Document oer272yZQ8bNMB7mQwO1m7xm8

IN THE UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF TEXAS GALVESTON DIVISION FLOYD L. CHAMBERS, ET UX, VS. MONSANTO CHEMICAL COMPANY ET AL. C. A. NO. G-S9-306 INSTANT ACCESS TRANSCRIPTION VIDEO DEPOSITION OF: RICHARD D. IRONS, PH.D. FEBRUARY 4, 1991 COPY 2 1 2 3 INDEX 4 5 VIDEO DEPOSITION OF RICHARD D. IRONS 6 FEBRUARY 4, 1991 7 8 9 Direct Examination-Mr. Galbraith 8 Examination-Mr. Barrie 58 10 Examination-Mr. Scott 140 Re-Examination-Mr. Barrie 193 11 Re-Examination-Mr. Scott 199 Re-Examination-Mr. Barrie 201 12 13 14 EXHIBIT INDEX 15 16 Exhibit No. Description Marked 18 Irons 1 Curriculum Vitae of 19 Richard D. Irons 21 20 Irons 2 Looseleaf notebook entitled "Chronic Lymphocytic Leukemia" 21 containing various excerpts of publications 36 22 Irons 3 Handwritten tabulation of 23 Mr. Chambers' blood counts back to May 9, 1967 51 24 Irons 4 Graph - Doubling Time Projection for Mr. Chambers 53 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 3 1 Irons 5 "Chambers Data," Doubling 2 Time Calculation 54 Irons 6 Schematic diagram of normal 3 blood cell development 149 4 Irons 7 12/11/90 letter from Robert Scott to Dr. Richard Irons 193 5 Irons 8 Year/Weight List 193 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 4 1 VIDEO DEPOSITION OF RICHARD D. IRONS, 2 Ph.D., called as a witness by Defendant Marathon 3 Petroleum Company, taken before Emanuel A. 4 Fontana, Jr., Certified Shorthand Reporter in and 5 for the State of Texas, in the law offices of 6 Goforth & Lewis, 2200 Texaco Heritage Tower, 1111 7 Bagby, Houston, Texas, on the 4th day of 8 February, 1991, beginning at 10:12 a.m., pursuant 9 to Notice, the Federal Rules of Civil Procedure 10 and the following stipulation and waiver of 11 counsel: 12 13 14 A P P E A R A N C E S 15 16 17 Mr. Martin D. Barrie, of the law firm of 18 Messrs. Umphrey, Burrow, Reaud, Williams & 19 Bailey, 8441 Gulf Freeway, Suite 600, Houston, 20 Texas, 77017-5001, appearing for the Plaintiffs. 21 22 Mr. James B. Galbraith, of the law firm 23 of Messrs. McLeod, Alexander, Powel & Apffel, 802 24 Rosenberg, Galveston, Texas, 77553, appearing for 25 Defendant Marathon Petroleum Company. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 5 1 Mr. Joe G. Hollingsworth and Ms. Evelyn 2 J. Pulliam, of the law firm of Messrs. Spriggs & 3 Hollingsworth, 1350 I Street, N.W., Washington, 4 D.C., 20005-3305, appearing for Defendant 5 Marathon Petroleum Company. 6 7 Mr. Robert P. Scott, of the law firm of 8 Messrs. Sewell.& Riggs, 333 Clay Avenue, Suite 9 800, Houston, Texas, 77002, appearing for 10 Defendant Monsanto Chemical Company. 11 12 Mr. Daniel O. Goforth, of the law firm 13 of Goforth & Lewis, 2200 Texaco Heritage Plaza, 14 1111 Bagby, Houston, Texas, 77002, appearing for 15 Defendant Monsanto Chemical Company. 16 17 ALSO PRESENT: 18 Mr. Steve Schuller, Videographer 19 Mr. Stephen L. Moll 20 21 22 23 24 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 6 1 IT IS STIPULATED and agreed by and 2 between counsel for the respective parties hereto 3 that the deposition of the witness named-in the 4 caption hereto may be taken at this time and 5 place before the officer named in the caption 6 hereto; that said deposition, or any part 7 thereof, when so taken, may be used on the trial 8 of this case with the same force and effect as if 9 the witness were present in court and testifying 10 in person; 11 THAT the necessity for preserving 12 objections at the time of taking is waived, and 13 that any and all legal objections to this 14 deposition, or any part thereof, may be urged at 15 the time same is sought to be offered in evidence 16 on the trial of this cause; except, however, that 17 objections to the form of the question and/or 18 responsiveness of the answer must be made at the 19 time of taking, or else such objections are 20 waived; 21 THAT the original of this deposition 22 shall be presented to Mr. Galbraith, who shall in 23 turn submit it to the witness for his examination 24 and signing and, thereafter, shall return same to 25 the officer taking this deposition; WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 7 1 THAT if the signed original is not 2 presented to Mr. Galbraith prior to the time of 3 trial, a copy may be used in lieu thereof. 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 8 1 RICHARD D. IRONS; Ph.D., 2 was called as a witness by Defendant Marathon 3 Petroleum Company and, being first duly sworn, 4 testified as follows: 5 6 DIRECT EXAMINATION 7 QUESTIONS BY MR. GALBRAITH: 8 9 Q. Can you please tell your name, please, 10 sir? 11 A. Richard D. Irons. 12 Q. How old a man are you, sir? 13 A. I'm 43. 14 Q. Where do you live? 15 A. Boulder, Colorado. 16 Q. Dr. Irons, you understand that you're 17 called upon to give your testimony in a 18 deposition here today in a lawsuit that's been 19 filed against my client, Marathon, and Union 20 Carbide and Monsanto -21 A. Yes, sir. 22 Q. -- three chemical plants? 23 And you have been contacted by us, 24 attorneys for Marathon in this lawsuit, to give 25 your opinions based upon your review of certain WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 9 1 documents and your experience in this field? 2 A. That's correct. 3 Q. Tell us about your -- well, I guess what 4 I want to ask now is: What is your field? And 5 tell me about your background, your educational 6 background and your present employment. 7 A. Well, I'm a toxicologist. I am Director 8 of the Molecular Toxicology and Environmental 9 Health Sciences Program at the University of 10 Colorado Health Sciences Center. I have a Ph.D. 11 in Toxicology from the University of Rochester, 12 in Rochester, New York. And I have spent the 13 last 14 years studying the mechanisms of toxicity 14 to the blood and bone marrow primarily associated 15 with benzene and the mechanisms of benzene 16 leukemogenesis. 17 Q. Okay. First of all, let me back you up 18 there. You said Director of the Department of 19 Molecular Tech -- Toxicology. Excuse me. 20 Tell me what that entails. 21 A. Well, the Molecular Toxicology Program 22 at the University of Colorado is a program that 23 involves research, teaching and service 24 associated with toxicology and environmental 25 health. It is based in the School of Pharmacy, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 10 1 and I have appointments as Professor of 2 Toxicology in the School of Pharmacy and as 3 Professor of Pathology in the School of 4 Medicine. 5 The major teaching obligations we have 6 are to train Ph.D. level toxicologists, to 7 provide teaching in toxicology for individuals 8 training in epidemiology. This will be graduate 9 students and/or clinicians and these that wish. 10 additional training in occupational health and 11 epidemiology. 12 And we provide teaching and training in 13 toxicology for graduate students undergraduate 14 students in pharmacy, and medical students. 15 Q. Okay. Teaching students of medicine as 16 well as students of pharmacy and pharmacology? 17 A. Yes, sir. 18 Q. In addition to your -- you said three 19 things, research, teaching and service -20 A. Yes. 21 Q. -- were involved in your position as 22 Director of Molecular Toxicology and 23 Environmental Health Sciences. 24 Tell me what-you mean when you say your 25 position involved service, first of all. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 11 1 A. Oh, the service we provide involves a 2 variety of different activities. It involves 3 providing expertise to the public and state 4 agencies related to environmental health issues n 5 toxicology, to the Department of Health, to the 6 Governor's office on issues of concern to the 7 public and Government agencies related to 8 environmental health within the State. 9 It involves providing, actually, 10 expertise for the University, in terms of meeting 11 its commitments with respect to occupational and 12 environmental health. 13 Q. Okay. And research, the third leg of 14 your -15 A. Yes. 16 Q. -- involvement, tell me about that. 17 What does that involve? 18 A. The program itself has very broad-based 19 research activities in the general area of 20 toxicology, with an emphasis on mechanisms of 21 toxicity, how chemicals cause adverse effects. 22 My own research program involves three 23 major areas. First and foremost, again, is an 24 extension of the work I've done for the past 14 25 years or so studying the role of the regulation WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 12 1 of stem cells in the development of diseases of 2 the blood, principally leukemia. 3 Stem cells are the cells that are 4 responsible for making all of our blood cells, 5 and they are intimately involved in a variety of 6 processes, both normal and abnormal. And a -- a 7 good part of my work involves studying the 8 alterations that occur in stem cells following 9 exposure to toxic agents, be they chemical, such 10 as benzene, or drugs. 11 I have two other programs that I'm 12 currently working on. One involves, again, 13 characterizing changes in the blood-forming 14 organs that are associated with extended space 15 flight. It's been found that -- that the immune 16 system and the blood system is susceptible to 17 alterations that are associated with conditions 18 in space that are of importance to understand in 19 the design of future extended space missions. 20 Another area that, again, is related 21 involves developing strategies for the 22 purification, separation of stem cells from 23 patients for use in bone marrow transplantation. 24 And that's another area that we're actively 25 working on at the present time. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 13 1 Q. All right. How long have you been the 2 Director of the Department of Molecular 3 Toxicology and Environmental Health Sciences at 4 the University of Colorado Health Sciences 5 Center? 6 A. It's a program technically, not a 7 department. 8 For the last slightly over two years. 