Document 28n19myZvOqDJEJ6m0NdGnKp

1 1 NORMAN W. ELLIS, 2 ET AL 3 4 VS. NO. 90-3696 5 INSURANCE COMPANY 6 OF NORTH AMERICA, 7 ET AL 8 9 DEPOSITION OF 10 RICHARD D. IRONS, Ph.D. 11 December 17, 1991 12 400 Poydras, 30th Floor 13 New Orleans, Louisiana 14 Reported by: 15 Joyce Ann Smith, RPR, CM 16 Texas CSR No. 2463 17 Louisiana CSR No. 83083 18 Nell McCallum & Associates, Inc. 19 2615 Calder Avenue, Suite 111 20 Beaumont, Texas 77702 21 22 23 24 25 *14th JUDICIAL DISTRICT COURT *PARISH OF CALCASIEU * STATE OF LOUISIANA 2 1 Appearances: 2 3 For the Plaintiffs: 4 HERSCHEL L. HOBSON 5 of the Law Office of 6 Herschel L. Hobson 7 2190 Harrison Street 8 Beaumont, Texas 77701 9 and 10 WILLIAM B. BAGGETT 11 of the Law Firm of 12 Baggett, McCall & Burgess 13 3006 Country Club Road 14 P. O. Drawer 7820 15 Lake Charles, Louisiana 70606-7820 16 17 For the Defendant Lloyds of London: 18 BARBARA L. ARRAS 19 STEPHEN HALL 20 of the Law Firm of 21 Phelps Dunbar 22 Texaco Center 23 400 Poydras Street, 30th Floor 24 New Orleans, Louisiana 70130-3245 25 NELL MC CALLUM & ASSOCIATES, INC. 3 1 For the Defendant Insurance Company of 2 North America: 3 GREGORY J. SPICER 4 of the Law Firm of 5 Guillory & McCALL 6 901 Lakeshore Drive, Suite 836 7 P. O. Drawer 1607 8 Lake Charles, Louisiana 70602-1607 9 For the Defendant Canadian Oxy Offshore 10 Products: 11 KENNETH R. SPEARS 12 of the Law Firm of 13 Jones, Tete, Nolen, Hanchey, 14 Swift & Spears 15 First Federal Building 16 1135 Lakeshore Drive 17 P. 0. Box 910 18 Lake Charles, Louisiana 70602 19 and 20 E. W. HACK 21 Attorney at Law 22 Oxy USA Inc. 23 Box 300 24 Tulsa, Oklahoma 74012 25 NELL MC CALLUM S ASSOCIATES, INC. 4 1 TABLE 0 F CONTENTS 2 PAGE 3 EXAMINATION BY MR. HOBSON8 4 5EXHIBITS 6 IRONS EXHIBIT NO. 1 7 7 LETTER ON THE LETTERHEAD OF BAGGETT, McCALL & 8 BURGESS DATED NOVEMBER 25, 1991, TO HONORABLE 9 JAMES ANDRES, CLERK OF COURT, FROM WILLIAM B. 10 BAGGETT, WITH NOTICE TO TAKE DEPOSITION 11 ATTACHED, CONSISTING OF 4 PAGES 12 IRONS EXHIBIT NO. 2 132 13 CV OF RICHARD D. IRONS, CONSISTING OF 15 14 PAGES 15 IRONS EXHIBIT NO. 3 132 16 BUTADIENE BIBLIOGRAPHY, CONSISTING OF 3 PAGES 17 IRONS EXHIBIT NO. 4 132 18 CORRESPONDENCE FILE PRODUCED BY THE WITNESS, 19 CONSISTING OF 29 PAGES 20 IRONS EXHIBIT NO. 5 132 21 ONE HANDWRITTEN DOCUMENT LISTING PLAINTIFFS 22 AND INFORMATION PERTAINING TO EACH PLAINTIFFS 23 IRONS EXHIBIT NO. 6 132 24 XEROX COPIES OF ARTICLES PRODUCED-BY THE 25 WITNESS, CONSISTING OF 207 PAGES NELL MC CALLUM & ASSOCIATES, INC. 5 1 Deposition of RICHARD D. IRONS, Ph.D., 2 a witness called by Plaintiffs on December 17, 3 1991, at 400 Poydras, 30th Floor, New Orleans, 4 Louisiana, commencing at 9:20 a.m., before Joyce 5 Ann Smith, RPR, CM, Texas CSR No. 2463, Louisiana 6 CSR No. 83083, pursuant to the following 7 stipulations: 8 COURT REPORTER: Pursuant to 9 Notice or agreement? 10 MR. HOBSON: Well, I guess 11 it's kind of both. Originally, 12 Notice, I guess; but we have agreed 13 to change the date. 14 MS. ARRAS: We never received 15 a copy of the original Notice. 16 MR. HOBSON: You didn't? 17 MS. ARRAS: No. 18 MR. HOBSON: (Tendering 19 document) 20 MR. BAGGETT: Can we agree 21 that the deposition was noted 22 noticed for a previous date, 23 continued by agreement, and is 24 taken today pursuant to Notice and 25 that all formalities are waived NELL MC CALLUM & ASSOCIATES, INC. 6 1 except the swearing and the reading 2 and signing and that all objections 3 are reserved except those with 4 reference to leading or 5 responsiveness of the answer -- or 6 to the form of the question, 7 rather? 8 MS. ARRAS: All right. I just 9 would like to make a statement that 10 there was never a subpoena served 11 on me with respect to this 12 deposition: and in fact, this is 13 the first time I have seen the 14 Notice. It wasn't sent to me. 15 MR. HOBSON: You have never 16 seen any of this, Dr. Irons, to 17 bring anything with you? 18 THE WITNESS: (Shaking head) 19 MS. ARRAS: No, because I was 20 told there was no Notice with 21 respect to Dr. Irons; and there was 22 certainly never a subpoena served. 23 (OFF-RECORD DISCUSSION) 24 MR. HOBSON: Any objection to 25 Mrs. Smith, who is a Texas Notary, NELL MC CALLUM & ASSOCIATES, INC. 7 1 administering the oath? There 2 being none 3 COURT REPORTER: May I correct 4 you that I am not a Texas Notary, 5 but I have my Louisiana CSR. 6 MR. HOBSON: I beg your 7 pardon. So, you can administer an 8 oath in Louisiana. 9 (IRONS EXHIBIT NO. 1 WAS 10 MARKED FOR IDENTIFICATION) 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NELL MC CALLUM & ASSOCIATES, INC. 8 1 RICHARD D. IRONS, Ph.D., 2 having been duly sworn, testified as follows, 3 to wit: 4 EXAMINATION BY MR. HOBSON: 5 Q. Dr. Irons, my name is Herschel Hobson. 6 We've met before on several occasions: correct? 7 A. Yes, sir. 8 Q. I understand from some preliminary 9 discussions we have had today that you never 10 received any request to bring anything with you to 11 the deposition: is that correct? 12 A. That's correct. 13 Q. What have you brought with you to the 14 deposition today in regard to this case? 15 A. I brought a folder with articles that I 16 intend to rely on: and I brought a recent CV; I 17 have a summary that I have made of the various 18 cases that are involved: I have brought a 19 bibliography of my own on butadiene: and I have my 20 correspondence from Ms. Arras. 21 Q. Could we have the correspondence, 22 please. 23 A. (Tendering file) 24 MR. HOBSON: With your 25 permission, I will ask Mr. Baggett NELL MC CALLUM & ASSOCIATES, INC. 9 1 to look at these while we continue, 2 if that's all right. 3 BY MR. HOBSON: 4 Q. May I look quickly, please, at the 5 articles in your bibliography? 6 MR. SPICER: What is that 7 correspondence? 8 MS. ARRAS: It's 9 correspondence with regard to this 10 case from my office. 11 BY MR. HOBSON: 12 Q. Are all the articles listed on your 13 bibliography included in the notebook? 14 A. No, they are really separate. 15 Q. Are all the articles in the notebook 16 included on the bibliography? 17 A. No, that bibliography is specifically 18 for butadiene: and the articles for the most part 19 deal with causation and with benzene. 20 MR. BAGGETT: Just on the 21 record, though, Mrs. Arras, isn't 22 it correct that when we had noticed 23 the deposition of December the 3rd 24 that it was changed -- the date was 25 changed at your request because of NELL MC CALLUM 8 ASSOCIATES, INC. 10 1 some emergency or something that 2 the doctor could not appear on 3 December the 3rd? 4 MS. ARRAS: That's correct, 5 but that has nothing to do with the 6 subpoena issue. 7 MR. BAGGETT: I know that. I 8 just 9 BY MR. HOBSON: 10 Q. Have you brought anything else with you 11 to New Orleans that deals with this case that you 12 have not brought to the deposition today? 13 A. No. 14 Q. Have you come to the deposition today 15 unaccompanied by anyone, or did someone come with 16 you? 17 A. By myself. 18 Q. Okay. I would like to start, if I 19 could, you are still at the University of 20 Colorado? 21 A. Yes. 22 Q. And when did you go there? 23 A. January 1989. 24 Q. And you went to the University of 25 Colorado from CIIT? NELL MC CALLUM & ASSOCIATES, INC. 11 1 A. Yes. 2 Q. What I would like to do is learn, if I 3 could, since you have been at the University of 4 Colorado, I would like to know all of the work 5 that you have proposed doing and to whom it was 6 proposed, what work actually was committed to be 7 done at the University of Colorado, what work has 8 been completed, and what work is ongoing that you 9 have been involved with. I am just giving you 10 that as a general overview and then I will start 11 by asking you, if we could, would you tell me what 12 work is currently going on at the University of 13 Colorado that you have been engaged in? 14 MS. ARRAS: I would like to 15 object to the word "work," and ask 16 if you could define that with a 17 little more specificity. 18 BY MR. HOBSON: 19 Q. Do you have trouble understanding 20 "work," Dr. Irons? 21 A. I would like you to clarify in 22 particular what you're referring to. I mean I can 23 list everything I have done since I got to the 24 University of Colorado, but I don't think we have 25 enough time for that. NELL MC CALLUM S ASSOCIATES, INC. 12 1 Q. I am not interested in every day. I am 2 particularly interested in research projects, 3 investigations that you have undertaken on behalf 4 of others or investigations that you, yourself, 5 have done. I am not interested in every day you 6 taught class or something. 7 A. Okay. Could you repeat the last 8 question? 9 Q. Yes, sir. I am interested in the 10 current investigations that you're doing as a part 11 of your work at the University of Colorado. 12 A. Okay. I have a research project that 13 is funded through the American Petroleum Institute 14 and Chemical Manufacturers Association to 15 elucidate and characterize the mechanisms of 16 altered stem cell regulation that are associated 17 with exposure to benzene metabolites. 18 I have a grant from the Chemical 19 Manufacturers Association to look at cell specific 20 metabolism and stem cell regulation associated 21 with exposure to butadiene metabolite. 22 I have a project funded from the 23 National Aeronautics and Space Administration to 24 examine potential mechanisms of toxicity and 25 altered stem cell regulation, hematopoiesis, and NELL MC CALLUM & ASSOCIATES, INC. 13 1 immune function that have been associated with 2 extended space flight. 3 Those are currently funded projects. 4 Q. Since you have been at the University 5 of Colorado, have you undertaken any 6 investigations for others or that you have funded 7 through some other mechanism at the University 8 that have been completed? 9 A. I have had some start-up -- I had some 10 start-up support from the State of Colorado, the 11 University, which basically went into establishing 12 my laboratory. I have had no other funded 13 projects at the University up until the present 14 time. I have projects pending and in development. 15 The first product of the research that I have 16 outlined for you is in submission at the present 17 time. 18 Q. So, the API-CMA project has -- you have 19 actually got it down in writing, the results, and 20 the results have been submitted to the sponsors? 21 A. No, they have been submitted for 22 publication. 23 Q. For publication. 24 A. None of these are contracts. They are 25 grants. So, the principal product is publication NELL MC CALLUM & ASSOCIATES, INC. 14 1 in peer-reviewed literature. 2 Q. Is that true for the NASA work, as 3 well? 4 A. That's correct. The NASA work is part 5 of a center grant that has been awarded to the 6 University of Rochester and the University of 7 Colorado from NASA. 8 Q. And the start-up activity is the only 9 work that was begun by you that was paid for by 10 others that has been completed? 11 A. If you want to call it completed. 12 There really was no -- there was no product or 13 time limit placed on it. 14 Q. The API-CMA project you told me about 15 first, can you give me some idea of about when 16 that project was begun? 17 A. I'm a little fuzzy, but I think it was 18 April or May 1989. 19 Q. And who were your contacts with regard 20 to those grants? Who periodically did you 21 correspond with or meet with to review those 22 projects as they progressed? 23 A. Hugh Spitzer, Ed Vernow. Those would 24 be the two principal individuals. 25 Q. What is their affiliation? NELL MC CALLUM & ASSOCIATES, INC. 15 1 A. API. 2 Q. Both? 3 A. Yes. 4 Q. Did you have contacts with anyone from 5 the member companies of the API and CMA? 6 A. Yes. We have approximately one meeting 7 a year to exchange information and go over 8 progress; and at that meeting there will be 9 usually company members from either CMA and/or 10 API, as well as API personnel. 11 Q. Who do you recall has attended those 12 meetings with regard to this project? 13 A. It varies. It varies dramatically from 14 one time to another. Peter Craig from Mobil. 15 That is the only person I can recall that would 16 have been there for every -- every meeting. There 17 are no doubt others, but I haven't really paid 18 attention to the attendance. 19 Q. Would you give me the overall review of 20 what it was you were trying to accomplish with 21 this investigation, and generally speaking, what 22 you found, sort of the executive summary sheet of 23 the report, I guess. 24 A. Well, it certainly at this stage would 25 be preliminary to outline all of the results; but NELL MC CALLUM do ASSOCIATES, INC. 16 1 I can certainly give you some initial findings. 2 The purpose of the project was to 3 characterize the cell specific metabolism and 4 mechanisms of altered regulation of growth and 5 differentiations that are associated with exposure 6 to bone marrow cells, benzene metabolites. My 7 hypothesis is that the mechanism of leukemogenesis 8 associated with benzene involves an obligate 9 alteration in stem cell differentiation, in 10 addition to the well-known cytotoxic effects of 11 benzene metabolites on dividing cells. Our 12 initial studies indicate that, in fact, benzene 13 metabolites do alter the response of committed 14 myeloid progenitor cells to recombinant growth 15 factors in such a way as to stimulate their 16 differentiation. 17 Q. When you say "obligates," how do you 18 use that term? 19 A. Could you repeat my answer, please? 20 Q. I think you used it as a noun. 21 (PART OF THE ANSWER WAS READ 22 BY THE REPORTER) 23 A. A necessary step in the overall 24 leukemogenicity, if you will, of benzene is a 25 requirement that there be a change in the response NELL MC CALLUM 8 ASSOCIATES, INC. 17 1 or the responding stem cell pool to growth factor 2 response. So, there is basically a shift in the 3 size of the committed stem cell pool that is 4 that can serve, if you will, as a potential target 5 for nondisjunctional events or cytotoxic events. 6 BY MR. HOBSON: 7 Q. I have had the pleasure of seeing some 8 of the charts that you used in Virginia, although 9 I didn't get to see you use them very much. Tell 10 me what your view is of where we are with the stem 11 cell in the human body. 12 MR. HALL: Let me object to 13 the form of the question. It's 14 vague and ambiguous. 15 A. The field of stem cell biology has 16 changed dramatically, even in the last two years. 17 The whole field of experimental hematology over 18 the last 20 or 30 years has evolved from one where 19 it's been fairly well known there was a single 20 cell or cell type that could give rise to all the 21 cells of the immune system, all the cells of the 22 blood system, including the various types of red 23 blood cells, white cells, what have you. 24 BY MR. HOBSON: 25 Q. What would we call that cell? NELL MC CALLUM & ASSOCIATES, INC. 18 1 A. It depends upon when you look in the 2 literature. It first was known as "the stem 3 cell." It has gone under the aegis of 4 pluripotential stem cell. Most recently, in order 5 to clarify distinctions, it's gone under the term 6 of totipotent stem cell. So, depending on who you 7 read when, you will find these terms used: and 8 they don't always necessarily refer to an ultimate 9 cell that is capable of giving rise to all the 10 various lineages. It depends upon its use and the 11 assumptions that have gone into its use at the 12 time that an individual chose to employ it. 13 Q. Do you believe that there is such a 14 cell that exists in the human body? 15 A. Now, you get into the rarefied arena we 16 now find ourselves in over the last year or two. 17 What has happened in the last year or two is it's 18 become clear that the various criteria we've had 19 to approach identifying this cell, this totipotent 20 cell, are not as reliable as we once thought and 21 that, in fact, this cell probably represents a 22 group of cells or a compartment that have a 23 continuum of differentiating capabilities and are 24 restricted in their ability to proliferate. So, 25 we're dealing with a compartment instead of a NELL MC CALLUM & ASSOCIATES, INC. 19 1 single cell. This is above and beyond cells that 2 are committed to produce either lymphoid or 3 myeloid erythroid cells. So, these cells are 4 still uncommitted. They are capable of giving 5 rise to either, but they are not homogeneous. 6 Q. Have you isolated one of those cells in 7 the uncommitted group? 8 A. In several of the studies we're doing 9 which involve enrichment, isolation, as well as 10 looking at function, we believe we have enriched 11 for a population that fits some of these criteria. 12 Whether we have isolated an early or a late 13 totipotent cell, I would say probably late: but at 14 this point in time, I don't have sufficient data 15 to confirm it. 16 Q. You think you probably have but you 17 can't confirm it, is that what you are saying? 18 A. That's correct. 19 Q. Now, the work that you are doing for 20 the CMA-API that we were talking about, I think 21 you told me that that work was on committed stem 22 cells. 23 A. Yes, we have been looking at the first 24 stage of commitment associated with the production 25 of red cells and granulocytes and macrophages and NELL MC CALLUM & ASSOCIATES, INC. 20 1 platelets, which is the myeloid progenitor cell. 2 Sometimes it's gone under the rubric of the 3 myeloid stem cell. I prefer to use progenitor 4 cell. 5 Q. You prefer to use the myeloid? 6 A. Progenitor cell. 7 Q. Progenitor cell. 8 A. Although depending upon the way in 9 which the terms are used, you could use either. 10 Q. So, there is one cell, though, that's 11 from the compartment group that we've talked 12 about, the uncommitted, that will give rise to 13 either the myeloid or the lymphoid lineage of 14 cells? 15 A. At least one, yes. 16 Q. At least one. And your work for the 17 API-CMA-is the next level down from this 18 uncommitted? 19 A. It has been to date. We're beginning 20 now to push back, but the work we've done over the 21 last three years has been focused on that 22 particular cell because of its importance in 23 understanding AML and -- acute myelogenous 24 leukemia, and it's the relative ease with which we 25 define the system to work with. NELL MC CALLUM do ASSOCIATES, INC. 21 1 Q. The committed stem cells of the myeloid 2 progenitor cell that you are working with, where 3 in the body is that cell found? 4 A. Bone marrow. 5 Q. The uncommitted stem cells that you 6 talked about earlier that you believe are a 7 compartment or a continuum of cells, where are 8 they located or what is your opinion as to the 9 best evidence as to where they are found? 10 A. Certainly in the human 11 Q. Yes, in humans. 12 A. -- they are predominantly found in the 13 bone marrow. There is evidence that they can 14 circulate, especially under conditions of stress, 15 to the system: but in general, certainly their 16 functional home is the bone marrow. 17 Q. Is there any evidence that you have 18 seen that the myeloid progenitor cell can 19 circulate? 20 A. No. I can't speak one way or the other 21 to that. I find it highly unlikely under normal 22 conditions. 23 Q. Now, if I understood what you told me, 24 you're looking at the effects of benzene 25 metabolites on these myeloid progenitor cells; is NELL MC CALLUM & ASSOCIATES, INC. 22 1 that right? 2 A. Yes. 3 Q. Which metabolites are you focusing on? 4 A. Phenol, hydroquinone, catecal. We have 5 done some work with the putative metabolite trans, 6 trans-muconaldehyde. 7 Q. Is your work singular when it comes to 8 these metabolites? In other words, are you using 9 only one metabolite; or are they being used in 10 combination? 11 A. We are using them singularly and in 12 combination. We basically have tried to create a 13 system that will allow us to take apart or dissect 14 the process of growth factor stimulation, stem 15 cell differentiation, and then cell replication in 16 the production of blood cells. Most culture 17 systems that have been used in the past have had 18 to use -- have had to look at this all together, 19 and we have been using newer technology and 20 available reagents to take this apart so we can 21 look at it in steps. The first step we have 22 succeeded in looking at is the recruitment or 23 activation of this population to a defined growth 24 factor stimulus. 25 Q. Okay. Could you go into some detail of NELL MC CALLUM & ASSOCIATES, INC. 23 1 what you mean by that so I have a better feel for 2 what you are saying your work shows in this 3 particular regard? 4 A. The way in which we make blood cells is 5 through a process of amplification, all the way 6 from your totipotent stem cell through 7 differentiation to committed stem or progenitor 8 cells; and then they may be multilineage cells, 9 capable of giving rise to several. And then there 10 will be a cell downstream from that that may give 11 rise to one or two different lineages. 12 If we're going to talk about 13 leukemogenesis, the targets for leukemia fall into 14 that compartment I have just described. So, cells 15 that are downstream further are not targets for 16 leukemogenesis. So, in order to understand what 17 is going on in that system, we need to know how 18 they are influenced with respect to exposure to 19 metabolites, compounds that we are interested in 20 determining what their influence is on either 21 hematopoiesis or leukemogenesis. 22 The way in which these cells are 23 regulated or communicated, if you will, is through 24 growth factors, cytokines, proteins that are 25 synthesized by either themselves or accessory NELL MC CALLUM & ASSOCIATES, INC. 24 1 cells that they then respond to in a very 2 cloistered environment within the marrow. Very 3 few cells, molecules are elaborated from one cell 4 and either directly passed to the other or it's in 5 a very localized gradient type of environment. 6 It's called a microenvironment. 7 What we have been focusing on is 8 looking at what influence benzene metabolites has 9 on resting cells that respond to the growth factor 10 and are, therefore, by definition committed 11 progenitor cells: and what we have found is that 12 depending upon the metabolite and it's interaction 13 with other metabolites that, in fact, benzene 14 metabolites do alter the response of resting cells 15 to a growth factor. 16 Q. If I am understanding what you are 17 telling me, then you have really focused on a 18 portion of this development of blood or 19 development of leukemia because the analytical 20 techniques and the procedures that you have 21 developed don't allow you to look at the system as 22 a whole; so, what you have done is you have 23 focused on a small part of this where you can get 24 control and see the results so that you can expand 25 this to the total system, or have I missed NELL MC CALLUM & ASSOCIATES, INC. 25 1 something here? 2 A. I would say it differently. It's 3 relatively easy to look at the whole. That's been 4 done several times in the past, but it doesn't 5 really provide us with any insight into what is 6 going on. 7 Q. The mechanisms? 8 A. Right. We have disaggregated the 9 system and we have focused on a particular portion 10 of the system that's never been examined before. 11 Looking at cytotoxic events is relatively 12 straightforward and is, in fact, part of what we 13 are proposing to do in the future: but we have 14 elected to focus on this area of regulation first 15 because, frankly, we think it's probably the most 16 important for understanding the ramifications of 17 exposure to benzene. 18 Q. And by "regulation," you're talking 19 about regulation of growth and replication? 