Document LJY4kjZBzByMjYwLnY7y9Z9Jw

1 IN THE GENERAL COURT OF JUSTICE SUPERIOR COURT DIVISION 2 STATE OF NORTH CAROLINA, COUNTY OF FORSYTH 3 Civil Action No. 07-CVS-3770 _______________________________________________________ 4 TELEPHONE DEPOSITION OF: DAVID W. PYATT, Ph.D. 5 August 11, 2009 _______________________________________________________ 6 ANDREW WOLFE and DENISE WOLFE, 7 Plaintiffs, 8 v. 9 E.I. DUPONT DE NEMOURS AND COMPANY, et al., 10 Defendants. 11 _______________________________________________________ 12 PURSUANT TO NOTICE the telephone 13 deposition of DAVID W. PYATT, Ph.D., was taken on behalf of the Plaintiffs at the St. Julien Hotel, 900 14 Walnut Street, Boulder, Colorado 80302, on August 11, 2009, at 10:07 a.m., before Teresa Coogle, Registered 15 Professional Reporter and Notary Public within Colorado. 16 17 18 19 20 21 22 23 24 25 1 1 APPEARANCES 2 For the Plaintiffs: RYAN KIWALA, ESQ. Simmons Browder Gianaris 3 Angelides & Barnerd, LLC 707 Berkshire Boulevard 4 East Alton, Illinois 62024 (Appearing Telephonically) 5 For the Defendants: VAUGHN K. SCHULTZ, ESQ. 6 PPG Industries, Inc., Dickie, McCamey & Chilcote, P.C and The Sherwin Two PPG Place 7 Williams Company Suite 400 Pittsburgh, Pennsylvania 15222 8 For the Defendant: RICHARD S. GOTTLIEB, ESQ. 9 E.I. DuPont De Nemours Kilpatrick Stockton, LLP 1001 West Fourth Street 10 and Company 11 Winston-Salem, North Carolina 27101 For the Defendant: TY M. SHEAKS, ESQ. 12 Safety-Kleen Jones Carr McGoldrick Systems, Inc. 5307 East Mockingbird Lane 13 Suite 600 Dallas, Texas 75206 14 For the Defendant: ANDREW J. DETHERAGE, ESQ. 15 Valspar Corporation Barnes & Thornburg, LLP 11 South Meridian Street 16 Indianapolis, Indiana 46204 17 Also present: Ellie Detherage 18 19 20 21 22 23 24 25 2 1 INDEX 2 EXAMINATION OF DAVID W. PYATT, Ph.D.: PAGE August 11, 2009 3 By Mr. Kiwala 4 4 INITIAL 5 DEPOSITION EXHIBITS: REFERENCE 6 1 Curriculum Vitae of David W. Pyatt 7 7 2 Testimony Given by Dr. David Pyatt 9 8 3 Declaration 15 9 4 Letter to Salveson from Pyatt, 7/9/09, 15 Subject: Andrew Wolfe and Denise Wolfe v. 10 E.I. DuPont De Nemours and Co., et al., In the General Court of Justice, Superior 11 Court Division, No. 07-CVS-3770 12 5 Article entitled, "The Environment and 21 Disease: Association or Causation?" 13 6 Article entitled, "Translocation 70 14 t(7;11(P15;P15) In A Patient With Therapy-Related Acute Myeloid Leukemia 15 Following Bimolane and ICRF-154 Treatment For Psoriasis" 16 7 Article entitled, "Benzene metabolites 104 17 antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIalpha 18 19 20 21 22 23 24 25 3 1 WHEREUPON, the following proceedings were 2 taken pursuant to the North Carolina Rules of Civil 3 Procedure. 4 ***** 5 DAVID W. PYATT, Ph.D., 6 having been first duly sworn to state the whole truth, 7 testified as follows: 8 EXAMINATION 9 BY MR. KIWALA: 10 Q. Dr. Pyatt, this is -- I'm sorry, have I 11 pronounced that correctly? 12 A. Yes, thank you, you did. 13 Q. Okay. This is Ryan Kiwala of Simmons 14 Browder Gianaris Angelides & Barnerd, LLC. Could you 15 state your full name for the record, please. 16 A. David William Pyatt. 17 Q. And, Dr. Pyatt, what is your current 18 business address? 19 A. 1944 Cedaridge Circle, Superior, 20 Colorado, 80027. 21 Q. Okay. And, Dr. Pyatt, by which party or 22 parties in this case have you been asked to provide 23 expert services? 24 A. I was -- my understanding is all of them. 25 I was asked to provide service for PPG, Sherwin 4 1 Williams, Valspar, Safety-Kleen, DuPont, and 3M. 2 Q. Are you prepared to render your opinions 3 in this case today? 4 A. Yes, sir. 5 Q. Have you brought any materials with you 6 today for the -- for the deposition? 7 A. Yes, I have. 8 Q. Okay. Could you tell me what you brought 9 with you? 10 A. Sure. I brought a copy of 11 Dr. Garabrant's, Dr. Natelson's, and my report, both 12 the original as well as the supplemental report. I 13 brought a copy of the various exposure expert reports. 14 I think there were five or so. All right. So those. 15 I have a copy of Dr. Zukerberg's, 16 Zahalsky, and Dr. Milman's reports that they produced 17 in this case. Then I have four binders with various 18 scientific studies that have all been produced to you, 19 at least that's my understanding. I -- I produced 20 them. But I have a hard copy in case you want to talk 21 about specific studies. And they are studies 22 regarding cytogenetics and benzene exposure, studies 23 regarding the disease APL, acute promyelocytic 24 leukemia, studies on formaldehyde, epidemiology, and 25 painters. The epidemiology on the painter literature. 5 1 So that's -- I have a hard copy of those studies. 2 Q. Okay. Those studies that you mentioned, 3 are those the studies that you have cited in the two 4 declarations that you made? 5 A. Yes. 6 Q. Are there any studies or other literature 7 in that collection of four binders that are not cited 8 in your declaration? 9 A. I'm sure there are. 10 Q. Would you be able to say which ones are 11 in there that are not cited? 12 A. Sure, I could do that. I mean, it would 13 be a fairly time-consuming process. We would just go 14 through my report and pick out the one. But I know, 15 like, the benzene cytogenetic binder, it's got every 16 single study in there where anyone has ever reported 17 or discussed cytogenetic abnormalities associated with 18 benzene exposure. And I -- there was no reason to 19 cite all of that in my report. 20 So, for sure, there's going to be a lot 21 of studies in that binder. The formaldehyde binder, I 22 think most of those I cited in my -- in my 23 supplemental report. There might be one or two that I 24 didn't. The APL binder, I suspect there are some 25 papers in there that are not in my report. 6 1 Q. Okay. Just for the sake of brevity, we 2 won't go through one by one and figure out which ones 3 are and which are not cited in the report. We'll just 4 move along. 5 Have you done all of the work required to 6 reach your opinion or opinions in this case? 7 A. I don't -- I don't think I understand 8 your question. Have I done all of the work? 9 Q. Well, is there any work that you had to 10 do that -- but you were unable to do before you signed 11 the declarations or before you came today for the 12 deposition? 13 A. Oh, I see. No. No, I'm prepared to 14 render my opinions. I mean, there -- yes, I'm 15 prepared to render my opinions. 16 Q. Okay. 17 MR. KIWALA: Teresa, I believe there were 18 some documents that were sent to you. Do you have 19 those with you there? 20 (Deposition Exhibit 1 was marked.) 21 Q. (BY MR. KIWALA) Dr. Pyatt, I'm going to 22 ask you to take a look at Exhibit 1. Is this your CV? 23 A. Yes. 24 Q. Is the CV up to date? 25 A. I'm checking. No. 7 1 Q. Okay. Can you tell me what's missing? 2 A. Well, yeah. This is actually probably 3 two years old. I mean, my last publication in this CV 4 that I'm looking at here was from 2006. And I've 5 published probably five or six, or maybe even more, 6 papers since then. The assistant clinical professor 7 on the first page, the Biometrics and Preventative 8 Medicine Department is no longer in existence. It's 9 now been folded into the new Colorado School of Public 10 Health, which I'm a -- you know, I have the same 11 appointment, but it's a different school. So -- I 12 mean, for the most part, it's going to be reasonably 13 accurate; but it is just not completely up to date. 14 Q. Okay. Do you have a more recent version 15 of your CV? 16 A. You know, I don't think I brought it. I 17 had in my mind that it would be here and that I didn't 18 need to. I can certainly send it to you. 19 Q. Okay. You don't have it with you, but a 20 more recent version does exist is what you're saying, 21 correct? 22 A. Yes. Oh, yes, absolutely. 23 Q. Okay. I would ask you to just give a 24 copy of that to counsel for defense, whoever you're 25 communicating with, and have them pass that along to 8 1 plaintiffs counsel. 2 A. You bet. 3 Q. And, Dr. Pyatt, what would you consider 4 to be your particular area or areas of expertise? 5 A. Well, by training, I am a toxicologist; 6 so I think that would be the broad category. I've 7 spent my whole career, including my training -8 post-doctoral training working in the hematopoietic 9 system. So bone marrow toxicity, hematopoietic 10 toxicity, immunological toxicity. That, I think, 11 would be my specialty within the broader category of 12 toxicology. Most of my work and research has been on 13 benzene and benzene metabolites as they are -- relate 14 to those first two categories. I mean, I think I have 15 expertise in that area as well. 16 Q. Okay. 17 MR. KIWALA: And, Teresa, could you go 18 ahead and mark the document that's entitled Testimony 19 Given by Dr. David Pyatt. 20 (Deposition Exhibit 2 was marked.) 21 Q. (BY MR. KIWALA) Dr. Pyatt, could you 22 take a look at Exhibit 2. And can you tell me, does 23 that accurately reflect all of the testimony that you 24 have ever given either by deposition or at a trial or 25 hearing? 9 1 A. The trial or hearing part is accurate. 2 There has been one additional deposition. 3 Q. Okay. 4 A. So I guess that would bring the list up 5 to 18. 6 Q. Okay. In that one additional deposition 7 that's not listed, what did that case involve? 8 A. The case was called Mallory versus. 9 Goodyear. And it was an allegation that Mr. Mallory's 10 disease was related to his occupational exposures as a 11 rigger and repair person in the Goodyear facility in 12 Ohio. 13 Q. Was there any claim of exposure to a 14 particular chemical or substance? 15 A. Yes, sir, it was -- it was benzene just 16 from the manufacturing of tires, et cetera, within the 17 -- within the facility. He didn't actually use that, 18 but that was the allegation. 19 Q. Okay. And did you testify for the 20 plaintiff or for the defendant in that case? 21 A. It was for the defendant. 22 Q. I take it that was Goodyear; is that 23 correct? 24 A. Yes. It was Goodyear, correct. 25 Q. Of the testimony that's listed on 10 1 Exhibit 2, which of those cases involved a claim of -2 or somebody alleging disease as a result of exposure 3 to benzene or benzene-containing products? 4 A. I -- they all have. That's really the 5 only area that I have ever given testimony in. 6 Q. And for -- for all of those, on which 7 side did you testify, plaintiffs or defendants? 8 A. I have -- I have never given testimony on 9 behalf of a plaintiff at this point in my career. 10 Q. Okay. I'm going to just get into some 11 questions about this case in particular. When were 12 you first contacted regarding this case? 13 A. I think it was -- I can't give you an 14 exact date, but it was sometime in the fall of 2008. 15 Q. Okay. And do you recall who contacted 16 you at that time? 17 A. I -- my recollection is that it was Chris 18 Stofko or Mike Sweeney from his office, or it might 19 have been Andrew Schirrmeister. But I -- I don't -20 it was -- it all kind of happened about the same time. 21 And then I believe they formed kind of a collaborative 22 agreement, and so then it -- I kind of was working for 23 everyone and it stopped mattering, really, who was the 24 first. But I believe it was Chris Stofko's office. 25 Q. And when you were first contacted by 11 1 Mr. Stofko's office, what did they tell you about the 2 case? 3 A. I don't remember that conversation, but 4 generally how this process works is that they will ask 5 me if I have time, based on what the scheduling is, 6 and if I will take a look at the case. And then I 7 agree or not. If I agree, then they send me 8 information, and I take a look at it. And then at 9 some point after that, we have a discussion about 10 what, you know, my initial thoughts are. And I have 11 no reason to think that this worked any differently. 12 Q. Okay. I think you said that they had 13 initial discussion where they asked if you had time to 14 take on the case. I take it you said yes. And am I 15 correct they sent you some materials to review? Is 16 that correct? 17 A. Yes. They would have -- I'm trying to 18 think what would have come in that earlier -- probably 19 the first volume of Mr. Wolfe's deposition, maybe the 20 original complaint. I -- some MSDS sheets. I know 21 that was kind of early from various defendants. And 22 medical records. 23 Q. Did you -- when did you first form any 24 opinion, formal or informal, about this case? 25 A. I would say that's going to be in the 12 1 fall of '08 as well. 2 Q. Okay. At the time that you were first 3 contacted? 4 A. Well, it wouldn't have been a spur of the 5 moment decision like that, but -- but sometime within, 6 say, a month or two months of that initial 7 conversation. 8 Q. Okay. So after you reviewed the -- the 9 initial materials that you were sent -- and I think 10 you said it was the first volume of the deposition, 11 the complaint, and some MSDS. There may have been 12 others -- other documents, but the record will speak 13 for itself. At that point, what was your initial 14 opinion from your review of those materials? 15 A. Yeah, in the list that I gave you -- and 16 that's the best that I can recall; but like you said, 17 there should be a record of what was sent. So I don't 18 have to remember all of that. 19 My initial opinion, which I probably 20 provided to whoever I originally talked to, was that 21 based on my understanding and my appreciation of the 22 literature, APL, the type of AML that Mr. Wolfe had, 23 was not a benzene-related malignancy. So I think that 24 was the overriding and the most important opinion that 25 I have in this case. And -- because I've worked on 13 1 another APL case, and I've thought about this a lot 2 through the years, that was something that I could 3 provide, you know, reasonably quickly. 4 Q. At what point -- was there any 5 information that you had asked for to review to arrive 6 at an opinion -- anything that you requested from the 7 defendants at that time when you gave -- after you 8 gave your initial opinion? 9 A. Anything that I requested? 10 Q. Yeah, any materials that you thought 11 would be particularly relevant for you in developing 12 your opinions or creating a report. 13 A. At that time or in general, the whole 14 time. 15 Q. Let's just start at that time. 16 A. I don't think there was anything that I 17 felt like I needed at that -- at that point in time. 18 And then as the case progressed, they were sending me 19 new information as it became available. So early on, 20 there wasn't anything that I felt like I needed that I 21 had asked for that -- at that point. 