9 Q. Okay. Now, you mentioned that your 10 research regarding cause of diseases, in terms of 11 chemical causes of diseases, has gone on for 12 longer than that. 13 A. Yes, sir. 14 Q. Tell me what preceded your directorship 15 of the department -- of the Program of Molecular 16 Toxicology and Environmental Health Sciences. 17 A. Well, following my graduation from the 18 Toxicology Program at Rochester, I was a fellow 19 in the Department of Pathology at Strong Memorial 20 Hospital in Rochester, New York. And there I 21 trained in general pathology, immunopathology and 22 hematopathology. 23 General pathology is pathology 24 general pathology, pathology covering a wide 25 range of topics, nothing in particular. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 14 1 Q. Pathology, in your t6rms, meaning 2 exactly what? 3 A. The pathogenesis of disease. The 4 structural and functional alterations that occur 5 in the body and the body tissues, as a function 6 of disease in the progression of disease. 7 In addition, I trained, in terms of 8 specialty, in immunopathology and 9 hematopathology, which is pathology that is 10 special -- a specialized area of pathology that 11 deals with diseases of the immune system and the 12 blood-forming organs. 13 I then went to the Chemical Industry 14 Institute of Toxicology in Research Triangle 15 Park, North Carolina, where, for 12 years, I was 16 responsible for and directed studies to 17 understand the mechanisms of benzene toxicity in 18 particular, as well as the effects of a variety 19 of other compounds on the blood and the immune 20 system. 21 Q. Okay. You mentioned that you had your 22 doctorate degree, Ph.D., in pharmacology and 23 toxicology. 24 A. Toxicology. 25 Q. Okay. Tell me, what preceded that, in WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 15 1 terms of education? You don't just jump out 2 there and get your Ph.D. as your first degree. 3 What preceded? 4 A. I obtained my bachelor's degree from 5 Raymond College, University of the Pacific in 6 Stockton, California, where I specialized in 7 liberal arts, chemistry and political science. 8 I then obtained advanced training and 9 certification in medical technology and 10 diagnostic hematology, laboratory diagnostics, 11 before going to the University of Rochester. 12 Q. All right. At the Chemical Industry 13 Institute of Tech -- Toxicology, tell me what 14 that organization is, first of all, in Research 15 Triangle Park, North Carolina. 16 A. It's a nonprofit institute that is 17 dedicated to research and training in 18 toxicology. It was founded by the chemical 19 industry as an institute that could provide basic 20 mechanistic, basic research studies on mechanisms 21 of toxicity of hazardous agents and initially was 22 funded solely by the chemical industry. 23 It's now diversified in its support and 24 is, as I understand it today, funded from a 25 variety of different sources, including Federal WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 16 1 Government, industry, and what have you. 2 Q. The purpose is solely to do scientific 3 research? 4 A. Yes, sir. 5 Q. Okay. And while you were there, your 6 area of scientific research included what? 7 A. As I said before, my principal area of 8 research involved studying the mechanisms of 9 toxicity to the blood and bone marrow, primarily 10 associated with benzene, as well as a variety of 11 other compounds and chemicals that produce 12 effects on the blood and immune system. 13 Q. Looking at how benzene acts on blood and 14 bone marrow? 15 A. Yes, sir. 16 Q. Okay. Do you have any particular 17 licenses or board certifications within your 18 field? 19 A. I'm certified in medical technology, and 20 I'm also board certified by the American Board of 21 Toxicology. 22 Q. Tell me what it means to be board 23 certified by the American Board of Toxicology. 24 A. The American Board of Toxicology is an 25 organization that reviews the academic and WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 17 1 training credentials of toxicologists and 2 administers a board examination to determine 3 their qualifications to practice toxicology. 4 Q. How long have you been certified, board 5 certified? 6 A. I was certified in, I believe, 1981, so 7 ten years. 8 Q. Okay. Tell me about some of the 9 Government activities or Government -- Government 10 programs you have been involved in, please. 11 A. Well, I have had considerable experience 12 in what we call the peer-review process, which is 13 the process whereby scientists review the 14 scientific merit of other scientists' research 15 proposals that are submitted to various agencies 16 for consideration for funding, grants, if you 17 will. 18 I've served on a number of Government 19 bodies that are responsible for reviewing these 20 applications. For example, I've served as 21 Chairman of the NIH Toxicology Study Section. 22 This is the 23 Q. First of all, excuse me. What is the 24 NIH? 25 A. National Institutes of Health. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 18 1 Q. Okay. 2 A. The National Institutes of Health is -3 is probably the single most important funding 4 source for research in the medical sciences, and 5 also one of the major sources of funding for 6 research in toxicology. 7 I served as the Chairman of the body 8 that is responsible for reviewing those 9 applications on the basis of their scientific 10 merit. 11 I also currently serve as a member of 12 the Environmental Protection Agency Health 13 Effects Review Panel, which has a similar 14 function for the Environmental Protection Agency. 15 Q. How is it that you came to be called 16 upon to serve in the peer-review capacity; in 17 other words, to look at other scientists' 18 projects and determine whether they have merit or 19 not? 20 A. A peer review is a very important aspect 21 of the whole process of research and the 22 publication of scientific research in the United 23 States. Papers that are submitted for 24 publication, manuscripts, if you will, that are 25 submitted by scientists to a journal will be WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 19 1 reviewed by independent reviewers to determine 2 whether or not it's accurate, whether it's well 3 presented, whether the experiment has been 4 designed properly, and basically that the work 5 says what the author thinks it says. 6 Peer review is a necessary pre -7 prerequisite for maintaining the quality of the 8 scientific literature, and also to evaluate the 9 quality of proposed research. 10 As a scientist enters a field, he will 11 be -- as he publishes work, he will be recognized 12 for that. And as he publishes high quality 13 science, he will be recognized by being asked, 14 first of all, to review papers for a journal. 15 And this will continue. And, in fact, he may be 16 asked by a Government body to participate in this 17 kind of activity, based upon his experience in 18 the field and his publication record. 19 MR. BARRIE: Let me object to the 20 nonresponsiveness of the answer. 21 Q. (By Mr. Galbraith) Okay. If I 22 understand correctly what you're telling me, 23 then, it's you get asked to serve on these 24 peer-review committees, passing upon the merit of 25 other scientists' work, based upon, first, you WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 20 1 having published, successfully, I guess, with 2 recognition -3 A. That -- that is a prerequisite, yes. 4 Q. Okay. Are there any authoritative 5 periodicals in your field to which you 6 contribute? 7 A. Oh, yes, several. Probably first and 8 foremost is the -- is "Toxicology and Applied 9 Pharmacology," which is the premier journal in 10 toxicology today. And I serve as an associate 11 editor for that journal at the present time. 12 Q. What do you do, in your capacity as 13 Associate Editor of "Toxicology and Applied 14 Pharmacology"? 15 A. As an Associate Editor, I'm responsible 16 for selecting reviewers, for reading the comments 17 of reviewers and making my own evaluation of 18 manuscripts that are submitted and rendering a 19 judgment as to whether or not the manuscripts are 20 appropriate for publication, whether they are 21 not, or whether they need to be revised in some 22 fashion prior to publication. 23 Q. Okay. Do you contribute in this fashion 24 to any other publications? 25 A. I serve as an editor for the journal, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 21 1 "Cell Biology and Toxicology. I serve on the 2 editorial board of a number of other journals, 3 including the journal of "Experimental and 4 Molecular Pathology." I've served on review 5 boards and in various editorial roles on a number 6 of journals in the past, as well. 7 Q. I confess to having been given a copy of 8 your curriculum -- your resume, and I would ask 9 that that copy be marked as Exhibit 1. Could I 10 present it to you now? 11 Is that a copy of your curriculum vitae 12 or resume? 13 A. Yes, it is. I believe it is not the 14 most current version. 15 Q. Okay. Approximately how up-to-date is 16 that copy? 17 A. I suspect it's a year old. 18 MR. GALBRAITH: Okay. Let me hand 19 it to the court reporter now and ask that it be 20 marked, please, sir. 21 22 (Whereupon, the instrument referred to 23 by counsel was marked for identification as Irons 24 Exhibit No. 1.) 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 22 1 MR. GALBRAITH: Thank you. 2 Q. (By Mr. Galbraith) Refer to it, I guess, 3 if you need to. 4 Are there organizations, scientific 5 organizations or organizations involving those in 6 similar research and in similar scientific study 7 that you have participated in? 8 A. I'm a member of several professional 9 societies. The Society of. Toxicology, which is 10 a -- the principal professional group to which 11 toxicologists in the United States belong. I 12 belong to the American Association of 13 Pathologists, which is the principal academic 14 society that pathologists belong to. 15 I've been elected a member of the 16 International Society of Experimental Hematology, 17 which is a group of -- it's an international 18 society that includes individuals who are active 19 in doing research in hematology. 