20 A. Yes, differentiation. 21 Q. And differentiation. 22 MS. ARRAS: Differentiation 23 and what? 24 THE WITNESS: Replication. 25 BY MR. HOBSON: NELL MC CALLUM 3 ASSOCIATES, INC. 26 1 Q. When you use the term "cytotoxic 2 events" in connection with your studies we've been 3 talking about, how are you using that term? 4 A. Well, there are two things that benzene 5 metabolites can do. One is they can suppress 6 growth or hematopoiesis. Bone marrow suppression 7 is a well-known characteristic of exposure to high 8 levels of benzene. This involves ultimately at 9 some level effects on the stem cells or progenitor 10 cells that give rise to blood cells. 11 There are two aspects to cytotoxicity. 12 One is suppression of growth response, and the 13 other are events that may result in genetic or 14 transmitted errors in replicating cells. These 15 would be nondisjunctional events, cytogenetic 16 abnormalities that would result from 17 nondisjunctional events. 18 There has been some hypotheses put 19 forward that benzene can act through direct 20 mutational events, but I see no evidence for that 21 in the chemistry of benzene or its metabolites or 22 really any data that would lead me to conclude 23 that that's the case. So, we have been focusing 24 on other potential mechanisms of toxicity that are 25 known to be associated with benzene metabolites NELL MC CALLUM do ASSOCIATES, INC. 27 1 and are also associated with certainly the 2 cytogenetic manifestations of acute myelogenous 3 leukemia. 4 Q. Now, the myeloid progenitor cell that 5 you are working with is the only potential form of 6 leukemia that can result from effects on the 7 myeloid progenitor cell AML? 8 A. I am sorry, could you -- I'm not sure I 9 understand the question. 10 Q. Are there other forms of leukemia that 11 can result from effects on the myeloid progenitor 12 cell that you are studying? 13 A. The myeloid progenitor cell is and 14 cells downstream from it are associated with and 15 are thought to be the predominant source for acute 16 myelogenous leukemia and its variants, which would 17 be any of the variants' family. 18 Q. But the other forms of leukemia, 19 chronic myelogenous, acute lymphocytic, chronic 20 lymphocytic, hairy-cell, those would come from 21 other lineages of cells than the myeloid 22 progenitor cell? 23 A. That's correct. 24 Q. Would you -- tell me how you do this. 25 How is it that you capture the myeloid progenitor NELL MC CALLUM & ASSOCIATES, INC. 28 1 cell and expose it? 2 A. Well, there are two -- there are two 3 interrelated approaches. One is to partially 4 purify bone marrow cells so that you are dealing 5 with cells that fall into the category of any 6 nucleated cells that don't have stroma or 7 macrophages lying around -- stromal cells or 8 macrophages -- and you characterize their response 9 to recombinant growth factor. 10 The particular growth factor we focused 11 on initially was called granulocyte macrophage 12 colony stimulating factor, which is the factor 13 that is responsible for the viability and 14 differentiation of the myeloid progenitor. When 15 we look at the colonies that are formed from these 16 cells that are descended from this cell, and as in 17 our system, the predominant colonies that are 18 formed contain both granulocytes and macrophages, 19 that is indicative of the fact that the cell that 20 we are targeting is, in fact, a myeloid 21 progenitor. 22 The other approach we have taken is 23 through physical separation of cells using surface 24 characteristics, and we can enrich functionally 25 for that cell type using the approach that I just NELL MC CALLUM & ASSOCIATES, INC. 29 1 described as a test. 2 Q. Have you been able to actually modify 3 the development of the myeloid progenitor cell 4 lineage chemically so that you could control the 5 outcome? 6 A. Which direction it goes? 7 Q. Yes. 8 A. We have been focusing predominantly on 9 looking at what goes on with that myeloid 10 progenitor cell. So, our end point is, in fact, 11 -- our principal end point is the production of 12 mixed cell types. That appears to be the major 13 effect of benzene metabolites in that system. The 14 effects on other cell types like macrophages is 15 appears to be -- it may be -- there may be effects 16 on macrophage development, but it doesn't appear 17 to be of the magnitude or importance that the 18 effects are that we have described on the early 19 differentiation. 20 Q. Okay. You might have answered a 21 different question than I asked. Has all of your 22 work been with the benzene metabolites as opposed 23 to any other chemicals that could alter the 24 development? 25 A. No, we have looked at -- we have begun NELL MC CALLUM & ASSOCIATES, INC. 30 1 to look at a variety of different compounds, 2 primarily chemotherapeutic agents and their 3 metabolites. 4 Q. What about any naturally produced 5 materials within the body? In other words, have 6 you found what it is -- how it is that the body 7 sends the message to develop the one line or the 8 other? 9 A. There is quite a lot of work on the 10 cytokines and interleukins that precedes our 11 studies, and this is the basis -- these are the 12 compounds that are produced by the body that we 13 know have some significant or biologically 14 important effect on stem cell behavior. So, these 15 are the compounds we are using as part of the 16 system to examine the effects of various chemicals 17 on the process. 18 Q. Do you know or do you have a clue as to 19 the benzene metabolite mechanism now? In other 20 words, is it direct or indirect, and if so, which 21 one, how? 22 A. Well, it's very clear in my mind that 23 the pivotal metabolite is hydroquinone. Now, 24 again, we're talking at the level of the bone 25 marrow, the microenvironment; and these cells have NELL MC CALLUM & ASSOCIATES, INC. 31 1 distinct metabolic capabilities to activate 2 hydroquinone. 3 Q. These cells being? 4 A. Stem cells. Certainly the progenitor 5 cell population; however, the other metabolites 6 are important for influencing the specific 7 magnitude, the dose response, and the outcome. 8 But in the absence of hydroquinone, along with the 9 other metabolites of benzene, you don't see the 10 effects that certainly we have observed. 11 Q. How large is your power, I guess is one 12 way to phrase it, to determine -- to detect these 13 differences between hydroquinone and the other 14 metabolites? 15 A. Well, I guess the best way to answer 16 that is the effects we see are equal to or greater 17 in magnitude than the effects that are seen with 18 the interactions of various regulatory molecules 19 that are known to be produced endogenously to 20 regulate the system. So, it's a fairly impressive 21 effect and the reproducibility is very 22 significant. 23 Q. What is the source of your cells, your 24 myeloid progenitor cells? You say that they come 25 from bone marrow, but where do you get your bone NELL MC CALLUM & ASSOCIATES, INC. 32 1 marrow? 2 A. From our murine studies from mice that 3 we have in our barrier facility. For our human 4 studies, we're obtaining bone marrow samples 5 either from stored transplant specimens or now 6 we're in the process of obtaining permission to 7 use donors. 8 Q. The studies that you have done to date 9 for the CMA and API, are these studies on stem 10 cells that come from laboratory animals? 11 A. Yes. 12 Q. Have you done any on human stem cells? 13 A. Yes. Very preliminary. 14 Q. And you say that this comes from stored 15 bone marrow? 16 A. We have had access to some stored bone 17 marrow. We are now in the process of getting a 18 uniform source of fresh material. 19 Q. Was the stored bone marrow that you had 20 access to from healthy individuals or from people 21 who had been diseased? 22 A. Both. 23 Q. Does it seem to matter? 24 A. Yes, I think it does. I think if you 25 are going to look at normal stem cell regulation, NELL MC CALLUM & ASSOCIATES, INC. 33 1 at this stage of the game until we have developed 2 a certain degree of clairvoyance, we need to look 3 at normal stem cells. 4 Q. From healthy individuals? 5 A. Yes. 6 Q. Or people thought to be healthy? 7 A. Yes. At least they have no disease 8 involving the bone marrow. 9 Q. How do you get your metabolites? 10 A. For the benzene metabolites, it's 11 fairly easy now to purchase them. For butadiene 12 metabolites, we are synthesizing them. 13 Q. When you say you purchase the benzene 14 metabolites, are these synthetic chemicals or are 15 they metabolites that are recovered? 16 A. They are synthetic. 17 Q. They are synthetic? 18 A. (Nodding head) 19 Q. When you mentioned hydroquinone as one 20 of the metabolites, is there anything different 21 about the hydroquinone produced by benzene 22 metabolism than hydroquinone that you would buy 23 that is reagent grade off the shelf? 24 A. Chemically, no, there is no difference 25 whatsoever. In terms of administration or NELL MC CALLUM & ASSOCIATES, INC. 34 1 modeling or attempt to reproduce the toxicity of 2 benzene, I think there are marked differences that 3 are associated with the complexities of 4 pharmacokinetics, pharmacodynamics, and target 5 organ metabolism. 6 Q. What do you think is the source of 7 those differences? 8 A. First of all, for benzene to be toxic, 9 it has to be metabolized. First, primary 10 metabolism occurs predominantly in the liver. 11 This produces the phenolic and polyphenolic 12 metabolites, primarily phenol. Secondary 13 metabolism of phenol leads to the production of 14 hydroquinone and some catecal. All of these are 15 subject to competing reactions. The most dominant 16 competing reaction in the liver is going to be 17 what is called conjugation, secondary metabolism 18 elimination. 19 In order for toxicity to occur in the 20 bone marrow, you have to have the metabolite, the 21 secondary metal' s -- phenol, hydroquinone and _ 22 catecal -- transported to the marrow: and there it 23 appears that, again, a third level of metabolism 24 is necessary, and our study suggests there may 25 even be competing mechanism of conjugation and NELL MC CALLUM 3 ASSOCIATES, INC. 35 1 elimination that go on there. There, the specific 2 cell populations have totally different profiles 3 -- it appears they have totally different profiles 4 of enzymatic capability to deal with these 5 compounds. 6 If you administer, say, hydroquinone to 7 a whole animal, it's going to be very quickly 8 eliminated via conjugation and excretion. Its 9 distribution is not anything like you would expect 10 to see. Certainly there is no evidence to suggest 11 it would be anything like you would expect to see 12 with benzene. In fact, although you can produce 13 some transient bone marrow toxicity if you inject 14 hydroquinone repeatedly into an animal, you have 15 to go through some fairly nonphysiologic 16 procedures to do that. If you administer phenol 17 and hydroquinone together, you can produce greater 18 effects on the bone marrow. Again, though, it's a 19 fairly unphysiologic situation. And if you 20 administer phenol exogenously by itself, you can't 21 produce bone marrow toxicity. 22 Q. Have you looked at where in the body 23 besides the liver benzene is metabolized? 24 A. The liver has been predominant -- it's 25 been thought predominantly to be the major source NELL MC CALLUM & ASSOCIATES, INC. 36 1 of benzene metabolism for years because there are 2 a number of classic studies that show that if you 3 hepatectomize the animal and induce metabolism in 4 the liver that you can variously protect and alter 5 benzene toxicity. 6 I would expect that the possibility for 7 some activity in the lung exists, although you 8 would have to characterize the specific 9 cytochromes that are present and deal with issues 10 like the accessibility or the transient time for 11 benzene through the tissue. So, I would say the 12 lung probably has some capability. The liver 13 certainly is the major one. 14 We did some studies early in the 15 eighties, very early eighties, that suggested that 16 at the level of the bone marrow, the ability of 17 benzene to be oxidized directly by that tissue, 18 that is metabolized, is infinitesimally low. 19 Q. What about the nasal passages? 20 A. I doubt the nasal passages could 21 constitute a major source of benzene metabolism. 22 Q. The nasal passages can metabolize some 23 material? 24 A. Some things, yes. Polyphenolics 25 certainly concentrate there. I know of no NELL MC CALLUM S ASSOCIATES, INC. 37 1 evidence that benzene is metabolized there. There 2 are certainly other organ systems that have 3 demonstrated the ability to metabolize 4 secondary metabolism, zymbol gland is one. 5 Q. Not very common is humans, though? 6 A. Not very common in humans. An 7 interesting model, but of questionable human 8 value. 9 Q. Have you looked at human bone marrow 10 metabolism of benzene? 11 A. That's on our wish list. That's one 12 thing we very much want to do. 13 Q. So far, the bone marrow metabolism you 14 have told me about has been in experimental 15 animals? 16 A. It's been experimental animals. I 17 expect that this year and into next we will either 18 be well into or accomplish that goal, being able 19 to compare on a cell specific basis the difference 20 between the species. It depends on the 21 availability of material. 22 Q. Material being bone marrow? 23 A. Bone marrow. 24 Q. What about the metabolites, has anyone, 25 to your knowledge, looked at the metabolism of NELL MC CALLUM & ASSOCIATES, INC. 38 1 benzene metabolites in human bone marrow? 2 A. No. 3 Q. Would you expect to find some 4 unmetabolized benzene, in other words, benzene 5 itself in the bone marrow, in humans who have had 6 airborne exposures to benzene? 7 A. Whether you could detect it or not I 8 think would be a matter of the amount to which 9 they were exposed over some period of time: so, I 10 wouldn't say categorically that you would be able 11 to. But if you had an individual who was exposed 12 to high levels for a significant period of time, I 13 think that sensitivities are such you probably 14 could detect benzene in the blood and you could 15 detect benzene in the bone marrow. I think that 16 the areas of bone marrow that are not occupied by 17 blood, contain fat, would be under certain 18 circumstances a source for the accumulation of 19 benzene: but I don't think there is any evidence 20 to suggest that that directly plays a role in 21 benzene toxicity. 22 Q. In fact, there have been studies 23 reported finding benzene in the bone marrow fat? 24 A. I think there are some older studies 25 that have seen that. NELL MC CALLUM & ASSOCIATES, INC. 39 1 Q. Have you seen any studies that show 2 benzene in the circulating blood for people with 3 airborne exposures to benzene? 4 A. The problem with those types of studies 5 would be the levels of exposure that you would 6 expect to find. You can't intentionally go around 7 exposing people to high levels of benzene, and if 8 you are going to look at -- I think you would even 9 get into ethical questions about intentionally 10 exposing people to low levels of benzene. But 11 everybody is exposed to benzene. So, if you are 12 using the most sophisticated technology available, 13 I think you would probably be able to detect 14 benzene levels in everything. 15 Q. Have you seen studies that report 16 benzene levels in circulating blood for workers 17 who are known to be exposed to airborne levels of 18 benzene? 19 A. If I have, I don't recall. 20 Q. Would those be of any value to you? 21 A. Well, as I just said, I think except 22 under the most extreme conditions, if you are 23 going to monitor blood levels, it would be 24 relatively ineffective. I don't think it would be 25 very useful. NELL MC CALLUM & ASSOCIATES, INC. 40 1 Q. No, I wasn't suggesting you monitor 2 blood levels. I was suggesting -- well, I was 3 inquiring as to whether or not that would be any 4 use to you in looking at your models of benzene 5 metabolism and effects on some lineage of stem 6 cell and how they all interrelate as to whether or 7 not -- really, what I am looking at, there is 8 benzene in the circulating blood. Does that have 9 any role to play in your overall research into how 10 benzene, benzene metabolites affects these stem 11 cells? 12 A. If we knew how benzene fluctuations or 13 levels in the circulating blood related to liver 14 metabolism, exposure, secondary metabolism in the 15 bone marrow, and toxicity between both cell 16 specific differences as well as species 17 differences, then it would be a useful component. 18 But you have to have all the components in place 19 to really make use of that, and that ultimately is 20 one thing we would like to see is to be able to 21 model the process in mouse and in man so that we 22 have an interactive system where we can begin to 23 look at the ramifications of various exposure 24 scenarios. 25 Q. And that's years down the road, you NELL MC CALLUM 8 ASSOCIATES, INC. 41 1 think? 2 A. Yes. I think it's a lot closer than it 3 was a few years ago. I couldn't put a time on it, 4 but I'd say we're certainly within five years of 5 seeing that. 6 Q. By the way, did you see the article in 7 Scientific American on stem cells? 8 A. Yes. If you would like to discuss 9 that, I would like to go off the record. 10 Q. Oh. We will talk about that off the 11 record, then. 12 Getting back to the API-CMA study, what 13 is it that you have concluded to date in your 14 work? What have you found as far as these benzene 15 metabolisms and how they affect the growth, 16 replication, and differentiation of the myeloid 17 progenitor cell? 18 A. In a disaggregated system, in a highly 19 isolated and refined in vitro system, these 20 metabolites appear to enhance the recruitment of 21 cells from pre-commitment to the myeloid progenitor 22 cell. 23 Q. How do you mean that? I didn't follow 24 that. 25 A. That if you have a defined system where NELL MC CALLUM & ASSOCIATES, INC. 42 1 you are looking at the production of colonies 2 actually the activity of myeloid progenitor cells 3 to a given growth factor stimulus, that for a 4 given stimulus you will see a range of a number of 5 cells that will act like myeloid progenitor cells. 6 They will respond to the growth factor and produce 7 progeny. Benzene -- pretreatment with benzene 8 metabolites of that pot of cells prior to 9 stimulation with a growth factor causes a 10 recruitment of a greater number of cells that 11 normally would not respond to the growth factor. 12 The interpretation that we have placed on it based 13 on this data is that we are essentially pulling or 14 recruiting a population that normally doesn't 15 respond, and that is really consonant with 16 differentiation. So, functionally, we are causing 17 a shift in differentiation and increasing the pool 18 of the responding myeloid progenitors. 19 Q. Is that the same thing as causing 20 cancer? 21 A. No. 22 Q. How do you, if you do, make any 23 connection between your forcing this change in 24 differentiation with the benzene metabolites to 25 does benzene cause cancer and how much, or can NELL MC CALLUM & ASSOCIATES, INC. 43 1 you? 2 A. First of all, we start with the premise 3 that benzene is a human leukemogen. Like several 4 other chemotherapeutic agents, high level exposure 5 does lead to an increased incidence of secondary 6 acute myelogenous leukemia. I don't think there 7 is any doubt about that. So, we're really not out 8 to prove or disprove that benzene causes leukemia. 9 What we're trying to do is understand not just for 10 benzene but in a broader context how 11 leukemogenesis occurs. 12 And in that realm we have a much larger 13 body of literature than just benzene. We've got 14 the whole chemotherapeutic experience, as well. 15 There are no -- I am sure you are familiar with 16 initiation promotion. There are no initiation 17 promotion paradigms for leukemia in any 18 experimental system, in any human system at all. 19 Studies over the last 20 years especially have led 20 to an appreciation that leukemogenesis is a 21 multifactorial process, and there are several 22 steps. If you want to get down to numbers, I 23 don't think anybody is seriously talking less than 24 three. There may be more. 25 Our focus has been to look at the NELL MC CALLUM & ASSOCIATES, INC. 44 1 mechanism of regulation of stem cells because we 2 feel this plays a major role in determining the 3 potential for leukemogenesis occurring. If you 4 look at the regulation of stem cell activation in 5 animal systems and what data we have on man, it's 6 incredibly tightly controlled. The number of stem 7 progenitor cells that are known to be active at 8 any one time is extremely restricted. 9 It was my hypothesis that if you 10 influence that restriction, you influence the 11 normal protective mechanisms that exist in the 12 body to prevent this from happening under any 13 conditions; and, therefore, as a step in a 14 multifactorial process that could lead to 15 leukemogenesis, this would be an important one to 16 evaluate. Now, where it leads us in terms of 17 being able to model precisely, this is a model for 18 secondary AML, in which we have this event 19 occurring and then this one and then we have this 20 event and this event, we're several years away 21 from that. 22 Q. The chemotherapeutic agents that you 23 were talking about, the studies that have been 24 done in humans, have most of those studies, if not 25 all, been done in individuals who already have NELL MC CALLUM 8 ASSOCIATES, INC. 45 1 cancer? 2 A. Cancer or similar diseases that require 3 chemotherapy, yes. The vast majority are cancer 4 patients. 5 Q. And they have compromised immune 6 systems to begin with? 7 A. Not necessarily. It depends on the 8 cancer type. I think you could get into long 9 protracted arguments whether or not you have 10 immune suppression or not. You can have a 11 functioning immune system and host resistance in a 12 patient who has cancer. 13 Q. I guess what I was wanting to ask about 14 is that you mentioned that these are secondary 15 acute myelogenous leukemias? 16 A. They are -- certainly the pattern for 17 cytogenetic abnormalities, pattern for expression, 18 and the target cell population appears to differ 19 between de novo AML's for which there is no known 20 etiology and those that are known to be due 21 secondary to either chemotherapy or to benzene 22 exposure. 23 Q. So, you would consider then in your 24 rubric benzene-induced AML to be a secondary AML? 25 A. Yes. NELL MC CALLUM & ASSOCIATES, INC. 46 1 Q. I must not have understood. I want to 2 make sure. How do you 3 A. Secondary to exposure to something. I 4 mean you could -- I mean you could put radiation 5 in the same category, but I think that would be 6 misleading. 7 Q. Why do you say that? 8 A. I think mechanistically radiation is 9 different. It targets predominantly a different 10 cell type. Radiation is very effective at hitting 11 resting cells. And I also don't think that 12 whatever the -- well, this is highly speculative, 13 but I don't think the mechanisms associated with 14 induction of whatever events lead to leukemia with 15 radiation are necessarily going to be the same as 16 for chemicals that target cycling cells. 17 Q. Why? 18 A. Because, number one, you are dealing 19 with a totally different -- you are dealing with 20 an activated versus a quiet population, and the 21 outcome of the insult -- I think the initial 22 outcome is likely to be different molecularly. 