potential for co-pollutants to pose 6 confounding -- so, that is an issue as part of 7 the uncertainties. 8 But this Charge Question 7 is really 9 getting at, have we raised the appropriate 10 considerations? And some of those 11 considerations are, what other evidence have 12 we got? We've got some small set of epi 13 studies that were in places where we met the 14 standard. When we focus it on those outcomes 15 most related to how we know CO to operate, we 16 get left with one study area, three studies, 17 one of which is clinically significant. 18 If we put weight on that, that seems 19 to push us towards the low end of the range 20 that we put here. That is how we constructed 21 the rationale that we present here that 22 supports the range that is presented here.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 436 1 So, we are asking -- I may or may 2 not be answering your question; I'm sorry -- 3 but we are asking for your views on, have we 4 teed up the appropriate considerations that 5 would support this end of the range, a 6 different range, an upper end of the range, et 7 cetera? That is what we are asking. 8 CHAIR BRAIN: Have we achieved 9 enough clarity for today? Okay, let's think

10 about that. 11 The other thing I would encourage 12 everyone to do is we have five more charge 13 questions on the Policy Assessment. We really 14 have only indicated one lead person, and then 15 it is says CO Panel members. So, if you have 16 a little time this afternoon and this evening, 17 if we can all look at those other charge 18 questions, and if others can make 19 contributions, and they are rather general, so 20 I know almost everyone has been thinking about 21 many aspects. Then, the latter ones deal with 22 the welfare consideration. So, if anyone can

### 202-234-4433 Neal R. Gross & Co., Inc. Page 437 1 add to those discussions tomorrow, that will 2 be terrific. 3 So, let's break now. If everyone 4 during the next few hours can pull together 5 your best shot at a consensus statement, then 6 Kyndall will print those up, and we will have

7 a chance to look at them tomorrow. 8 Again, there will be time for you to 9 improve them, but we really want to make sure 10 that they are on track and that we have 11 achieved consensus that the general thrust of

12 these statements are such that we can all 13 support them. 14 Okay, thank you for a very 15 productive day. Thank you, EPA, for your 16 presentation and for asking clarifying 17 questions. 18 We will see you tomorrow. 19 (Whereupon, at 5:06 p.m., the 20 proceedings in the above-entitled matter were 21 adjourned for the day, to reconvene Tuesday, 22 March 23, 2010.)

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