22 Q. Okay. Was there ever a point where you 23 asked for something and you did not receive it from 24 counsel for the defense? 25 A. I can't think of anything, no. They have 14 1 been very responsive. 2 Q. And there are two declarations that you 3 -- that you signed. 4 MR. KIWALA: And, Teresa, could go ahead 5 and mark those as Exhibits 3 and 4. 6 (Deposition Exhibits 3 and 4 were 7 marked.) 8 Q. (BY MR. KIWALA) And, Dr. Pyatt, if you 9 take a look at what's been marked as Exhibit 4, it 10 appears to be a second declaration or supplemental 11 declaration for this case. It's addressed to an Erik 12 T. Salveson. Would it be -- is it correct that at 13 some later point, you were asked to give an opinion 14 about what the existing scientific and epidemiological 15 evidence was regarding formaldehyde exposure in 16 leukemia? 17 A. That's -- that's precisely what happened. 18 Q. Okay. Do you know when you were 19 initially contacted to -- regarding this supplemental 20 opinion and declaration? 21 A. I -- no, not specifically. I mean, if I 22 had the report, July 9, it was a fairly short 23 turn-around when Mr. Salveson called me and asked if 24 -- if I knew anything about this and whether I could 25 address it in a supplemental report. So I'm going to 15 1 say sometime mid-June, but I don't -- you know, I 2 didn't write it down. I don't know precisely when, 3 but somewhere two or three weeks prior to when this 4 report was submitted. 5 Q. And in preparing this supplemental 6 declaration or report, did defense counsel provide you 7 with any additional materials? 8 A. Not that I recall, no. Things were 9 coming all the time, so I -10 Q. Okay. 11 A. But nothing -- you know, nothing 12 specifically -- I had all of the formaldehyde 13 literature. This is something that I've done some 14 other work on, so there wasn't really anything that I 15 needed. 16 Q. Over the course of this case, has there 17 been any scientific or medical literature that was 18 supplied to you by counsel for the defendants? 19 A. No, sir. I think the converse is true. 20 Q. And can you tell me, do your declarations 21 -- well, before I get to that, if you would take a 22 look at Exhibit 3. Do you recognize that as your 23 original declaration for this case? 24 A. It -- it looks -- I mean, it's got this 25 funny box around it, so it's not exactly my -- the 16 1 original one that I submitted, but I have no reason to 2 doubt that it's accurately reproduced. It looks like 3 it's been scanned or something, so it's not actually 4 what I -- what I produced, but it's -- I'm sure it's 5 right. 6 Q. Okay. At any rate, do you have any 7 reason to believe that Exhibit 3 did not set forth a 8 true and accurate reflection of your opinions in this 9 case? 10 A. No. No, sir, and I didn't mean to imply 11 that. 12 Q. Okay. Nothing inferred. And do -- your 13 declarations set forth in Exhibit 3 and 4, do they -14 do those two declarations set forth all of the 15 opinions that you're prepared to give in this case? 16 A. I -- I think there could be additional 17 information regarding plaintiff experts that I might 18 be asked to discuss; but as far as my own professional 19 opinions about this case, these two reports accurately 20 reflect that. 21 Q. Would you agree that the opinions 22 that are stated in your declaration are generally -23 generally deal with what's known as general causation? 24 MR. DETHERGE: Objection, lack of 25 foundation. And, Ryan, can we agree that an objection 17 1 by one defendant is good for all as we have in the 2 other depositions? 3 MR. KIWALA: Sure. 4 A. Well, I guess I'm not quite sure how to 5 answer that. While I addressed both with formaldehyde 6 and benzene in APL, what the scientific literature 7 says with regards to those exposures and the disease, 8 since Mr. Wolfe had APL, then those opinions are 9 relevant and directly germane to my opinions regarding 10 him as well when that would be more of a specific 11 causation. So I'm not quite sure how to answer your 12 question. 13 Q. (BY MR. KIWALA) Let me see if I 14 understand you correctly. Do you mean to say that you 15 have an opinion as to specific causation in this case 16 insofar as your opinion on general causation is that 17 benzene exposure and formaldehyde exposure cannot 18 cause APL specifically or leukemia or -- well, APL 19 specifically? 20 MR. DETHERGE: Same objection. 21 A. Yeah, I don't think I said it very 22 clearly, and so what you said wasn't very clear to me 23 either. Let's try again. I don't believe the 24 literature supports an association between APL and 25 benzene or APL and formaldehyde. So from that 18 1 standpoint, that is more of a -- I guess you would 2 classify that as a general causation argument. But 3 that analysis and that literature is directly germane 4 to Mr. Wolfe, because that's the kind of disease that 5 he had. 6 Q. (BY MR. KIWALA) And just to follow-up, 7 the point is that you can't have specific causation 8 without general causation established first, correct? 9 MR. DETHERGE: Same objection. 10 A. I think that's a reasonable 11 interpretation, yes. 12 Q. (BY MR. KIWALA) Dr. Pyatt, if you'll go 13 ahead and turn to Exhibit 3. You spent some time 14 discussing Bradford-Hill criteria. Can you tell me 15 what the Bradford-Hill criteria are? 16 A. Well, it was a presidential address that 17 Sir Bradford-Hill gave to a medical conference. And 18 it was -- set forth a criteria or a guideline, or 19 however you want to describe what his list was, that 20 would, to some degree, formalize the process that 21 would allow scientists to evaluate the difference 22 between causation and association. And that's the 23 title of his -- title of his address. 24 So it set forth a series of 25 considerations that one needs to have in order to be 19 1 able to say, yes, I -- I think this disease was, in 2 fact, caused by these exposures. That's the 3 Bradford-Hill so-called criteria or whatever you -4 you know, whatever term you would like to put on them. 5 It's not the only ones that are out 6 there. As I referenced in my report, Evans had 7 something very similar. The koch postulates are very 8 similar. You know, it's just a methodology for 9 establishing causation. 10 Q. Okay. And if you'll take a look 11 specifically at paragraph 7 in Exhibit 3. 12 A. Yes, I'm there. 13 Q. You set forth seven questions that you 14 say must be addressed to reach a tenable conclusion on 15 general causation, correct? 16 A. Well, these -- I mean, I didn't set these 17 forth. These were the ones that came directly from 18 Dr. Hill's address. 19 Q. Are there any in that list that are -20 any questions in that list that are not set forth in 21 Dr. Hill's address? 22 A. I -- not that I am aware of, no. 23 Q. Okay. Are there any guidelines or 24 criteria that were set out in Dr. Hill's address that 25 don't appear on that list of seven questions? 20 1 A. I think I might have combined a couple. 2 Let's see. Because I know he has nine and I have 3 seven. But without comparing them directly, I 4 couldn't tell you which ones those are. I mean, these 5 are, I think, by everyone's interpretation, the most 6 important. But I may have -- I may have combined one, 7 because I know he has nine. 8 Q. Okay. 9 (Deposition Exhibit 5 was marked.) 10 Q. Dr. Pyatt, is this a copy of the address 11 that you mentioned earlier that was given by Austin 12 Bradford-Hill? 13 A. Yes. 14 Q. And can you tell me from looking at that 15 address what factors you believe you may have combined 16 into those seven questions and specifically how? 17 A. It's -- okay. Looks like I didn't 18 include No. 9, the analogy. 19 Q. Okay. Is that an important question to 20 consider when rendering an opinion as to causation? 21 A. Well, I don't think it's nearly as 22 important as the first two or three. 23 Q. Okay. 24 A. Coherence, I kind of think of that really 25 in terms of plausibility, what we know about the 21 1 disease, what we know about the chemical. So that one 2 -- that might be a combination. 3 It looks like most of the first ones are 4 -- are the same. Specificity, consistency, strength 5 of the association. Those are really the most 6 important. 7 Q. Okay. The seventh question you had in 8 paragraph 7 mentions -- well, it says, "Are there 9 alternative mechanisms or known risk factors that 10 potentially could have caused the disease or 11 confounded interpretation of the results?" 12 Where do those -- where does that 13 question fit in, in your opinion, to the Bradford-Hill 14 criteria? Or does it? 15 A. I'm looking. That's a good question. 16 Well, I don't -- I'm not seeing it specifically 17 addressed in this one, so perhaps that came from 18 reference 1, Evans, "Causation and disease: The 19 henkle-koch postulates revisited". It may have come 20 from that Yale publication. I don't -- I don't see it 21 in Bradford-Hill's paper. 22 Q. Okay. Let's move along to paragraph 8 in 23 Exhibit 3. 24 A. Okay. 25 Q. You mention -- you state in paragraph 8 22 1 -- and I'll go ahead and read it directly -- "The 2 minimum standard within the scientific and 3 epidemiological communities for determining 4 quantitatively if the risk of disease is truly higher 5 in the exposed population is a relative risk (or some 6 comparable measurement) greater than 1.0 with a 7 95 percent confidence interval that does not include 8 the value of 1.0." 9 Did I read that correctly? 10 A. Yes. 11 MR. DETHERGE: Actually, you left out the 12 word statistical, Ryan, which is probably an important 13 word in that sentence. 14 MR. KIWALA: Oh. 15 THE DEPONENT: I thought he did say 16 statistical. 17 MR. DETHERGE: I don't think so. 18 A. Okay. The minimal statistical standard. 19 We all agree with that. 20 Q. (BY MR. KIWALA) I would agree to that. 21 It does say that. Can you -22 A. Thank you. 23 Q. Can you explain to me what you mean by 24 that, the phrase "minimal statistical standard"? 25 A. Well, what I mean by that is if you want 23 1 to -- I mean, if it's -- in order to decide whether or 2 not there's truly an increase in an exposed 3 population, which is something that you obviously want 4 to do if you think exposure caused the disease, you -5 you -- the relative risk, however you define that, 6 whether it's standard mortality ratios or odds ratios, 7 or whatever, need to be greater than 1, whereas 1 8 would be there is no difference between the two 9 populations. But because there is variability and, 10 basically, noise in all of these experiments, then you 11 conduct a statistical analysis to rule out or at least 12 limit the possibility that chance played in the 13 numbers that you're looking at. And so that's where 14 the 95 percent confidence interval or a p-value of 15 less than .05 comes in, because it will allow you to 16 get your arms around the role that chance may have 17 played in your number. 18 Q. Okay. I guess what I'm asking is -- and 19 maybe I didn't phrase the -- the question very well. 20 Do you mean to say that a study showing a relative 21 risk greater than 1.0 with a 95 percent confidence 22 interval -- is that something that you have to have in 23 order to render an opinion that there's a positive 24 cause -- you know, causal association? Is that 25 relative risk higher than 1 something you absolutely 24 1 have to have? 2 MR. GOTTLIEB: Object to form. 3 A. Yeah, sorry. That was a fairly 4 convoluted question. Can we try that again? 5 Q. (BY MR. KIWALA) Sure. Are you saying 6 that a relative risk higher than 1 and a -- with a 7 confidence interval of 95 percent -- is that a -- is a 8 study showing that something necessarily you have to 9 have in order to render an opinion as to causation? 10 MR. GOTTLIEB: Object to form. 11 A. Okay. The way you worded your question, 12 you just said a 95 percent confidence interval. 13 Q. (BY MR. KIWALA) Um-hum. 14 A. I don't know what that means. I mean, 15 you need to calculate the 95 percent confidence 16 interval, but you didn't put any values with that. So 17 I don't know how to answer your question. 18 Let me -- let me try this: If you have a 19 relative risk that's greater than 1, then that means 20 by definition that you saw more of the disease in the 21 exposed population than you did in the control group. 22 All right. If it's less than 1, then you saw less. 23 It's just a simple ratio, it's not magic. But there's 24 a lot of variability and there's all kinds of 25 uncertainties in these studies. And so that's why you 25 1 need to do a statistical analysis or a statistical 2 comparison that you can, with any degree of scientific 3 confidence, say, yes, there really was an increase in 4 the exposed population compared to the control 5 population. And that needs to happen irrespective of 6 what the relative risk is. 7 The relative risk could be 1.2 or the 8 relative risk could be 12. And that doesn't negate 9 the requirement of having some statistical analysis 10 done to rule out the role that chance could play in 11 your findings. 12 The scientific standard that is used 13 today is that the 95 percent confidence interval 14 cannot include the value of 1. So then if the 15 95 percent confidence interval is greater than 1.0, 16 then you can be 95 percent sure that whatever the 17 right answer is, it is also greater than 1.0, which 18 would indicate that there is, in fact, an increase. 19 Q. Okay. 20 A. Even with that, you still have a 21 5 percent chance that -- well, a 5 percent chance that 22 chance is what happened and that you're really not 23 seeing a true association or a true -- anything that 24 has anything to do with the causal effect 25 relationship, but that at least limits it based on the 26 1 statistical comparison. 2 Q. Okay. And I guess my question is, What 3 you just described there, is that the bare minimum? 4 You have to have a study that shows a relative risk 5 higher than 1.0 and also has -- that value has a 6 95 percent confidence interval; that without a study 7 showing that, you cannot make a determination as to 8 whether a particular substance or agent, or whatever 9 you want to call it, has a causal association with a 10 given health effect? 11 MR. GOTTLIEB: Object to form. 12 MR. DETHERGE: Objection, lack of 13 foundation. 