23 That -- I mean that could all be disproven a year 24 from now. So, I mean that's speculative. 25 Q. I understand. I'm just trying to NELL MC CALLUM & ASSOCIATES, INC. 47 1 understand some of your reasoning. Why do you 2 think that there is a difference in whether these 3 cells that are attacked or activated or not? 4 A. The vast majority of chemotherapeutic 5 agents target cycling cells. Radiation doesn't 6 require that, that they be cycling, that they be 7 -- they be dividing. 8 Q. But in reality, wouldn't any human have 9 some dividing cells of these type at any given 10 time? 11 A. That's true: but as I said before, the 12 numbers game, if you will, is very heavily 13 restricted and controlled. If you assume that 14 chromosomal nondisjunctional events, which benzene 15 metabolites are very effective in causing, and 16 aneuploidy, cytogenetic abnormalities play a role 17 in leukemogenesis, certainly we have evidence for 18 the secondary leukemias that there is an 19 overwhelming majority of them have cytogenetic 20 aberrations. This kind of phenomenon goes on 21 mechanically in everybody all the time. We make 22 mistakes. Cell division is not an error-free 23 process. It's an error-prone process. 24 So, the ability to restrict the number 25 and to control growth and division in a NELL MC CALLUM 6 ASSOCIATES, INC. 48 1 susceptible target cell population, I think, is a 2 characteristic of evolution. That is to protect 3 us. I think that system is tremendously effective 4 and that it takes more than a slight insult to 5 disrupt it. 6 If a compound or substance has the 7 ability to alter that process in addition to or 8 independent of producing other events, I think it 9 must have some influence in explaining the process 10 of leukemogenesis. But the magnitude of that 11 influence remains to be seen. It remains to see 12 how, to what degree I'll be able to successfully 13 test my hypothesis. 14 Q. Doesn't it appear that benzene and its 15 metabolites cannot only cause the event but affect 16 the system, too? 17 A. Yes. 18 Q. Whereas radiation does not, is that 19 what you are saying? 20 A. No, not necessarily. Radiation is 21 certainly a complete leukemogen, there is no doubt 22 about it. How it -- you know, what are the 23 mechanics of how that is -- how that occurs and 24 how is that distinguished from chemotherapeutic 25 agents is by no means well understood. I am NELL MC CALLUM & ASSOCIATES, INC. 49 1 simply saying that the resting cell population 2 appears to be uniquely susceptible to radiation, 3 in terms of certainly cytogenetic abnormalities: 4 and whatever happens downstream from there is, 5 again, probably a multifactorial process. 6 Radiation plays one role or two roles or some 7 number. I think you can say the same thing -- or 8 I think ultimately you will be able to say the 9 same thing for drugs and chemicals. Some can do 10 the whole thing, some can do part of it, some can 11 do none. 12 Q. You hypothesize, also, that radiation 13 -- because of these cells being resting, radiation 14 can actually gain access to the interior of the 15 cell? 16 A. Radiation is -- yes. Yes. 17 Q. In a resting cell, chemically, the 18 chemicals have no opportunity to invade the 19 cell 20 A. Well 21 Q. -- but radiation can, even though the 22 cell doesn't appear to be penetrated? 23 A. It's not -- I think some aspect -- I 24 think there is some aspects of what you have 25 suggested that may, in fact, be true. Obviously, NELL MC CALLUM 8 ASSOCIATES, INC. 50 1 radiation penetrates a cell. Issues with respect 2 to resting cell involve whether the cell has 3 access to whatever the compound is, whether it can 4 activate it if it requires activation, whether 5 it's got the metabolic machinery to do so. 6 Resting can mean many things. We 7 normally think of it in terms of DNA synthesis but 8 we're beginning in our laboratory to appreciate 9 that metabolism plays a major role, too; and 10 that's separate and distinct from whether you are 11 producing DNA. Ostensibly all cells have the same 12 opportunity in a given environment for exposure, 13 whatever that is; but that does not mean they have 14 the same susceptibility or the same machinery 15 capability of either doing themselves harm or 16 protecting themselves. Understanding how all 17 those interplay is what will be necessary to 18 really get at the crux of that. But I think 19 susceptibility plays a major role. 20 Q. When you say "susceptibility," is this 21 susceptibility of the organism, the organ? 22 A. The cell. 23 Q. The cell. You used a term awhile ago 24 that I am not familiar with, "aneuploidy." First 25 of all, would you spell it? Because I don't know NELL MC CALLUM & ASSOCIATES, INC. 51 1 if we will be able to find it. Or a reasonable 2 attempt at it? 3 A. A-N-E-U-P-L-O-I-D-Y. 4 Q. I don't know that term. Would you 5 explain it? 6 A. It is an abnormal number of 7 chromosomes, either a gain or a loss. 8 Q. Is anyone, to your knowledge, looking 9 at any of the other stem cells and any effects of 10 benzene? 11 A. I don't know anyone outside my 12 laboratory who is doing these types of studies. 13 Q. Have you looked at any other cells 14 besides the myeloid progenitor cell? 15 A. We have begun to look at -- we've just 16 begun to do studies looking at other cytokines, 17 stimulate other cells, and to develop systems that 18 will allow us to look at an earlier cell in the 19 differentiation pathway. It would be in that 20 totipotent compartment. And also ideally, 21 hopefully, to be able to look at lymphoid 22 differentiation, as well. 23 Our first foray into this arena looking 24 at benzene metabolites suggests, but doesn't 25 prove, that the response is cytokine specific: NELL MC CALLUM & ASSOCIATES, INC. 52 1 that is, it depends on the specific growth factor, 2 and as a result of that, the responding cell is 3 different. So, in other words, the cell that 4 would normally respond to GMCSF appears to be 5 affected. A cell that responds to interleukin 3, 6 with is another growth factor thought to operate 7 both in the myeloid and the lymphoid lineage, at 8 least in the mouse, we have some data that 9 suggests it is not affected by benzene metabolites 10 in the same way. 11 Q. How preliminary is that? 12 A. Very. This has -- we have reproduced 13 it, but I want to -- the best way to describe 14 these studies are two or three experiments 15 followed by 50 control experiments: and anytime we 16 find a phenomenon that is remarkable enough to 17 merit publication, it requires tremendous amount 18 of work to demonstrate the rigor of the analysis 19 and that the end points are valid. We have been 20 able to do this with one cytokine. We are now 21 starting on another. 22 Q. Which one have you used so far? 23 A. GMCSF, IL-3. We have looked at M-CSF, 24 which is -- or CSF-1 macrophage colony stimulating 25 factor, and that is the substance of the studies NELL MC CALLUM & ASSOCIATES, INC. 53 1 that I referred to earlier when I said it doesn't 2 look like we have as dramatic an effect on 3 certainly macrophages downstream. But we have 4 I would also say there, I would have to entertain 5 the caveat that those studies aren't completed. 6 Q. Do you believe there is evidence that 7 benzene causes any of the lymphoid lineages of 8 leukemias in humans? 9 A. That's more than one question: but I 10 would say in general, no. 11 Q. If benzene does not cause the lymphoid 12 lineage of leukemias, what do you expect that your 13 experiments will show when you get into the 14 lymphoid stem cell lineage and you do these 15 similar tests that you have done with the myeloid 16 progenitor cell? 17 MS. ARRAS: I am going to 18 object that it calls for 19 speculation. 20 A. That is just about as speculative as I 21 think -- I think you have asked as speculative a 22 question as you could possibly ask me. 23 BY MR. HOBSON: 24 Q. I just would like to have your answer. 25 MS. ARRAS: I am not sure the NELL MC CALLUM & ASSOCIATES, INC. 54 doctor can answer if it's 2 speculative. 3 MR. HOBSON: Oh, I think he 4 has thought about it many times. 5 A. The problem with the lymphoid lineage, 6 is that with the exception of multiple myeloma, if 7 you look at the very tumor types that are 8 associated with lymphoid cells, the 9 differentiation process occurs outside the bone 10 marrow. Bone marrow is not a target: and, in 11 fact, if we're going to look at neoplasms like 12 NHL, we're probably looking -- several authorities 13 have suggested that we have to deal with 14 antigen-processing stimulation and a response to 15 some kind of an antigenic stimulus on the 16 periphery before we set up those conditions. So, 17 lymphoid lineage is a totally different ball of 18 wax. 19 In the myeloid, everything goes on in 20 the bone marrow. Differentiation is not a locked 21 step but it's confined to one space. It occurs 22 normally every day to provide us with the cells we 23 need for red cells and for leukocytes other than 24 lymphocytes. Lymphocytes -- the cells that leave 25 the bone marrow from the myeloid compartment are NELL MC CALLUM 6 ASSOCIATES, INC. 55 1 apoptotic. They are incapable of division. They 2 have one role in life, and this is to perform 3 their function and die. 4 The prelymphocyte or lymphocyte that 5 leaves the marrow has got the capability to 6 divide, the capability to differentiate, the 7 capability to invade tissues, the capability to go 8 on and become a malignant cell. The cells of the 9 myeloid lineage don't. So, when we talk about 10 leukemia involving the myeloid lineage, we're 11 talking about a bone marrow-derived event. In the 12 case of NHL, we are most inevitably talking about 13 an event that occurs in secondary lymphoid organs. 14 One exception is multiple myeloma. 15 BY MR. HOBSON: 16 Q. With respect to the bone barrow? 17 A. At least ostensibly, yes. 18 Q. Do you believe there is more evidence 19 that benzene causes multiple myeloma than the 20 lymphoid leukemias? 21 A. I would say yes, but I would also like 22 to explain. I don't think there is sufficient 23 evidence to indicate that benzene causes multiple 24 myeloma. So, we are talking about grades of 25 insufficient evidence. I believe there is no NELL MC CALLUM S ASSOCIATES, INC. 56 1 evidence that benzene is associated with lymphoid 2 leukemias. 3 Q. Would it be accurate to say that the 4 work you have done has not addressed the lymphoid 5 leukemias as far as benzene causation? 6 A. No, I wouldn't say that entirely. 7 Certainly the work I have done for the last 20 8 years has included looking at lymphoid activation, 9 the effects on signal transduction and lymphocyte 10 response of lymphocytes to benzene metabolites. 11 So, I think certainly in terms of cytotoxicity and 12 the ability of benzene metabolites to alter immune 13 function or regulation of lymphocyte 14 differentiation, my work has contributed to that 15 arena. Although I will -- I will quickly admit 16 that those have been in animal systems and certain 17 rodent systems: and certainly from the standpoint 18 of a whole animal, we're dealing with a totally 19 different biological model than we are man. 20 Q. This may be a question you won't want 21 to answer, and that is: How good a model is the 22 rodent? And I guess most of your work has been 23 with rats, some with mice? 24 A. Rats and mice. 25 Q. How good a model is the rat and the NELL MC CALLUM do ASSOCIATES, INC. 57 1 mouse for human myeloid leukemias? 2 A. For human myeloid leukemias, lousy. 3 It's a bad clinical model. It's very 4 controversial. It's controversial whether you 5 even have a malignancy. 6 Q. In the rat or mouse? 7 A. In the mouse. The rat, it's very 8 difficult to produce the lesions. Although 9 parenthetically, if you take all the studies in 10 aggregate that have been done in rats exposed to 11 high levels of benzene chronically and you compare 12 them to the incidence of -- increased incidence of 13 AML that's been seen in human populations with 14 high exposure to benzene, there may not be that 15 much difference. 16 Fifty years from now we may regard the 17 rat as an appropriate model for man because of the 18 numbers issue. We don't do studies with a hundred 19 thousand rats. We can't. It's just not 20 economically feasible. So, you do a study with a 21 thousand rats and you have equivocal results and 22 you can't defend them scientifically but they may, 23 in fact, be relatively representative. 24 Q. What would be a better species of 25 experimental animal than man for human myeloid NELL MC CALLUM & ASSOCIATES, INC. 58 1 leukemias? 2 A. Man. 3 Q. I understand that's the best one, but 4 that's not a model. 5 A. I think with all the caveats that I 6 have said about the mouse, it's all we have got. 7 I think that the biology of stem cell regulation 8 is probably similar, and we are certainly in a 9 position now where we can take it apart. So, we 10 can ask the question "At this level is the mouse 11 similar to man" and begin to reconstruct what is 12 and what is not appropriate to use in the mouse. 13 This is getting very philosophical. I think that 14 ultimately we may end up having composite systems 15 where we know enough about it that we can say this 16 is relevant from this species, this is relevant 17 from this species, and this is relevant from this 18 species; but we are by no means there yet. 19 Q. What are the species that have been 20 looked at that's a model for leukemias, the 21 myeloid leukemias in humans? 22 A. Well, in the forties, fifties, and 23 sixties, even in the seventies, there was a 24 paradigm that was frequently used by various 25 people doing studies. I call them a "zoo" study, NELL MC CALLUM & ASSOCIATES, INC. 59 1 where people would look at a few of several 2 different species. It was state of the art then. 3 It's by no means state of the art now. I mean 4 people have attempted to use the dog in one system 5 or another, people have attempted to use rabbits, 6 people have attempted to use guinea pigs, rats, 7 mice. 8 Q. Pigs? 9 A. Yes, pigs. The problem with, for 10 instance, pigs, which for all I know might be a 11 decent model, is, one, we don't have the reagents 12 to look at the biology of differentiation 13 hematopoiesis in the pig that we do for mouse and 14 man: and I would expect doing a study with large 15 ends, large numbers for a species like that, even 16 using a minipig, would just be exorbitant. 17 People have proposed using chimpanzees 18 or monkeys. There have been some studies looking 19 at -- at least short-term exposure, to look at 20 metabolism in various primate species. Again, 21 there are tremendous problems in designing an 22 experiment to successfully test whether you could 23 use them as a useful model, and it hasn't been 24 done in any -- for any compound or any system that 25 I am aware of. NELL MC CALLUM & ASSOCIATES, INC. 60 1 I think just to amplify that a bit, if 2 you look at experimental clinical hematology 3 today, the state of the art is still the mouse, 4 even though as a clinical model it is not useful. 5 MR. HOBSON: Let's take a 6 break. 7 (RECESS) 8 BY MR. HOBSON: 9 Q. Dr. Irons, getting back here a little 10 bit more to your API-CMA study, has the work that 11 you have been doing looked at changes in the DNA 12 or the chromosomes of these cells: or have you 13 just being looking at the chemical influence of 14 differentiation in cell growth? 15 A. To date, we have been looking at the 16 influence of chemical exposure and differentiation 17 in cell growth. So, we've been looking at 18 response to stimulus, gene expression. We have 19 not been looking at effects on DNA. 20 Q. When do you get to that phase, if you 21 do? 22 A. I am actually proposing -- in the 23 presence of writing a proposal now for submission 24 to NIH that will do this, and if successful, we 25 will probably proceed with that by next year, like NELL MC CALLUM & ASSOCIATES, INC. 61 1 the end of '92. 2 Q. When you propose it, or when you get 3 funded? 4 A. Ideally, when we get funded if we are 5 successful. 6 Q. Can you give me a feel for the 7 magnitude of the funding from the API-CMA for this 8 project? 9 A. For my laboratory, we're getting on the 10 order of $270,000 per year. 11 Q. And you say for your laboratory. Do 12 you have some collaborators? 13 A. Yes. 14 Q. Who is collaborating with you? 15 A. I am collaborating with Dr. David Ross 16 in my group, who is looking at metabolism in 17 isolated cell populations. 18 Q. So, all of the collaborators on this 19 particular project are located in your department 20 there at the University of Colorado? 21 A. Yes. 22 Q. Going on now to the CMA grant for 23 butadiene that you mentioned earlier, would you 24 give me an overview of that project, please? 25 A. That project is designed to investigate NELL MC CALLUM & ASSOCIATES, INC. 62 1 similar phenomenon associated with the exposure of 2 bone marrow cells to butadiene metabolites and to 3 look at the cell specific metabolism of butadiene 4 in bone marrow cells. It's starting from a 5 position of -- well, there is some disadvantages 6 and advantages there. The disadvantage is we 7 don't know as much about the metabolism, the 8 behavior of butadiene metabolites in the bone 9 marrow as we do with benzene. The advantage is we 10 can take advantage of what we have learned in 11 developing the systems we have to look at the 12 effects of benzene metabolites to begin to 13 approach looking at butadiene. 14 Q. When was this project begun? 15 A. This last year. 16 Q. 1990? 17 A. '91. 18 Q. '91. And the early part of the year? 19 A. I believe, April: but I could be 20 mistaken on that. 21 Q. When we started talking about the 22 API-CMA study, you told me that one of the things 23 -- and I'm paraphrasing now -- that was considered 24 in organizing that study was that there was an 25 association between benzene exposure at high NELL MC CALLUM & ASSOCIATES, INC. 63 1 levels and the development of AML. Is that your 2 view for butadiene, as well? 3 A. No. 4 Q. How is it, then, that you fit the 5 butadiene work into your pattern of using this 6 protocol that you have developed or procedures 7 that you have developed? 8 A. Well, we know that butadiene will cause 9 a megaloblastic anemia in the mouse at very high 10 levels of exposure. We also know that butadiene 11 influences or alters certainly early steps in 12 lymphoid differentiation in the mouse model: and 13 we are hoping to, by comparing and contrasting the 14 behavior of different compounds, metabolites -- be 15 they benzene, butadiene, or chemotherapeutic 16 agents -- begin to segregate out what the various 17 differences there are and the effects these 18 compounds can have on the regulation of 19 hematopoiesis. 20 Q. What is your opinion regarding whether 21 or not benzene -- I am sorry -- butadiene is the 22 cause of human leukemias? 23 A. I think the evidence is very 24 contradictory and does not provide us with an 25 answer to the question. NELL MC CALLUM 8 ASSOCIATES, INC. 64 1 Q. Do you support IARC's recent change to 2 suspect a human carcinogen for butadiene? 3 A. Well, if you look technically at the 4 definition of the term, I have to agree that there 5 is sufficient evidence in experimental animals and 6 there is inconclusive evidence in man. 7 Q. So, by their rubric you agree with 8 their determination? 9 A. Based upon the precise definition of 10 their ranking, yes. 11 Q. I think you said just a moment ago that 12 when it comes to butadiene, you're looking at 13 lymphoid cell differentiation? 14 A. We hope to. Our first comparison is 15 going to be in the same system we have because we 16 do know that butadiene will alter the development 17 of red cells in the mouse. That's what is 18 that's part and parcel of what we are talking 19 about when we say causes a megaloblastic anemia. 20 So, we want to examine the effects it has on 21 regulation of stem cell behavior, as well. 22 If you are going to understand how 23 regulating the biology of blood formation 24 influences bone marrow toxicity in general, this 25 is where you have to start, whether you are NELL MC CALLUM & ASSOCIATES, INC. 65 1 talking about leukemia or whether you are talking 2 about anemia or anything else. So, although we 3 obviously hope to be able to pursue lymphoid 4 differentiation with butadiene, because that is a 5 model that is very interesting in the mouse, we 6 are also going to look at its effects on 7 myelopoiesis, as well. 8 Q. I may have misunderstood what you said, 9 but I thought you told me that it had been 10 determined that butadiene affected lymphoid 11 differentiation. 12 A. To the -- in vivo, it certainly appears 13 to. It does not -- I mean obviously in the mouse 14 it causes a T cell leukemia. It's a very complex 15 model system, and not just for butadiene but for a 16 variety of compounds that have been shown to cause 17 leukemias or lymphomas in the mouse, it would be 18 worthwhile to be able to understand that model 19 better. 20 Q. You say that butadiene has produced a 21 T cell leukemia in the mouse? 22 A. Yes. 23 Q. Is there a comparable disease in 24 humans? 25 A. No, with the caveat that, of course, NELL MC CALLUM 8 ASSOCIATES, INC. 66 1 there is an adult T cell leukemia in man: but it's 2 a totally different disease. 3 Q. And that would be, the disease in man 4 would be what? 5 A. ATL, adult T cell leukemia, 6 HTLV1-induced leukemia. It's a viral origin. 7 Q. In either the mouse or the rat, can you 8 find acute myelogenous leukemia? 9 A. In any system? I mean is it possible 10 to get an acute myelogenous leukemia in the mouse 11 or the rat, is that the question? 12 Q. Yes. 13 A. Depending on the strain, there have 14 been reports that you can get a myelogenous type 15 of proliferative disease in the mouse. A CBA/CA 16 mouse is a strain of mouse that has been 17 suggested. It is very controversial as to whether 18 the presentation of the disease, the tissue 19 involvement, the nature of the lesion is, in fact, 20 a malignant disease, and how to distinguish it 21 from a nonmalignant disease. 22 There are probably some hematologists 23 who think that it is an appropriate model for 24 leukemia. I don't, because you certainly can't 25 distinguish between -- there are aspects of it NELL MC CALLUM & ASSOCIATES, INC. 67 1 that clearly look like a chronic proliferative 2 syndrome, and there are aspects of it that may 3 look acute. I just think it is -- we don't know 4 enough about it to use it as a model for human 5 leukemogenesis, and certainly the major attempt that I have taken in that direction was not 7 successful. 8 Q. Would it be true, then, that there 9 certainly is no disease in mice or rats called 10 chronic myelogenous leukemia that's known to man? 11 A. I would not be comfortable with using 12 either AML or CLL to describe the types of 13 diseases that are seen in certain mouse strains 14 that involve the bone marrow and the myeloid 15 lineage. There are proliferative abnormalities 16 that roughly -- you know, that have various 17 aspects of primarily chronic phenomena associated 18 with them, but to distinguish clinically those 19 disease entities as we do in man I think is not 20 possible at the present time. 21 Q. For instance, the Philadelphia 22 chromosome associated with CML, that's just not 23 something you could do in a rat or a mouse: 24 correct? 25 A. No. NELL MC CALLUM 8 ASSOCIATES, INC. 68 1 Q. I am correct? 