20 Q. Okay. Let me ask you about that 21 International Society of Experimental 22 Hematology. 23 First of all, what's hematology? 24 A. Hematology is the study of diseases of 25 the blood and normal blood production. It's the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 23 1 study of the blood, both normal and abnormal. 2 Q. Okay. How was it that you came to be 3 involved in the International Society of" 4 Experimental Hematology? 5 A. On the basis of the research that I've 6 done, I was asked to join by some of the members 7 of the Society, and was elected to membership in 8 that Society. 9 Q. What does that membership involve? What 10 does it do for you, and what do you do for it, I 11 guess? 12 A. I attend meetings, annual meetings in 13 which research in hematology is discussed. I 14 correspond with and occasionally collaborate with 15 other members of the Society on research we have 16 a mutual interest in. And I take the journal 17 that is published by the Society. 18 Q. Okay. You have mentioned that in your 19 present position, you have some academic teaching 20 responsibilities of medical students and 21 pharmacology students. Have you had any other 22 academic-type positions or experience? 23 A. I've -- I'm involved, at the present 24 time, in designing a course in toxicologic 25 pathology, which is pathology specializing WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 24 1 that specializes in the adverse effects of 2 chemicals or agents on the body and its 3 tissues. 4 I lecture frequently in a variety of 5 different courses. I've lectured at Duke 6 University in toxicology and in occupational 7 medicine. This past year, most recently, I've 8 lectured at the University of Nebraska, at Johns 9 Hopkins University and at Rutgers University. 10 I lecture probably four or five times a 11 year in other programs and universities, and I'm 12 currently lecturing in the Epidemiology Program 13 in the School of Medicine at the University of 14 Colorado. 15 Q. Okay. What does it mean -- I notice in 16 your resume here you've got a number of 17 post-doctoral fellows. Tell me what those are 18 and what they mean. 19 A. Those are individuals that have trained 20 in my laboratory after obtaining their doctoral 21 degrees, either an M.D. or a Ph.D., and have gone 22 on to careers in the field. 23 Q. Okay. Tell me -- I notice in your 24 resume you've got a number of research interests, 25 some in sciences and some in applied sciences. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 25 1 Tell me what the distinction is there. 2 A. Well, basic science really deals with 3 understanding mechanisms of how the body and the 4 cells of the body work, how they are regulated 5 and how they function, and how diseases are 6 initiated and how they progress and, hopefully, 7 in some respects, what strategies can be used for 8 treating them. 9 Applied -- applied science deals with 10 the use of this knowledge in a more practical 11 vein, if you will, in terms of some immediate 12 practical objectives, such as the use of a method 13 to obtain an end such as diagnosis, or the 14 development of techniques for use in basic 15 science. 16 Q. Okay. I'm looking through the pages 17 here of the books, book chapters and published 18 articles, and I keep seeing recurrent themes, 19 such as, first of all, toxicology, hematology, 20 blood, bone marrow, and even some leukemia or 21 leukemogenesis. And here's a benzene or two 22 sprinkled around among the titles of these books 23 and articles. 24 Tell me, what's the interrelationship 25 between all those things, and why do I keep WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 26 1 seeing them here? 2 A. Well, the reason you keep seeing them is 3 because my principal area of research interest is 4 the blood and bone marrow and the immune system, 5 which are all interrelated. And it's well known 6 that, at high concentrations of exposure, chronic 7 exposure, benzene will cause toxicity to the bone 8 marrow. And that's been one of my principal 9 areas of research and expertise now for many 10 years. 11 Q. Okay. What is the relationship between 12 leukemia and blood or bone marrow? 13 A. Leukemia is, in -- to put it very 14 crudely, or simply, cancer of the blood or bone 15 marrow. And there are several different types of 16 leukemia that differ with respect to their 17 origin, their prognosis, what the process of the 18 disease is, the cells they involve, and their 19 ultimate -- the ultimate outcome of the disease. 20 Leukemia is one of my principle areas of research 21 interest. 22 Q. Okay. Do you have any particular 23 scientific research project ongoing at present, 24 that is, occupying a good bit -- bit of your 25 interest? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 27 1 A. Yes. As I mentioned earlier, I have 2 three different research projects that are 3 underway at the present time. 4 Q. Okay. Talking about regulation of stem 5 cells? 6 A. Yes. 7 Q. Okay. I remember that now. 8 As a result of us calling upon you in 9 this lawsuit, what documents have you had an 10 opportunity to review, as they might relate ;to 11 this case? 12 A. I reviewed the -- what I believe is the 13 First Amended Complaint. I reviewed the medical 14 records of Mr. Chambers. I reviewed summaries of 15 the depositions of Mr. and Mrs. Chambers. I 16 reviewed the depositions of Dr. Savitz and 17 Dr. Fehir, and I've reviewed the medical 18 literature and scientific literature that I feel 19 pertains to the issues that are involved here. 20 Q. Okay. Have you come to a conclusion -21 or what is the basis of your understanding about 22 what exposures, if any, Mr. Chambers is alleging? 23 A. It's my understanding, from my review of 24 those records and from discussions that I've had 25 both with you and with Mr. Scott, that the -WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 28 1 there are alleged exposures to benzene 2 Mr. Chambers had while -- during the course of 3 his employment. 4 Some of those seem quite remarkable or 5 unique to me, in terms of my experience with the 6 industry, so he has alleged that he has been 7 exposed to benzene under some fairly outrageous 8 circumstances. 9 Q. Okay. Which exposure do you reference 10 there? 11 A. I believe there's -- there's a reference 12 to 55-gallon drums of benzene that were made 13 available for washing hands and tools, which -14 Q. Why -- why do you find that outrageous, 15 I believe, as you said? 16 A. Well, in my experience, I've never known 17 that to be a practice of the industry. That 18 would be outlandish to me. 19 Q. What is your knowledge about 55-gallon 20 drums of benzene? 21 A. Knowledge of fifty-five thousand 22 Q. Fifty-five 23 A. Fifty-five gallon 24 Q. -- gallon drums. 25 A. It would be an extremely -- I can't WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 29 1 think of a use for that much benzene except in an 2 industrial commodity use. I can't -- using it in 3 those quantities for -- for cleaning is 4 outrageous, to me. 5 Q. Okay. Well, let me just ask you: As a 6 result of your review of these documents in this 7 case and a result of your prior experience and 8 your research itself, have you arrived at any 9 opinions as they relate to this lawsuit? 10 A. Yes. 11 Q. What -- what are those opinions or 12 conclusions? 13 A. I have reached two opinions in this 14 case. 15 The first is that chronic lymphocytic 16 leukemia is not caused by exposure to benzene. 17 And the second is that more probably 18 than not Mr. Chambers' chronic lymphocytic 19 leukemia began shortly after birth, or before. 20 Q. Okay. Let me take those one at a time. 21 You first concluded that in this case, 22 or in general, I guess you would say, chronic 23 lymphocytic leukemia is not caused by exposure to 24 the chemical benzene? 25 A. That's correct. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 30 1 Q. What is the basis for that opinion? 2 A. There's no reliable evidence to suggest 3 that CLL or chronic lymphocytic leukemia is 4 caused by benzene or, for that matter, any other 5 agent, and there's considerable evidence to 6 indicate that it is not. 7 This is a widely held view in the 8 medical and scientific community. It appears 9 in -- it's supported by the original literature. 10 It's supported by the review literature. It is a 11 textbook concept as recent as this year. This is 12 a widely held opinion. 13 Q. Okay. You said two things. Number one, 14 there's never been evidence, reliable evidence to 15 support a relationship between benzene and 16 chronic lymphocytic leukemia. 17 And, two, there is evidence to show the 18 absence of a relation -- of a causal 19 relationship. 20 A. That's correct. 21 MR. BARRIE: I object to counsel 22 testifying for this expert. 23 Q. (By Mr. Galbraith) Did I understand that 24 correctly? 25 A. Yes, sir. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 31 1 Q. Okay. First of all, when you said even 2 textbooks as recent as this year have refuted the 3 relationship between chronic lymphocytic leukemia 4 and benzene, to what did you refer? 5 A. There -- well, I can show you, if you 6 would like. There are a number of recent reviews 7 in textbooks which reiterate a commonly held 8 opinion that, in fact, there are no known causes 9 of chronic lymphocytic leukemia. 10 For example, radiation, which is 11 generally regarded as a universal leukemogen, an 12 ionizing radiation, and exposure to ionizing 13 radiation is known to lead to the development of 14 a variety of different types of leukemia. 15 Chronic lymphocytic leukemia is 16 distinguished among these in not being caused by 17 even exposure to radiation. 18 Q. So -- I want to make sure I understand 19 that. So things like radiation that cause other 20 leukemias are known not to cause chronic 21 lymphocytic leukemia? 