14 Q. (BY MR. KIWALA) Do you understand the 15 question? 16 A. Well, what I heard was you still did the 17 same thing with the 95 percent confidence interval, 18 and you didn't put any values for it. You just said 19 that it has a 95 percent confidence interval. 20 Q. Okay. 21 A. So if you -- if you -- yeah, just -- I 22 mean, if you're wanting to ask me that with regard to 23 that that is greater than 1, let's try it again, and 24 I'll try to answer your question. 25 Q. Okay. 27 1 A. I'm not trying to be difficult. I'm -2 Q. I'm just trying to understand -- you're 3 the expert here. I'm just trying to get along. Let's 4 say you have -- I want to make sure I understand this. 5 I understand -- what I'm getting wrong -- what I'm 6 getting wrong is when I say 95 percent confidence 7 interval, correct? 8 A. Right. You're not providing values for 9 what that 95 percent confidence interval tells you. 10 Q. Okay. So, for instance, if the relative 11 risk was 2 and the confidence interval was yet a 12 p-value of .05, let's say, that -- at that point, that 13 study shows a causal association or indicates a causal 14 association, correct? 15 A. No. 16 MR. GOTTLIEB: Object to form. 17 Q. (BY MR. KIWALA) No? 18 A. No, that's -- I mean, your question was 19 understandable. 20 Q. Um-hum. 21 A. So my answer is no. My answer is the 22 answer to that question is no, not that I don't 23 understand your question. 24 Q. Okay. Let me -- I don't know if I'm 25 going to be able to phrase this correctly, but let me 28 1 move on to the -- further on in the paragraph. You 2 state, in general, the higher the risk ratio, the less 3 likely that a given finding is artifactual. Did I 4 read that correctly? 5 A. In general, the -- yes, you did. 6 MR. GOTTLIEB: Ryan, where are you 7 reading? 8 MR. SCHULTZ: Paragraph 8 still? 9 THE DEPONENT: Yeah, five lines down. 10 Q. (BY MR. KIWALA) Now, does a lower risk 11 ratio necessarily indicate the given finding is 12 artifactual? 13 A. It doesn't necessarily indicate that, no. 14 And that's where you rely on the statistical 15 comparison, which is indicated by the p-value and the 16 95 percent confidence interval. 17 Q. Okay. Let's go on to the next paragraph, 18 the second criterion that you described. And I 19 believe you state here in paragraph 9, "If one study 20 reports marginally positive findings (even if they are 21 statistically significant), but others are negative or 22 inconclusive, it is scientifically unsound and 23 speculative to rely solely on the one positive study 24 and opine unequivocally that a positive relationship 25 exists." 29 1 Did I read that correct? 2 A. Yes. 3 Q. Okay. If a study had not been repeated, 4 is it your opinion that it would be unsound or 5 speculative to rely on that study in arriving at a 6 conclusion about causation? 7 MR. DETHERGE: Objection, lack of 8 foundation. 9 A. Okay. So you're saying that you have a 10 positive study that is statistically significant? 11 Q. (BY MR. KIWALA) Yes. 12 A. And it is describing an association 13 between some disease and some chemical exposure and 14 there is no other data in the world that would allow 15 you to evaluate that finding. So it was just that one 16 stand-alone study, right? 17 Q. Yes. Let's just say one stand-alone 18 study. 19 A. Okay. And your question is based on that 20 scenario -- what's your question based on that 21 scenario? 22 Q. Well, based on that scenario, would it be 23 unsound or speculative to rely on that study and -- in 24 arriving at a conclusion about causation? 25 MR. DETHERGE: Same objection. 30 1 A. Well, it's a hypothetical that certainly 2 doesn't apply to this case; but, yes, I think even in 3 that situation, it would be fairly speculative. I 4 mean, I don't think anyone would do that. I think 5 people would say, All right, this suggests that there 6 is an association. We need to repeat this. Other 7 people need to look at this. Does it fit in with our 8 understanding of the chemical, the disease, et cetera? 9 I don't believe anyone would take a single finding and 10 run with it and say, yes, we have established 11 causation. I certainly wouldn't. 12 Q. (BY MR. KIWALA) Okay. What if repeating 13 that study would be impossible? Would it still be 14 your conclusion -- or, I'm sorry, would it still be 15 your opinion that it would be unsound or speculative 16 to rely on that study at arriving at a conclusion 17 about causation? 18 MR. DETHERGE: Same objection. 19 A. I don't -- I don't -- I mean, if you did 20 it -- if the study was done, how can it be impossible 21 to repeat it? Because the people are all gone or dead 22 or -- I mean, this is just pretty far out there. 23 You're -- I mean, I guess if there's -- if you had 24 this piece of data and there was no other data that 25 could ever be derived for whatever reason, I think you 31 1 would say, Okay, there is a suggestion that something 2 is going on here. 3 Q. (BY MR. KIWALA) What -- continuing with 4 this, what if you have -- if you have one study that 5 shows a positive relationship and it's statistically 6 significant and you don't have any other studies out 7 there, but you all have evidence or data that is 8 relevant to other Bradford-Hill criteria -- for 9 instance, there is evidence of a biologically 10 plausible mechanism -- at that point, is that level of 11 information or evidence sufficient to reach a sound 12 conclusion as to causation? 13 MR. GOTTLIEB: Objection. 14 MR. DETHERGE: Same objection. 15 A. I don't think you could ever reach a 16 conclusion on causation with a single -- with a single 17 epidemiological study. I just think that would be 18 really hard to do. I mean, the way you describe, you 19 know, changing the scenario, that certainly would give 20 someone confidence and it would strengthen their 21 opinion that maybe this is, in fact, real. But there 22 are just too many examples throughout, you know, our 23 scientific history where one study popped up and it 24 was elevated and it was statistically significant, 25 like coffee and pancreatic cancer, and people got 32 1 pretty worked up about it. And then it never came 2 again. People reviewed it over and over and over. 3 And the association was never repeated. So, you know, 4 you see that enough times, and epidemiologists and 5 scientists across the board start taking a more 6 cautious view of this kind of data. 7 Q. (BY MR. KIWALA) Okay. If one study 8 finds positive findings that are statistically 9 significant and you have a second study that reports 10 negative findings or inconclusive findings, would your 11 opinion be that the second study refuted the first 12 one? 13 MR. DETHERGE: Same objection. 14 A. Well, I don't think you could make that 15 determination without looking at the studies. I mean, 16 if they were exactly the same study, the same 17 population done the same way, the same numbers, the 18 same investigators, well, yeah, I mean, I don't see 19 how you could not come to that conclusion. But if 20 there were differences between the way the studies 21 were set up or designed, different statistical powers, 22 et cetera, I don't know that you would necessarily say 23 that it refuted it, but you would say that it's 24 inconsistent with an association being present, and 25 you would still be left with a question mark. 33 1 Q. (BY MR. KIWALA) Okay. So at that point, 2 it would be scientifically unsound and speculative to 3 draw a conclusion, correct? 4 A. I think it would be scientifically 5 speculative and unsound to draw a conclusion on 6 causation. 7 Q. Okay. 8 A. And say that that first study is all that 9 we need. I think anyone would look at that data set, 10 as you just described it, and say this is 11 inconsistent. This doesn't match. 12 Q. Okay. Let's look at paragraph No. 10. 13 You say, "The remaining criteria as outlined by 14 Bradford-Hill are also important in reaching a 15 conclusion on medical causation, but cannot serve as 16 adequate substitutions for fulfilling the first two." 17 Did I read that correctly? 18 A. Yes, sir. 19 Q. Can you tell me what you mean by that 20 statement? 21 A. Well, what I mean by that, in terms of 22 causation in -- medical causation with disease, having 23 statistically significant findings that have been 24 reproduced for multiple studies from independent 25 investigators in other countries -- you know, 34 1 reproducibility and consistency in the findings, 2 that's the most important criteria in any scientific 3 discipline. And epidemiology is no different. 4 Having -- you see a -- see a finding in 5 one laboratory, and that's the only place you ever see 6 it, you start wondering whether or not there's 7 something going on with that investigator or something 8 is going on in that particular lab. 9 When you see that same finding in four or 10 five different labs, then you start developing a 11 stronger confidence that it's real; that what you're 12 looking at is truly occurring. I don't think that's 13 any different -- perhaps it's even more important -14 in epidemiology. So my point is, yeah, anyone that 15 understands the science and has been trained in this 16 area can probably come up with some biological 17 plausible pathways that may or may not have any data 18 supporting them. 19 You can say, Well, this chemical could do 20 X, Y, and Z, and that will allow it to cause this 21 disease. We can all do that. You can do that in your 22 sleep. That's really easy to do. So biologic 23 plausibility really doesn't get you very far in terms 24 of establishing causation. 25 So that's -- the point was that these 35 1 first two, consistency and reproducibility in the 2 epidemiological evidence and the strength and 3 statistical analysis associated with those findings 4 is, by far, the most important aspect of medical 5 causation. 6 Q. Okay. Just to go back -- we talked a 7 little bit about epidemiological studies. Let me ask 8 you about a case report. Would a case report 9 indicating a causal association between a given 10 substance and a given health effect -- would that be 11 enough to -- to render a scientifically sound and not 12 speculative opinion about causation, that causal 13 relationship? 14 MR. GOTTLIEB: Objection. 15 A. That's not possible. I mean, the context 16 of your question is impossible. You said a case 17 report that indicates a causal relationship. There's 18 no way. A case report does not indicate a causal 19 relationship. At the absolute best, and no matter how 20 speculative you want to be, a case report suggests 21 there might be an association. But without control 22 populations and all of the other things that you need 23 in quantitative epi, a case report, by no stretch of 24 the imagination, indicates a causal association or a 25 causal relationship. 36 1 Q. (BY MR. KIWALA) Okay. I just want to be 2 clear that what you're saying is that a case report is 3 absolutely insufficient to establish causation; is 4 that correct? 5 A. A case report is absolutely insufficient 6 to establish causation, you bet. 7 Q. Okay. Let's go back to paragraph 10 and 8 the "consistently positive results obtained from 9 quantitative epidemiology studies." 10 Is it your opinion that if you have 11 consistently positive results obtained from 12 quantitative epidemiology studies, but evidence or 13 data relevant to the other Bradford-Hill criteria do 14 not exist, would it be -- would it still be 15 scientifically sound to conclude that a causal 16 relationship exists? 17 For instance, to give you an example, you 18 have a series of studies that all find a -- a 19 statistically significant positive finding, but there 20 is no -- nothing that would indicate a biologically 21 plausible mechanism, none of the other guidelines or 22 criteria that are mentioned by Bradford-Hill in his 23 article are present for this particular association. 24 If the only two things you have -- well, if the only 25 two things you have are strength of the association 37 1 and reproducibility of it, is that -- are those two 2 elements alone enough to reach a conclusion about 3 causation? 4 MR. DETHERGE: Objection. It's compound 5 and lacks foundation. 6 A. Well, the only one that Bradford-Hill -7 and I think everyone would agree, the only one that is 8 absolutely essential is the temporality. And the 9 exposure has to come logically before the disease, or 10 no one will think that the disease was caused by the 11 exposure, right? So that's a given. So the answer to 12 your question would be, of course not. If no other 13 Bradford-Hill criteria are satisfied, then the 14 temporality part would not be satisfied, and there 15 would be no way that you could think that the disease 16 was caused by the exposures. 17 Q. (BY MR. KIWALA) Okay. 18 A. So if you -- if that's positive, then we 19 can discuss the next part, I guess. 20 Q. Well, if -- let's say if you have 21 positive -- if you have strength in the association, 22 you have the temporal relationship, you have 23 consistency in the findings, but information as to the 24 remaining criteria or guidelines is simply not there, 25 given the information that you have at that point, is 38 1 that enough to reach a conclusion about causation 2 that's scientifically sound and not speculative? 3 MR. GOTTLIEB: Objection. 4 MR. DETHERGE: Ryan, can we have a 5 continuing objection to lack of foundation to these 6 incomplete hypotheticals so we don't have to keep 7 objecting? 8 MR. KIWALA: Yeah, okay. 9 A. I don't know that I can answer that. You 10 know, it would be on a case-by-case, kind of, 11 evaluation. I mean, it would depend on the -- what 12 these studies looked like and what that data really 13 tells you. You know, if you have a dose response 14 relationship in these studies, then that would 15 strengthen my confidence that there really was 16 something going on. If that was lacking, then I'm not 17 sure what I would think about them. 18 I mean, the biologic plausibility is 19 important, but if you had consistent -- truly 20 consistently positive epidemiological findings 21 indicating an association between exposure and 22 disease, but you didn't know how it worked, so there 23 was no biological plausible explanation for it, I 24 don't think that would prevent people from making a 25 conclusion that at least there appears to be something 39 1 here, and we just don't know enough about it. I've 2 never seen that situation. 