2 A. You are correct. The Philadelphia 3 chromosome is a human entity. That doesn't mean 4 that you couldn't find translocations involving a 5 stem cell population in those species, but it has 6 not been described. 7 Q. And if it were described, it would 8 certainly be different than the Philadelphia 9 chromosome translocation? 10 A. Well, since the chromosomes -- since 11 the gene location on chromosomes in the mouse and 12 the rat is not the same as in man, it would by 13 definition have to be different. 14 Q. For humans, is the Philadelphia 15 chromosome -- this translocation described as a 16 Philadelphia chromosome, is that found in any 17 other kind of disease besides CML? 18 A. It appears in a certain subset of ALL. 19 Q. Any others? 20 A. Precisely, I don't think so. You have 21 to keep in mind that although we tend to talk 22 glibly about the Philadelphia chromosome as an 23 entity, if you want to look at the molecular 24 rearrangements that are occurring involving the 25 affected genes, it can occur -- there are NELL MC CALLUM & ASSOCIATES, INC. 69 1 differences in molecular arrangements that appear 2 to correlate with different presentations of 3 malignancy and there can, in fact, can be 4 rearrangements that don't have the morphological 5 appearance of the Philadelphia chromosome. 6 Q. I didn't understand that. 7 A. Okay. The Philadelphia chromosome 8 involves a translocation. It involves bringing 9 one gene into a position with another. The exact 10 place in which they come together and rearrange 11 varies somewhat. That variation, as I recall, is 12 important in determining -- you can tell the 13 difference between, say, an ALL and a CML 14 associated with that. By the same token, you can 15 have rearrangements that can occur in the absence 16 of complete morphologic translocation of the 17 chromosomes that you can identify doing a 18 chromosome analysis: and that probably represents 19 a very small proportion of those cases that have 20 been clinically described as Philadelphia 21 chromosomes negative CML. 22 Q. Does the rat or mouse develop an 23 equivalent disease to human multiple myeloma? 24 A. Not really. The same cell types are 25 involved. I mean lymphoma by definition involves NELL MC CALLUM de ASSOCIATES, INC. 70 1 lymphoid cells; but there are several different 2 diseases that have different cell types, have 3 different origins, that come under this rubric. 4 You can say that the mouse and the rat 5 develop lymphomas. That doesn't mean that they 6 are -- that you can clinically take any given 7 lymphoma in the mouse or the rat and compare it 8 directly, clinically, to a lymphoma in man. But 9 there are certain types of comparisons that you 10 can make with respect to cell type, potential 11 mechanisms, and this type of thing; but it's not a 12 clinical model for human lymphomas. 13 Q. I digressed a little bit from your 14 butadiene work, and I apologize. I would like to 15 get back to that. 16 What metabolites of butadiene have you 17 been working with? 18 (OFF-RECORD DISCUSSION) 19 A. The 1,2-buteneepoxide, the 20 1,2,3,4-butanediepoxide, the epoxy diol, 21 intermediates, crotonaldehyde. 22 My caveat would be we are looking at 23 metabolism and we are not at this point convinced 24 that what we know about butadiene metabolism is, 25 in fact, accurate. NELL MC CALLUM do ASSOCIATES, INC. 71 1 BY MR. HOBSON: 2 Q. Have you actually proceeded with each 3 of these metabolites or putative metabolites? 4 A. We are not in the same -- these are not 5 being run side by side. We have developmental 6 problems that we have had to overcome 7 methodologically in working with these compounds 8 and culture systems, and we have been in the 9 process of doing that and synthesizing 10 intermediates. For these metabolites and to 11 follow the actual metabolism of butadiene in bone 12 marrow cells, we need to be able to characterize 13 the metabolites in culture and we have been in the 14 process of developing those systems. 15 Q. At what level of funding is CMA 16 providing for you, approximately? 17 A. On the order of a hundred thousand. 18 There is some that's going to metabolic studies in 19 other laboratories. 20 Q. Laboratories outside the University of 21 Colorado? 22 A. No, in my group but different 23 laboratories. 24 Q. When we talk about the University of 25 Colorado, how much total funding would be for this NELL MC CALLUM & ASSOCIATES, INC. 72 1 project, as best you recall? 2 A. I think I'm receiving about 100,000, 3 roughly. About 35 or 40 is going into metabolic 4 studies at the present time. 5 Q. The figure you gave me for the earlier 6 study, the approximately $270,000 per year, is 7 that all of the moneys that goes to the University 8 of Colorado or is that just you? 9 A. No, that's just for my laboratory. 10 There is overhead and there is also, as I said, 11 Dr. Ross' participation, also. 12 Q. All total, how much would be to the 13 University of Colorado per year? 14 A. About 350. 15 Q. Who is your principal contact for the 16 butadiene study? 17 A. Betty Moran at CMA. 18 Q. Are there any member company contacts 19 that you have had with the butadiene study? 20 A. Chris Bevan at Exxon. 21 Q. Bevan? 22 A. Yes, B-E-V-A-N. 23 And I don't recall any others at the 24 present time. There are others, but I just can't 25 recall. NELL MC CALLUM do ASSOCIATES, INC. 73 1 Q. Does it appear to you that you can have 2 an exposure to benzene and then the presentation 3 of leukemia some years later that you would say 4 was caused by that benzene exposure? 5 MR. HALL: Let me object to 6 the question as being an incomplete 7 hypothetical. 8 MS. ARRAS: Right. 9 A. I'm not sure how that differs from the 10 question does benzene, in fact, cause acute 11 myelogenous leukemia. If that's what you are 12 asking me, the answer is yes. 13 BY MR. HOBSON: 14 Q. No. I'm not trying to play games with 15 you. Here's what I am trying to get to is in the 16 rationale of your work should you expect to see a 17 benzene exposure followed relatively soon by the 18 presentation of leukemias, or is any of your work 19 directed at looking at this lag time that appears 20 in the literature from exposure to onset of 21 disease? That's really where I am going. 22 A. Leukemia doesn't happen overnight. 23 There is obviously lag time; and in looking at the 24 various regulatory steps and abnormalities that 25 can occur with time, it is an important aspect of NELL MC CALLUM & ASSOCIATES, INC. 74 1 understanding that and how it's regulated or 2 expressed. I don't think that you can simplify 3 the issue of what steps occur when in the case of 4 leukemia or assume a requirement for continuous 5 exposure over the length of the time it takes for 6 development. 7 Q. How does your work fit into those 8 considerations, if it does? Maybe it doesn't. 9 A. Well, it does in the sense that if we 10 are able to segregate out now the individual steps 11 that are likely to occur as a function of 12 exposure, we can determine what the influence of 13 other factors are in the process and also 14 determine what the probability of subsequent 15 events will be. 16 Q. Can you take me beyond that? Can you 17 tell me in more detail how your work is involved 18 in this determination of how the lag time between 19 exposure and manifestation of leukemia occurs? 20 MR. HALL: Let me just enter 21 another objection. And I don't 22 mean to interrupt this dialogue, 23 but are we talking about AML or are 24 we talking about other species of 25 leukemias for which the doctor has NELL MC CALLUM do ASSOCIATES, INC. 75 1 expressed an opinion? 2 MR. HOBSON: I am talking 3 about his work that he is doing on 4 the myeloid progenitor cells 5 from 6 MR. HALL: I appreciate the 7 focus of your question but you 8 categorized leukemia as a generic 9 term when, in fact, we all know 10 there are many types of leukemias, 11 some of which may or may not be 12 caused by exposure to benzene; and 13 I think in fairness to the doctor 14 you should be more specific. 15 BY MR. HOBSON: 16 Q. Do you understand what I was asking you 17 or not? And if you want to state what you 18 understand the question to be so that it's clear, 19 I have no problem with that. 20 A. You are asking me to expand on how the 21 work we are doing impacts on understanding the 22 process of leukemogenesis associated with the 23 myeloid progenitor cell? 24 Q. And how it fits into this apparent lag 25 time between exposure and manifestation of NELL MC CALLUM IIC ASSOCIATES, INC. 76 1 disease. 2 A. In the case of secondary leukemias, 3 there is a very high proportion -- by secondary, 4 I'm talking about AML secondary to chemical 5 exposure or drug exposure. A very high proportion 6 of those have specific cytogenetic abnormalities, 7 loss of chromosomes 5 or 7, or parts of both. I 8 don't think anybody who's really working 9 extensively in this area would assume that that's 10 the only thing that happens in these cells, but 11 it's certainly a common finding. 12 It will be of interest to know what 13 other steps are that are involved in this process 14 before you get to the point where you have a cell 15 that acts like a leukemia cell and has these 16 cytogenetic abnormalities. We have been initially 17 looking at the recruitment and regulation of the 18 movement of cells into this target cell 19 compartment. We need to finish that, characterize 20 and compare it. 21 We have done this in a murine system. 22 We now need to compare it to human and then begin 23 to look at what other events can occur subsequent 24 to that. If we're successful in isolating out 25 various events, we may be able to determine what NELL MC CALLUM & ASSOCIATES, INC. 77 1 other steps occur along the way. Heretofore, we 2 have only been able to kind of look at the system 3 in aggregate and not -- it's very difficult to try 4 to distinguish what is going on. We are now 5 trying to separate events out. 6 Once we have done that, if we are 7 successful, we need to put the system back 8 together again, which may mean no mean feat, 9 either: but this is the first step in being able 10 to segregate out what processes are involved in 11 leukemogenesis, similar to what -- for AML, 12 similar to what was done in the fifties and 13 sixties and early seventies with respect to some 14 of the more simplistic models of carcinogenesis, 15 initiation and promotion, for example. 16 Q. You have mentioned some of the 17 chemotherapeutic drugs. Your work, as I 18 understand it, has involved some of those, as 19 well? 20 A. Yes. 21 Q. When it comes to the chemotherapeutic 22 drugs, are you talking there about work with their 23 metabolites or the drugs themselves or both? 24 A. Both. It depends on -- depends on what 25 we know about their metabolism. The object there NELL MC CALLUM & ASSOCIATES, INC. 78 1 is -- well, eventually we may be able to say 2 something about the individual agents but at the 3 present time we are using those agents as probes 4 or tools. So, I really can't say much about our 5 characterization of individual agents other than 6 that they are useful to allow us to compare what 7 the effects of other chemicals or agents are on 8 these processes. 9 Q. Which drugs have you used in your work? 10 A. We have started looking at 11 cyclophosphamide and its metabolites. We are 12 we have looked at hydroxyurea and some of the 13 Vinca alkaloids. We are in the process now of 14 evaluating an additional tier of drugs we haven't 15 made a decision on yet which ones to use. 16 Q. In what kinds of therapy or what kind 17 of diseases are the three that you have mentioned 18 typically used? 19 A. They are used for treating various 20 leukemias or conditions associated with leukemia 21 or lymphoma in various paradigms. 22 Cyclophosphamide is frequently used, so is 23 hydroxyurea and vincristine. 24 Q. Is it your understanding, then, that in 25 individuals who have leukemia, these drugs are NELL MC CALLUM & ASSOCIATES, INC. 79 1 administered and there is a different leukemia 2 produced by the drugs? 3 A. No. No. I'm not following -- I'm not 4 following that line of question. 5 Q. Are these drugs themselves that you are 6 testing, the three categories you just gave me, 7 are they capable of causing leukemia themselves or 8 the metabolites? 9 A. In the particular case of the drugs 10 we're talking about, if you look at the clinical 11 study, cyclophosphamide is, hydroxyurea is not, 12 and vincristine is not. At least there is no 13 evidence that they do. They do cause -- they all 14 cause bone marrow damage, but they do not all 15 cause leukemia. 16 Q. If they couldn't cause bone marrow 17 damage, they wouldn't be effective in treating 18 leukemias? 19 A. That's correct. Benzene does the same. 20 Benzene is a reasonably efficient myelosuppressive 21 agent. 22 Q. What comparisons are you hoping to make 23 by using these chemotherapeutic drugs? 24 A. By using chemotherapeutic agents that 25 have a different spectrum of side effects, NELL MC CALLUM & ASSOCIATES, INC. 80 1 determining what changes in cell behavior are 2 associated with the potential to cause those side 3 effects. 4 Q. How does that tie into your hypothesis 5 regarding benzene? 6 A. Well, we know that benzene does cause a 7 small but significant increase in the incidence of 8 AML in chronically exposed populations of high 9 concentrations. We also know that some of the 10 chemotherapeutic agents do the same thing. Some 11 don't. If we can dissect out at what particular 12 level of cell these events occur and what the 13 differences are between them, it will help us in 14 determining what are likely to be the most 15 important things to look at with respect to the 16 mechanisms of leukemia. 17 Q. Have you gotten to that step yet? Can 18 you now make some of these differentiations 19 between the drugs and benzene? 20 A. It would be premature to comment on 21 that now until we've really looked at all the 22 data. We are not in a position to discuss with 23 any degree of confidence that data base right now. 24 Q. The paper that's in the process of 25 being published, I think you said it has been NELL MC CALLUM S ASSOCIATES, INC. 81 1 submitted, can you tell me the kinds of things 2 that you are reporting in that paper? How far are 3 you able to report in the scientific literature 4 with that report? 5 A. It characterizes the effects -- it 6 establishes the system, characterizes the dominant 7 effects of hydroquinone on stem cell regulation in 8 that system. It looks at the interaction of 9 hydroquinone with various other metabolites, their 10 individual effects, and draws some of the 11 conclusions that we have been discussing here with 12 respect to the potential role of this model if, in 13 fact, it withstands further testing. 14 Q. Where did you submit it? 15 A. Proceedings in the National Academy of 16 Sciences. 17 MS. ARRAS: Just for the 18 record, that's the CMA -- which 19 paper is it you are referring to 20 that's a publication with respect 21 to? 22 THE WITNESS: The CMA. It's 23 in review now. It has not been 24 formally accepted as of yet. 25 BY MR. HOBSON: NELL MC CALLUM & ASSOCIATES, INC. 82 1 Q. It has been sent to the peer reviewers 2 for comment? 3 A. Yes. 4 Q. Have you received comment yet? 5 A. Some of them, yes. 6 Q. So, you are probably three or four 7 months from resubmitting after all the comments 8 are in? 9 A. Hard to tell. 10 Q. When the comments are back in, 11 frequently the reviewers are asked to review any 12 suggested changes they made and the responses; 13 correct? 14 A. Yes. At this point -- well, it's 15 impossible for me to tell. At this point I don't 16 anticipate it's going to be very long. 17 Q. It should be in print within the next 18 four or five months, maybe? 19 A. I would hope so. 20 Q. When did you receive funding from the 21 NASA grant? 22 A. Last spring. 23 Q. And at what level are you funded by 24 NASA? 25 A. Total budget is slightly over a hundred NELL MC CALLUM do ASSOCIATES, INC. 83 1 thousand per year. 2 Q. Is that for all of the University of 3 Colorado or just your laboratory? 4 A. That's just me. 5 Q. Is there another aspect that is funded 6 to the University of Colorado, as in these other 7 studies? 8 A. Well, the university is part of a 9 center: and yes, the total funding is on the order 10 of a half million dollars, or -- excuse me. It 11 may be less than that. It may be 300 to $400,000. 12 Q. What work will you be doing? 13 A. Again, we're devising models to look at 14 the interaction of chemicals, microgravity, and 15 radiation on regulation of hematopoiesis and 16 immune function. So, we are basically trying to 17 isolate systems that allow us to look at combined 18 influences of different things on stem cell 19 behavior and immune function. 20 Q. Are you looking at ways to develop 21 microgravities on earth, or are you going to put 22 systems in space and see the effects? 23 A. I think we're going to put them up 24 there. That is my proposal, basically to develop 25 a system that it is compatible with space flight, NELL MC CALLUM & ASSOCIATES, INC. 84 1 because it's my preliminary conclusion that 2 microgravity surrogates on earth are not adequate 3 surrogates of microgravity. 4 Q. Is the NASA work that's being done 5 right now to develop the potential for this system 6 to go into space? 7 A. Yes. We're using a variety of 8 compounds that may be potential contaminants in 9 spacecraft as a point of departure for the design 10 of that system. 11 Q. Is it accurate that this is the only 12 grant for work or funding from an outside source 13 that you have received that did not come from the 14 chemical refining industry? 15 A. At the present time, yes. 16 Q. Are there any chemicals that are of 17 particular interest in the NASA grant? 18 A. The chemicals we are currently 19 approaching, which is by no means -- this is not 20 -- this project is not linked to a given chemical. 21 It's really linked to looking at a process and 22 evaluating the influences of various conditions on 23 that process. 24 We're currently looking at some 25 aldehyde derivatives, acrolein. We are looking at NELL MC CALLUM & ASSOCIATES, INC. 85 1 hydrazine metabolites. Hydrazine is a rocket fuel 2 that's been slated for extensive use in space. 3 And we are tooling up to look at some of the 4 pyrolysis breakdown products of teflon. 5 Q. So, basically, you are looking for what 6 you might find inside a space capsule? 7 A. Yes. 8 Q. And the fuels to be used in space? 9 A. Yes. 10 Q. Are there any other projects that you 11 have initiated since you have been at the 12 University of Colorado we have not talked about 13 that are of the investigative nature? 14 A. We have begun to look at purification 15 schemes and culture conditions for the support and 16 growth of human bone marrow. These are still in 17 the initial stages, although they have been 18 perking along now for about two years. 19 Q. And how do you get your funding for 20 that work? 21 A. Spare time. 22 Q. Beg Peter to pay Paul? 23 A. To a certain extent. There is a great 24 deal of interest in developing procedures for the 25 purification of human stem cells and bone marrow NELL MC CALLUM & ASSOCIATES, INC. 86 1 transplantation. The transplantation center is 2 very interested in pursuing this. So, we have 3 received support in terms of cells and time and 4 facilities from them: and also part of what we 5 propose to do for API and CMA involves developing 6 analogous human systems. So, it's an above-board 7 use of the support that we have: but we're 8 basically diversifying our sources of funding to 9 pursue those studies. All of these are extremely 10 expensive types of studies. 11 Q. Where is your -- what is your 12 understanding of where science is or medicine is 13 in the isolation of these compartmentalized stem 14 cells now? Is there enough uniformity from how 15 things are reported in the literature that you can 16 say I have seen this stem cell reported as opposed 17 to this one? 18 A. We're dealing with two different data 19 bases. The data bases that have evolved from 20 looking at secondary leukemias, CML, in humans, 21 patients, using techniques involving cytogenetics, 22 genetic markers, have provided very sound data 23 base on which to evaluate clonality and the 24 general site of origin of these tumor types. That 25 hasn't changed. What has changed is our knowledge NELL MC CALLUM & ASSOCIATES, INC. 87 1 of the resolution or heterogeneity of the 2 compartments where these cells reside. 3 And in the last two years, the 4 pluripotential stem cell compartment, the 5 totipotential stem cell compartment has become a 6 compartment. I can tell you characteristics of 7 those cells. I can tell you characteristics of 8 some of them that don't pertain to others. 9 But we're dealing with -- what I am 10 trying to say is we're dealing with two different 11 sets of information and approaches to similar 12 questions that overlap but don't detract from one 13 another. 14 Q. It appears there are different cells, 15 you just can't tell me the characteristics of each 16 one and for sure how many there are? 17 A. I can tell you roughly how many there 18 are in one compartment or another, given certain 19 conditions. I can tell you some of their 20 behaviors. But certainly in the murine model, the 21 totipotent stem cell compartment has become more 22 complicated in terms of its structure 23 differentiationwise. The earliest cell we can 24 find will provide long-term repopulation of an 25 animal: but it won't provide short-term survival NELL MC CALLUM & ASSOCIATES, INC. 88 1 from lethal radiation, for example. The spleen 2 colony-forming cell, which has been a benchmark 3 for looking at stem cell behavior in the mouse 4 since the sixties, has basically been shown not to 5 be a very good indicator of "stem cell-mess". I could go through several others, but the point is 7 that it now appears to be much more complicated 8 compartments than we have tended to think of it in 9 the past. 10 Q. How about in humans? 11 A. We are -- we can't resolve it into 12 with the same -- we cannot look at it with the 13 same resolution we can with the mouse. I would 14 expect that from what we do know that it's 15 configured similarly, if not -- it's probably not 16 identical, but it's configured similarly. We do 17 have markers now that allow us to enrich for 18 certainly early cells that have the capability of 19 reconstitution. Whether that cell is the end cell 20 in the pyramid is anybody's guess. 21 Q. Does it appear that the end cell in the 22 pyramid, as you have described it, which I think 23 is a good description, does that cell divide 24 without differentiating? 25 A. You're asking what is now one of the -NELL MC CALLUM & ASSOCIATES, INC. 89 1 it's probably the most philosophically oriented 2 conundrums that's facing the field. The way it's 3 usually put is: Is the pluripotential or 4 totipotential stem cell capable of self-renewal? 5 For 30 years that's been the concept of what a 6 stem cell is; and in the last two years the 7 hypothesis has been put forward that, in fact, if 8 the compartment is large enough and division is 9 slow enough, you don't have to invoke self-renewal 10 as a characteristic of any cell. So, I would say 11 that at this point -- for 20 years that was a 12 comfortable question to answer. It's no longer a 13 comfortable question to answer. 