22 A. Yes, sir. 23 Q. And radiation is one you cited, and 24 benzene -25 A. Right. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 32 1 Q. -- is another you cited? 2 A. Yes. 3 Q. Okay. Go ahead, if you would, tend point 4 to me the textbooks that -- to which you can now 5 have reference, let's say. 6 And recent reviews, I believe, is what 7 you referred to. 8 A. Yes. Well, the first one that reflects 9 on this is a review by Drs. Foon, Rai and Gale 10 that was published in October of 1990 in the 11 "Annals of Internal Medicine." And it's a 12 review article on Chronic Lymphocytic Leukemia: 13 New Insights into Biology and Therapy." 14 Q. What is the significance of that 15 publication? 16 A. It's representative of any number of 1? recent publications that review the 18 state-of-the-art with respect to CLL. And it's 19 very consistent with -- it's representative of 20 all of them. I can -21 Q. What does it provide or say that is 22 consistent with other research? 23 A. Well, the -- with respect to the 24 questions that we're discussing now, there's a 25 statement here which I think summarizes it quite WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 33 1 succinctly. Can I read it? 2 Q. I wish you would, please. 3 A. Okay. 4 "The cause of chronic lymphocytic 5 leukemia is unknown. Unlike other forms of 6 leukemia, the incidence of chronic lymphocytic 7 leukemia is not increased by exposure to 8 alkylating drugs, radiation or chemicals." I, 9 Q. Okay. All right. You've got before you 10 there a three-ring binder. What is -- what is 11 that? 12 A. It's a collection of articles from the 13 literature that I put together in support of the 14 views that I presented here. 15 Q. Could I -- could I take a look at that? 16 A. Certainly. 17 Q. All right. This -- this constitutes 18 articles that you have pulled from what types of 19 sources? 20 A. Primary scientific literature, the 21 medical literature. There are also some reviews 22 this there, recent reviews of the literature. 23 A review would be an article that 24 summarizes existing knowledge, as opposed to 25 being an original scientific article. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 34 1 I also have some expert -- excuse me, 2 excerpts from a recent pathology textbook which 3 simply illustrates that the -- the current -- our 4 current understanding of biology and nature of 5 CLL is, as I have said, and, in fact, is what is 6 taught as state-of-the-art in the typical general 7 pathology textbook. 8 Q. Is that what I'm looking at here, 9 entitled "Pathology" by Drs. Rubin and Farber? 10 A. Yes. 11 Q. Okay. I see something from the 12 "American Industrial Hygiene Association 13 Journal." 14 A. What -15 Q. Do you recall that? It's abbreviated, 16 and I take that to be "American Industrial 17 Hygiene -18 A. Yes. 19 Q. -- "Association Journal"? 20 A. Yes, yes, yes. 21 Q. Okay. I'm not going to go through these 22 individually. "American Journal of Industrial 23 Medicine," is that also referenced? 24 A. Yes. 25 Q. What is the "American Journal of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 35 1 Industrial Medicine"? 2 A. It's a journal that publishes articles 3 on medicine, that is, basically specialties in 4 occupational medicine or diseases and/or problems 5 associated with occupational exposure. 6 Q. You've got here an article on chronic 7 lymphocytic leukemia in the "American Journal of 8 Hematology." What is the "American Journal of 9 Hematology," if I can ask? 10 A. The "American Journal of Hematology" is 11 one of the premier journals in hematology. It 12 publishes clinical studies on hematology, as well 13 as some experimental work. Primarily clinical 14 work. 15 Q. Okay. Apparently, you have articles 16 from a hematology journal entitled "Blood," as 17 well as from a textbook entitled "Blood." Is 18 that right? 19 A. "Blood" is, again, another very 20 well-regarded journal in hematology. 21 Q. There are a large number of articles. 22 Could I simply ask -- could we, with your 23 permission, have this marked as Dr. Irons' 24 Exhibit No. 2? 25 A. Yes. I should mention, as well, that WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 36 1 I've brought a very recent version of a text 2 which is entitled "Leukemia" and is devoted 3 entirely to the issue of the biology and clinical 4 manifestations of leukemia and the various types 5 of leukemia that also reflects the opinions that 6 I have in this case. 7 Q. That you've told us about a moment ago? 8 A. Yes. 9 Q. In fact, that's a 1990, as a matter of 10 fact. 11 A. Yes. It's a very recent edition. 12 Q. Published by a Dr. Edward S. Henderson, 13 a medical doctor of the State University of New 14 York at Buffalo, in Buffalo, New York, and 15 T. Andrew Lister, a medical doctor from the 16 Department of Medical Oncology, St. Bartholomew's 17 Hospital in London, England. 18 A. Yes. 19 Q. Okay. 20 21 (Whereupon, the instrument referred to 22 by counsel was marked for identification as Irons 23 Exhibit No. 2.) 24 25 Q. (By Mr. Galbraith) You said that there WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 37 1 was no known cause of CLL. I've heard chronic 2 lymphocytic leukemia referred to as 3 "idiopathic." Are you familiar with that term? 4 A. Yes. 5 Q. What does it mean? 6 A. That is a fancy word that simply means 7 there's no known cause. 8 Q. Okay. Has benzene itself been looked at 9 as a possible cause for chronic lymphocytic 10 leukemia? 11 A. Oh, yes. Benzene is known to cause 12 acute myelogenous leukemia, which is a different 13 type of leukemia in some people who are exposed 14 to high concentrations for long periods of time. 15 That relationship is generally accepted and 16 widely established. 17 As a result of that, the hypothesis, or 18 the suggestion that benzene might be the cause of 19 other types of leukemia, specifically CLL, has 20 been the point of departure, if you will, for a 21 number of different studies, studies of 22 individuals in industry, a wide variety of 23 different types of studies, and epidemiology 24 studies. So that it's a reasonable -- it has 25 been a reasonable hypothesis that that might be WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 38 1 the case. 2 But these studies have not borne that 3 out. And, in fact, there are a number of studies 4 which suggest that benzene is not associated with 5 CLL. 6 Q. Okay. If you can, quickly, in a 7 shorthand fashion, if it's possible, tell me the 8 difference between a myelogenous leukemia and a 9 lymphocytic leukemia? 10 A. In shorthand fashion? Okay. 11 Q. I apologize for the question, but I 12 don't withdraw it. 13 A. There are bone marrows responsible for 14 making all the different type of blood cells that 15 we have, and it's ultimately responsible for also 16 making the cells of our immune system, the 17 lymphocytes. These all are produced, ultimately, 18 by a single type of cell, called the 19 pluripotential stem cell. It's capable of giving 20 rise to all the different types of blood cells 21 through a fairly complicated process of 22 development. 23 The first step in this development is 24 the production of two different types of 25 progenitor cells, or -- or stem cells, lymphoid WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 39 1 cells and myeloid cells. 2 Myeloid stem cells are the cells that 3 are responsible for making red cells that carry 4 our oxygen; white cells, the granulocytes and 5 macrophages, these are cells that are associated 6 with helping us fight off infections; and 7 platelets, which keep our -- which cause our -8 which cause clotting and keep us from bleeding. 9 On the other side of the coin, there's a 10 cell called the lymphoid progenitor cell, or stem 11 cell, that is responsible for giving rise to 12 lymphocytes, which are our immune system, 13 comprise our immune system. 14 And these are two separate lineages or 15 directions or pathways that these cells-can 16 take. So our blood, in terms of its origin, is 17 separated into two major compartments, the 18 lymphoid compartment and the myeloid compartment, 19 and then there are a number of other compartments 20 that branch out from these. 21 . What you're telling me is such things as 22 radiation and certain chemicals like benzene may 23 have an impact or an effect upon myeloid cells, 24 that radiation or chem -- certain chemicals don't 25 have on lymphoid cells? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 40 1 A. And -- yes. Yes. Well, not exactly to 2 that degree. Radiation can have effects on -- on 3 the development of a variety of different 4 leukemias, principally myeloid, but not 5 restricted entirely to the myeloid lineage. But 6 it has never been associated with chronic 7 lymphocytic leukemia. 8 Q. Okay. All right. You mentioned that 9 there was considerable evidence to show that 10 benzene doesn't cause chronic lymphocytic 11 leukemia. 12 A. Yes. 13 Q. To what did you refer? 14 A. The principal quantitative studies that 15 have been conducted in this area have been 16 conducted in the rubber industry, and the rubber 17 industry is unique in -- with respect to the 18 types of neoplasms that have been seen in the 19 rubber industry, compared to those that have been 20 seen in conditions where you have relatively pure 21 exposure to benzene, because it's a very 22 complicated work environment and numerous agents 23 and numerous compounds to which an individual is 24 potentially exposed in that situation. 25 Initial -- as I said, the hypothesis, if WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 41 1 you will, that benzene was associated with 2 lymphoid neoplasms formed the point of departure 3 for studies in this area. The most -4 Q. Meaning studies were undertaken to see 5 if -6 A. If 7 Q. -- benzene had a relationship with 8 chronic lymphocytic leukemia? 9 A. That's correct. 10 Q. Okay. 11 A. Or lymphoid neoplasms in general. 