3 I mean, I've seen where there is some 4 inconsistent epidemiological support. There's a lot 5 of inconsistent epidemiological support that goes 6 along with it, and it is not biologically plausible. 7 So, I mean, there's a whole bunch of permutations to 8 that; but I really can't answer the question in the 9 general sense. 10 Q. (BY MR. KIWALA) Okay. Let me -- let me 11 make sure I've got this correct. Your opinion is that 12 you need to have consistently positive results 13 obtained from quantitative epidemiological studies to 14 reach a scientifically sound conclusion on a causal 15 relationship, correct? 16 MR. SHEAKS: Objection, form. 17 A. I'm -- say that again, that I -- that you 18 need to have -19 Q. (BY MR. KIWALA) You need to have 20 consistently positive results obtained from 21 quantitative epidemiological studies. 22 A. Well, consistently, what does that mean 23 to you? 24 Q. Well, let me -- let's just take it as you 25 -- as you meant it in paragraph 10 where you say the 40 1 -- these cannot substitute for consistently positive 2 results obtained from quantitative epidemiology 3 studies. 4 A. Well, what I mean by that is if you have 5 got inconsistent results, and you've got one study 6 that's positive, and you've got four studies that 7 aren't, and then you've got one study that maybe 8 doesn't really address the question very well, so 9 you've got this pile of data that doesn't really get 10 you there, it doesn't really help you, in my opinion, 11 you can't then go to and say, Well, it's biologically 12 plausible, and here's how, and make up a story that 13 the chemical can cause the disease through these 14 various mechanisms and then have that support the 15 epidemiological data. That's what I mean in this 16 paragraph, that these other -17 Q. What your -- your opinion -- what you're 18 saying is that you can't take studies -- such studies 19 that have inconsistent findings, and then look to the 20 other Bradford-Hill criteria to help you reach a 21 conclusion about causation. At this point, you have 22 inconsistent findings in the epidemiological studies, 23 and that there's just necessarily a question mark; is 24 that correct? 25 MR. DETHERGE: Objection, 41 1 mischaracterizes. 2 A. Yeah, I don't think that's what I said. 3 Q. (BY MR. KIWALA) Okay. What if you have 4 four studies that have positive findings that are 5 statistically significant and one study that has 6 negative findings? 7 MR. GOTTLIEB: Objection. 8 Q. (BY MR. KIWALA) Based on those studies 9 alone, can you make a conclusion as to causation? 10 MR. GOTTLIEB: Objection. 11 A. Well, I don't -- I don't -- I don't know. 12 I mean, if the four studies that are positive are all 13 small questionnaire-based community case-controlled 14 studies, and then the one negative is a large cohort 15 with really good exposure data and, you know, 16 well-defined -- yeah, well-defined exposure data, and 17 that doesn't support it, I'm not sure that you could 18 take that and reach a conclusion of causation. I 19 mean, it would just depend on the relative strengths 20 and what those studies told you. It's really hard to 21 answer these questions in the abstract. 22 Q. (BY MR. KIWALA) Okay. I guess what I'm 23 trying to get at here, Doctor, is you say in your 24 report -- or your declaration in paragraph 6 that 25 "Only through the use of a standardized" -- I'm sorry. 42 1 Are you with -- are you with me there at paragraph 6? 2 A. Yeah, I got there. 3 Q. Okay. "Only through the use of a 4 standardized and accepted methodology, can the 5 evidence in support of a hypothetical relationship 6 between the chemical exposure and the development of 7 disease be rigorously tested and evaluated." 8 Did I read that correctly? 9 A. Yes. 10 Q. And what I'm trying to figure out is how 11 these -- these Bradford-Hill criteria or the seven 12 questions that you've set out in the subsequent 13 paragraph there, paragraph 7, if this is a methodology 14 that is supposed to be used to support a relationship 15 between chemical exposure and the development of 16 disease, I'm trying to figure out how this -- how 17 these work. 18 MR. DETHERGE: Is there a question? 19 MR. KIWALA: Well, I'm getting there. 20 Q. (BY MR. KIWALA) Are these -- are the 21 seven questions merely a -- are these something you 22 have to answer? Each of the seven questions that you 23 set out in paragraph 7, do you have to have an answer 24 to each of those before you can come to a conclusion 25 about -- about the causal relationship? 43 1 A. Well, I think we've discussed that, and 2 the answer would be, no, with the exception of, 3 perhaps, the fourth one. If you don't have a temporal 4 relationship, I don't think that anyone would think 5 there was a causal relationship or even association. 6 And then I discussed in paragraph 8, you know, the 7 consistency and reproducibility of the findings and 8 epidemiological studies is more important than some of 9 these other -- other criteria in terms of establishing 10 causation. So, I mean, I think we -- we have 11 discussed that. 12 Q. Okay. 13 A. I just can't apply these criteria to 14 these abstract scenarios that you're presenting me in 15 these questions and necessarily give you an answer 16 without looking at the actual data. 17 Q. So at the end of the day, it's really a 18 case-by-case analysis, correct? 19 MR. DETHERGE: Objection, 20 mischaracterizes. 21 Q. (BY MR. KIWALA) You need a set of 22 specific facts before you can come to a conclusion 23 about whether a causal relationship exists? 24 MR. DETHERGE: Compound. 25 A. I don't know what that means. I mean, I 44 1 think -- I think my answer speaks for itself. 2 Q. (BY MR. KIWALA) Okay. Let's go ahead 3 and move on then. If you look at paragraph 12 on 4 Exhibit 3 -5 A. Yes, sir. 6 Q. -- you state that -- let me make sure I 7 get this right -- that "acute myelogenous leukemia," 8 or AML, "itself is not a single disease, but a 9 collective grouping of seven or eight different 10 subtypes." 11 Did I read that correctly? 12 A. You read that correctly, yes. 13 Q. I guess my first question, why is it 14 seven or possibly eight? Is there a disagreement as 15 to how many subtypes there are? 16 A. I wouldn't think there's a disagreement. 17 This is based on the FAB, French American British, 18 classification system. And some classification 19 systems have what's called an M0, which is acute 20 myelogenous leukemia that is undifferentiated, and you 21 don't always see that in some characterization. So 22 you've got M1 through M7, and then you either have M0 23 or you don't, and that's where you get the 7 or, 24 possibly, 8, depending on how you consider the M0. 25 And, again, this is based on the FAB classification 45 1 system, which is kind of on its way out in terms of 2 nosology and what people are doing to classify these 3 diseases. So the World Health Organization has a more 4 sophisticated classification system for AML, and its 5 quite a bit larger in terms of the groupings. 6 Q. Okay. Further on in that paragraph, you 7 say, "APL is distinctly different from other subtypes 8 of AML, in terms of its diagnostic criteria, 9 treatment, prognosis, cell of origin, and of 10 particular relevance to this case, etiology." 11 Can you tell me how APL is different from 12 the other subtypes of AML in terms of diagnostic 13 criteria? 14 A. Certainly. 15 Q. Please do. 16 A. Well, I mean, there's lots of morphologic 17 characteristics that would allow one to classify or 18 diagnose a case of APL, but the easiest one is -- the 19 hallmark of APL is a cytogenetic abnormality involving 20 a balance translocation between chromosomes 15 and 17. 21 No other subtype of AML has that. Only APL has it. 22 You need to see it to classify a disease as APL. So 23 that's probably the easiest example of where that is a 24 unique criteria for APL and nothing else. 25 Q. Okay. How is APL different from the 46 1 other subtypes of AML in terms of treatment? 2 A. Because of the molecular base of the 3 disease, it is treated predominantly with a drug 4 called altransretinoic acid which induces terminal 5 differentiation of the promyeloctye. There is no 6 magical treatment like that for any other AML. It's 7 the only one that is treated with altransretinoic 8 acid. It's the only one that is treated with these 9 agents that induce differentiation. So it has an 10 absolutely unique treatment regiment than any other 11 form of AML. 12 Q. Okay. And how is APL different from 13 other subtypes of AML in terms of cell of origin? 14 A. The cell of origin -- and this is through 15 a very eloquent system of experimentation -- has been 16 pretty conclusively shown -- although you can 17 certainly find some disagreement in the literature, 18 but has been pretty conclusively shown to occur at a 19 granulocytic-committed progenitor cell, not at a 20 myeloid stem cell or early progenitor cell, which is 21 most of the other forms of AML are thought to have 22 arised, the cell origin for those other forms of AML. 23 So it is a more mature committed differentiated cell 24 type that is thought to harbor the first (15;17) 25 cytogenetic lesion. 47 1 Q. What can you tell me about these -- all 2 of these subtypes? How are all of these subtypes 3 similar such at that they are able to be collectively 4 identified as AML? 5 A. Well, I think they are collectively 6 classified as AML because they are all acute. So 7 that's the A. They are not chronic diseases, and they 8 all are arising in cells of a myeloid lineage. So 9 there's your M. And they are all leukemia, so there's 10 your L. But other than that pretty broad brush 11 generalization, APL is really very different than 12 these other subtypes of AML. 13 Q. Okay. Would you agree with the statement 14 that all subtypes of AML are -- they all derive from a 15 genetically damaged pluripotent stem or progenitor 16 cell which can differentiate into all myeloid cell 17 types? 18 A. No, I would -19 Q. That statement. 20 A. -- I would not. I think the evidence is 21 pretty clear -- I mean, that's a pretty important "or" 22 that you had in that sentence, that it's a primitive 23 or a stem cell or a progenitor cell. I think you 24 would describe the cell of origin as best understood 25 today that it isn't a myeloid committed progenitor 48 1 cell, but that progenitor cell does not retain 2 multiple lineage capacity, and it is committed to 3 going down the granulocytic pathway. So I would not 4 agree with that sentence the way you read it. 5 Q. Okay. I didn't think you would. Can you 6 tell me -- can you tell me if there's anything in the 7 medical or scientific literature that you can cite for 8 me today that you rely on for that disagreement with 9 the statement? 10 A. Certainly. There's a nice study by 11 Grimwade, G-r-i-m-w-a-d-e, that discusses in great 12 detail the cell of origin for APL. There's a study by 13 an author N-a-s-r that was published in 2008. There 14 are probably five or six other studies that -- where 15 they were basically, like I said, conducting some 16 fairly sophisticated analysis to try to determine 17 where the (15;17) is arising, at what point in the 18 hematopoietic differentiation you start to see that 19 lesion. And you don't ever see it in a lymphoid cell. 20 So if you never see it in a lymphoid cell in APL, then 21 it is not likely occurring at a stem cell that still 22 has the ability to go down those different lineages. 23 So there's a lot of data out there 24 discussing the cell of origin for APL and how it is 25 likely to be different. I mean, we don't know 49 1 differently where the cell of origin is for any of 2 these diseases. So it's not with 100 percent 3 certainty, but it certainly appears to be different. 4 You can find it Yandell's textbook from 5 1997 where he's got a really nice little diagram of 6 the hematopoietic flow chart. And he points to these 7 various cells and says this is where AML occurs and 8 this is where APL occurs. And it's pointing to a 9 different place. I mean, I think that is pretty 10 well-established. 11 Q. Okay. 12 MR. KIWALA: Dr. Pyatt, I've just seen 13 that we've been going a little bit for an hour now one 14 thing I didn't tell you before we got started if at 15 any point you want to take a break, you know, please 16 ask, and we can do that. Are you ready to keep going 17 or do you want to take a break at this point? 18 THE DEPONENT: No, let's -- let's take a 19 five minute break, if you're okay with that. 20 MR. KIWALA: I'm fine with that. 21 (Recess taken, 11:24 a.m. to 11:41 a.m.) 22 Q. (BY MR. KIWALA) Dr. Pyatt, what is the 23 threshold of benzene exposure for the development of 24 AML? 25 A. Well, can we agree for this deposition 50 1 that when we talk about AML, we are talking about it 2 collectively, but we're excluding APL from that 3 classification? 4 I mean, since, really, the whole bulk of 5 my opinion is that APL is not caused by benzene, then 6 it's going to be hard for me to answer that question 7 including APL as a subtype of AML. But if you want to 8 take APL out of it and we're just going to talk about 9 all of the other forms of AML, then that will be 10 easier. 11 Q. Okay. Let's -- let's go ahead. We'll 12 take APL out of the mix. But what is the threshold 13 level of benzene exposure for the development of AML 14 with that -- with that caveat? 15 A. Thank you. I would say that the 16 scientific literature supports that the threshold 17 appears to be somewhere around 40 to 50 part per 18 million years to meaningfully statistically increase 19 the risk of developing AML. And that exposure needs 20 to have occurred sometime within, say, 15 years, 20 21 years, at the outside, prior to diagnosis. So those 22 are really the two kind of important criteria. 23 Q. Okay. Let me get that correct. It was 24 40 to 50 ppm years? 25 A. Correct. 51 1 Q. Okay. And within that exposure that had 2 to occur within 15 to outside -- well, to within a 3 total of 20 years, at the very least, of the 4 development of AML? 5 A. At the very most. 6 Q. Okay. 7 A. Yeah, 15, I think, is a reasonable 8 estimate, but it goes somewhere between 10 and 15 -9 10 and 20. So somewhere in that range, the exposures 10 need to have occurred within 20 years of diagnosis. 