14 Q. The comfortable answer for the last 20 15 years has been yes and now it's maybe not? 16 A. Yes. I will say that although we are 17 having to grapple with some new biology, it really 18 doesn't negate the overall structure of the system 19 or our knowledge of how things have been 20 regulated. We haven't turned the field on its 21 head. We have just had to deal with some new 22 concepts and dimensions that we haven't had to 23 deal with before, but this is how science 24 progresses. ,25 Q. You are no doubt familiar with the NELL MC CALLUM de ASSOCIATES, INC. 90 1 argument that materials like benzene may cause 2 some change in chromosomes at one of the early 3 stem cell levels, that as the cell differentiates 4 then into the lineage of blood cells that this 5 could result in the different kinds of leukemias 6 and lymphomas. What I would like to know is: Has 7 any of your work been able to address that one way 8 or the other? 9 A. Well, I think we have been able to show 10 that certainly in the murine system the target for 11 AML is, in fact, a very interesting target with 12 respect to the effects of benzene metabolites and 13 that the requirements for differentiation into 14 that compartment that would be a part and parcel 15 of that model appears to certainly in vitro in one 16 test appear to be valid. So, as far as linking 17 the potential of benzene to cause AML with a model 18 that involves the cell type that is a target for 19 the majority of AML's, I think we have been 20 initially successful. 21 Q. And I appreciate that, but I don't 22 think that's the question -- the answer to the 23 question I was asking. 24 I'm interested in going above the 25 myeloid progenitor cell and finding out whether or NELL MC CALLUM 8 ASSOCIATES, INC. 91 1 not you have done any work that would look at any 2 genetic damage to any of those cells and how that 3 affects the outcome of differentiation from those 4 cells, from a leukemia or lymphoma standpoint. 5 MS. ARRAS: By "those cells," 6 you are referring to myeloid cells? 7 MR. HOBSON: I beg your 8 pardon? 9 MS. ARRAS: By damage to 10 "those cells," are you referring to 11 the myeloid cells? 12 MR. HOBSON: No, those above 13 the myeloid cells, the 14 undifferentiated cells. 15 A. I have seen no model that would 16 adequately explain the effects of benzene or any 17 other chemical on a resting stem cell that leads 18 ultimately to a cytogenetic abnormality. 19 BY MR. HOBSON: 20 Q. That leads ultimately to 21 A. To a cytogenetic abnormality in a 22 replicating cell that would explain or even begin 23 to explain the mechanism involving the 24 pluripotential stem cell compartment. I think our 25 data reflects the fact that the cells that -- we NELL MC CALLUM & ASSOCIATES, INC. 92 1 may be shifting differentiation in that 2 compartment, but the cell that's responding is no 3 longer a totipotent cell. That's differentiation. 4 I know of no model other than the 5 obvious relationship between radiation exposure 6 and CML that would involve directly a resting stem 7 cell as a target for any agent causing a 8 malignancy in the hematopoietic system. And 9 there, the question I think at this point would be 10 whether the cytogenetic abnormalities that are 11 associated with CML, i.e., the Philadelphia 12 chromosome, is causal step, permissive step. 13 Whether it's initial step or a secondary event is 14 by no means clear. 15 Q. The myeloid progenitor cell, can it 16 reproduce itself without differentiation? 17 A. Theoretically, no. I don't think 18 technically that is -- once you reach that level 19 of commitment, you are going to have some change. 20 Now, to say that we know what every little change 21 is along the road, we don't know that. But I 22 think it is certainly generally accepted that in a 23 committed progenitor cell compartment, you are 24 looking at a process in which proliferation and 25 differentiation are linked. NELL MC CALLUM & ASSOCIATES, INC. 93 1 Q. And the work that you are doing on the 2 myeloid progenitor cell is a committed cell? 3 A. Yes, it's a multilineage -- it's a 4 multilineage cell, but it is committed. 5 Q. And the compartment above the myeloid 6 progenitor cell, those cells are not committed? 7 A. Those -- as far as we know, that is 8 that is the first demarcation that we have with 9 respect to commitment is at that level. 10 Q. That level being the myeloid progenitor 11 cell? 12 A. Yes. 13 Q. In this compartment that's above the 14 myeloid progenitor cell, is there evidence that 15 those cells can reproduce without differentiating? 16 A. The compartment obviously is able to 17 maintain itself, but that does not mean 18 necessarily that it has an absolute requirement 19 for every cell in there to be able to divide 20 without differentiating. The answer is basically 21 nobody knows. The compartment is certainly 22 capable of maintaining itself and that is a 23 it's one of the controversies that's bubbling in 24 the field today. 25 Q. Where in the process of fetal NELL MC CALLUM & ASSOCIATES, INC. 94 1 development does it appear that the totipotential 2 stem cell develops? 3 A. Well, it rises in the yolk sac: and in 4 fetal development, the liver is the first place 5 you begin to see extensive blood cell production. 6 It moves from the liver to the spleen to the bone 7 marrow. 8 Q. Would the totipotential stem cell exist 9 before the liver in the developing fetus? 10 A. Well, if you follow the model that we 11 have a fixed number of them that evolve during 12 embryogenesis and that that number is what we have 13 at birth, then obviously so. That's an area right 14 now I would say is, again, subject to considerable 15 controversy. 16 Q. Has anyone looked, to your knowledge, 17 at radiation of developing fetuses to see the 18 effects of leukemia on the resultant fetus in 19 order to answer that question? 20 A. There have been hundreds of studies 21 done on radiation. Whether or not there have been 22 any on in utero radiation and followed 23 development, at this point I can't recall. I 24 wouldn't be surprised, but I don't recall. 25 Q. Your CV that you brought with you NELL MC CALLUM S ASSOCIATES, INC. 95 1 today, are there any publications that have been 2 added in the last two years? 3 A. Yes. 4 Q. Is this CV relatively current? 5 A. Yes. 6 Q. I haven't had a chance to look at it 7 here. Do you have an extra copy there so we can 8 both look? 9 A. Yes. 10 Q. You went to the University of Colorado 11 in January of 1989? 12 A. Yes. 13 Q. And, so, you have three publications 14 that have come out since then: is that what I am 15 seeing here? 16 A. In terms of standard journal articles, 17 yes. One in submission and then two that have 18 been published. There have been other 19 publications, but they have either been symposium 20 or book chapters. 21 Q. The one listing that says manuscript 22 submitted, is that the one we have been talking 23 about, the CMA-API work? 24 A. Yes. 25 Q. The two just before that, the '89 and NELL MC CALLUM do ASSOCIATES, INC. 96 1 the '90 submissions, is that based on work that 2 was done by you at CIIT? 3 ,A. In large part, yes. Some of the final 4 -- in the case of the 1990 one, I think some final 5 changes were made while I was at Colorado. 6 Q. I am sorry, say that again. 7 A. I think some changes -- the manuscript 8 may have been altered during that period. 9 Q. But the underlying research was all 10 done at CIIT? 11 A. Yes. 12 Q. So, the only publication is the one 13 that you have submitted here that reflects work 14 done while you were at the University of Colorado? 15 A. Yes, other than, as I mentioned, 16 symposium chapters and book chapters. 17 Q. Are those listed? 18 A. Yes. 19 Q. They would be under which section of 20 your resume? 21 A. Let's see. "Books and Book Chapters." 22 Q. The recent ones would be on page 9, 23 then? 24 A. 8. For Books and Book Chapters, it's 25 reversed. NELL MC CALLUM & ASSOCIATES, INC. 97 1 Q. I see. The most recent at the 2 beginning? 3 A. Yes, the modern wonders of computer 4 technology. I have managed to get those reversed. 5 I haven't done it for my published articles. 6 Q. All right. What was your contribution 7 in the reference with Kreiger? 8 A. I'm co-author. We both authored the 9 chapter together. 10 Q. Which part in particular did you 11 author, if there was a particular part? 12 A. We wrote it together. If there was any 13 distribution of effort, he probably participated a 14 little bit more heavily in looking at some of the 15 physical characteristics of electromagnetic 16 radiation and I focused on the clinical and 17 biological. But we both collaborated extensively 18 on that. 19 Q. Could you give me a summary of what you 20 wrote in this article? 21 A. It is an extensive book chapter. I 22 mean it covers -- it covers virtually the entire 23 field with respect to the biology and the 24 epidemiological data surrounding nonionizing 25 electromagnetic radiation. I would hate to NELL MC CALLUM do ASSOCIATES, INC. 98 1 characterize it in a sentence or even a paragraph. 2 Q. Is that the only work that you have 3 published that deals with nonionizing radiation? 4 A. Yes. 5 Q. Have you done any investigations, 6 laboratory investigations involving nonionizing 7 electromagnetic radiation? 8 A. We have had some talks about looking at 9 various aspects of this question as it relates to 10 extended space flight, but nothing has 11 materialized at the present time. 12 Q. Have you considered setting up the same 13 sorts of investigations that you have done for the 14 CMA and API but doing them in various strengths of 15 electromagnetic fields? 16 A. As I said, we have had some discussions 17 in this area: but I would characterize these as 18 excruciatingly difficult experiments to design and 19 to control. I would say most of the attempts to 20 do so have lack -- have been lacking in very 21 important aspects. So, the question remains on 22 how to do them: and I have not approached that 23 lightly. It's not something you set up on a 24 Saturday afternoon. 25 Q. Have you approached the electric NELL MC CALLUM 8 ASSOCIATES, INC. 99 1 utilities or their trade associations for support? 2 A. No. 3 Q. What was the benzene case study that 4 you presented? 5 A. Benzene case study in that context 6 doesn't mean what I think you would think normally 7 as a case study. I was asked to use benzene as an 8 example to discuss the state of the art, the 9 advantages and disadvantages of pharmacokinetic 10 base modeling, using benzene as an example. 11 Q. Do you maintain reprints of what's 12 listed in your resume? 13 A. I have an incomplete set of reprints. 14 Q. Would you have copies of those for 15 which you have no reprints? 16 A. Not all of them. I probably am lacking 17 one or two. 18 Q. Would you know which ones those are? 19 A. Not reliably. I would have to check. 20 I just know that some of the more -- one or more 21 of the obscure ones when I have tried to find them 22 I have not been successful. But they are all in 23 the literature. 24 Q. Yes. 25 A. For the vast majority of them, I have NELL MC CALLUM & ASSOCIATES, INC. 100 1 copies. 2 Q. If I wrote you, would you be kind 3 enough to give me a copy of those I am having 4 difficulty finding? 5 A. Yes. 6 Q. What is it that you have been asked to 7 do in this case? 8 A. I have been asked to render an opinion 9 as to whether or not the diseases of four 10 individuals listed in this case was or could be 11 caused by exposure to benzene, ethylene oxide, or 12 butadiene. 13 Q. Have you written a report? 14 A. No, sir, I have not. 15 Q. Have you been asked to at all? 16 A. No. 17 Q. Do you depend on any of the 18 toxicological studies in support of your opinions 19 in this case? 20 MS. ARRAS: I am going to 21 object to the broadness of the 22 question. 23 BY MR. HOBSON: 24 Q. As opposed to epidemiological studies. 25 A. When I view literature as a whole, I NELL MC CALLUM do ASSOCIATES, INC. 101 1 rely on data that comes from experimental studies, 2 from clinical toxicology studies if they are 3 available, as well as epidemiological literature. 4 I don't know where I would draw the line. Could 5 you be more specific? 6 Q. Sure. Can you direct me to any 7 toxicological studies that in your view tend to 8 rule out non-Hodgkin's lymphoma being caused by 9 any of these three agents? 10 A. With respect to the specific study, no. 11 With respect to the weight of the evidence that 12 comes from an evaluation of the appropriateness of 13 animal models to man, as well as the human 14 experience, the epidemiology literature, yes. 15 Q. Tell me which ones of the toxicological 16 studies you view as part of the total picture that 17 supports your opinions. 18 A. Certainly the studies that look at the 19 differences in the biology, the tumor formation, 20 the differences in metabolism, species difference 21 in metabolism and activation of compounds such as 22 butadiene. And there, there are several. 23 Q. Could you give me specifics? 24 A. How about if I mark them? 25 Q. That would be fine. And by "them," you NELL MC CALLUM d, ASSOCIATES, INC. 102 1 are talking about the listings in your 2 bibliography? 3 A. Yes. 4 (Marking bibliography with check marks) 5 Q. All right, sir. I noticed one of your 6 other sheets that you told me about earlier is the 7 summary of the four cases: is that right? 8 A. Yes. 9 Q. The diagnosis that you put down for 10 each one of these gentlemen, can you tell me the 11 source of that diagnosis? 12 A. It's either -- well, it's a combination 13 of the medical summaries that I have read, as well 14 as the medical reports and histopathology reports 15 obtained from the medical records for each of the 16 individuals. 17 Q. Are you aware of any controversy about 18 the diagnosis of these individuals? 19 A. With respect to what? 20 Q. Has anyone come to you and said, for 21 instance, Mr. Ellis, we have some evidence that he 22 did not have well-differentiated small cell 23 non-Hodgkin's lymphoma. We have evidence that 24 perhaps he had some other disease or some other 25 variant of this disease? NELL MC CALLUM & ASSOCIATES, INC. 103 1 A. I think that it's obvious from his 2 history that at the initial time of diagnosis 3 there was some question as to whether or not the 4 presentation was that of chronic lymphocytic 5 leukemia or NHL: and subsequent to that, there is 6 still some questions that could be raised but in 7 general it appears to be much more like an NHL. 8 Q. Would it matter in your opinions 9 whether it was a lymphoma or a leukemia? 10 MR. HALL: Let me object to 11 the form of the question. Again 12 it's over broad. Any leukemia or 13 CLL? 14 MR. HOBSON: The one he 15 putatively had. 16 A. There is some difference in the data 17 that I would use to support my opinion. My 18 opinion would be the same that neither are caused 19 by exposure to benzene, but the literature would 20 be different that I would use to support them. 21 BY MR. HOBSON: 22 Q. How about butadiene and ethylene oxide? 23 A. Well, it's not compound related. It's 24 disease related; and there is nothing that's ever 25 been demonstrated to cause CLL, not even NELL MC CALLUM & ASSOCIATES, INC. 104 1 radiation. So, from that stand point, I would 2 distinguish CLL from NHL. In this particular 3 case, the prevailing diagnosis appears to be NHL. 4 Q. Is there any difference that you have 5 any -- let me start over. 6 Some of these -- all four of these 7 gentlemen have some form of non-Hodgkin's 8 lymphoma: correct? 9 A. Yes. 10 Q. Where I want to go with my question is: 11 Some of these listed as well-differentiated small, 12 well-differentiated diffuse, these different 13 descriptions that proceed non-Hodgkin's lymphoma, 14 do they play any part in your opinions at all? 15 A. With respect to causation? 16 Q. Yes, sir. 17 A. No. 18 Q. Are they the same disease? 19 MS. ARRAS: I object to the 20 form of the question. 21 A. They all go under the rubric of 22 non-Hodgkin's lymphoma. One of the 23 characteristics that defines different lymphomas 24 is the nature of the cell type and its behavior, 25 susceptible to treatment, its rate of growth, its NELL MC CALLUM 8 ASSOCIATES, INC. 105 1 ability to invade tissues, and a variety of other 2 distinctions that are a result of the particular 3 cell type in terms of differentiation and a 4 variety of factors which we don't understand, as 5 well. I think that it is important from the 6 histopathologic and a prognostic standpoint to 7 distinguish them one from another. That's the 8 obvious purpose of spending so much time on 9 differential diagnoses. 10 BY MR. HOBSON: 11 Q. Do these different variants of 12 non-Hodgkin's lymphoma come from the same stem 13 cell lineage? 14 A. Yes, but that's -- you could also ask 15 the question: Do all the cells of the body come 16 from the same fertilized egg? 17 Q. Good point. I'll withdraw the 18 question. 19 Let me ask it this way: If we find -20 for instance, I think you said that the myeloid 21 progenitor cell is the differentiated cell 22 committed differentiated cell that develops into 23 AML. Can you give me a similar committed 24 differentiated stem cell that develops into 25 non-Hodgkin's lymphoma and tell me if it's the NELL MC CALLUM 8 ASSOCIATES, INC. 106 1 same for these different variants? 2 A. Theoretically, there is a cell that is 3 a common lymphoid progenitor cell that ultimately 4 is thought to give rise to both the T and the B 5 cell lineages of the lymphoid system. But to 6 compare that process of differentiation with the 7 myeloid side is comparing, in the case of the 8 myeloid, a pretty straight tract to what in the 9 case of the lymphoid is a very labyrinthine and 10 complicated differentiation process. 11 As I mentioned earlier, a major 12 distinction between the lymphoid cells and the 13 myeloid cells is that the vast majority of 14 commitment, differentiation, and regulation of 15 that compartment and cell function occurs outside 16 the marrow. The cells that leave the marrow are 17 capable of division and activation and a variety 18 of processes that make them work, synthesize. So, 19 although ultimately they may be descended from the 20 same cell -- and there is some argument about that 21 -- and you can obviously say that at some point 22 they are descended from the same totipotent stem 23 cells, the transformation process, origin in terms 24 of their ontology is much more complicated. 25 Q. Could you delineate it for me? In NELL MC CALLUM do ASSOCIATES, INC. 107 1 other words, start back at a point in time at one 2 of these pluripotent levels where they are all 3 common and take me through the lineage to get me 4 to each of these variants for these gentlemen? 5 A. Well, I can certainly give you a 6 paradigm that would depict what we know about 7 differentiation for either the B or the T cell 8 lineage. The individual lymphomas are thought to 9 be a result of an abnormality occurring in the 10 cell at a given stage in the differentiation 11 process. 12 As I mentioned earlier, some people 13 think that antigenic stimulation and cells 14 responding to antigenic stimulation are, in fact, 15 one of the sites for the evolution of a lymphoma. 16 These cells arise in peripheral nodes, the 17 exception, as I mentioned, being multiple myeloma; 18 and I don't think that it's fair to classify 19 multiple myeloma as an NHL from a biological 20 standpoint. 21 If you want me to go through it, I can 22 talk about T cell differentiation, B cell 23 differentiation. 24 Q. For these four gentlemen, does it 25 matter if it is B cell or T cell differentiation? NELL MC CALLUM S ASSOCIATES, INC. 108 1 A. There is some discussion in the case of 2 Mr. Lilly, I believe, as to whether or not it's a 3 T cell origin. I'm not comfortable with that 4 diagnosis on the basis of what I have seen. I 5 certainly haven't seen enough to make a definitive 6 -- to reach a definitive conclusion. I think it's 7 more likely than not that we are looking at a 8 poorly differentiated diffuse B cell lymphoma, 9 although it may -- there is some argument as to 10 whether -- histopathologically it resembled what I 11 believe is called Lennerts. As far as taking him 12 as a whole, I think it's more likely than not that 13 we are looking at a series of B cell lymphomas. 14 MR. HOBSON: Lunch. 15 (LUNCH RECESS) 16 BY MR. HOBSON: 17 Q. Doctor, we're back from lunch. I'll 18 try to get on expeditiously here. I know you have 19 got a plane to catch. 20 Did you put together the list of 21 information that's here on this yellow sheet? 22 A. Yes. 23 Q. What all did you have to draw from to 24 gather this information on here? 25 A. I had the depositions of the NELL MC CALLUM & ASSOCIATES, INC. 109 1 plaintiffs. I recall the Culver report, which I 2 may have used; some maps that were provided me of 3 the facility: discussions that I have had with the 4 attorneys in this case, some of the information 5 that's on there has been represented to me with 6 respect to their work history: my own reading of 7 the various reports and materials that I had 8 available in the case. I basically am using that 9 just to keep the individual situations separate. 10 Q. Under Mr. LeBlanc's entry here, there 11 is a -- I don't know what this means. "P." 12 something. Can you tell me what this means, 13 please? 14 A. Yes. I have been told that there is 15 personnel monitoring data from Mr. LeBlanc that is 16 subsequent to 1977, and in that particular sample 17 there was no benzene detected. That's what that 18 means. ---19 Q. Have you seen any personnel monitoring 20 records other than the ones that are listed on 21 this one sheet of paper, which I see two entries? 22 A. No. 23 Q. Have you asked for any? 24 A. I have inquired as to personnel 25 monitoring data, and I am told that that's what is NELL MC CALLUM & ASSOCIATES, INC. 110 1 available. 2 Q. Have you been made aware of whether or 3 not there is any monitoring data for other 4 individuals who did similar work to these 5 gentlemen? 6 A. I can't say one way or the other. I 7 don't know whether I have asked that question. 8 Q. You don't know one way or the other if 9 any data exists? 10 A. No. 11 Q. I am correct? 12 A. That's correct. 13 Q. Would you be able to tell us at all 14 your impressions or opinions of these gentlemen's 15 exposure to the three chemicals that are involved 16 here, benzene, butadiene, or ethylene oxide? 17 MS. ARRAS: I am going to 18 object to the form in terms of 19 impression. What do you mean by 20 "impression"? 21 MR. HOBSON: Well, opinion. 22 A. I think they have all been exposed to 23 benzene at one level or another because we all 24 have. Basically, I think benzene is ubiquitous. 25 So, you are talking about some level of exposure NELL MC CALLUM 8 ASSOCIATES, INC. 111 1 clearly. I would like to look at my sheet, if I 2 may. 3 BY MR. HOBSON: 4 Q. Sure (tendering document). 5 A. (Reviewing document) Do you have 6 specific questions? 7 Q. Yes, sir. Let's talk about Mr. Ellis. 8 Can you give me your opinion of Mr. Ellis' 9 occupational exposure to benzene? 10 MR. HALL: I'm going to object 11 to the form of the question in the 12 sense that Dr. Irons has not been 13 retained by us to review data or to 14 render or form an opinion relative 15 to qualitative or quantitative 16 exposures to any of the chemicals 17 with respect to any of the 18 plaintiffs. To the extent that he 19 has seen any information which is 20 factual rather than opinion, he 21 certainly is entitled to answer 22 that; but I think that the question 23 calls for an opinion of a person 24 which in this instance is improper 25 opinion testimony from a lay NELL MC CALLUM & ASSOCIATES, INC. 112 1 witness. 