12 Q. Okay. 13 A. Many of these studies, most of them have 14 not distinguished between chronic lymphocytic 15 leukemia and acute lymphatic leukemia or 16 lymphosarcomas, a variety of lymphoid neoplasms, 17 so it's difficult to segregate out the various 18 diseases within the broad category. 19 One study that purported to show a -- a 20 potential effect with respect to benzene and 21 lymphoid neoplasms, and maybe CLL was a study by 22 McMichaels at the University of North Carolina. 23 Now, this study, a major criticism of 24 this study is that efforts were not made to 25 really quantitate or evaluate potential exposure WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 42 1 to benzene very well. And this study suggested 2 that there might be an increased incidence of 3 lymphoid neoplasms in the population of tubber 4 workers. 5 Now, this study was followed up by the 6 same group with some case control studies that 7 looked very carefully at the exposure histories 8 of these individuals. And the -- the principal 9 authors on these two studies were a Dr. Wilcosky 10 and a Dr. Checkoway. And these are all from the 11 University of North Carolina. 12 These studies determined that, in fact, 13 the greatest association with the lymphoid 14 neoplasms was not benzene, but was, in fact, 15 related to other solvents. Whether or not those 16 findings will bear up under the test of time is 17 anybody's guess, because those particular agents 18 have never been associated previously with 19 leukemia. But the principal importance of those 20 studies is that they demonstrate, that with very 21 careful evaluation of the exposure groups, 22 benzene was not associated with any increased 23 incidence of lymphoid neoplasms. 24 That's consistent with the fact that the 25 pattern of neoplasms seen in rubber workers is WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 43 1 not the same as is seen in individuals who have 2 been exposed chronically to benzene in the past. 3 Q. Okay. Any others that you can point to 4 me? 5 A. Well, I think -- I think that 6 summarizes, in general, the -- the most reliable 7 datasets that we have. 8 There are numerous other studies that 9 have impacted on this subject. There are, for 10 instance, nonquantitative studies involving 11 collections of cases which are not very useful 12 for quantitating or determining causation, but, 13 nevertheless, point to the same pattern, where 14 the hypothesis was, in fact, that one would 15 expect to see a relationship between benzene 16 exposure and CLL. And, in fact, when populations 17 have been examined where the exposures were very 18 high, you, in fact, see fewer CLL than you do in 19 the normal population. 20 So there's really no substantive 21 evidence to support that link. 22 Q. Okay. All right. Now, I want to ask 23 you about your second opinion that you mentioned 24 some time ago. 25 You said that it was your opinion, based WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 44 1 on your review of information in this case, that 2 the chronic lymphocytic leukemia process in 3 Mr. Chambers himself started before birth or 4 shortly thereafter. Tell me what you mean by 5 that, first of all. 6 A. Well, I arrived at this opinion by 7 performing what is called a "lymphocyte doubling 8 time analysis." 9 Q. What is a "lymphocyte doubling time 10 analysis"? 11 A. Well, chronic lymphocytic leukemia is 12 unique amongst the leukemias in that the rate at 13 which the tumor cells increase in number is very 14 constant, the kinetics of cell replication, when 15 cells -- cells make other cells simply by 16 dividing. And this process, in some leukemias, 17 such as acute myelogenous leukemia, is very fast 18 and very rapid and very complex, in terms of the 19 rate at which the cells divide. In -20 Q. In other words, the rate at which the 21 myelogenous leukemia progresses? 22 A. Yes. 23 Q. Okay. 24 A. Yes. In the case of CLL, the cells 25 replicate at, that is, they divide at a WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 45 1 relatively slow rate. And the principal cell 2 type that's seen, that's associated with the 3 disease, is actually a very long-lived cell that 4 does not divide very rapidly at all. 5 The total cell number, abnormal cell 6 number in a patient increases slowly as the di -7 disease progresses. It's been demonstrated that 8 a very reliable indicator of the -- the 9 prognosis, or the.-- how the patient is likely to 10 fair, is the lymphocyte doubling time. 11 This involves making an estimate of the 12 patient's total tumor cell body burden, the 13 number of cells in his body, based on his 14 peripheral blood count, with time. 15 If you look at any individual blood 16 value, especially in a patient with CLL, it may 17 or may not really reflect, at that moment, what 18 the overall progress of the disease is. And, in 19 fact, the lymphocyte count, if you will, this is 20 a disease of lymphocytes, is not a very reliable 21 indicator of how the patient is doing or will 22 do. 23 The doubling time, however, relates to 24 an estimate of the total number of cells that are 25 abnormal within the person, and with time, that's WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 46 1 proven to be a very reliable prognostic 2 indicator, and it's reliable because it's so 3 constant. 4 Q. Okay. You -- where has it -- where does 5 it come from, that you have the -- your 6 information about the doubling time and its 7 constancy -8 A. Well -9 Q. -- or how reliable doubling time is with 10 chronic lymphocytic leukemia? 11 A. There's considerable literature on the 12 subject that has been published over the last 13 decade or two. And this -- the interest here is 14 developing very useful indicators of how a 15 patient will fair. 16 One of the -- the history behind this 17 is -- is that CLL is the most frequent type of 18 leukemia seen, certainly in the western world, 19 representing about 30 percent of total 20 leukemias. 21 It is really a disease of old age, in 22 that the disease becomes manifest after the age 23 of 40. Over 90 percent of the cases appear after 24 the age of 40. The median age is about 60. So 25 it's a disease of old age, basically. And it is WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 47 1 very heterogeneous with respect to its 2 prognosis. Some patients can do very well for 3 over 10 years without any treatment, where other 4 patients may need very aggressive therapy and 5 may, in fact, die within a year or two of 6 diagnosis. 7 So it's been important, in the course of 8 studying the disease and studying patients with 9 the disease, to develop means of predicting how a 10 patient is going to do early on. And one of 11 the -- in -- in current practice, one of the 12 techniques that has -- that is receiving a great 13 deal of interest, in terms of its potential 14 value, is the lymphocyte doubling time, because 15 by using the doubling time, it's been 16 demonstrated that you can distinguish individuals 17 into two broad categories, those that have a 18 relatively poor prognosis and those that have a 19 relatively good prognosis. 20 MR. BARRIE: I'm going to object to 21 the nonresponsive portion of the answer. 22 Q. (By Mr. Galbraith) Okay. I want to make 23 sure I understand what you've just said. 24 Certain patients with chronic 25 lymphocytic leukemia will have a doubling time WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 48 1 where the number of cells, leukemic cells will 2 double more quickly than others. 3 A. It's the -- the total population of 4 tumor cells that a patient has is a function of 5 two things: how fast the cells divide and how 6 fast they disappear, or how long they live -7 excuse me. 8 In the case of chronic lymphocytic 9 leukemia, this is a very dynamic process. You 10 actually -- the cells are actually dividing 11 slower than normal lymphocytes would. The rate 12 of division, the rate -- the proportion of cells 13 that are actively dividing is relatively less 14 than in a normal individual, but you have many 15 more cells present, and so you have a larger 16 total entry of cells into that compartment. 17 They also live a long time. And so you 18 slowly build up a larger tumor load. 19 Q. Okay. So to get a prediction on the 20 future, in other words, how someone will do after 21 a diagnosis of chronic lymphocytic leukemia, you 22 look at this doubling time? 23 A. Yes. 24 Q. Okay. How do you get the information, 25 on a specific patient basis, for doubling time? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 49 1 A. The principal tool that you use is the 2 peripheral blood count, and you determine the -3 actually, the number of lymphocytes in the 4 peripheral blood count. 5 Using data that's been published in the 6 literature in the characterization and study of 7 lymphocyte doubling time, one can estimate, based 8 on the patient's weight, what the total body 9 burden is. This is a rough estimate. It's not 10 necessarily an exact figure, in terms of the 11 precise estimate of the number of cells. 12 What is most useful about this technique 13 is if you have data on which to calculate the 14 rate at which the tumor cells double, en masse, 15 it is more reliable than any individual 16 datapoints. You're calculating the number of 17 years or months that it takes for the total tumor 18 mass to double. 19 Q. Okay. And if you can calculate that 20 rate, that gives you an indication of when the 21 disease process started, itself? 22 A. It's principal use at present, in a 23 clinic, is to project the rate at which the cells 24 will double for prognostic reasons. 25 Q. To predict how the patient is going to WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 50 1 do in the future? 