11 Q. Okay. What scientific or medical 12 literature do you rely on for that statement of a 13 threshold level, that range? 14 A. I rely on all of the quantitative 15 epidemiology that's been conducted for benzene and AML 16 specifically. 17 Q. Okay. Are there any studies or 18 literature that statistically point out the 40 to 50 19 ppm year in the 10- to 20-year time period, any -20 anything in the scientific literature that basically 21 states that as the threshold level? 22 MR. GOTTLIEB: Objection. 23 A. Well, I think that -- yes, there are 24 definitely studies that are more important than others 25 in terms of what they have looked at and what they 52 1 have evaluated that support my opinion with regard to 2 the quantity -- quantity and the duration. 3 Probably the most important study -- and 4 particularly in the United States, because it forms 5 the basis of all of our regulatory positioning on 6 benzene, is the pliofilm cohort. And it's pretty 7 clear that you need exposures greater than 40 to 50 8 part per million years in order to significantly 9 increase the risk. And the range is based on the fact 10 that in the original study, Bob Rinsky's study from 11 '87 looked at 40 to 200. But then there have been -12 and I think even in that study, it was something 13 greater than 200 before there was a statistically 14 significant increase. 15 But anyway, there have been at least two 16 and, perhaps, three other quantitative exposure 17 assessments of that cohort. And Mary Paxton did a 18 really nice summary of that data and put them into 19 slightly different exposure bins. And that is where 20 the 50 ppm came from. 21 Otto Wong and others argue -- and there's 22 certainly studies that support it -- that it has to be 23 as high as 200 ppm years before you have a meaning 24 fully increased risk of AML. 25 Then the pliofilm also supports the 53 1 latency argument, the 15-year latency argument. The 2 NCI China study supports that. The Health Watch study 3 supports that. It's supported by just about every 4 analysis of chemically-induced AML associated with 5 chemotherapeutic agents, radiation, smoking, et 6 cetera. So it's a very consistent cogent picture with 7 regard to the timing of exposure and the development 8 of AML. 9 Q. (BY MR. KIWALA) Okay. Now -- but you 10 say you've considered all the -- all of the relevant 11 scientific literature out there on this issue, 12 correct? 13 A. Yes, sir. 14 Q. Okay. And you find all of it valuable, 15 but you feel that the -- some -- some of the 16 literature is more important than others. In 17 particular, I believe you mentioned Paxton, Rinksy, 18 Wong in terms of arriving at the -- the range for the 19 ppm years, correct? 20 A. I think that is the clearest study, 21 because there were -- they had a nice dose response. 22 They were using pure benzene. There was reasonably 23 decent description of what these workers were doing. 24 There was not a lot of confounding chemical exposures, 25 so -- and that's the reason why OSHA bases their PEL, 54 1 the ACGIH basis their TLV. I mean, our regulatory 2 standards for benzene are based on that cohort. But 3 it is consistent with Constantini, it's consistent 4 with Rishtan and Snadder, it's consistent with Hays 5 '97, the NCI China study. I mean, all of those have 6 done quantitative analysis of benzene exposure. They 7 have all got pluses and minuses, strengths and 8 weaknesses, but it presents a consistent picture. 9 Q. Okay. If you go ahead and take a look at 10 paragraph 14 back on -- I believe it's still 11 Exhibit 3. 12 A. I'm with you. 13 Q. Okay. Let me read portions of this -14 the last full sentence of the paragraph before it 15 carries on to the next page. It states, "Potential 16 biological mechanisms for benzene-induced AML include 17 toxic disruption of regulatory processes involving 18 cell growth and differentiation, dysregulation of 19 hematopoiesis" -- did I say that correctly? 20 A. I would know what you meant if you said 21 that. 22 Q. Okay. -- "via genetic or epigenetic 23 clastogenic (chromosomes) in hematopoietic progenitor 24 cells, direct damage to the bone marrow stroma and/or 25 microenvironment or some combination of these events." 55 1 And then it goes on to say that "All of 2 these potential molecular or cellular steps would 3 likely exhibit a threshold providing a strong 4 biological rationale for the existing epidemiological 5 evidence." 6 And let me make sure I'm setting these 7 out -- these -- potential biological mechanisms, if 8 I'm reading your -- your declaration correctly, you're 9 saying it's a -- there are three potential mechanisms 10 or is there -- the fourth option is a combination of 11 those mechanisms? Do I have that correct? 12 A. Well, I mean, I -- each of these 13 processes, there could be -- there are multiple papers 14 written on them discussing various aspects. I mean, I 15 think this is a fair summary. I wouldn't say that 16 this is the only possibility that people have raised 17 or hypothesized that benzene may be doing. 18 For example, the topoisomerase II 19 inhibition argument has been raised about benzene and 20 its various metabolites. So these are ones that have 21 solid scientific documentation that these are likely 22 occurring. 23 Whether or not they are an underpinning 24 for the ultimate pathogenesis or the ultimate 25 leukemogenesis of benzene's metabolites, we don't know 56 1 that. But we know that these things are occurring. 2 Q. Okay. And, really, it's just -- my 3 question was really just about the -- the comma usage. 4 I just want to make sure that -- I guess there are -5 you say several potential mechanisms, but the -- the 6 mechanisms are grouped, so the mechanisms -- I think 7 you can summarize into three separate ones; is that 8 correct? Is that -- do that I have correct? 9 A. Let's see. So you've got growth and 10 differentiation, dysregulation of hematopoiesis, 11 various sources, that's second. Cytogenetic 12 abnormalities. Perhaps genotoxic effects, that would 13 be third. 14 Q. Okay. 15 A. Potential damage to the bone marrow. The 16 microenvironment that maybe plays a role. So in terms 17 of groupings, I think there are four -18 Q. Four? 19 A. -- or some definition of the various 20 things that are in there with the caveat that we 21 really don't know today how benzene does what it's 22 doing. 23 Q. Okay. Let's go to the -- the toxic 24 disruption of regulatory processes involving cell 25 growth and differentiation. You say that that would 57 1 likely exhibit a threshold. What specific literature 2 are you relying on for that statement? 3 A. Well, you could look at some of my work 4 and Patrick Kerzic's work looking at TNF alpha 5 dysregulation, which could very well be important, and 6 it's clearly a threshold. You could look at Rich 7 Iron's work. He published in '92, published it again 8 in '96 regarding GM-C SF dysregulation. We looked at 9 AP-1 alterations. Dave Ross looked at reactive oxygen 10 in various transcriptional regulatory elements that 11 have to do with hematopoiesis and how these cells 12 behave. And in all of this in vitro experimentation, 13 there was clearly a threshold. There were doses below 14 which nothing was happening. 15 So if those are playing a role in 16 leukemia, then there's going to be doses of benzene 17 that are not going to be leukemogenic because they are 18 not capable of causing these types of disregulatory 19 events. 20 Q. Okay. And I think -- what was the -21 going back to that -- that sentence, the second 22 grouping, dysregulation of hematopoiesis -- I'm going 23 to mess that word up all day -24 A. Hematopoiesis. 25 Q. Hematopoiesis. Thank you. 58 1 A. Yes. 2 Q. -- dysregulation of hematopoieses via 3 genetic or epigenetic -- I'm sorry, is that -- do I 4 have that right? 5 A. Yes, epigenetic, correct. 6 Q. All right. What specific literature are 7 you relying on for your statement that the 8 dysregulation of hematopoiesis via genetic or 9 epigenetic would likely exhibit a threshold? 10 MR. DETHERGE: I think you might correct 11 that, Ryan. The sentence goes on. 12 MR. KIWALA: Clastogenic damage? 13 MR. DETHERGE: Right. 14 Q. (BY MR. KIWALA) I'm sorry. Is that part 15 of the same -- that's why I'm getting confused on 16 these commas. 17 A. Well, I didn't, perhaps, write it that 18 clearly. I mean, the genetic would certainly be -19 the most common one that people have written about are 20 clastogenicity or chromosomal damage. And there's 21 in vitro studies, there's animal studies, there's 22 occupationally exposed workers who were healthy. 23 There are studies looking at people who actually have 24 disease and what their diseases look like. 25 So there's a lot of data associated with 59 1 that. The epigenetic simply means that it's having 2 something to do perhaps with the DNA, like methylation 3 status, or other things, that's not directly 4 interacting with the specific DNA sequence. That is 5 not completely separate from the first grouping. I 6 think there's going to be some overlap there. 7 So George Kalf has done some of this 8 work, Rob Snyder has done some of this work, Steven -9 well, his is a little different. Martin Smith has 10 done -- I mean, there's a lot -- there's a lot of 11 literature to support all of these. 12 Q. And the work that you describe there, you 13 say that is -- those works support your statement that 14 the -- that the process would likely exhibit a 15 threshold? 16 A. Right. That when you look at the data, 17 there are doses below which you don't see anything 18 occurring. So to the extent -- I mean, you can always 19 argue -- you know, this notion of a threshold can turn 20 into a theological argument pretty quickly because you 21 just get out of where there's any data to support it. 22 But -- I mean, so the argument is, well, yeah, but 23 your assays weren't sensitive enough to detect 24 changes. You know, I can't disprove that, but the 25 fact remains when you look at these studies and you 60 1 look at these mechanisms that there are doses below 2 which you don't see any kind of alterations. And Dick 3 Albertini and others, you know, really smart guy, 4 really well-respected, he thinks that even a genotoxic 5 mechanism, which Milman pointed out as one that is 6 clearly not going to have a threshold, that's 7 incorrect. 8 You look at the radiation data, you look 9 at some of the mechanisms about how chemicals actually 10 damage DNA, and when you look at the precise 11 mechanism, even then you're going to -- you're going 12 to see a threshold. You're going to see doses that it 13 takes a certain amount to cause these kinds of 14 changes. 15 Q. Okay. Now you've mentioned names. Are 16 there any specific studies that you can cite to in 17 support for that statement? 18 A. Well, I mean, I gave you authors in terms 19 of specific studies. No, I'm not -- I don't have them 20 all memorized, so I can't give you dates, but -21 Q. Are any of them cited in your -- in your 22 declaration -- do you have any notes at the back? In 23 particular at the end of paragraph 14, you mention end 24 notes No. 36 and then 38 through 45. 25 A. Okay. 36 is a good one. And what are 61 1 the other ones? 38? Okay. That's an epidemiology 2 study, so was Aksoy, but I think it supports. 40 is 3 Irons '92 paper, which I talked about. 41, 42, those 4 are Mary Paxton's analysis. So this is kind of a 5 combination up to 45. So Rinsky, Rushton, Wong, those 6 are more of the epidemiology. So it looks like there 7 were only two cites in there that talk about these 8 potential mechanisms. 9 Q. Let's move on to the -- the next one in 10 the group on paragraph 14. Do I have this correct, 11 it's damage in the hematopoietic progenitor cells? Is 12 that the next one of the four? 13 A. Well, that's associated with the 14 clastogenetic damage, so that's the chromosomal thing. 15 And Rich Irons published in the '80s that hydroquinone 16 and/or para-Benzoquinone's ability to disrupt 17 microtubule formation, which is required for 18 chromosomal separation, is clearly a threshold. It is 19 a stoichiometric process. And you have to have a 20 certain amount of hydroquinone before you can start 21 seeing those changes. 22 So that is clearly -- you can argue that 23 that's not playing a role, but you cannot argue that 24 there will not be a threshold for those kinds of gross 25 chromosomal abnormalities that you can see in 62 1 benzene-exposed cells. Or -- you know, by benzene, I 2 mean the metabolites. 3 Q. Okay. And the next one there was direct 4 damage to the bone marrow stroma? 5 A. I think Dave Ross has published some 6 papers on that. George Kalf has published some papers 7 regarding cytokine disruption. Even the one that I 8 mentioned that Patrick Kerzic published with regard to 9 TNF alpha, that's going to be part of this 10 microenvironment. 11 It's associated with the fact that most 12 evidence suggests that leukemias and other hemopoietic 13 malignancies do not arise in isolation. They arise 14 within the bone marrow stroma or their 15 microenvironment. And that microenvironment likely 16 plays some role in the pathogenesis of the disease. 17 So it is conceivable that damage to the 18 microenvironment to the bone marrow stroma, or 19 whatever, is an integral part of the leukemogenic 20 process. 21 Q. Okay. Is there -- what specific studies 22 are out there that suggest that direct damage to the 23 bone marrow stroma and the microenvironment would 24 exhibit a threshold? 25 A. Well, just sitting here right now, I 63 1 would have to say George Kalf's work and, maybe, some 2 of David Ross's studies. 3 Q. Okay. But there's no specific references 4 to the literature you can give to me today? 5 A. No. 6 Q. Okay. 7 A. And it wasn't in the ones that I 8 referenced in that statement. 9 Q. Okay. If you do -- I would ask that if 10 you could go back and find the -- the specific studies 11 that you used to rely on the statement that all of 12 these cellular and molecular steps would likely 13 exhibit the threshold, if you could collect those and 14 maybe give those to counsel so that they can be sent 15 along to the plaintiff's counsel. 16 MR. DETHERGE: Ryan, that's certainly 17 something we can talk about as counsel. I suspect 18 there are things that went both ways. So as long as 19 we have some mutuality in that kind of work, we can 20 discuss it. 21 MR. KIWALA: Okay. I mean, we can 22 discuss that later. 