2 MR. HOBSON: "I don't know" 3 will suffice, then. 4 MR. BAGGETT: You can go ahead 5 and answer the question. 6 A. I am not an industrial hygienist. I 7 rely on industrial hygiene data in reaching an 8 opinion. But I would -- I would not wish to 9 speculate on what individual exposures would be in 10 the absence of data to support it. 11 BY MR. HOBSON: 12 Q. Would it be fair to say that you don't 13 intend to offer any opinions in these cases that 14 we're here for today with regard to the amount of 15 benzene exposure that any of these gentlemen have 16 had? 17 A. That's correct. 18 Q. Would that be true for ethylene oxide 19 and butadiene, as well? 20 A. With regard to these individuals, yes. 21 Q. You were sent Nancy Culver's work in 22 this case, were you not? 23 A. Yes. 24 Q. Did you review that information? 25 A. Yes, I did. NELL MC CALLUM & ASSOCIATES, INC. 113 1 Q. What did you glean from that 2 information that is useful to your opinions in 3 this case, if anything? 4 A. It was a useful description, general 5 description of the facility. I found a lot of the 6 data in it unsubstantiated with respect to -- and 7 unqualifiable, unquantifiable in terms of degree. 8 For instance, there were comments such as benzene 9 present frequently in the document, as an example: 10 and I didn't know what to make of that. 11 Q. Were there any obvious errors that came 12 to light on your review of Nancy Culver's work, 13 things where you looked at them and said I know 14 this is wrong? 15 A. I don't recall. I reviewed that 16 earlier in October, and I do not recall 17 specifically the details. 18 Q. I see here that Ms. Arras provided you 19 with other monitoring data from Cities Service. 20 What data was that, please? 21 A. I have seen some monitoring data taken, 22 I believe -- I don't recall the precise year, but 23 I've seen -- I've seen monitoring data on the 24 facility taken at various times and in various 25 places. NELL MC CALLUM & ASSOCIATES, INC. 114 1 Q. I see that you've been provided with 2 this paper by Dr. Young from the American Journal 3 of Industrial Medicine. Is there anything about 4 what is said in that paper that comes to mind that 5 you feel Dr. Young was wrong in? 6 MR. HALL: Let me enter an 7 objection. First of all, it's 8 characterizing it as a paper; and I 9 am not certain it is a paper. 10 Subject to that objection, you may 11 answer, Dr. Irons. 12 A. In my opinion, he has misrepresented 13 the findings in several of the studies that he 14 cites, and I don't believe that one in evaluating 15 those studies necessarily comes to the same 16 opinion that -- I certainly don't, that Dr. Young 17 did. 18 MR. BAGGETT: Steve, in view 19 of your statement that you made 20 awhile ago, I mean it may eliminate 21 an awful lot of questioning, but 22 you furnished him Nancy Culver's 23 reports and the monitoring data. 24 Is it our understanding, for the 25 record, that you are not going to NELL MC CALLUM S ASSOCIATES, INC. 115 1 use him in any way as an expert 2 concerning the plaintiffs' 3 exposures? 4 MR. HALL: we can discuss this 5 off the record or on the record, 6 Bill, but 7 MR. BAGGETT: In view of your 8 objection, I think that it is 9 proper for us to ask this. 10 MR. HALL: He is not going to 11 render an opinion that plaintiff 12 "X" was exposed to. levels of 13 benzene in the amount of "Y" on a 14 date certain or on dates certain. 15 MR. BAGGETT: And he is not 16 going to rely on the monitoring 17 data that was furnished him, it 18 will not form any basis of his 19 opinion? 20 MR. HALL: You will have to 21 ask him that question because you 22 are not asking me. You will have 23 to ask the witness that question. 24 BY MR. HOBSON: 25 Q. Is the amount of exposure to benzene, NELL MC CALLUM S ASSOCIATES, INC. 116 1 butadiene, or ethylene oxide that these gentlemen 2 received in their occupation in any way import 3 to the opinions that you intend to express in this 4 case? 5 A. In my opinion, the diseases that these 6 gentlemen have are not caused by benzene: and 7 there is no evidence that the other agents caused 8 them. To the extent that -- in that context, 9 exposure really is in large part moot. By the 10 same token, I don't see any evidence here that 11 would suggest exposure certainly to benzene that 12 would be indicative of the types of abnormalities 13 that benzene is known to cause. 14 Q. Well, that brings me then back to my 15 question that I asked before: What is the 16 quantitative exposure for Mr. Ellis to benzene? 17 A. I have no -- for any of these 18 gentlemen, I do not have any information that 19 would lead me to any exposure data that I would 20 find reliable to determine or to assess what their 21 exposures were. I see no evidence that would lead 22 me to be able to do that. 23 Q. So, in other words, you don't know what 24 their exposure was to benzene occupationally? 25 A. I have seen no data that would allow me NELL MC CALLUM & ASSOCIATES, INC. 117 1 to reliably conclude what their exposure was. 2 Q. Can you then tell me that their 3 exposure was not high? 4 MR. HALL: Object to the form 5 of the question. 6 A. I see no evidence to quantitate what 7 their exposures are. I have said before that they 8 all obviously have had some exposure to benzene. 9 We really -- I don't see any data that would allow 10 me to indicate for an individual or to conclude 11 for any individual that they had high exposures to 12 benzene. 13 BY MR. HOBSON: 14 Q. Or that they did not? 15 A. Or that they did not. 16 Q. When it comes to information that could 17 be used for you to determine exposure levels, what 18 have you seen so I can know the basis of your 19 statements? We talked about Nancy Culver's 20 report, and you have got here in this letter some 21 documents from Ms. Arras about monitoring data. 22 Is there anything else that you recall? 23 A. I have read the personal statements of 24 the individuals. 25 Q. Their depositions? NELL MC CALLUM & ASSOCIATES, INC. 118 1 A. Yes. 2 Q. Anything else? 3 A. Not that I recall. 4 Q. Have you been provided any documents 5 that came from the Cities Service refinery in Lake 6 Charles that showed any information about spills 7 of benzene or benzene-containing materials? 8 A. I have seen sampling data that was 9 associated with individual incidence, area 10 sampling. 11 Q. Were you aware from reading Mr. Lilly's 12 deposition that he washed people's clothes with 13 benzene? 14 A. I recall the statement, yes. 15 Q. Is that a significant exposure in your 16 mind? 17 A. If, in fact, one were to wash people's 18 clothes in benzene and do it repeatedly, that 19 would be significant exposure. I, however, find 20 it very hard to believe, bas d on my knowledge of 21 industry practice and benzene in general, that his 22 description is compatible with the use of benzene. 23 Q. Is that the only basis for saying that 24 you doubt what he said is true? 25 A. That I find it incredulous that one NELL MC CALLUM do ASSOCIATES, INC. 119 1 would be able to work with benzene in that kind of 2 environment without posing a hazard from explosion 3 and a variety of other things, yes. I think it's 4 -- it doesn't make sense. 5 Q. Did I understand you to say that you 6 find that the description that Mr. Lilly gave of 7 washing people's clothes with benzene in that era 8 and that industrial setting is just incredible? 9 A. Yes. I think it's fair to say that 10 Mr. Lilly may have washed somebody's clothes with 11 a solvent. I think it is highly unlikely that he 12 was using benzene. 13 Q. If it turns out to be true that it was 14 benzene, would you say that the supervision at 15 that refinery was totally negligent in allowing 16 that to occur? 17 MR. HALL: Let me object to 18 the form of the question on a 19 couple of grounds. One, it calls 20 for a legal conclusion: number two, 21 it asks for an opinion outside his 22 field of expertise: number three, 23 it's an incomplete hypothetical. 24 BY MR. HOBSON: 25 Q. You may answer, if you can, Dr. Irons. NELL MC CALLUM & ASSOCIATES, INC. 120 1 A. I think that the conditions and the 2 situation are clearly undefined, and on that basis 3 I don't think I can answer that question. 4 Q. Should a supervisor allow an employee 5 that he supervises to wash clothes with benzene? 6 MR. HALL: Let me reiterate 7 the same objection I just stated 8 moments ago and make them 9 continuing for this line of 10 questioning. 11 MR. HOBSON: Fine. 12 MR. SPICER: We join in that 13 objection. 14 BY MR. HOBSON: 15 Q. You may answer, if you can. 16 A. Could you repeat the question? 17 Q. Yes, sir. I want to know if you think 18 that a supervisor should allow employees that he 19 supervises to wash people's clothes with benzene. 20 MR. HALL: Same objection. 21 MR. HOBSON: I think we said 22 you could ,have the continuing. 23 MR. HALL: I know I said it 24 but I am always leery of it and I 25 like to repeat myself. NELL MC CALLUM & ASSOCIATES, INC. 121 1 A. In this particular day and age, I would 2 find that a very improbable, if not impossible 3 situation. Certainly if it's within somebody's 4 power or knowledge to prevent or suggest 5 otherwise, that would be a very intelligent thing 6 to do. 7 BY MR. HOBSON: 8 Q. Would it have been unwise in the 9 1950's, as well, based on your review of the 10 literature? 11 MR. HALL: Same objection. 12 A. In the 19 -- I don't understand exactly 13 the frame of your question. If you are asking me 14 if based on what was known in the 1950's would it 15 be -- would it be unwise, I think the concern over 16 it in the 1950's would have been a lot different 17 than it would be today because in the 1950's it 18 was not by any means well established that benzene 19 was a leukemogen. 20 MR. BAGGETT: Was what, sir? 21 THE WITNESS: Was a 22 leukemogen. 23 BY MR. HOBSON: 24 Q. You are aware, though, aren't you, that 25 the American Petroleum Institute had published his NELL MC CALLUM & ASSOCIATES, INC. 122 1 toxicological reviews for benzene, in which it was 2 stated that benzene was related to leukemia? 3 A. Could you refer to a specific document? 4 I don't know what you are talking about. 5 Q. The American Petroleum Institute 6 toxicological review for benzene published in 7 1948. 8 A. I think that represented an opinion. I 9 think that there are some aspects of that review 10 itself which I don't find authoritative. 11 Q. But you are aware that it existed? 12 A. It was a comment that was made in an 13 API document at that particular point in time, I 14 believe that's correct. 15 Q. Would you agree with me that for a 16 supervisor to allow someone to wash clothes with 17 benzene would be an unsafe act that would be 18 recognized in the 1950's? 19 MR. HALL: Let me interpose 20 the same three objections. 21 MR. SPICER: We again join. 22 A. Chronic exposure to benzene was 23 certainly recognized by the fifties as being 24 associated with some bone marrow toxicity. The 25 vast majority of cases that were available in the NELL MC CALLUM & ASSOCIATES, INC. 123 1 literature at that time dealt with bone marrow 2 suppression, aplastic anemia, pancytopenia, 3 lymphocytopenia, thrombocytopenia. The number of 4 leukemia cases on record at that point in time was 5 an extremely small percentage of the total cases 6 that dealt with benzene toxicity. 7 Certainly chronic prolonged exposure 8 would be inadvisable, but by the same token I can 9 see where based on our knowledge at that time that 10 the stringent restriction of the use of benzene as 11 a solvent for those types of procedures would not 12 necessarily reflect our knowledge of the toxicity 13 of benzene at that point in time. 14 BY MR. HOBSON: 15 Q. Am I hearing you say that you wouldn't 16 jump on a supervisor who didn't stop the washing 17 of clothes with benzene? 18 MR. HALL: Same objection. 19 Not only that, it's argumentative. 20 MS. ARRAS: It's also vague 21 since it is not quantified by year. 22 A. Based on the state of the art at that 23 time I would still think it reasonable to restrict 24 the use of benzene in a chronic repeated exposure 25 scenario, based on toxicity of the blood; but, NELL MC CALLUM & ASSOCIATES, INC. 124 1 certainly the dangers associated with chronic 2 benzene exposure and leukemia were not well 3 appreciated in the fifties and, therefore, its 4 occasional use as a solvent would not necessarily 5 be, I think, restricted to the extent that it is 6 today. 7 BY MR. HOBSON: 8 Q. There is a sheet here in your file that 9 says "Index to Documents Transmitted." May I ask 10 who prepared that? 11 A. I'm not certain. That was sent to me 12 in one of the packages that I received from 13 Ms. Arras' office. 14 Q. So, it was prepared at least by someone 15 other than you or your office? 16 A. It was not prepared by me. 17 Q. Did you actually get all these things? 18 A. I believe so. 19 Q. Have you read them? 20 A. I have -- I have read and looked at all 21 of them. I can't recite them from memory, but I 22 have read them. 23 Q. Were you named as an expert in the 24 Chargois case? 25 A. Not to my knowledge. NELL MC CALLUM & ASSOCIATES, INC. 125 1 Q. Are you named as an expert in the Wing 2 case? 3 A. Not to my knowledge. 4 Q. Have you had any participation in 5 either the Chargois case or the Wing case other 6 than reading these documents that are listed here 7 in your packet for this case? 8 A. I don't believe so. 9 Q. There are some stapled together 10 documents here for the four gentlemen that sort of 11 appear to be sort of a typed-up summary, also. 12 Can you tell me where these came from? 13 A. Those were provided to me by Ms. Arras. 14 Q. Have you verified the accuracy of 15 what's contained in these four typed-up summaries? 16 A. In general, they are consistent with my 17 own reading. I have -- I can't speak to every 18 point on them: but in general, I recall that they 19 are representative of my own review of the 20 material. 21 Q. Would you have any idea as to what the 22 exposures of someone working on the loading rack 23 loading ethylene oxide would be? 24 A. No. I think it highly -- that would be 25 very difficult to ascertain that without NELL MC CALLUM & ASSOCIATES, INC. 126 1 industrial hygiene data. 2 Q. And you have seen no such data: is that 3 correct? 4 A. Not that would allow me to reach an 5 opinion as to what their exposures may have been. 6 Q. Would you have even seen any exposure 7 data of any kind, any airborne levels to ethylene 8 oxide or butadiene in the 1964 to '70 time period? 9 MS. ARRAS: I am going to 10 object to vagueness in referring to 11 this Cities Service plant. 12 BY MR. HOBSON: 13 Q. Anyplace, whether it's Cities Service, 14 PCI, PCD, the world, have you ever seen any data 15 for monitoring for ethylene oxide and butadiene 16 loading rack operations for worker exposure in the 17 world's literature, published or unpublished? 18 A. Not that I recall. 19 Q. Have you seen reference made to benzene 20 being present in the waste collection system at 21 the refinery, Cities Service refinery? 22 A. Yes. 23 Q. Are you in a position to dispute or 24 confirm any of that information? 25 A. On my personal -- based on my personal NELL MC CALLUM & ASSOCIATES, INC. 127 1 knowledge, no. 2 Q. How about from reviewing any records in 3 this case, would you be able to say that that's 4 true or not true? 5 A. I have seen some area sampling that was 6 associated with the waste system that suggests for 7 specific points in time there were measurable 8 amounts of benzene present. 9 Q. There are some -- two sheets of paper 10 typed horizontally on the page that have the style 11 of this case in the upper left-hand corner and 12 again appear to be some kind of a summary. Do you 13 know who prepared these documents? 14 A. Again, that was given to me by 15 Ms. Arras. I think it generally corresponds to my 16 own notes. It's not identical. 17 Q. I notice that there is a reference here 18 "Hiroshima - 1 day (1946)" for Mr. Ellis. Can you 19 tell me where that came from? 20 A. Well, as I recall, he stated that he 21 was present at Hiroshima after the fall of Japan. 22 Q. In your opinion, is that in any way 23 causative of his condition of what is listed here 24 first of all as CLL and then secondly as lymphoma? 25 A. No. NELL MC CALLUM & ASSOCIATES, INC. 128 1 Q. So, the fact he was an in Hiroshima one 2 day you don't find significant at all in causation 3 for his disease: correct? 4 A. No. 5 Q. I am incorrect? 6 A. I do not see that that's relevant to 7 the issue of causation. 8 Q. Are these medical records that are in 9 your file folder all on Mr. Lilly? 10 A. Can I see them? 11 Q. Sure (tendering document). 12 MR. HALL: Herschel, I didn't 13 understand your question. It's 14 ambiguous. It could be is that all 15 you have on Mr. Lilly, or it could 16 be do these reports all pertain to 17 Lilly. I am not certain which you 18 are asking. 19 MR. HOBSON: I was trying to 20 ask do they all pertain to 21 Mr. Lilly. 22 MR. HALL: Thank you. 23 A. Some of these are some records from 24 this one is from Virgil Talbott. 25 BY MR. HOBSON: NELL MC CALLUM & ASSOCIATES, INC. 129 1 Q. They are hard to read. I thought you 2 could tell me rather than me trying to cipher 3 them. 4 A. I just received these yesterday. I 5 think I have copies of these already in my 6 records, but these are -- of this, but I just 7 received these. 8 Q. Are these all the medical records that 9 you have brought with you from Colorado? 10 A. Yes. 11 Q. There is mention in here -- you pointed 12 out Mr. Talbott's records are part of those, and I 13 see on your summary sheet that is handwritten, you 14 have under diagnosis, well-differentiated, diffuse 15 non-Hodgkin's lymphoma, January '85, age 66. Then 16 you have small cell, what appears to be, cancer of 17 the lung. 18 A. Yes. 19 Q. 1991. What do you make of the small 20 cell cancer of the lung in relationship to his 21 non-Hodgkin's lymphoma? 22 A. It's a separate -- it's a separate 23 disease, distinct cancer. 24 Q. Do you see one being related to the 25 other at all? NELL MC CALLUM & ASSOCIATES, INC. 130 1 A. Not -- no, not really. 2 Q. Are you intending to give an opinion as 3 to which was the cause of his death? 4 MS. ARRAS: I object. It's 5 outside the area of the expertise 6 of this witness. 7 MR. HOBSON: All he has got to 8 do is say no. 9 MR. HALL: Not only that, it 10 assumes one or the other was and, 11 therefore, may be an improper 12 question. 13 MR. BAGGETT: Well, he knows 14 whether he is going to testify to 15 it or not, I think. 16 A. I believe he died of pneumonia. That 17 was the diagnosis, and I would not want to or feel 18 qualified to presume as to what the contributing 19 causes were. I don't have enough information. 20 BY MR. HOBSON: 21 Q. Would you defer that question to the 22 treating physician to make the call? 23 A. I would certainly defer it to 24 physicians who are more experienced in that than I 25 am. NELL MC CALLUM & ASSOCIATES, INC. 131 1 Q. Are you in a position to say whether or 2 not that would include his treating physician? 3 A. I don't know anything personally about 4 his treating physician: so, I couldn't comment one 5 way or the other. 6 Q. By the way, did you read Dr. Gore's 7 deposition in this case? 8 MR. HALL: I don't think it's 9 been transcribed yet. 10 MS. ARRAS: No, for the record 11 it has not been transcribed: so, it 12 would be physically impossible for 13 the witness to have read it. 14 A. I was going to say I don't recall. If 15 I read it, it certainly escaped me. 16 MR. HOBSON: A simple "no" 17 would have sufficed for me and my 18 simple mind, or "I don't remember." 19 Any of those would have done fine 20 for me. 21 MR. HALL: Well, something 22 that Bill Baggett has taught me, 23 Herschel, over the years is you 24 never want to leave a negative 25 inference on the record; and it NELL MC CALLUM & ASSOCIATES, INC. 132 1 could be inferred that perhaps 2 Dr. Irons was not doing his 3 homework. So, that's the basis of 4 the comment. 5 MR. HOBSON: Let me mark some 6 of these so I can have them 7 attached, please. 8 (OFF-RECORD DISCUSSION) 9 (IRONS EXHIBIT NOS. 2, 3, 4, 10 5, AND 6 WERE MARKED FOR 11 IDENTIFICATION) 12 BY MR. HOBSON: 13 Q. Dr. Irons, we have marked as exhibits 14 to your deposition your CV as No. 2; the benzene 15 bibliography as No. 3, including the check marks 16 that you put next to the numbers that indicated 17 the toxicity studies. 18 A. It's butadiene, not benzene. 19 Q. I have said that wrong every time. You 20 are right. Butadiene. And we have marked your 21 handwritten sort of summary by plaintiff: is that 22 right, as Exhibit No. 5? And we have marked your 23 folder -- and how would you characterize what you 24 keep in this folder? 25 A. Correspondence received from Ms. Arras NELL MC CALLUM & ASSOCIATES, INC. 133 1 with respect to this case. 2 Q. All right, sir. We have marked that as 3 Exhibit No. 4. I have got those all correct, have 4 I not? 5 A. Yes. 6 Q. And then No. 6 here is all of your 7 technical articles that you bound up in a little 8 black binder for us. I don't mean to imply that 9 that's all that there are, but these are the ones 10 that you brought with you? 11 A. Yes. 12 MR. HOBSON: Okay. If you all 13 want to take those, I am finished 14 with those, I think. 15 (OFF-RECORD DISCUSSION) 16 BY MR. HOBSON: 17 Q. I would just kind of like to run 18 through these articles in Exhibit No. 6. 19 "Hematologic Effects of Benzene: A Thirty-Five 20 Year Longitudinal Study of Rubber Workers," by 21 Kipen, et al. Can you point to me what it is in 22 summary fashion that you find in this article that 23 you in some way rely upon for your opinions in 24 this case? 25 A. I think it demonstrates the levels of NELL MC CALLUM A ASSOCIATES, INC. 134 1 abnormalities that are associated with peripheral 2 blood that have been found in workers chronically 3 exposed to benzene in which you have some evidence 4 of an increased incidence of AML. 5 Q. Anything else? 6 A. It points out some of the limitations 7 in hematologic monitoring for benzene exposure. 8 Q. Do you know where this plant or where 9 these plants were that are reflected in this 10 study? 11 A. They are the same plants that were the 12 subject of the Rinsky and Infante studies. 13 Q. The Ohio Pliofilm workers from 14 Goodyear? 15 A. Yes. 16 MR. HALL: The record won't 17 reflect this, but I would like it 18 to, that Mr. Hobson is asking 19 questions of the witness while 20 Mr. Hobson is looking at the 21 documents and Dr. Irons is 22 testifying from memory. I just 23 want the record to reflect that. 24 BY MR. HOBSON: 25 Q. If you feel like I treat you unfairly NELL MC CALLUM & ASSOCIATES, INC. 135 1 at any time, speak up, because I will try not to 2 be unfair to you. 3 A. That's fine. 4 Q. So, if you want to see something, don't 5 hesitate. 6 A. If I wish to see the documents, I will 7 tell you. 8 Q. Speak up, please. 9 MR. SPICER: You are referring 10 to the documents in the black 11 binder as Exhibit No. 12 MR. HOBSON: 6. 13 MR. SPICER: -- 6? 14 MR. HOBSON: Yes. 15 BY MR. HOBSON: 16 Q. I notice in the acknowledgements here 17 that the American Petroleum Institute provided the 18 data and the support for this particular study. 19 Were you aware of that? 20 A. Not in particular. I think it's very 21 reasonable that if they were going to get access 22 to the data, they probably would have to go 23 through the industry. 24 Q. This was a Goodyear plant? 