2 A. Right. Now, the reason it is reliable 3 in that context is that the doubling times is a 4 very constant feature of CLL. 5 Now, another piece of information you 6 have to have, to reach the conclusion that I have 7 in this case, is the fact that CLL is what is 8 called a "monoclonal disease." It is derived 9 from a single cell. All the cells that are tumor 10 cells are ultimately derived from a single 11 malignant cell. And in order to do that, that 12 cell had to be initiated, it had to become a 13 cancer cell, and it then had to undergo 14 divisions. 15 The first doubling time is the second 16 cell, and then progressively, with time. This 17 rate in CLL is very constant. 18 Q. Okay. So tell me what you have done in 19 this case to look into or to calculate that rate 20 and that doubling time to lead to your opinions 21 about when Mr. Chambers' chronic lymphocytic 22 leukemia process started? 23 A. Now, the first thing that I did was to 24 review his medical record and to look at all the 25 blood tests that have been done that were WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 51 1 reported in the record on Mr. Chambers dating 2 back to 1967. 3 Q. And what did that tell you? 4 A. That gave me the -- what's called the 5 I calculated the absolute lymphocyte could, which 6 is the number of lymphocytes circulating in his 7 peripheral blood. In this case, it's -- it's 8 measured in microliters, or cubic millimeters, if 9 you will. 10 Q. Okay. 11 A. And then, in order to -- because this 12 the estimates of body burden were first made by 13 Dr. Stryckmans -- and his article is in here 14 and I used his nomogram for calculating or 15 estimating the total body burden. 16 Q. Okay. You've come out with a sheet of 17 paper, and I guess I'd like to have that marked 18 as Exhibit 3. Could we do that before we start 19 referring to what's on it? How about it? 20 A. Yes. 21 22 (Whereupon, the instrument referred to 23 by counsel was marked for identification as Irons 24 Exhibit No. 3.) 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 52 1 Q. (By Mr. Galbraith) A11 right. Taking a 2 look at Exhibit 3, that is your tabulation of his 3 blood counts back to nineteen -- May 9th of 1967 4 was the first one? 5 A. That's correct. 6 Q. And it-has what entries? 7 A. The white blood cell count, or WBC, the 8 differential lymphocyte count or percent 9 lymphocytes as determined on the smear, the 10 absolute lymphocyte count, which is basically -11 this is a percentage, and so this simply 12 represents the total white cell count times the 13 fraction that are lymphocytes, to give us a total 14 lymphocyte number. 15 Now, the work by Stryckmans and 16 colleagues has determined, or has demonstrated 17 that it is -- you can obtain a more reliable 18 indicator of the estimated body burden of tumor 19 cells if you relate this to the individual's 20 weight, because, obviously, fluctuations in 21 weight could alter the respective body burden 22 that is reflected in the cell counts in the 23 blood. 24 So just in case there were fluctuations 25 in weight, I used that estimation based on weight WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 53 1 to -- for the rest of my analysis. I actually 2 could have just used, as it turns out, the 3 peripheral lymphocyte count, because Mr. 4 Chambers' weight has not varied that much over 5 the course of the last twenty some years. 6 Q. Okay. So, from the medical records, you 7 had the blood counts, you had the percent 8 lymphocytes and you had the weights? 9 A. Yes. 10 Q. Okay. And from that, you arrive at what 11 conclusion or what figures? 12 A. Well, basically what I did, was I 13 plotted the average yearly body burden, as 14 determined from these analyses. And when you do 15 that -16 Q. Over time? 17 A. Over time. 18 MR. GALBRAITH: All right. Could 19 we take that plot and refer to it as Exhibit No. 20 4, please? 21 22 (Whereupon, the instrument referred to 23 by counsel was marked for identification as Irons 24 Exhibit No. 4.) 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 54 1 Q. (By Mr. Galbraith) Sb Exhibit 3 has -2 so Exhibit 3 has the actual numbers from 3 Mr. Chambers' medical records, from actual blood 4 counts? 5 A. Yes, sir. 6 Q. And then Exhibit 4 takes that 7 information and puts it on a -- a graph over 8 time? 9 A. Yes. I think you need to include this, 10 as well. These are the average values for each 11 year. 12 Q. Okay. 13 A. Mr. Chambers had several blood tests 14 done in the course of some of these years, and I 15 averaged those to come up with estimated body 16 burden for this purpose. 17 Q. On a year-by-year basis? 18 A. A year-by-year basis. 19 Q. Okay. Could we refer to that, then, 20 your average cell body burdens, as Exhibit 5? 21 22 (Whereupon, the instrument referred to 23 by counsel was marked for identification as Irons 24 Exhibit No. 5.) 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 55 1 Q. And so these numbers from Mr. Chambers' 2 medical records are plotted on Exhibit 4? 3 A. Yes. 4 Q. What does -- what does Exhibit 4 do for 5 you? 6 A. Well, this analyses, in total, tells me 7 a number of things. 8 First of all, the data suggests a very 9 reliable doubling time analysis, because the 10 points clearly depict an increase that is 11 constant and progressive with time, and the 12 doubling time is over three years by this 13 analysis, 3.31 years, actually. 14 Q. What does that mean, the doubling time 15 of chronic lymphocytic leukemia in Mr. Chambers' 16 case is 3.31 years? 17 A. It means, first of all, that it takes 18 over three years for the tumor cells that he has 19 to double in number, for the mass to increase by 20 two. So every 3.31 years, it has been increasing 21 in size by twice. 22 Q. Okay. 23 A. That's number one. 24 Number two, because it's well over one 25 year, the time it takes for this to happen, it WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 56 1 places him in a very good pro4nostic category. 2 The doubling time analyses that have been 3 conducted by Montserrat and others in the 4 literature have indicated there are two major 5 groups of individuals: those that have a very 6 rapid doubling time of less than a year; and 7 those that have a slower doubling time of greater 8 than a year. 9 Those that have a slower doubling time 10 of greater than a year show a more favorable 11 prognosis and go for a much longer period of time 12 before they need treatment, in general, than 13 individuals with a more rapid period of time. 14 This is -- this is consistent with the 15 lack of problems that Mr. Chambers has had 16 related to his CLL in his medical history. 17 Q. Okay. I take it this chart indicates 18 that you can graph backwards through time, as 19 well, that it's constant and reliable in 20 reverse. 21 A. At this point, we are basically looking 22 at the state-of-the-art with respect to our 23 understanding of the biology of CLL. It's clear 24 that CLL has, compared to other leukemias, a 25 very -- a very decided familial disposition. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 57 1 There's a tendency on the part of different 2 family members within the same family to develop 3 CLL. 4 The doubling time is very constant. And 5 because the slope of this line is very reliable 6 in projecting and/or predicting the outcome of 7 the patient, it is reasonable to project a line, 8 as well, going the other direction, in terms of 9 developing an understanding of where this event 10 may have occurred. 11 Other leukemias, you can't do this, 12 because the kinetics are far too complicated, and 13 there are events that are going on during the 14 course of the progression of the disease that 15 change the rate of division. Since the rate of 16 division is so constant in CLL, it's reasonable 17 to project backwards to determine, within some 18 reasonable margin of error, where the initial 19 event might have occurred that led to the 20 development of the disease. 21 Q. Okay. 22 A. And if you do this with Mr. Chambers, 23 you arrive at a conclusion that the initial cell 24 population either was present before he was born, 25 or shortly thereafter. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 58 1 Q. And carrying that slime reasoning 2 forward, in terms of the rate of the progression 3 of Mr. Chambers' disease, he is one of those 4 individuals who has an unfavorable future in 5 terms of the progression of the disease, or a 6 more favorable prognosis or future? 7 A. Certainly, based on the literature, he 8 has a favorable prognosis. 9 Q. Dr. Irons, thank you. 10 MR. GALBRAITH: And I'll pass the 11 witness at this time. 12 Might this be a good time for a break? 13 MR. SCOTT: I need to take one. 14 THE VIDEOGRAPHER: It's 11:17. 15 We're off the record. 16 17 (Whereupon, after a brief recess, the 18 video deposition continued as follows:) 19 20 THE VIDEOGRAPHER: It's now 11:32. 21 We're back on the record. 22 23 EXAMINATION 24 QUESTIONS BY MR. BARRIE: 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 59 1 Q. Good morning, sir. How are you? 2 A. Hi. 3 Q. My name is Martin Barrie, and I 4 represent Mr. Chambers and his wife in this cause 5 of action. And I understand, sir, you've been 6 retained as an expert in this case by the 7 Marathon Oil Company, correct? 8 A. That's correct. 9 Q. All right,. Is it Dr. Irons? 10 A. Yes. 11 Q. Is that a title conferred upon you, sir, 12 by virtue of a doctorate of philosophy? 13 A. Yes. 14 Q. You, sir, are not a medical doctor? 15 A. No, I'm not. 16 Q. May I call you "Doctor"? 17 A. Yes. 18 Q. Dr. Irons, I'd like to have a few 19 general agreements with you, if I can, during 20 this deposition. 21 Sir, if you don't understand any of my 22 questions during his deposition, I want you to 23 stop me. I want to be sure that I can rely on 24 your answers that you have given in answer to my 25 questions. So if you don't understand them, will WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 60 1 you stop and ask me to rephrase it? 2 A. Yes. 3 Q. Dr. Irons, have you ever had occasion to 4 give your deposition before? 5 A. Yes, I have. 6 Q. Would you tell the jury, sir, how many 7 times you've been giving your deposition 8 testimony? 9 A. Three or four,, I believe. 