23 Q. (BY MR. KIWALA) But, Dr. Pyatt, would 24 you be amenable to doing something like that? 25 A. Sure. I don't have a problem with that. 64 1 Sitting here talking to you about it, I probably 2 should have had some more references in this 3 paragraph. No one has ever argued with me about it 4 before. You're the first person who has, you know, 5 questioned me on this paragraph. And now, for future 6 reference, I will certainly have some more citations 7 there. 8 Q. It pleasures me to be the first. Let's 9 see. Let's move along. Before I move along, 10 actually, let's go back -- before we got into the 11 discussion of benzene and the threshold for the 12 capacity to cause AML, we talked about excluding APL 13 from -- from the definition of AML. 14 Do the -- do any of the studies that you 15 relied on for your statement that there is a threshold 16 for the development of AML from benzene exposure -- do 17 any of those studies separate out APL from the 18 analysis? 19 A. Well, most of the mechanistic work that 20 we discussed, this was done in bone marrow cells and 21 peripheral lymphocytes and cell lines and things that 22 people are using. 23 Q. I'm sorry. What I meant was the -- the 24 epidemiological studies that -25 A. Okay. 65 1 Q. -- you discussed, you know, the works 2 particular by Paxton, Rinsky, Long, any of those, did 3 any of those separate out -- exclude APL from the 4 analysis? 5 A. The -- the Rinsky -- the pliofilm 6 analysis did not specifically address APL, even though 7 at that time it was a recognized clinical entity, but 8 it would -- did not appear on any birth certificates. 9 So you could either -- sorry -- death certificates. 10 So you could either argue that there were none or that 11 the pathologist or funeral director, or whoever filled 12 out the death certificates, didn't know or didn't 13 write it down. 14 So within that cohort, there -- there is 15 no evidence that it exists, but I can't definitively 16 say there wasn't one. The Long analysis seemed to be 17 in that list, and he -- he separate -- well, it would 18 be the same argument, because he looked at AML only. 19 And I think maybe one of those could potentially have 20 been APL just based on the limited information that 21 was present. 22 In the NCI China study, while the 23 analysis of the cumulative exposures and the risks 24 associated with those cumulative exposures, they used 25 ANLL of which APL would have been part of that overall 66 1 discussion and overall calculation, but they also did 2 separate out the various subtypes and made mention of 3 the M3 subtype that -- that was in that cohort. 4 So those investigators didn't make a 5 quantitative evaluation, but at least made a 6 qualitative separation of the various subtypes. 7 Q. So just to recap, the study that -- the 8 epidemiological study that you're relying on for your 9 statement for a threshold for the development of 10 benzene-induced AML, they all include -- none of them 11 exclude specifically APL, correct? 12 MR. GOTTLIEB: Objection. 13 A. None of them specifically exclude APL, 14 no. 15 Q. (BY MR. KIWALA) Okay. But in your 16 statement of your opinion as to what the threshold for 17 -- the threshold level for benzene-induced AML, in 18 this case, you are excluding APL from that definition, 19 correct? 20 A. Well, I just didn't want it to be 21 mistaken where you're asking me questions about AML, 22 and then somehow that gets turned around to say that I 23 support that all forms of AML are caused by benzene. 24 Since this is an APL case, and I've made 25 that pretty clear, that's important to my opinion. I 67 1 just wanted the record to be clear that when I'm 2 talking about AML in a general sense, I am not talking 3 about APL as part of that grouping. 4 Q. Okay. Just as a general question, is it 5 your opinion that before reaching a conclusion about 6 whether or not benzene exposure is capable of causing 7 APL, one must consider all of the available literature 8 on the topic of benzene exposure and it's relationship 9 to APL? 10 MR. GOTTLIEB: Objection. 11 A. Could you say the first part of that 12 again? 13 Q. (BY MR. KIWALA) Sure. Is it your 14 opinion that before reaching a conclusion about 15 whether or not benzene exposure is capable of causing 16 APL, one must consider all of the available literature 17 on the topic of benzene exposure and its relationship 18 to APL or its potential relationship to APL? 19 MR. GOTTLIEB: Objection. 20 A. Of course. I mean, I think you've got to 21 evaluate the data that's relevant to your opinions. 22 MR. DETHERGE: Hey, Ryan, can we 23 stipulate to that on both sides? 24 MR. KIWALA: I'm just going to move on. 25 Q. (BY MR. KIWALA) Have you considered all 68 1 of the available literature on the topic of benzene 2 exposure and its relationship to APL in reaching the 3 opinions to which you're testifying today? 4 A. As far as I know, I have looked at and 5 carefully considered every piece of data that is in 6 the published literature that addressed the potential 7 relationship between benzene and APL. I mean, I can't 8 rule out the possibility that there's some obscure 9 journal somewhere that's published something that I've 10 never seen; but every study that discusses this, to my 11 knowledge, I have evaluated and have with me. 12 Q. Okay. Let's take a look at paragraph 15. 13 And in paragraph 15, you mention the NCI China study. 14 And did that study report an increase in APL among 15 benzene-exposed workers? 16 A. No. 17 Q. Okay. And one of your criticisms of this 18 study is it failed to account for the potential use of 19 -- I believe it's called bimolane? 20 A. That's what it's called, yes. 21 Q. And you state "Bimolane was widely used 22 in China as a treatment for psoriasis and is an 23 established epidemiological risk factor for the 24 development of AML." 25 A. APL. 69 1 Q. I'm sorry, "APL." 2 A. Correct. 3 Q. Now, does that mean that bimolane is 4 established as being capable of causing APL? 5 A. Yes. 6 Q. Okay. 7 MR. KIWALA: Teresa, if you could go 8 ahead and mark the article. It's entitled 9 "Translocation" -10 (Deposition Exhibit 6 was marked.) 11 MR. DETHERGE: Hang on, Ryan. Can we see 12 what you've marked? 13 THE DEPONENT: I have it, too. I have a 14 copy of it, if you want to look at that one. In fact, 15 I think that's my reference 49. It is. Yeah, it's 16 reference 49 in my declaration. Okay. I'm looking at 17 it. 18 Q. (BY MR. KIWALA) Okay. Going back to 19 paragraph 15 on Exhibit 3, you state, "Bimolane was 20 widely used in China as a treatment for psoriasis and 21 is an established etiologic risk factor in the 22 development of APL." And then you specifically cite 23 this article, No. 49, correct? 24 A. Yes. 25 Q. Okay. In this article, can you tell me 70 1 what was the reported relative risk for 2 bimolane-induced APL? 3 A. Not sitting here. Let me look through 4 it. I'm not seeing it. I thought they had 12 out of 5 24 cases. So their first report was 14 cases of 6 therapy-related AML caused by bimolane with 8 cases of 7 M3 and 4 of M2. So that was their earlier study. 8 Q. Well, let me -- let me ask you, 9 Dr. Pyatt, what kind of quantitative epidemiological 10 study is Exhibit 6? 11 A. It looks like this study is a case 12 report. 13 Q. Okay. So it's a case report and not a 14 cohort study or a case-controlled study, correct? 15 A. This particular one is, yes. 16 Q. Okay. And the -- the other -- earlier 17 study that you mentioned -- let's see, it's -- on 18 here, it's page 109 at the top right-hand corner 19 beginning at -- it mentions 14 cases of t-AML caused 20 by bimolane therapy for psoriasis in 1992, and it 21 references No. 5. Do you know if the -- that article 22 reference in No. 5, what kind of quantitative 23 epidemiological study is that? 24 A. I -- I don't know sitting here, but hold 25 on a second. I think I have it. I guess this would 71 1 be best classified as a case series. 2 Q. Okay. So it would be a collection of 3 case reports, basically, correct? 4 A. Well, it's not a collection of case 5 reports, but it's a series where they are just 6 reporting the 14 or 15 cases that they conducted or 7 that they did this evaluation on. So it's not a 8 collection of independent case reports. 9 Q. Okay. But at any rate, it's not a 10 quantitative epidemiological study, is it? 11 A. It doesn't appear to be, no. 12 Q. Okay. Are you aware of any quantitative 13 epidemiological studies that report a positive 14 association between -- positive association between 15 exposure to benzene and APL? 16 A. I don't know. I don't have it -- I don't 17 have it with me. 18 Q. Okay. I would ask that if you do conduct 19 a search and are able to find any that you would pass 20 those along to defense counsel so they can be, in 21 turn, passed on to plaintiffs' counsel. 22 A. Sure. That's fair. 23 MR. DETHERGE: Subject, obviously, to the 24 same discussion we had earlier, Ryan, about follow-ups 25 being mutual on both sides, right? 72 1 MR. KIWALA: Okay. 2 MR. DETHERGE: To be discussed between 3 the lawyers. 4 MR. KIWALA: We can -- we can discuss 5 that off the record. 6 Q. (BY MR. KIWALA) But let me -- let me get 7 back -- is it your -- it is your testimony today that 8 consistently positive results obtained from 9 quantitative epidemiological studies are necessary to 10 reach a scientifically sound conclusion about 11 causation, correct? 12 A. That's certainly a very important 13 feature, yes. 14 Q. And you stated in your report that 15 bimolane is an established cause of APL, correct? 16 A. I did. 17 Q. But as you sit here today, you're not 18 able to cite for me a single quantitative 19 epidemiological study finding a correlation between 20 bimolane exposure and APL, correct? 21 A. I'm not able to point you to a 22 quantitative epi study, I agree with that, and would 23 change the wording of this paragraph or change the 24 wording of this sentence. I just had not read those 25 studies carefully enough. I mean, it's pretty 73 1 compelling data, the number of cases that they saw; 2 but you are correct, it is not a quantitative study. 3 Q. Based on those -- well, I guess, 15 4 individual cases, would you say it's sound enough 5 evidence to reach a conclusion about causation as to 6 bimolane and APL? 7 MR. GOTTLIEB: Object to form. 8 A. I would say that it's -- it's consistent 9 with our understanding of that drug, and those two 10 reports are very consistent. It actually -- it's kind 11 of like what you were asking me about earlier, it's 12 going to be hard to repeat it, because bimolane is not 13 used anywhere else other than in China. And once 14 these case reports or studies came out, that was 15 sufficient for the medical community in China to stop 16 using this drug to treat psoriasis. So it was 17 certainly compelling enough evidence for them, but you 18 -- you are correct in your question. 19 Q. Okay. Let's move along to paragraph 17. 20 A. Okay. 21 Q. You state in your report at paragraph 17 22 that "There is no reliable scientific evidence that 23 the (15;17) translocation is related to benzene or any 24 other occupational exposure," correct? 25 A. Yes. 74 1 Q. And have you considered all of the 2 relevant scientific literature on the topic of the 3 t(15;17) and its possible relationship to benzene 4 exposure? 5 A. I think I've considered all of the 6 scientific data. I mean, I can always be proven 7 wrong, but I think I've looked at everything that has 8 to bear on that topic. 9 Q. Okay. And do you agree with the 10 statement that benzene is clastogenic and is capable 11 of breaking and rearranging chromosomes? 12 A. Well, I certainly agree with the 13 statement that benzene is clastogenic. And by 14 benzene, we're all talking about the metabolites. 15 That's fine. I mean, I certainly agree with that. 16 And that has been known for as long as we've known 17 about human chromosomes. And the breaking part seems 18 to be pretty clearly documented. The last part of 19 your question, the translocations, that's a little 20 harder to answer; and there's certainly a lot less 21 data to support that. 22 Q. I think I heard you mention this earlier, 23 but I'll ask you now just to make sure. Are you 24 familiar with the substance called topoisomerase II? 25 A. Yes, very familiar with that. 75 1 Q. Okay. And can you explain what it is and 2 what its function is inside the cell? 3 A. Topoisomerase II is an enzyme. It's 4 found in the nucleus. It's involved in the -- the DNA 5 is wound up pretty tightly when it's inside of 6 chromosomes. The double helix, which everyone knows 7 about, and then it's wrapped around histones and -- it 8 doesn't matter, but it's wound up very tightly, so 9 tightly that it's not possible to replicate the DNA 10 when it's in that state. So it has to unwind the DNA 11 in order for the DNA to replicate and in order for the 12 cell to divide. In order to divide, it has to 13 replicate the DNA. And topoisomerase is the enzyme 14 that clips the DNA, allows it to unwind during the 15 replication process, and then reanneals the two ends 16 so that you then have a solid DNA strand again. So 17 it's an important enzyme in DNA replication and 18 cellular division. Does that help? 19 Q. Yes. Are you familiar with the group of 20 substances known as topo II inhibitors? 21 A. Yes, sir. 22 Q. And can you explain what they are and 23 what they do? 24 A. Well, topo II inhibitors -- it's a broad 25 classification, but essentially you're talking about 76 1 drugs that -- chemicals that inhibit the enzyme 2 topoisomerase II and prevent the cell from replicating 3 its DNA and, therefore, prevents the cell from 4 dividing. So topo II inhibitors will cause cells to 5 die that are trying to divide in its presence. 6 Q. Now, is there actually -- there are two 7 kinds of topo II inhibitors, is that correct, or two 8 classifications? Would that be correct? 9 A. There are at least two. 10 Q. Okay. And from what I've seen, there are 11 -- there's a group called catalytic inhibitors and 12 then also a group called topo II poisons? 13 A. That's correct. 14 Q. Okay. Can you explain the difference 15 between those two? 16 A. In general terms, catalytic inhibitors 17 means that it's inhibiting the enzyme in a catalytic 18 fashion. It seems to happen before the enzyme has an 19 opportunity to bind to DNA. So it doesn't allow for 20 the formation of cleavable complexes, which is a side 21 effect of this process, whereas topo II poisons do 22 allow for the formation of these cleavable complexes 23 and poisons the enzyme wherever it is in its catalytic 24 cycle, is my understanding. 