25 A. It was Pliofilm during the war. I NELL MC CALLUM A ASSOCIATES, INC. 136 1 really can't say what the -- I'm not certain what 2 the ownership was during the war. 3 Q. Would you know if Goodyear Tire & 4 Rubber Company or any Goodyear entity has ever 5 been a member of the American Petroleum Institute? 6 A. I couldn't answer that question. 7 Q. Is there any particular table or 8 summary that's a part of this paper that you find 9 particularly sets out a portion that you are 10 relying upon? 11 A. I am relying on that paper in its 12 entirety for one thing or another. I would say 13 that the abstract certainly gives a good overview 14 of the results and their significance. 15 Q. Was there an excess of any disease 16 other than AML in this population? 17 A. Based on that study, as well as report 18 from the War Production Board on these plants, 19 there was evidence of blood dyscrasias and lost 20 worker time due to anemia and other abnormalities. 21 Q. How about any other cancers? 22 A. Not to my knowledge other than those 23 that have been reviewed and published in Infante 24 and Rinsky's papers. 25 Q. Are you saying that Rinsky and Infante NELL MC CALLUM & ASSOCIATES, INC. 137 1 have reported other excess cancers besides AML? 2 A. They have reported cases, and in the 3 follow-up they have enlarged the size of that 4 study. 5 Q. Going to the next paper here, "Benzene 6 (Benzol) Poisoning in the Rotogravure Printing 7 Industry in New York City," by Greenburg, et al. 8 Can you tell me what part this study plays, if 9 any, in supporting your opinions in this case? 10 A. It demonstrates the hematologic 11 abnormalities that have been associated with high 12 level exposure to benzene in a chronic situation. 13 It's the first controlled study of benzene 14 exposure in humans that I'm aware of. It 15 characterizes the blood abnormalities and did not 16 find any malignancies in the study group. 17 Q. Have you ever discussed this paper with 18 any of the authors? 19 A. Yes, I have. 20 Q. Which one, Dr. Goldwater? 21 A. Dr. Goldwater, many years ago. 22 Q. "Disturbances in the Blood Following" 23 -- and it appears that there has been part of the 24 page obliterated, so I don't know if that's all 25 the title or not. NELL MC CALLUM & ASSOCIATES, INC. 138 1 A. I think it is. 2 Q. Okay. "Disturbances in the Blood 3 Following Exposure to Benzol" by Goldwater. Is 4 this a paper reporting on the same rotogravure 5 workers? 6 A. Yes. There were two papers that came 7 out very closely together. 8 Q. "Types of Leukemia in Chronic Benzene 9 Poisoning. A study in Thirty-Four Patients" by 10 Aksoy, et al. What in here do you find that 11 supports your opinions in this case, if anything? 12 A. The predominance of acute myelogenous 13 leukemia associated with benzene exposure. 14 Q. Are you aware of Dr. Aksoy reporting 15 excesses of any other kinds of leukemia in 16 benzene-exposed populations? 17 A. I am aware that Dr. Aksoy holds an 18 opinion that, in fact, benzene may cause a variety 19 of difficult neoplasms; but if I look at his data 20 separately in the aggregate, I reach the 21 conclusion that he really only has evidence to 22 support AML. 23 Q. So, when you and he look at the same 24 data you get different opinions: is that what you 25 are saying? NELL MC CALLUM 3 ASSOCIATES, INC. 139 1 A. If we took it on an individual basis, 2 if you want to discuss that paper, we can. I 3 would hate to have to just summarize in general 4 what we agree on and what we disagree on. 5 Q. I am talking about the different kinds 6 of leukemia that benzene can induce. 7 A. I think that Dr. Aksoy's data in the 8 aggregate can support a relationship with AML and 9 a deficit for some of the other leukemias in 10 benzene-exposed workers. 11 Q. But he interprets his data differently? 12 A. I think it's fair to say that he 13 interprets his data differently than I do. 14 Q. "Mortality of Rubber Workers with 15 Reference to Work Experience" by -- I never can 16 say this man's name and apologize -- Andjelkovich? 17 A. Well, it's a lady; and it's 18 Andjelkovich. 19 Q. A lady. Well, I am even worse than I 20 thought. I am wrong on both counts. My apologies 21 to whoever reads this transcript. 22 What in this paper do you rely upon in 23 support of your opinion, if anything? 24 A. If you will permit me, there is a 25 series of papers that examine or follow the work NELL MC CALLUM & ASSOCIATES, INC. 140 1 of the group at the University of North Carolina 2 over the years, looking at the relationship 3 between occupational exposure in the rubber and 4 tire industry and lymphoid neoplasms. They begin 5 with McMichael and Andjelkovich and continue on 6 through Arp, Checkoway, and Wilcosky: and as a 7 total body of work they represent, to me, an 8 evolution in understanding and characterizing the 9 relationship between occupational exposure in the 10 rubber industry and lymphoid neoplasms. If you 11 would like, I can characterize that further: but I 12 would rather not just take a single paper. 13 Q. Sure, that's fine. I would accept the 14 aggregate characterization. 15 A. Early studies by McMichael defined 16 suggested that there was possible relationship 17 between exposure -- occupational exposure in the 18 rubber industry and lymphoid neoplasms. There was 19 no industrial hygiene data in that study. The 20 surrogate for exposure was simply the assumption 21 of which categories or workers might be exposed to 22 benzene. Benzene formed the basis for the 23 assumption, that benzene was associated with their 24 findings. 25 In further studies, when actual NELL MC CALLUM & ASSOCIATES, INC. 141 1 exposure measurements were made, the same finding, 2 that is the relationship between exposure in the 3 tire and rubber industry and lymphoid neoplasms, 4 was confirmed: but the relationship to benzene 5 was, in fact, disproven. The final conclusion of 6 the group is that the relationship between 7 occupational exposure and disease does not 8 correlate with benzene but, in fact, there are 9 higher associations with other solvents. 10 Q. Such as? 11 A. I think the two that were suggested 12 were carbon disulfide and carbon tetrachloride. I 13 don't believe that those studies provide a 14 reliable basis for reaching that conclusion, but 15 they certainly point out the disparity between 16 exposure to solvents in general and benzene in 17 particular. 18 Q. Are you aware of any literature that 19 suggests that carbon disulfide or -- I have 20 forgotten what else you said already. 21 A. Carbon tetrachloride. 22 Q. -- carbon tetrachloride can induce 23 leukemias in humans? 24 A. No, I'm not. That's the only reference 25 I know to that. NELL MC CALLUM 3 ASSOCIATES, INC. 142 1 There is a study not in there simply 2 because I couldn't put my hands on it quick enough 3 by Monson and Fine from 1978 that independently 4 confirms that the incidence of lymphoid neoplasms 5 in the rubber industry appears to have been 6 sharply reduced in the transition from a coal 7 based -- coal tar-based solvent to petroleum-based 8 solvent, which I think is consistent with the 9 findings from this group. 10 Q. Can you attribute any chemical 11 difference to the solvents that are coal derived 12 versus petroleum derived? 13 A. I think that in order to give a 14 responsible answer to that question, I would have 15 to have a lot more information than I do. There 16 are certainly major differences both in the 17 content of benzene, as well as other compounds. 18 Naphthas, a variety of other agents. 19 Q. Is there any relationship between 20 polynuclear aromatic hydrocarbon exposures and 21 leukemia? 22 A. There have been some suggestions in 23 what I would consider to be a confusing literature 24 base that cigarette smoking has been in at least 25 one study associated with a slight increase in the NELL MC CALLUM do ASSOCIATES, INC. 143 1 incidence of leukemia. In other studies, that 2 hasn't proven to be the case. 3 That is a source for exposure to 4 polyaromatics in general, but it's also very 5 complicated. Cigarette smoking is a very 6 complicated exposure scenario. 7 Other than that, I am not aware of 8 individual studies looking at polyaromatics. For 9 one reason, you don't often find in an 10 occupational setting a defined exposure to 11 polyaromatics. 12 Q. Are there sources of exposure to 13 polyaromatics in rubber plants, such as the kind 14 that are described in the North Carolina studies? 15 A. I wouldn't be surprised, but I don't 16 have any specific hygiene information. The rubber 17 -- rubber plants are an exceedingly complex 18 occupational setting. Very complex. Exposure 19 scenarios are almost impossible to define. I 20 think it's fair to say that there is a problem 21 with respect to occupational exposure in that 22 setting and the development of lymphoid neoplasms, 23 although it's by no means yet clear what the 24 distinction amongst those are. But by the same 25 token you cannot, I think, based on the NELL MC CALLUM & ASSOCIATES, INC. 144 1 literature, assign or assume that causation is due 2 to benzene. 3 Q. What would be the sources of PNA 4 exposure in a synthetic rubber plant or a rubber 5 goods manufacturing plant such as the kind studied 6 by the University of North Carolina in these 7 articles? 8 A. In coal tar-derived products, I would 9 expect that you could find some, and certainly 10 naphthas associate in the solvent base. In 11 petroleum based, I don't expect you would find the 12 same constituents. 13 Q. How about some? 14 A. Some is a relative term. I won't say 15 as a scientist that you never can find something 16 if you look for it. I don't know at what levels 17 you would expect to find it. 18 Q. You know, of course, that the rubber 19 solvents that have been used for the last 15, 20 20 years in the manufacture of tires is just a cut 21 off of the crude still in a refinery? You know 22 that? 23 A. It's a -- I think it's defined a little 24 bit more precisely than that. Certainly the 25 benzene content has been examined, in an effort to NELL MC CALLUM & ASSOCIATES, INC. 145 1 reduce it or eliminate it. 2 Q. And there is polynuclear aromatic 3 hydrocarbon material contained in crude oil? 4 A. Sure. 5 Q. Would you not expect, then, that in 6 this rubber solvent cut from the simple 7 distillation of crude oil that you would get some 8 polynuclear aromatic hydrocarbons? 9 A. Again, the question is the amount and 10 whether it's analytically measurable or 11 biologically significant; and I am not in a 12 position at this point to address that 13 responsibly. 14 Q. Can you even tell me for sure that 15 there is a difference in PNA content 16 quantitatively or qualitatively between coal tar 17 -- coal-derived solvents and petroleum-derived 18 solvents? 19 A. Definitively, no. I would suspect that 20 there are differences. I would expect to find 21 more in the coal tar-based product. 22 MR. HOBSON: If you wouldn't 23 mind, to satisfy yourself we have 24 an accurate copy: and we will give 25 the copy to Joyce. NELL MC CALLUM S ASSOCIATES, INC. 146 1 BY MR. HOBSON: 2 Q. What other sources of polynuclear 3 aromatic hydrocarbons would you expect it to be in 4 a synthetic rubber plant or a tire plant such as 5 the ones in the North Carolina study? 6 A. In particular, at this -- at this 7 particular point, I can't think of any. 8 Q. The next article here that you have is 9 "Hodgkin's disease and Acute Leukemia." It looks 10 like case reports by Rosner, et al. 11 A. There are a series of papers there that 12 are representative of the literature on secondary 13 malignancies -- malignancies secondary to 14 chemotherapy for other primary diseases: and they 15 basically characterize what I said to you earlier 16 today with respect to the overwhelming 17 predisposition for AML as the secondary malignancy 18 in these patients. 19 Q. Is AML the only disease that is 20 secondary to the chemotherapeutic agents? 21 A. Virtually, yes. 22 Q. There are no reported instances of 23 multiple myeloma, non-Hodgkin's lymphoma, 24 Hodgkin's disease? 25 A. There -- well, I can characterize -- I NELL MC CALLUM do ASSOCIATES, INC. 147 1 can sum up certainly the opinions of some of the 2 authors there in the context of the data you see 3 there, as well as more recent publications such as 4 the last edition of the text "Leukemia," that 5 although they have been an occasional case report 6 of one type of lymphoid neoplasm or another that 7 they are so sporadic and uncommon that they 8 probably are incidental and not -- coincidental 9 and not related to chemotherapy. 10 Q. Meinhardt's report "Environmental 11 epidemiologic investigation of the 12 styrene-butadiene rubber industry." Can you tell 13 me how this plays a part in your opinion, if it 14 does? 15 A. It's one of the papers that has 16 characterized epidemiologic exposure to butadiene. 17 It was one that I was able to place my hands on 18 quickly. It isn't in there because it bears any 19 more or less weight than the others. It just 20 happened to be one that I physically had in my 21 hand. The others are listed in the bibliography 22 that I gave you. 23 Q. I notice at the top of this article you 24 have written "butadiene." Does Meinhardt's paper 25 have anything to do with benzene, as well? NELL MC CALLUM & ASSOCIATES, INC. 148 1 A. It looks at synthetic rubber plants 2 which it's often difficult to segregate or 3 separate out exposures: but I think that the 4 Meinhardt study, as I recall, reflects primarily 5 butadiene exposure. I would not expect to see 6 very heavy benzene exposure in that setting. 7 Q. What do you mean by "very heavy"? 8 A. Significant. 9 Q. Would you expect there to be benzene 10 exposure at approximately 1 part per million in 11 the synthetic rubber plant, particularly in this 12 plant study by Meinhardt and reported here? 13 A. Can I see the paper? 14 Q. Absolutely (tendering document). 15 A. (Reviewing document) 16 The reported detectable levels of 17 benzene in samples in this study I take to be 18 trivial with respect to the benzene exposure. 19 Q. I am sorry, would you say that again, 20 please? 21 A. The exposures are extremely small. I 22 don't think they are of biologic significance. 23 Q. And what level is being reported there? 24 A. They range between .08 and .14 ppm, 25 with a mean of .1 ppm. NELL MC CALLUM do ASSOCIATES, INC. 149 1 Q. And does it report there when those 2 studies -- when those samples were made in 3 relation to when these people actually worked 4 there? 5 A. (Reviewing document) It's contemporary 6 with the study, but it's not historical data. It 7 was taken at the time of the study. 8 Q. Historical data could be much more 9 meaningful as far as being representative than 10 something done by a government inspector coming in 11 after the fact? 12 A. I think it depends on the 13 characterization of what was going on in the plant 14 with respect to operations in process. If, in 15 fact, the process hasn't changed depreciably or 16 the conditions of use, then I think you could take 17 it to be reasonable representation. 18 Q. Do you know one way or the other what 19 was done here? 20 A. It does not appear to me from looking 21 at the ingredients that are used in the process 22 that there would have been any drastic changes, 23 certainly over the time that we're talking about. 24 Q. Do you know one way or the other? 25 A. No. NELL MC CALLUM & ASSOCIATES, INC. 150 1 Q. For instance, you wouldn't know if the 2 styrene that was received at that plant at one 3 time before it was loaded into the barges to be 4 transported was loaded in over a benzene heel, so 5 that the styrene became contaminated with benzene? 6 Have you ever heard anything like that? 7 A. I have heard descriptions of that sort: 8 but by the same token, you have to look at what 9 the range of benzene concentrations were 10 associated with styrene. In any event, if you 11 look at the pattern of neoplasms that were seen in 12 this facility and the results of the study in 13 these two plants, it's not consistent with benzene 14 exposure. 15 Q. More consistent with butadiene 16 exposure? 17 A. Well, it's inconsistent with any 18 causative exposure. It does not follow the 19 pattern for benzene. 20 Q. All right. The next article, 21 Dr. Downs' report and others "Mortality Among 22 Workers at a Butadiene Facility." Do you know if 23 workers at that facility were ever exposed to 24 benzene? 25 A. Well, I have said before, everyone is NELL MC CALLUM & ASSOCIATES, INC. 151 1 exposed to benzene in one form or another. 2 Q. Touche. Occupationally exposed. 3 A. I am not aware of that. 4 Q. Would it matter? 5 A. It would depend upon the relationship 6 between exposure and disease, whether or not that 7 would have any impact at all. Certainly in the 8 case of butadiene, there is no dose dependent 9 relationship between the clustering of 10 lymphosarcoma and butadiene exposure. I think 11 that's been updated recently by Divine, Barbara 12 Divine. 13 Again, I didn't have that in front of 14 me: so, I just put that one in there. 15 Q. Would you know if there is any 16 butadiene exposure in a tire manufacturing plant? 17 A. My understanding is there is very 18 little. 19 Q. What's the basis of that understanding? 20 A. The nature of the chemical, nature of 21 butadiene by the time it gets into a tire, its a 22 polymer; and the out-gassing from tire manufacture 23 I don't think is -- as I recall, the deliberations 24 on the workshop at Research Triangle Park on 25 butadiene, I think it was generally accepted by NELL MC CALLUM & ASSOCIATES, INC. 152 1 most people present that that was not a major 2 source of butadiene exposure. 3 Q. So, generally speaking, you are saying 4 that tire builders and tire workers are not 5 exposed to butadiene occupationally? 6 A. The initial compounding of the rubber 7 polymer and in the manufacture of butadiene are 8 potential occupation sources of exposure to 9 butadiene, but I don't think tire manufacture is a 10 significant occupational source. 11 Q. I missed the very first part. Are you 12 talking about compounders? 13 A. The two places where there is potential 14 exposure to butadiene is in its obvious production 15 and in the manufacture of the polymer. 16 Polybutadiene, butadiene-styrene, acrylonitrile 17 butadiene, whatever. Those are the -- I think 18 exposure to butadiene is relatively restricted. 19 Q. And that's not based on any sampling, 20 it's discussions with others? 21 A. Yes. 22 Q. And you have here "Hazardous Materials 23 Toxicology, Clinical Principles of Environmental 24 Health," edited by Sullivan and Kreiger. Can you 25 give me a summary of why this is here? NELL MC CALLUM 8 ASSOCIATES, INC. 153 1 A. It's a book chapter that I was asked to 2 write in that textbook on hematotoxicity. 3 Q. And I don't see the second page. Do 4 you recall the date this was published? It may be 5 in your resume. 6 A. It's '91. 7 Q. Hot off the press. 8 A. Hot off the press. 9 Q. In the interest of time, I won't try to 10 go through all of this chapter. Do you relate in 11 here at what exposure level you believe to be 12 causative of leukemia for benzene? 13 MR. HALL: Let me object to 14 the form of the question. Again, 15 Herschel, you are using a general 16 term to describe very specific 17 diseases. 18 BY MR. HOBSON: 19 Q. You may answer if you can, Doctor. 20 A. I think you will find that in there I 21 characterize the evidence that's available with 22 respect to levels of benzene exposure that have 23 been associated with an increased incidence of 24 acute myelogenous leukemia. You have asked me 25 that question before, and I think you will find NELL MC CALLUM & ASSOCIATES, INC. 154 1 that statement in there just recounts what I said 2 before. 3 Q. Did anyone assist you with this 4 chapter? 5 A. No. 6 Q. I notice that you list the glycol 7 ethers in your chapter. Where do you think we are 8 causation wise with glycol ethers and leukemia? 9 A. We're not there. There are a lot of 10 issues that are discussed in that book chapter 11 that relate to incomplete or partial data in 12 support or against various relationships between 13 exposure and disease. The fact that it's in there 14 does not mean that I accept it as a proven. 15 Q. Do you believe that there is evidence 16 that supports causation of leukemias by ethylene 17 oxide? 18 A. I think the ethylene oxide data is 19 contradictory and confusing. We had some 20 relatively poorly designed studies that suggested 21 a relationship early on. The exposures were 22 almost causaly described. We have had studies 23 suggesting a relationship with lymphoid neoplasms, 24 and we have had studies suggesting no relationship 25 for leukemia or lymphoid neoplasms. I think there NELL MC CALLUM & ASSOCIATES, INC. 155 1 are questions you can raise about most of the 2 studies. Certainly in the aggregate it doesn't 3 lead you to the conclusion that ethylene oxide has 4 been established as a human leukemogen. 5 MR. HOBSON: Let me give you 6 this book for copying. 7 BY MR. HOBSON: 8 Q. Dr. Irons, let me progress onward here, 9 hopefully. At least onward in the day. 10 You have said that it is your opinion 11 that high levels of exposure to benzene are 12 causative of AML in humans. Have I got enough 13 qualifiers in there to make you comfortable with 14 that? 15 A. I can live with that. 16 Q. All right. What is it that has led you 17 to that conclusion? 18 A. The sum total epidemiologic and 19 clinical history of benzene, as well as our 20 knowledge of the relationship between bone marrow 21 toxicity and exposure to chemotherapeutic agents 22 and secondary AML. 23 Q. When you write a chapter in a book like 24 the one we just talked about and here's ethylene 25 oxide and you assess the data, what's the NELL MC CALLUM & ASSOCIATES, INC. 156 1 yardstick that you use for you, Dr. Richard Irons, 2 saying I believe this relationship is established? 3 A. Obviously if you have access to 4 reliable human data, it should be certainly a 5 primary source of information. The problem that 6 we have there is that epidemiology studies, 7 quantitative studies that you can rely on and 8 hopefully draw some relationship between exposure 9 and the incidence of disease are extremely 10 difficult to control and to conduct properly. 11 They are very hard to test hypotheses because you 12 can't treat humans and manipulate them like you 13 can animals. As a result, it's very difficult to 14 obtain a definitive quantitative epidemiology 15 result unless you have got an overwhelming 16 relationship or incidence of disease to a defined 17 exposure. 18 As a result, you have to look at -- I 19 look at the pattern. We have multiple studies. 20 Do we see a consistent pattern? Do we see a 21 pattern between exposure and disease that allows 22 us to arrive at a general conclusion that there is 23 a relationship here? It's also very useful when 24 you have questions of this nature to be able to 25 rely on mechanistic or animal studies to at least NELL MC CALLUM 3 ASSOCIATES, INC. 157 1 determine whether or not there is a basis for that 2 relationship, and whether what you see in 3 epidemiology studies can be supported by 4 mechanistic data. 5 In the case of benzene, we have a clear 6 pattern. We have a clear pattern for AML, and I 7 think we have a clear pattern in the occupational 8 rubber industry to suggest benzene is not 9 associated with NHL. 10 For the other two agents we are talking 11 about, I don't think we have a clear pattern at 12 all. We do not have consistency in the ethylene 13 oxide literature. We have got some major 14 questions that suggest that in these studies there 15 are uncontrolled variables. 