10 Q. Were those on behalf of individuals who 11 were injured, or were they on behalf of 12 corporations, or can you tell the jury any sort 13 of distribution about those depositions? 14 A. Three have been for corporations who 15 have been defendants in cases, and one has been 16 for a plaintiff. 17 Q. Let's talk about these three depositions 18 you've given for corporations. Can you tell me, 19 sir, who those corporations were? 20 A. Monsanto. And one case involving 21 multiple defendants. I believe one of them was 22 Shell. 23 Q. Can you tell, me, sir, when the 24 deposition testimony was given? 25 A. I gave two depositions in a case called WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 61 1 Skeen, Skeen 2, which was approximately -- it was 2 over two years ago. One was in November or 3 December, I believe -- or January, January of 4 1989. And the other one was in the fall of '88, 5 I believe. 6 I gave a deposition in a case called 7 Buchaj, which I failed to mention. I'm sorry. 8 And the defendant in that case was Texaco. And 9 that was in November of this last year. 10 Q. Can you recall any other names, other 11 than the Skeen trial, in which you were an expert 12 for a defendant, or the Buchaj case that you 13 were, again, an expert for a defendant. Can you 14 recall any other styles or names of cases, sir? 15 A. Yes. One. It's -- there are three 16 plaintiffs, Carter, Sleuter and Riddle. And I 17 gave that deposition in August of 1990. 18 Q. Where was that case filed, sir? 19 A. It's in Roan Oak, Virginia. 20 Q. Were you representing these three 21 plaintiffs, or were you representing a corporate 22 entity? 23 MR. SCOTT: I object to the form of 24 the question. Lawyers represent people. 25 Witnesses appear behalf of parties. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 62 1 Q. (By Mr. Barrie) Well, when you were 2 retained by a party, were you retained by these 3three plaintiffs, or were you retained by a 4 corporate entity? 5 A. By the corporations that are defendants 6 in the case. 7 Q. Can you tell me, sir, what those 8 corporations were -9 A. I 10 Q. -- by name? 11 A. I believe I mentioned Shell is one of 12 them. I'm afraid I can't remember exactly who 13 the others are. It's not Monsanto. 14 Q. Would it have been Marathon? 15 A. No. I don't think so. 16 Q. Union Carbide? 17 A. I don't think so. To the best of my 18 recollection, it's not. 19 Q. Do you keep copies of your deposition 20 testimony, sir? 21 A. Yes, I do. 22 Q. Are they in your office in Colorado? 23 A. I believe so, yes. 24 Q. This Skeen trial, was this the Skeen 25 trial, sir, where there was another gentleman who WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 63 1 worked at Monsanto who got leukemia? 2 MR. SCOTT: Object to the form of 3 the question. "Another" implies that there is 4 some in this case. There's certainly no evidence 5 of that. 6 Q. (By Mr. Barrie) Dr. Irons, was the 7 person involved in the Skeen case, was he an 8 individual who had leukemia who worked in the 9 Monsanto facility? 10 A. I believe he worked in the Monsanto 11 facility, yes. 12 Q. Did the plaintiff in the case have 13 leukemia? 14 A. Yes, he did. 15 Q. And was one of the issues in that case, 16 sir, that you were looking at was whether benzene 17 caused that gentleman's leukemia? 18 A. That's correct. 19 Q. And you came to a conclusion, sir, that 20 that leukemia wasn't caused by benzene exposure; 21 is that correct? 22 A. That's correct. 23 Q. The Buchaj case, was that a case 24 involving a gentleman with a leukemia? 25 A. Yes. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 64 1 Q. Was that case also, sir, involving one 2 of the allegations whereby that gentleman was 3 exposed to benzene and whether that was the 4 result of his leukemia? 5 A. Yes, sir. 6 Q. And did you testify, also, in that case, 7 sir, that that gentleman's leukemia was not 8 caused by benzene exposure? 9 A. Yes, I did. 10 Q. So the jury is able to understand what 11 we're talking about in this case when we use the 12 word "benzene," benzene is a chemical, is it not, 13 sir? 14 A. Yes. 15 Q. And it is true, is it not, sir, that 16 benzene is a constituent or is found in other 17 types of solids, correct? 18 A. On occasion, yes, it is. 19 Q. Well, you're aware, sir, that benzene is 20 found in various concentrations in gasoline, 21 correct? 22 A. Yes. 23 Q. And you're certainly aware that benzene 24 is found in naphtha, correct, in some 25 concentration? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 65 1 A. It can, yes. 2 Q. And you're also aware, sir, that benzene 3 is found in distillate that may be coming off of 4 a distillation column in a refinery, correct, 5 sir? 6 A. It can. It depends on the particular 7 distillate fraction. 8 Q. You're not suggesting that there's 9 distillate that contains no benzene, are you? 10 A. There's virtually no distillate or a 11 variety of other compounds or substances that 12 contain no benzene. "No" is a -- is an absolute 13 term, and in toxicology, we think in terms of 14 relative terms. 15 There's benzene in distillate fractions, 16 there's measurable benzene in eggs, there's 17 benzene in cigarette smoke. 18 MR. BARRIE: Well, I'll object to 19 the nonresponsiveness. 20 Q. (By Mr. Barrie) But there is benzene 21 found in distillate, correct? 22 A. Technically, yes. You can measure 23 benzene in a variety of different fractions, 24 including distillate. 25 Q. Looking at your resume, sir, I notice WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 66 1 that you've been in the academic arena, the 2 academic world, from approximately 1965 until you 3 completed your doctorate of philosophy in about 4 1974, '75; is that fairly correct? 5 A. Yes. 6 Q. Have you ever had an occasion, sir, to 7 work in a refinery? 8 A. No, sir, I have not. 9 Q. Have you ever had occasion to do any air 10 monitoring or monitoring of an individual's blood 11 or urine to do assessment of any potential 12 blood-forming organ crises as a result of 13 exposures in refineries? 14 A. In refineries, no, sir. 15 Q. Have you ever had an occasion to visit 16 the Monsanto refinery? 17 A. I don't believe I have. 18 Q. Have you ever visited the Marathon Oil 19 Company refinery or chemical facility? 20 A. Marathon? No. No, sir. 21 Q. You certainly don't know Mr. Chambers 22 personally, do you, sir? 23 A. No, sir, I do not. 24 Q. You've never worked with Mr. Chambers in 25 a refinery or chemical plant at all, have you? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 67 1 A. No, sir. 2 Q. You certainly haven't worked with any of 3 his co-workers who have worked with him on a 4 day-to-day basis and performed tasks with him, 5 have you, sir? 6 A. No, sir. 7 Q. In your doctorate of philosophy, did you 8 have an occasion to write a dissertation, sir? 9 A., Yes, sir, I did. 10 Q. Would you be so kind as to tell me the 11 title? 12 A. "Characterization of Low Molecular 13 Weight Cadmium and Copper-Containing Proteins." 14 Q. Essentially, if we can just reduce that 15 to fairly simplistic terms, for my benefit, are 16 we talking about heavy metals -17 A. Yes. 18 Q. -- and what effects they may have? 19 A. Yes. 20 Q. Do you have a copy of that dissertation 21 in your files? 22 A. Someplace, yes, I do. 23 Q. In your offices in Colorado? 24 A. I'm not certain where it is, but I'm 25 sure I have it someplace. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 68 1 Q. You've identified, sir, that Exhibit 2 No. 1 is a copy of your curriculum vitae, am I 3 correct? 4 A. That's correct. 5 Q. And I think you've already told the jury 6 that this is not an up-to-date copy. Am I 7 correct? 8 A. That's correct. 9 Q. Do you have an up-to-date copy? 10 A. Oh, yes. 11 Q. Okay. Would you be so kind as to 12 provide me a copy, so I can take a look at it? 13 A. I'd be happy to. 14 Q. Let me just hand you your curriculum 15 vitae. It's Exhibit No. 1, Doctor. And let me 16 just ask you if there's anything that's omitted 17 from that particular CV, whether it be an 18 article, whether it be experience, whether it be 19 training, or anything of that nature, that I need 20 to know about that you may be relying on in the 21 formation of any opinion in this case? 22 A. Certainly not that I'm aware of. 23 Q. Are you going to be relying, sir, on 24 some specific article at the trial of this case 25 that's not reported in that CV? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 69 1 MR. GALBRAITH: I guess I object to 2 the form of the question because he's already 3 referred to articles here today that aren't 4 authored by himself or in his CV. So the 5 answer -- I guess -- I guess I don't object to 6 the form because the answer is "Yes." He's 7 already indicated "Yes." That makes me think I 8 don't understand the question. That's all -- the 9 reason for my interjection. 10 Q. (By Mr. Barrie) With regard to your CV, 11 is there any article that you have in a CV, 12 whether it's that CV or one that's more recent, 13 that you're going to cite to some book, cite to 14 some article, cite to some training, or any other 15 experience in the formation of an opinion in this 16 case? 17 A. If I understand your question, I intend 18 to rely on the articles and the documents that I 19 have provided, the background that's in my 20 curriculum vitae. If you, or anyone else, asks 21 me questions that require that I rely on other 22 documentation or books or articles within my 23 knowledge, I will, but it's not my intention to 24 do so, based upon the opinions that I've rendered 25 here. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 70 1 Q. So with regard to the opinions that 2 you're going to render in this case, I'm going to 3 be able to rely on the articles that you've 4 brought and the text that you're brought here 5 before us today, as well as what's in your resume 6 in the formation of those opinions; am I correct? 