25 Q. Are you aware of any studies that show 77 1 that topo II inhibitors induce APL? 2 A. There are a class of topo II inhibitors 3 of which bimolane is an example that are thought to be 4 able to cause the (15;17) translocation and cause APL. 5 Q. Okay. So I think you've answered that 6 question also. The next question I was going to ask, 7 are you aware of any studies linking exposure to 8 topo II inhibitors linking those to that translocation 9 (15;17)? And I take it your answer to that question 10 would be yes? 11 A. Well, they are the same. (15;17) is APL. 12 APL is (15;17), so they are essentially synonymous. 13 Q. Now, you mentioned this before, but just 14 to be clear, would you agree that it's not generally 15 believed in the scientific community that benzene 16 directly triggers DNA damage, but, rather, it acts 17 through a series of metabolites? 18 A. It has been very well-established through 19 a series of nice experiments that benzene has to be 20 metabolized in order to be toxic, however you want to 21 define toxicity. 22 Q. Okay. And are you aware of any studies 23 that show benzene metabolites act as topo II 24 inhibitors? 25 A. Let me just add one other thing to the 78 1 earlier question. 2 Q. Sure. 3 A. High-dosage exposure to benzene has 4 narcotic effects, just like any type of organic 5 solvent. By high dose, I'm talking thousands of ppm. 6 And that probably is independent of any type of 7 metabolism. 8 Q. Okay. 9 A. So when I said it has to be metabolized 10 to be toxic, that wasn't complete. All right. Then 11 the next question is various phenolic metabolites of 12 benzene have been reported under very controlled 13 experimental conditions to inhibit topoisomerase II. 14 Q. Okay. 15 MR. KIWALA: And, Teresa, if you could go 16 ahead and mark the last document. 17 (Deposition Exhibit 7 was marked.) 18 MR. DETHERGE: What is Exhibit 7, Ryan? 19 MR. KIWALA: Why don't we hand it to -20 A. This is a paper I published with Rich 21 Irons and David Kroll where we were looking at the 22 mechanism by which benzene metabolites could inhibit 23 this enzyme. 24 THE DEPONENT: Would you mind if I just 25 take a really quick break? It won't take but just two 79 1 minutes. Is that okay? 2 MR. KIWALA: We can take a two-minute 3 break. 4 (Recess taken, 12:29 p.m. to 12:31 p.m.) 5 THE DEPONENT: So did I answer your -- is 6 there a question pending or where are we? 7 Q. (BY MR. KIWALA) I think you answered 8 what the article is, right, and what it is is an 9 article that you co-authored with some other 10 individuals a few years back, correct? 11 A. Yes, specifically dealing with 12 metabolites of benzene and its ability to inhibit 13 topoisomerase II. 14 Q. Okay. If you take a look at -- it's 15 marked as page 832 on the top left-hand corner. 16 A. The gels, the actual data? 17 Q. Well, I just want to make sure you've got 18 the correct page. 19 A. Yeah, I'm on page 832, top left are three 20 gels. 21 Q. And I want you to take a look at actually 22 the second-to-last paragraph before you get to the 23 acknowledgment. 24 A. Okay. 25 Q. First -- the first sentence of that 80 1 paragraph. 2 A. Okay. 3 Q. And it says, "In contrast to these topo 4 II poisons, benzene metabolites and their 5 peroxidase-activated congeners appear to inhibit 6 topo II via a distinct and upstream mechanism." 7 Does that mean that you include benzene 8 in that first group the catalytic inhibitors? 9 A. In what first group? 10 Q. Well, we mentioned there are two kinds of 11 topo II inhibitors, the catalytic inhibitors and then 12 the topo II poisons, correct? 13 A. Generally speaking, yes. And I think the 14 answer to your question would be that that is somewhat 15 debatable in the scientific literature; but, yes, that 16 is -- that seems to be the case. 17 Q. At any rate, is that what you say in -18 in the article here? 19 A. Well, I don't -- yes, classified as 20 catalytic inhibitors of topo II similar to those 21 described as these other drugs. 22 Q. Are you aware of any studies done in the 23 literature that show -- are you aware of any studies 24 in the literature that show metabolites of benzene to 25 be topo II poisons? 81 1 A. Oh, I think that's what Neil Osheroff 2 said. I mean, he basically said that we had -- based 3 on these clearly defined or specifically defined 4 experimental conditions, we had too much of a reducing 5 agent in our assay, and that's why we didn't see the 6 cleavable complex formation, and that he was able to 7 demonstrate cleavable complexes in his assay. So I 8 think that's what Neil Osheroff said, but I'm not -9 I'm not positive. I know that David Eisman, early -10 and he was the first one that kind of got into this 11 area back in the '80s. I know that's what he believed 12 is that it was acting just like a topocide. 13 Q. All right. Let's move on to paragraph 14 18. And you mention there the concept of comparative 15 inhibition. 16 A. Yes, sir. 17 Q. Can you explain what that concept is? 18 A. It is a well-characterized phenomenon. 19 It occurs with lots of chemicals. But for this 20 particular instance, since benzene has to be 21 metabolized in order to be toxic, it's being 22 metabolized. Its first oxidation step is occurring 23 through an enzyme called cytochrome P450 2E1. And if 24 you are exposed through other chemicals that are also 25 being oxidized by that enzyme, then the enzyme is busy 82 1 basically metabolizing the other chemicals and it is 2 less efficient at metabolizing benzene. 3 So by co-exposure to toluene or xylene or 4 any aromatic hydrocarbon that's going through the 2E1 5 pathway, ostensibly that will reduce benzene's 6 metabolism and, therefore, reduce benzene's toxicity. 7 Q. Okay. And in preparing your report 8 today, have you considered all of the available 9 literature on the topic of competitive inhibition 10 specifically as to toluene's competitive inhibition 11 metabolism of benzene? 12 A. I'm very familiar with that literature. 13 With regard to -- yes, I've -- I've evaluated that 14 literature. 15 Q. Okay. Are you aware of any studies that 16 have shown that low-dose levels of exposure, toluene 17 exposure, can enhance the metabolism of benzene? 18 A. I'm not aware of any that shows that 19 low-dose exposure to toluene enhances the metabolism 20 of benzene, no. 21 Q. Well, let me rephrase that question. 22 Low-dose levels -- let's say -- and, obviously, you 23 would have to have a mixture of both toluene and 24 benzene, or whatever you're being exposed to. Given 25 that situation, low-dose levels of such a mixture that 83 1 the toluene, you know, in the solution actually 2 enhances the metabolism of benzene or increases the 3 metabolism of benzene? 4 MR. GOTTLIEB: Object to form. 5 A. Yeah, I don't know of any that would 6 indicate that toluene would change the metabolism rate 7 of benzene. 8 Q. (BY MR. KIWALA) Let's move to paragraph 9 21 on Exhibit 3. 10 A. Okay. And before I move on, what I meant 11 by change the metabolism of benzene, increase it the 12 way that you were -13 Q. Okay. 14 A. -- you were asking your question, because 15 we were just talking about how well it could be 16 changed going the other direction. All right. 17 Paragraph 21. 18 Q. Now, in this paragraph, you mention there 19 is -- there's some older literature that suggests that 20 toluene was toxic to the -- I'm going to mess it up 21 again -- hematopoietic system and bone marrow, but the 22 same toxic effect has not been found in more recent 23 studies. Is that correct? 24 A. Yes. 25 Q. And you also mention a possible 84 1 explanation of the -- there have been significant 2 reductions in the benzene concentrations in toluene 3 and other petroleum-based solvents. Do you see that? 4 A. Yes. 5 Q. What specifically do you rely on for your 6 statement that there have been significant reductions 7 in the benzene concentration in toluene and other 8 petroleum-based solvents? 9 A. Well, that's pretty general knowledge, 10 but which ones do I have here? Significant reduction 11 of benzenes -12 Q. Is there anything that documents that, 13 anything in the literature that you can rely on? 14 A. The ATSDR tox profile for toluene. 15 That's one that I relied on. IARC, that Volume 69. 16 The toxicology of toluene. The ones that I put in 17 here, and that's just -- everyone knows that. And the 18 levels of toluene -- the levels of benzene that were 19 in toluene in the '50s and '60s in some of these 20 cruder preparations are -- there's orders of magnitude 21 more benzene in those than with the better 22 distillation processes. In the hydro treatment of 23 toluene in today's refineries, there's virtually no 24 benzene left in the toluene. So that's a pretty 25 commonly accepted premise. 85 1 Q. Do you have any expertise in refining 2 processes? 3 A. I don't know. What do you mean by 4 expertise? I'm familiar with what they do. I've 5 visited a couple. I'm not a refinery petroleum 6 engineer. I know you can look at the MSDS sheets for 7 any toluene that you can purchase now and you can 8 compare those with the historic levels that were 9 reported back in the '60s. And it's clear that there 10 is much less benzene in that product than there used 11 to be. 12 Q. But as far as -- as far as anything 13 reported in the literature that you're citing in 14 support of this statement, there aren't any statements 15 that effect -16 MR. DETHERGE: Asked and answered. He 17 just gave you the support for it, Ryan. 18 MR. KIWALA: I'm asking him if there's 19 anything that he cited in this literature. 20 MR. DETHERGE: He referenced the 21 literature. If you want to go back and pull out those 22 studies and go line by line through them or those 23 references. 24 MR. KIWALA: I'm just asking if he knows 25 if it makes any mention. 86 1 A. I'm -2 MR. DETHERGE: Without going back to the 3 document, you're asking if you by memory he can 4 remember a particular line or phrase in there? 5 A. I don't have the ATSDR documentation for 6 toluene, but I could get it. And my recollection is 7 it -- it discusses this very topic. 8 Q. (BY MR. KIWALA) And that's the ATSDR for 9 toluene? 10 A. Correct. 11 Q. Okay. Okay. Let's move along. Are you 12 familiar with the IARC evaluation of formaldehyde? 13 A. IARC's evaluation of formaldehyde? I've 14 read it. I mean, I don't have it memorized, but I've 15 read it. 16 Q. Do you happen to have that with you in 17 the materials that you brought with you today? 18 A. It's possible. Hold on. No, I brought 19 all of the epidemiology. I have another binder that 20 has the regulatory documents for formaldehyde, and I 21 didn't bring that. I have all of the studies, but not 22 that particular document. 23 Q. Well, in your report -- I believe it's in 24 the second declaration, the one dated July 9, if you 25 could go ahead and take a look at that. 87 1 A. Okay. I have it. 2 Q. And in there, you note that "There are 3 numerous studies of embalmers, anatomists, 4 pathologists and other professions where formaldehyde 5 was used. These studies reported increases, decreases 6 or frequently no effect on the risk of leukemia 7 associated with these various occupations." 8 A. Correct. 9 MR. GOTTLIEB: Ryan, where are you 10 reading? 11 THE DEPONENT: First page. 12 MR. KIWALA: First page. 13 THE DEPONENT: First paragraph, six lines 14 down. 15 A. Yes. 16 Q. (BY MR. KIWALA) Okay. Now, do you know 17 how many of those studies found excess mortality for 18 leukemia? 19 A. A number? No, not without going back and 20 counting them up. 21 Q. Okay. And one of your criticisms of the 22 studies is generally that there's almost complete 23 lack-of-exposure information, correct? 24 A. Well, I'm not sure that I would call that 25 a criticism. It's just an observation. That's just 88 1 what they were doing. It would only be a criticism if 2 someone was trying to say that the findings in these 3 studies are specific to formaldehyde. That would be a 4 reach. 5 Q. Okay. And in your declaration, you 6 mention three particular large cohort studies that you 7 identify as being of some importance, correct, on the 8 discussion of whether or not formaldehyde is capable 9 of causing leukemia or APL? 10 A. I'm -- where are you? 11 Q. Well, I would look at the top of -12 A. Page 2? 13 Q. -- page 2. 14 A. The large cohorts. Okay. Yeah, to date, 15 there have been three. Yes, okay, I'm with you. 16 Q. Okay. And one of the studies you 17 mentioned is -- well, you mentioned there's the NCI 18 study and its update, the NIOSH study of the garment 19 workers and its update, as well as the MRC study of 20 British chemical workers. Those are the three cohort 21 studies, right? 22 A. Correct. 23 Q. Do you know in the -- in the NCI study, 24 what -- what was the exposure information that was 25 supplied in that study? 89 1 A. I don't understand your question. 2 Q. How could they -- the -- the people -3 individuals that were reviewed in that study, in that 4 cohort, how were they assigned, you know, a level of 5 exposure? 6 A. Which -- I mean, I've got them here. 7 They basically looked at several different exposure 8 metrics. They looked at peak, they looked at 9 cumulative, intensity. I think those were the three 10 big ones. Average intensity, peak exposure. 11 Cumulative is in there somewhere. Yeah, those were 12 the three. I think that's true for both of them, 13 Hauptmann as well as the Beane-Freeman update. Is 14 that your question? 15 Q. Well, what I'm -- I guess what I'm trying 16 to get at, how did they assign -- my understanding of 17 that study of the cohort, they assigned each 18 individual a particular level of exposure; is that 19 correct? 20 A. I -- I don't -- I don't know that much 21 detail about it. I mean, I suspect that would be 22 discussed in the methods, if you'd like to find it; 23 but I can't answer that just sitting here. 24 Q. Okay. Would the same be true for the 25 NIOSH study, the garment workers? 90 1 A. How they went about attributing -2 Q. Attributing the level of exposure for any 3 individuals in that study. 4 A. At that level of detail, yes, I would 5 have to go back and specifically read to find that. 6 Yes, I didn't put it in my report. 