16 We also, as I said, have confounding 17 results. We have the same picture in the 18 butadiene epidemiology literature where we have 19 inconsistent results. We have inverse 20 relationships to exposure, and I don't think that 21 one can draw a conclusion from the data as it 22 currently exists. 23 Q. So, for ethylene oxide and butadiene, 24 you are just not prepared to take a position one 25 way or the other to say butadiene does cause human NELL MC CALLUM do ASSOCIATES, INC. 158 1 cancers or butadiene does not cause-human cancers? 2 A. Well, if you take butadiene, for 3 example, you have studies that would suggest a 4 potential relationship with acute myelogenous 5 leukemia: and you have studies that suggest there 6 is a deficit. You have studies that suggest a 7 relationship with lymphosarcoma that is not dose 8 responsive, and then in other studies you don't 9 see that at all. 10 In the aggregate, I don't know what to 11 draw. In order to assume that butadiene is 12 associated with any one of those diseases, you 13 have to assume that butadiene exposure will cause 14 different diseases in different people, and that 15 does not make sense. I think it's more likely 16 that we're looking at the artifacts associated 17 with the difficulty of designing and conducting 18 definitive epidemiology studies. 19 Q. I take it that there are some 20 relationships that you would feel comfortable with 21 saying, "no, I am convinced this does not exist'; 22 and you gave me an example of your view of the 23 rubber workers and non-Hodgkin's lymphomas? 24 A. Yes. That relationship for benzene, 25 not for rubber workers. NELL MC CALLUM & ASSOCIATES, INC. 159 1 Q. Yes. 2 A. I am not -- in fact, I think there is a 3 pattern present that comes through the rubber 4 studies that suggests there is a potential problem 5 there, but I think that the data at the same time 6 discounts the association with benzene exposure. 7 Q. But if we talk about butadiene, you 8 don't see any studies that are as convincing as 9 benzene and non-Hodgkin's lymphoma deficit in the 10 rubber workers or that are as convincing as 11 benzene and AML in other workers, in refinery 12 workers, for instance? 13 A. I think I agree with you, but I'm not 14 sure that I fully comprehended the question. Can 15 I restate it? 16 Q. Surely. 17 A. If what you are asking me is does the 18 butadiene literature provide the same basis for 19 saying that butadiene is not associated with these 20 diseases as the benzene literature and the rubber 21 literature is, no, it does not. 22 Q. I guess just to kind of boil it down to 23 layman's terms, your comfort index with saying 24 that butadiene does not cause cancer, it's just 25 not as high as it is in saying that benzene in NELL MC CALLUM & ASSOCIATES, INC. 160 1 rubber workers does not cause non-Hodgkin's 2 lymphoma? 3 MR. HALL: I want to enter an 4 objection to the form of the 5 question. Cancer is much too broad 6 a term in the context of the case 7 that brings us here today. 8 A. As a scientist, I have to rely on the 9 rigor and reliability of the data that I have to 10 reach a conclusion. In the case of butadiene 11 epidemiology literature, that rigor and data is 12 not sufficient for me to render an opinion that 13 butadiene is associated with the development of 14 leukemia or lymphosarcoma. By the same token, 15 there is no data that I can rely upon to say 16 definitively that there is no relationship. The 17 evidence is just not there to make the case. 18 BY MR. HOBSON: 19 Q. When you talk about the rigors that you 20 apply as a scientist -- I'm talking about now you, 21 Dr. Richard Irons -- can you quantify that for me 22 someway? 23 A. As I said, if we even had a 24 reproducible consistent pattern of disease, it 25 would be helpful, even if the exposure data was as NELL MC CALLUM 6 ASSOCIATES, INC. 161 1 poor as it is; but we don't even have that. We 2 have inconsistency. We just don't have reproduced 3 -- we don't have reproducible studies on which to 4 base a conclusion that butadiene is associated 5 with either leukemia or with lymphoid neoplasms. 6 Q. But don't we have some degree of 7 inconsistency even though for benzene and AML? 8 A. Inconsistency in what context? If you 9 look at -- if you look at a variety of studies in 10 the case of benzene with AML, the one thing -- you 11 have inconsistency with respect to the magnitude 12 of the increased incidence from one study to 13 another. But where you have a relatively pure 14 play on benzene, there is not much question about 15 what benzene does. 16 Q. You have a relative what? I didn't 17 hear the term. 18 A. When you have a relatively pure 19 exposure to benzene. By that I mean where you can 20 define benzene as the predominant agent you are 21 talking about, I think the studies are fairly 22 consistent. 23 Q. But not totally? I mean if you look at 24 workers in the shoe industry in Turkey where there 25 were high exposures, long-term, to benzene, you NELL MC CALLUM & ASSOCIATES, INC. 162 1 don't always find predominating AML in those 2 groups of workers, do you? 3 A. If you compare the incidence of 4 hematopoietic and lymphoid neoplasms across the 5 board for those that were in the shoe industry and 6 are defined as exposed compared to those that have 7 been collected and defined in Aksoy's studies as 8 unexposed, you do see consistency. You see an 9 elevation in AML in the benzene. You see a 10 deficit of lymphoid neoplasms and CML and CLL in 11 the benzene-exposed workers compared to whatever 12 groups of controls he has put together. 13 Now, those studies suffer from problems 14 of experimental design and ability to reconstitute 15 what the criteria were that were used; but you 16 have to remember that Dr. Aksoy is even 17 predisposed to consider other malignancies as 18 being caused by benzene. And his own data will 19 support that. 20 Q. When you render your opinion as to 21 causation, such as you have in this case, such as 22 you did in your chapter of the textbook that we 23 looked at, is more probable than not enough for 24 you to say this material causes this disease? 25 A. Given a scientific evaluation of the NELL MC CALLUM 8 ASSOCIATES, INC. 163 1 data and the studies that are available, more 2 probable than not is sufficient. But in arriving 3 at a decision as to whether or not the evidence in 4 a given study is reliable or can be used in that 5 context, I may apply a different standard. 6 Q. So, when you look at an individual 7 study and you evaluate that study, more likely 8 than not is not enough? It's a higher standard 9 for you? 10 A. There is a difference between using 11 statistical methodology to determine whether or 12 not a study has sufficient power or reliability to 13 distinguish between an exposed and an unexposed 14 population or a difference in incidence. That is 15 a separate issue than whether or not based on that 16 study one can arrive at a conclusion that it's 17 more probable than not that this disease was 18 caused by this exposure. 19 Q. I didn't know if you were finished. 20 A. Yes. 21 Q. Dr. Irons, do you, in your work, 22 utilize a term called "scientific certainty"? 23 A. Yes. 24 Q. What does that mean to you? 25 A. It means a number of things. It NELL MC CALLUM & ASSOCIATES, INC. 164 1 depends upon the definition you want to place on 2 it. Scientific certainty in the legal context I 3 think has a different meaning than scientists tend 4 to use it with respect to statistical analysis in 5 establishing the power of a study to reach a 6 certain finding. Reasonable scientific certainty 7 to me in a legal sense means more probable than 8 not. 9 If we're going to talk about 10 uncertainty in experimental design, then we talk 11 about statistics, and that's a separate issue. 12 There is a difference between something being 13 if a study cannot statistically -- does not have 14 the statistical power to determine the difference 15 between two opposing conclusions, then the study 16 is not useful in that context. You can derive no 17 benefit from it. 18 If in the case of epidemiology studies 19 you see consistent trends, even though you don't 20 see enough power from an individual study, you can 21 begin to draw some conclusion as to whether or not 22 there is any association there at all. It's just 23 not possible to determine with confidence because 24 the power of the studies is too low. 25 But in the cases we're talking about, NELL MC CALLUM & ASSOCIATES, INC. 165 1 we're talking about inconsistent and opposing 2 results, not trends. 3 Q. In talking about statistical analysis, 4 is scientific certainty arbitrary? 5 A. To the extent that a scientist should 6 at the outside -- outset of an experiment 7 determine what level of uncertainty he will allow 8 within his study, yes. That's the whole -- that's 9 the premise on which statistics is based. 10 Q. And what number do you pick in 11 evaluating studies that you review when you look 12 at scientific certainty of an epidemiological 13 nature? 14 MR. HALL: I object to the 15 form of the question because I 16 don't understand it. 17 Dr. Irons, if you do, you can 18 certainly answer it. 19 A. I am not certain exactly what you mean. 20 BY MR. HOBSON: 21 Q. Do you require that there be some level 22 of statistical significance before you will accept 23 causation in an epidemiological study? 24 A. I think most people feel as a general 25 rule -- and it depends upon the design of the NELL MC CALLUM & ASSOCIATES, INC. 166 1 study -- accept a confidence interval of .05, 5 2 percent error as a benchmark for determining 3 whether or not something is or is not likely to be 4 due to chance. That's a benchmark that's used 5 throughout the medical-scientific literature. 6 Q. What do you choose? 7 A. I think for the most part that a 8 statistic of .05 is a reasonable figure. 9 Q. That number, though, is an arbitrary 10 picking, is it not? 11 A. Yes. 12 Q. And some scientists might choose .O1? 13 A. Which would be much more rigorous. 14 Q. Yes. And some might choose .9 -- or .1 15 I should say. 16 A. .9? 17 Q. .1, if we are being consistent with 18 terminology. 19 A. .1, I think you could get a lot of 20 argument as to whether or not .1 would be a useful 21 statistic for most experimental design paradigms 22 because of the problem of random error. 23 Q. You say "random error." You are 24 applying random statistics, are you not? 25 A. The whole -- yes, for the most part NELL MC CALLUM do ASSOCIATES, INC. 167 1 we're talking about nonparametric statistics. 2 There are some types of tests in which you have to 3 use parametric statistics, and they tend to be 4 less stringent. 5 Q. If data is collected in a nonrandom 6 fashion, applying random statistics to that data 7 will give you -- is more likely to give you error, 8 isn't it? 9 A. It all depends on the experimental 10 design. If data is collected in a nonrandom 11 fashion, that can often bias and/or critically 12 flaw a study. 13 Q. And that's a major concern of 14 researchers and scientists, is it not, the bias 15 that can result from nonrandom sampling? 16 A. The whole purpose of statistical 17 analysis is to reduce bias and to provide some 18 uniform evaluation of the power of a given study 19 to say whatever it says and what it doesn't say. 20 Q. Can't you, as a statistician, calculate 21 for any given set of data what the statistical 22 significance level is for that data? 23 A. Depending upon what assumptions go into 24 it, yes, and depending upon the types of analyses 25 you are performing, that can become an extremely NELL MC CALLUM S ASSOCIATES, INC. 168 1 complex, complicated enterprise. 2 Q. Don't we see these days more and more 3 trend in epidemiological studies to report the 4 level of significance as opposed to picking an 5 arbitrary value of .05 or .O1 and just saying it 6 does or does not meet this value? 7 A. Within a range, yes. By the same 8 token, it depends upon how you segregate and 9 design your study. I think you can increase the 10 power of a test and increase the significance of a 11 finding and completely lose track of the biologic 12 significance by lumping, for instance, categories 13 that are biologically different. That is a 14 that's been a constant controversy or problem, if 15 you will, certainly in the hematologic field, 16 where there is a tendency on the part of the 17 epidemiologists to lump tumor types and there is a 18 tendency on the part of hematologists and those of 19 us who study the mechanisms of disease to separate 20 them because they are biologically distinct. 21 Q. Or at least thought to be biologically 22 distinct? 23 A. I think there is a lot of hard evidence 24 to suggest they are. 25 Q. I guess in the abstract neither one of NELL MC CALLUM & ASSOCIATES, INC. 169 1 us know what we're talking about now. 2 How many times have you testified this 3 year, either in deposition or at trial? And I 4 would like to know in what cases; so: if you could 5 recite them as you count them, it would help. 6 A. I testified in Carter, Riddle, and 7 Slueter in Roanoke, Virginia. 8 I think I gave a deposition in the case 9 characterized as Chambers. 10 Q. Pending in Texas? 11 A. It settled. 12 Q. But I mean it was pending 13 A. Yes. 14 Q. It was a case in Texas? 15 A. Yes. 16 I think that may be it. 17 Q. Two depositions or trial testimony in 18 1991 besides this deposition? 19 A. Yes. 20 Q. How about '90? 21 A. Two or three depositions in '90. 22 Q. Do you remember the names of the cases? 23 A. Buchaj. 24 Q. I am sorry? 25 A. Buchaj. NELL MC CALLUM & ASSOCIATES, INC. 170 1 Q. With a "B"? 2 A. B-U-C-H-A-J. 3 Q. Where was that pending? 4 A. Los Angeles. 5 Little. 6 Q. That's a Texas case? 7 A. Yes. I gave a deposition in a case 8 Anschutz, A-N-S-C-H-U-T-Z. 9 Q. And where was that pending? 10 A. It was pending in Missouri. I think 11 that's it. 12 Q. No trial testimony in '90? 13 A. I testified in a case called Jones. 14 Q. And where was that, please? 15 A. New York. 16 I testified in a case called Mason, I 17 don't know what year. I think it might have 18 been 19 Q. In Kansas? 20 A. Yes. It was in '90. I think it could 21 have been '89, end of '89. 22 Q. What other cases can you recall giving 23 depositions in or trial testimony? 24 A. I think we have just about exhausted 25 it. NELL MC CALLUM & ASSOCIATES, INC. 171 1 Q. You were in Skeen. 2 A. Skeen. 3 Q. Any others out of that Monsanto plant 4 that you were deposed in? 5 A. (Shaking head) 6 Q. You will need to answer orally. 7 A. No. 8 Q. Have all of these cases been benzene 9 cases? 10 A. No. 11 Q. Which ones were not benzene cases? 12 A. Jones is not a benzene case, and 13 Anschutz was not a benzene case. 14 Q. What was the causative agent there or 15 putative causative agent? 16 A. Jones was putative agent to chlordane. 17 MR. HALL: I am sorry? 18 A. Chlordane and heptachlor. 19 Anschutz was a civil CERCLA case. 20 BY MR. HOBSON: 21 Q. May I ask how much you were paid for 22 your work in Carter, Slueter, and Riddle? 23 A. I haven't seen that yet. I don't know. 24 I can't tell you. 25 Q. You don't know? NELL MC CALLUM & ASSOCIATES, INC. 172 1 A. No. 2 Q. How is it that you couldn't know? 3 A. I haven't been paid yet. I don't 4 recall what I have in billing. 5 Q. Can you give me an estimation? 6 A. No. 7 Q. Could we leave a place in your 8 deposition and ask you to look? 9 A. I'll have to wait until the billings 10 come in because I really don't know at this point. 11 Q. When you say you need to wait for the 12 billings to come in, I'm not sure I understand. 13 A. I have billed the client for my time in 14 that case. I have done it over a series of two or 15 three times, and I have yet to see it all added 16 up. 17 Q. Is there a time in which you expect to 18 be paid? 19 A. Ideally? 20 MR. HALL: You took the words 21 out of my mouth. 22 A. I would expect to be paid by the end of 23 the year, but I am not clairvoyant. 24 BY MR. HOBSON: 25 Q. Have they been invoiced? NELL MC CALLUM do ASSOCIATES, INC. 173 1 A. Yes. 2 Q. Would it be possible for you to add up 3 your invoices for me and indicate the invoiced 4 amount in your deposition when you get it to read 5 and review? 6 A. To the extent that I can -- I can put 7 that together, I could try: but I can't guarantee 8 if it's accurate. 9 Q. If you could do the best you could with 10 what you have been paid and what is invoiced but 11 not paid, if you could give me a total figure at 12 this point in the errata sheet, I would appreciate 13 it. 14 A. I will try to. 15 MR. HALL: So that we're clear 16 on the record, Herschel, "paid" has 17 a different connotation than 18 reimbursed. He may have invoiced 19 travel and hotel and meals and 20 whatnot. Do you wish to include 21 that or not wish to include that? 22 MR. HOBSON: Time for services 23 rendered. 24 MR. HALL: Thank you. 25 BY MR. HOBSON: NELL MC CALLUM S ASSOCIATES, INC. 174 1 Q. I should -- one more thing, too. I 2 know that you had a bunch of exhibits when you 3 showed up at Roanoke. Were those yours or someone 4 else's? 5 A. Some of them were mine: some of them, I 6 think, are still technically the property of 7 Monsanto. 8 Q. Those were used in the Skeen case? 9 A. Yes. 10 Q. Which one -- which ones of the exhibits 11 were yours? 12 A. All of the photographs were mine. 13 Q. The microphotographs? 14 A. (Nodding head) 15 Q. Photo micrographs. 16 What else? 17 A. Some of the illustrative material is 18 mine. The exhibits on stem cell differentiation, 19 hematopoiesis, are the property of Monsanto. 20 Q. How about the bone? 21 A. I think I have been made a gift of the 22 bone, although I think there is some question as 23 to its ownership. I think it -- it certainly is 24 in my possession. I will put it that way. 25 Q. can you give me an estimation of how NELL MC CALLUM & ASSOCIATES, INC. 175 1 much time you have spent on this case to date? 2 A. I haven't added it up yet. I'd say 3 that it's going to be somewhere between 20 and 40 4 hours. 5 Q. And would you give me your current 6 billing rates? 7 A. $300 an hour. 8 Q. .Is that irrespective of what you do as 9 far as deposition or 10 A. For litigation consultation it's $300 11 an hour, irrespective of what I am doing. 12 MR. HOBSON: Take a break. 13 (RECESS) 14 BY MR. HOBSON: 15 Q. Dr. Irons, have you had any meetings or 16 conversations with any other experts in this case? 17 A. Yes, on the 21st of November in Denver. 18 Q. And with whom did you meet? 19 A. Dr. Wallerstein, Dr. Bickers -- is that 20 correct? Did I get that right, Bickers? 21 MS. ARRAS: Yes. 22 A. Dr. Wong, Dr. Thomas. I think that's 23 it. 24 BY MR. HOBSON: 25 Q. Is it still your view that there need NELL MC CALLUM do ASSOCIATES, INC. 176 1 not be a clinical manifestation of aplastic anemia 2 or some predisposing of -- predisposing blood 3 condition before benzene can be causative of AML? 4 A. I think that is a misrepresentation, to 5 the extent that I have said repeatedly that the 6 literature and the opinion of most hematologists 7 is that the prevailing preservation for secondary 8 AML, whether it's benzene or not, is almost always 9 associated with some preleukemic phase. I have 10 said that on the basis of mechanistic studies that 11 it would be impossible to rule out that you 12 couldn't have a manifestation at the level of stem 13 regulation that might not be demonstrable or 14 reflected in a peripheral blood abnormality. I 15 still don't know of any evidence to suggest that 16 it occurred, but I personally can't make a strong 17 statement as never. 18 Q. Did you discuss this aspect of AML and 19 benzene with Dr. Wallerstein? 20 A. I don't recall whether we talked about 21 preleukemia or not. I don't recall. I doubt we 22 did per se. 23 Q. Do you know his view? 24 A. Directly, no. 25 Q. Or indirectly. NELL MC CALLUM & ASSOCIATES, INC. 177 1 A. Well, I wouldn't be surprised if he 2 doesn't hold to that as certainly an important 3 criteria. 4 Q. That being the establishment of a 5 preleukemic stage before 6 A. Many hematologists will tell you it's 7 an absolute requirement. I'm just not prepared to 8 say it's an absolute requirement, although I don't 9 know of a single case where it hasn't been 10 established. 11 Q. If you found a situation where there 12 was a heavy exposure to benzene, by your 13 definition, and an AML without a preleukemic 14 stage, would you automatically rule out benzene as 15 the cause because there was not a preleukemic 16 stage? 17 A. I would not, but I also think that 18 exposures that will lead to leukemia involving 19 more than one individual are very likely to 20 produce demonstrable bone marrow suppression and 21 hematologic abnormality. 22 Q. Would you have any opinions regarding 23 being cured of AML? 24 A. A cure? 25 Q. Yes. Are people cured who get AML? NELL MC CALLUM & ASSOCIATES, INC. 178 1 A. Prognosis for AML is quite dismal. 2 It's not as bad as CML.' but certainly in terms of 3 chemotherapy, the cure of AML is only a remote 4 possibility. With the advent of bone marrow 5 transplantation techniques, there is an increase 6 survival rate amongst individuals who have been 7 successfully transplanted, whereas before, 8 certainly in the case of CML, prognosis was almost 9 defined at diagnosis. 10 Q. But the prospect of a cure of an AML is 11 not good? 12 A. No. None of them -- they are not 13 diseases you would wish to have. The prognosis 14 for CML is worse than AML, although the 15 progression is slow. 16 Q. What about the prognosis for NHL, 17 non-Hodgkin's lymphoma? 18 A. Its varies with the particular 19 histological presentation, but the prognosis in 20 some categories can be called good. 21 Q. How about for the three gentlemen who 22 now survive, would you render any opinion on 23 prognosis for these folks? 24 A. In the case of Mr. Lilly, I believe he 25 is in complete remission. From what I have read, NELL MC CALLUM do ASSOCIATES, INC. 179 1 that may, in fact, be the case. Whether or not -2 I can't -- I would have to review the data on 3 these individuals to discuss prognosis in any 4 greater detail. 5 Q. So, even though Mr. Lilly is in 6 remission now, you cannot say what the prospects 7 would be for him staying in remission without 8 reviewing the records further? 9 A. I don't know how one is clairvoyant 10 when someone is in remission. I mean he -- I 11 wouldn't want to comment on prognosis without 12 reviewing the records again. I haven't looked at 13 them with that in mind and I haven't really 14 considered it in sufficient detail to give a 15 responsible answer. 16 Q. What was the occasion that you and the 17 other experts met? What brought that about? 18 A. I think the -- well, the principal 19 principal of the meeting was called by Ms. Arras 20 and colleagues: and I think we all welcomed it as 21 an opportunity to see some of the monitoring data 22 and see the layout of the facilities that are in 23 question. That was the principal reason for the 24 meeting. 25 Q. And about how long did it last? NELL MC CALLUM & ASSOCIATES, INC. 180 1 A. I'd say four or five hours. 2 Q. Do any of your opinions that you have 3 expressed rely upon the opinions of the other 4 experts in this case, or do your opinions that you 5 have expressed stand independently of theirs? 6 A. They stand independent. 7 MR. HOBSON: I appreciate your 8 patience. That's all I have got. 9 Thanks, Doctor. 10 (THE DEPOSITION WAS CONCLUDED) 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NELL MC CALLUM do ASSOCIATES, INC.