7 Q. And when -- would the same be true of the 8 MRC study, the British chemical worker, you don't 9 know, as you sit here today, how they went about in 10 that cohort to assign a particular level of exposure 11 for the individuals who were in that cohort? 12 A. No. 13 Q. Okay. Are you familiar with IARC's 14 conclusion about the -- whether or not there is a 15 causal association between occupational exposure to 16 formaldehyde? 17 A. You cut out there. 18 Q. I'm sorry. Are you aware of what -- I'm 19 sorry. I'm getting a significant back -- let me go 20 ahead and restate it. 21 Are you aware of what IARC concluded 22 about the causal association between occupational 23 exposure to formaldehyde and leukemia? Are you 24 familiar with what their conclusion was in the 25 evaluation? 91 1 A. Not word for word, no. 2 Q. Okay. Can you tell me generally what 3 they stated? 4 A. As I recall, I believe they said that 5 there was evidence of an association, but the lack of 6 biologic plausibility rendered them unable to -- I 7 don't -- I mean, they said there was some evidence, 8 but the lack of a biologically plausible mechanism 9 didn't make sense to them. So that's a big 10 paraphrase. 11 Q. If their conclusion was that there is 12 strong evidence of causal association with 13 insufficient evidence of causal -- a strong but 14 insufficient evidence of a causal association between 15 occupational exposure to formaldehyde and leukemia, 16 would you agree with that statement? 17 MR. GOTTLIEB: Object to form. 18 A. I -- what do you mean? Would I agree 19 that that's true or would I agree that that's what's 20 in the IARC document -21 Q. (BY MR. KIWALA) Let's just take it as a 22 general statement. Would you agree that there is 23 strong but insufficient evidence of a causal 24 association between occupational exposure to 25 formaldehyde and leukemia? 92 1 A. Well, there is certainly suggestive 2 evidence. So I mean it's not uniformly negative, 3 which is why it is still an ongoing issue. 4 The studies, for example, the NCI, which 5 are probably the most important, are very inconsistent 6 with a lot of the other literature, and really even 7 inconsistent within themselves. And the terminology 8 leukemia is a very general classification. And that 9 makes it really hard to try to -- to understand what 10 this data is telling you. When they break out the 11 various forms of leukemia, then those associations 12 become even weaker. In fact, in the latest one, the 13 strongest association was with multiple myeloma and 14 Hodgkin's lymphoma and not leukemia at all. So, no, I 15 don't think I would agree with that -- that 16 interpretation of the literature as it stands right 17 now. 18 Q. In your opinion, would it be 19 scientifically unsound or speculative to conclude from 20 all of the available scientific literature that 21 formaldehyde exposure is capable of causing leukemia? 22 MR. GOTTLIEB: Object to form. 23 A. Leukemia as a general classification? 24 Q. (BY MR. KIWALA) Yes. 25 MR. DETHERGE: As in any type of 93 1 leukemia? 2 MR. KIWALA: That is correct. 3 A. I -- yes, I think that would be overly 4 speculative to take the position that formaldehyde can 5 definitively cause any type of leukemia. But like I 6 said, there is certainly some positive evidence in the 7 literature that something might be going on with some 8 form of hemopoietic malignancy, but there's just no 9 consistency there. 10 Q. (BY MR. KIWALA) Okay. So it would be 11 unsound and speculative to draw that conclusion from 12 the available scientific literature, correct? 13 MR. GOTTLIEB: Objection. 14 A. I didn't say it would be unsound. 15 Q. (BY MR. KIWALA) Oh, I'm sorry. 16 A. I think that the scientific literature, 17 as it exists right now, is insufficient to -- to form 18 a definitive opinion on causation. 19 Q. Okay. I'm going to ask you the same 20 question with regard to AML. Would it be 21 scientifically unsound or speculative to conclude from 22 the available scientific literature that formaldehyde 23 exposure is capable of causing AML? 24 MR. GOTTLIEB: Object to form. 25 A. Most of the studies don't even look at 94 1 AML, they look at myeloid leukemia. If you take the 2 classification of myeloid leukemia, which includes 3 chronic and acute myeloid leukemia, yes, I think that 4 would be a reach. I think that would be speculative. 5 I don't think the scientific evidence, as it exists 6 right now, is sufficient to say that formaldehyde can 7 cause myeloid leukemia in any person. 8 Q. (BY MR. KIWALA) Okay. Would -- and the 9 same question, finally, with regard to APL. Would it 10 be scientifically unsound or speculative to conclude 11 from the available scientific literature that 12 formaldehyde exposure is capable of causing APL? 13 A. Yes. That would be unsound and 14 speculative and purely hypothetical. There is no 15 evidence of that. 16 Q. Would reaching a conclusion that 17 formaldehyde exposure is capable of causing AML based 18 on the available scientific literature -- would that 19 be more or less speculative than reaching an opinion 20 about causation based on only case report? 21 MR. GOTTLIEB: Object to form. 22 A. I didn't -- sorry. I can't -- I didn't 23 understand that question. 24 Q. (BY MR. KIWALA) Well, you said it would 25 be a reach to conclude, based on the available 95 1 scientific literature, that formaldehyde exposure is 2 capable of causing AML, correct? 3 MR. DETHERGE: That mischaracterize. 4 MR. GOTTLIEB: Object to form. 5 MR. DETHERGE: I think he actually had 6 something more definitive to say than that. 7 A. Start again, please. 8 Q. (BY MR. KIWALA) Do you agree -- is it 9 your -- is it your testimony -- strike that. Is it 10 your testimony that it would be scientifically unsound 11 or speculative to conclude from the available 12 scientific literature that formaldehyde exposure is 13 capable of causing AML? 14 MR. GOTTLIEB: Object to form. 15 A. We -- we've already done that question, 16 haven't we? Well, what was my answer? 17 Q. (BY MR. KIWALA) I believe your answer -18 A. I was asking the court reporter to read 19 it back. 20 (The question and answer referred to were 21 read back as follows: 22 Question: "I'm going to ask you the same question 23 with regard to AML. Would it be scientifically 24 unsound or speculative to conclude from the available 25 scientific literature that formaldehyde exposure is 96 1 capable of causing AML?" 2 Answer: "Most of the studies don't even look at AML, 3 they look at myeloid leukemia. If you take the 4 classification of myeloid leukemia, which includes 5 chronic and acute myeloid leukemia, yes, I think that 6 would be a reach. I think that would be speculative. 7 I don't think the scientific evidence, as it exists 8 right now, is sufficient to say that formaldehyde can 9 cause myeloid leukemia in any person.") 10 A. I like that answer. 11 Q. Okay. So based on -- there was a lot in 12 that answer, but the -- would you agree that the short 13 answer to that question was yes? 14 MR. GOTTLIEB: Object to form. 15 MR. DETHERGE: Asked and answered. He 16 gave you the answer. 17 A. I did. And I can't -- I mean, your 18 question was really long, so I had a long answer. I 19 think that's appropriate. I don't -- I don't know how 20 to shorten it. We can try again, if you'd like. 21 Q. Okay. But you -- I believe you said that 22 such a conclusion would be speculative, correct? 23 MR. GOTTLIEB: Among other things. 24 Objection. 25 MR. DETHERGE: Same objection. I mean, 97 1 he answered the question. 2 Q. (BY MR. KIWALA) Go ahead and answer it, 3 if you can. 4 A. I did. I answered the question. I don't 5 think the literature supports an association between 6 formaldehyde exposure and myeloid leukemia. There is 7 practically no data that would allow you to even 8 evaluate the relationship between formaldehyde 9 exposure and acute myelogenous leukemia, and no data, 10 zero data that would allow you to evaluate the 11 association between formaldehyde exposure and APL. 12 Does that help? 13 Q. Yes. In light of all that, if one 14 reached a conclusion that formaldehyde exposure was, 15 indeed, capable of causing AML, would that conclusion 16 be more speculative or less speculative than reaching 17 an opinion about causation based on only case reports? 18 MR. DETHERGE: Object. 19 MR. GOTTLIEB: Object to form. 20 MR. DETHERGE: Object lack of foundation. 21 I'm not sure what it means to be more or less 22 speculative. It's like more or less pregnant, isn't 23 it? 24 A. Yeah, I don't -- I don't know how to 25 answer that. 98 1 Q. (BY MR. KIWALA) Well, let me -- let me 2 ask you this: You cite in your report that bimolane 3 is an established cause of APL, correct? 4 A. Yes. 5 Q. And that was based on case reports, 6 correct? 7 MR. DETHERGE: Objection, 8 mischaracterizes. 9 A. It was based on one or two case reports 10 and then a large case series. And my understanding of 11 the scientific and medical communities in China is 12 that they stopped using bimolane as a result of those 13 studies. But I did agree with you that I probably 14 should have caveated that sentence with -- I mean, 15 unless -- I thought there was a cohort study. I 16 thought there was a quantitative epidemiological 17 evaluation done. And I'm still not 100 percent 18 convinced there's not. If there is, I'll send it to 19 you. If there's not and it's just those studies and 20 the response that the Chinese community had to those 21 studies, then I would have worded that a little 22 differently. 23 Q. (BY MR. KIWALA) But at any rate, you do 24 agree that there were -- as far as you know, there are 25 no quantitative epidemiological studies showing 99 1 consistent positive findings associating exposure to 2 bimolane and APL, correct? 3 MR. GOTTLIEB: Objection, asked and 4 answered multiple times. 5 MR. DETHERGE: Ryan, it just 6 mischaracterizes what he just told you. 7 Q. (BY MR. KIWALA) Go ahead and answer, if 8 you can. 9 A. I agree. We can go back and have the 10 court reporter read it again, if you'd like. 11 Q. So just to be more specific, would a 12 conclusion based on the available scientific 13 literature that formaldehyde exposure is capable of 14 causing AML, would that conclusion be more speculative 15 or less speculative than reaching an opinion about 16 causation whether or not bimolane is capable of 17 causing APL based on just case reports? 18 MR. GOTTLIEB: Objection. 19 MR. DETHERGE: Same objection. You've 20 asked -- it's been asked and answered, and it lacks 21 foundation for the same reasons we've discussed 22 before. 23 Q. (BY MR. KIWALA) Go ahead and answer, if 24 you can. 25 A. You're -- the question doesn't make much 100 1 sense to me, but I'll try. I mean, the -- these two 2 issues are very different. And you're asking me to 3 compare them with regard to their speculativeness, and 4 I don't know exactly how to do that. 5 In the bimolane and APL, to my knowledge, 6 those two studies -- maybe there's another one that 7 I've forgotten about, but I'm not sure, so that might 8 be it. That is the sum total of the literature. And 9 as I've told you earlier, that was sufficient for 10 bimolane to basically be taken off of the list for 11 treatment of psoriasis. I mean, it made a big deal in 12 the Chinese medical community. That's how I heard 13 about it. So it was established. 14 With regard to formaldehyde and myeloid 15 leukemia, you don't have two case reports. You have a 16 long list of epidemiological studies, quantitative and 17 otherwise, going back 40 and 50 years. You've gotten 18 embalmer studies and funeral directors, plus all of 19 these cohort studies that are in existence right now. 20 So this collectively, this body of 21 literature does not support an association between 22 formaldehyde exposure and AML in my opinion. Now, I 23 can't rank it in terms of speculativeness. I don't 24 know how to do that. 25 Q. Okay. Last question. Dr. Pyatt, what's 101 1 the hourly rate that you charge for your expert 2 services? 3 A. $300 an hour. 4 Q. Okay. Is that the same for deposition 5 and for trial testimony? 6 A. Yes. I don't differentiate one from the 7 other. 8 Q. And for the time that you spend preparing 9 or researching issues or preparing reports, is it 10 still the same rate? 11 A. It's all the same, correct. 12 Q. Okay. 13 MR. KIWALA: Thank you very much, 14 Dr. Pyatt. Those are all the questions I have. 15 THE DEPONENT: Okay. 16 WHEREUPON, the within proceedings were 17 concluded at the approximate hour of 1:06 p.m. on the 18 11th day of August, 2009. 19 20 21 22 23 24 25 102 1 ***** 2 I, DAVID W. PYATT, Ph.D., do hereby 3 certify that I have read the above and foregoing 4 deposition and that the same is a true and accurate 5 transcription of my testimony, except for attached 6 amendments, if any. 7 Amendments attached ( ) Yes ( ) No 8 9 10 __________________________ DAVID W. PYATT, Ph.D. 11 12 13 14 The signature above of DAVID W. PYATT, 15 Ph.D., was subscribed and sworn to before me in the 16 county of ______________, state of 17 _____________________ , this _____ day of 18 ________________, 2009. 19 20 21 _________________________ Notary Public 22 My commission expires 23 24 Andrew Wolfe and Denise Wolfe 8/11/09 (tc) 25 103 1 REPORTER'S CERTIFICATE 2 STATE OF COLORADO ) ) ss. 3 CITY AND COUNTY OF DENVER ) 4 I, TERESA COOGLE, Shorthand Reporter and Notary Public, State of Colorado, do hereby certify 5 that previous to the commencement of the examination, the said DAVID W. PYATT, Ph.D., was duly sworn by me 6 to testify to the truth in relation to the matters in controversy between the parties hereto; that the said 7 deposition was taken in machine shorthand by me at the time and place aforesaid and was thereafter reduced to 8 typewritten form; that the foregoing is a true transcript of the questions asked, testimony given, 9 and proceedings had. 10 I further certify that I am not employed by, related to, nor counsel for any of the parties herein, 11 nor otherwise interested in the outcome of this litigation. 12 IN WITNESS WHEREOF, I have affixed my 13 signature this 12th day of August, 2009. 14 My commission expires May 8, 2010. 15 16 __X__ Reading and Signing was requested. 17 _____ Reading and Signing was waived. 18 _____ Reading and Signing was not required. 19 20 21 22 23 24 25 104