7 A. Yes, sir. 8 Q. Can you cite me, sir, to any specific 9 article within your CV that you're going to be 10 relying on in rendering those two opinions that 11 you've already expressed to us today? 12 A. Specifically, no, sir. Not 13 specifically. With respect to my background, I'm 14 relying on my experience. I've published in 15 several of the areas that are germane to the 16 analyses and my opinions 17 Q. There's not an article specifically you 18 can say, "This is an article I'm going to be 19 relying on at the time of the trial of this case 20 because it helps support my opinion"? 21 A. Not specifically, no, sir. 22 Q. Thank you, sir. 23 Your activity at the Colorado Health 24 Science Center, can you tell me, sir, how much 25 time you devote to teaching? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 71 1 A. Somewhere between 10 and 20 percent. 2 Q. That leaves us somewhere in the order of 3 between 80 percent and 90 percent of the time 4 you're doing something else, right? 5 A. That's correct. 6 Q. Would you tell me what else you are 7 doing, other than teaching, those 10 percent or 8 20 percent of the time? 9 A. I would say I spend somewhere between 10 10 and 20 percent doing administrative -- what I 11 would call administrative duties related to the 12 program or the University: I spend approximately 13 10 percent of my time consulting and in providing 14 advice to external agencies and parties. And the 15 remainder of my time is spent in research. 16 Q. Would it be fair to say approximately 50 17 percent of your time or less would be devoted to 18 research? 19 A. About half -- that's -- that's about 20 right. 21 Q. You mentioned that approximately 10 22 percent of your time is involved in consulting. 23 Do you devote some of your time within that 24 framework to legal consulting? 25 A. Yes, sir. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 72 1 Q. How much of a percentage does that take 2 up of that 10 percent of your time, in terms of 3 providing expert opinions to lawyers involved in 4 cases? 5 A. Last year, I think it was about nine 6 percent. It's -- it -- I can't give you an 7 absolute precise figure, but I'd say that 8 certainly in terms of guidelines, we're talking 9 between 10 and 15 percent. Last year, it was 10 nine. This year, I don't know what it would be. 11 It's about that. 12 Q. Would it be fair to say, that of the 13 consulting activities you do, a majority of it is 14 spent in providing benefits and services to 15 lawyers involved in cases? 16 A. In that fraction we're talking about, 17 yes. The remainder of it is spent consulting 18 with attorneys general, health departments, the 19 Governor's office, a variety of different -- the 20 EPA, a variety of different Government bodies, as 21 well. 22 MR. BARRIE: I'll object to the 23 nonresponsive portion of the answer. 24 Q. (By Mr. Barrie) Can you tell me, sir, 25 what fees that you charge to provide legal WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 73 1 services? 2 A. Well, I don't provide legal services, in 3 the sense that I'm not an attorney. I provide 4 expertise related to areas of concern to the 5 various parties. I charge a fee of three hundred 6 dollars an hour. 7 Q. Is this three hundred dollars an hour 8 that you charge for your services, is that for 9 deposition testimony only? 10 A. It's for anything. It's for review of 11 the literature, it's for travel, it's for 12 testimony, whatever. 13 Q. Can you tell me, sir, how much have you 14 billed, to date, the attorney representing 15 Marathon -16 A. I haven't 17 Q. -- for your services? 18 A. I haven't billed him yet at all. I 19 have -- at this point, oh, I guess I've probably 20 worked two days. 21 Q. Forty-eight hours? 22 A. No, no. Sixteen -- two days, eight 23 hours a day, roughly, I think. I'm not sure. 24 But certainly before coming here, that was about 25 right. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 74 1 Q. So the amount owing to you is sixteen 2 hours, approximately, times three hundred dollars 3 an hour? 4 A. Approximately, for that work, yes. 5 Q. You mentioned you were involved with the 6 molecular toxicology Environmental Health 7 Sciences in Colorado. 8 Can you tell me, sir, does that group, 9 if you will, require funding from outside 10 services or companies in order to provide your 11 activities, grants, if you will? 12 A. Yes. 13 Q. Who provides the grants to the Molecular 14 Toxicology and Environmental Health Sciences 15 A. We have a number 16 Q. -- Group? 17 A. We have a number of different sources of 18 funding for various activities. 19 Q. Do chemical companies provide grants for 20 you? 21 A. Yes. 22 Q. That's the money, sir, that you rely on 23 in order to perform your services and activities 24 within that department or that group? 25 A. It's primarily for teaching and WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 75 1 training. It's really not used for other 2 activity, per se. The program funds and/or gifts 3 or donations to the program are used for -- in 4 support of training graduate students in 5 toxicology. 6 Q. Are you saying, sir, that none of the 7 grants or monies provided by chemical companies 8 are going to the running of any of this 9 activities that takes place under this Molecular 10 Toxicology Environmental Health Group? 11 A. No, sir, that's not what I said. I said 12 that the monies that are obtained as gifts for 13 use by the program itself are dedicated to 14 training and education. 15 All of us in academia, certainly within 16 my program, have grants for research that are 17 obtained from a variety of different 18 organizations in support of the work we do. It's 19 very expensive. I personally have grants from 20 both Government and corporate entities in support 21 of my research. 22 Q. You mentioned that for a period of time, 23 approximately ten years or so, you were involved 24 in the Chemical Industry Institute of Toxicology 25 at Research Park, North Carolina. Am I correct? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 76 1 A. I was employed by CIIT, yes. 2 Q. And you mentioned that the funding for 3 that institute came primarily, in the -- in the 4 initial period of time, from chemical companies, 5 correct? 6 A. That's correct. 7 Q. Do you have any idea, sir, when the 8 transition took place from major funding from 9 chemical companies to funding from chemical 10 companies plus other agencies? 11 A. Well, it began gradually. I couldn't 12 put a precise date on it, but to my best 13 recollection, the Institute was accepting some 14 Federal funds as early as, say, 1987, maybe 15 1986. I can't -- I really wasn't involved in 16 those decisions, so I couldn't tell you 17 precisely. 18 Q. All right. That's the first time period 19 that you're aware of that funds outside of the 20 chemical industry were being provided to that 21 Institute? 22 A. Yes. 23 Q. And it's fair to say, even today, as we 24 speak, sir, that industry is a major supplier of 25 funds to that particular Institute, correct? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 77 1 A. I would hesitate to speak about the 2 funding profile for CIIT today, because I really 3 have no idea. I would expect that they are 4 receiving a considerable amount of support from 5 the industry, but I also am generally aware that 6 they have been active and successful in obtaining 7 Federal funding, as well. 8 Q. You mentioned that when you were at the 9 Chemical Industry Institute, you performed or did 10 some investigation in the mechanism of toxicology 11 and the toxicity of the chemical benzene. Did I 12 understand that correctly? 13 A. That's correct. 14 Q. Did you perform any studies, sir, that 15 would fall under the umbrella term of 16 "epidemiological investigations;" that is to 17 say, identifying the sorts of individuals, such 18 as workers, who were working in an industry that 19 may have exposure to the chemical benzene or 20 other products containing benzene and matching 21 them to similarly situated individuals with the 22 exception that they weren't exposed? 23 A. For benzene, no, I didn't. I have done 24 that for other compounds, however. 25 Q. When you were at the Chemical Industry WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 78 1 Institute? 2 A. Yes. 3 Q. What compounds did you perform that type 4 of an epidemiological investigation for? 5 A. I performed the initial feasibility 6 studies of conducting such a study as you 7 described on butadiene in the People's Republic 8 of China. 9 Q. Butadiene has been linked with causing 10 specific types of cancers, has it not? 11 MR. SCOTT: I object to the form of 12 the question. What do you mean "linked"? 13 Q. (By Mr. Barrie) There's a, causal 14 relationship between butadiene exposure and some 15 cancers, is there not? 16 A. In my -- yes. 17 Q. Is it your testimony that butadiene does 18 not have a causal relationship to any cancers in 19 humans? 20 A. It's my opinion that a causal 21 relationship between butadiene and human cancer 22 has not been definitively established. 23 Q. Well, what about the relationship 24 between styrene and butadiene? 25 Are you aware, or do you have any WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 79 1 opinion whether styrene plus butadiene would 2 cause any type of cancer in humans? 3 A. I -- I -- the question is -- I'm -- I'm 4 afraid I don't know quite how to answer your 5 question. 6 Q. Well, have you 7 A. If you're asking me whether there are 8 epidemiology studies on the relationship between 9 potential exposure to styrene and human cancer, 10 yes, there are. There are also studies, 11 epidemiology studies on butadiene. 12 The nature of those studies, they differ 13 from one to the other, and the precise 14 relationship between exposure to those agents and 15 various human cancers, if any, is by no means 16 clear at this time. 17 Q. In your opinion? 18 A. In my opinion. 19 Q. So, in your opinion, exposures to 20 butadiene, singularly, or in combination with 21 styrene, in your mind, does not have a causal 22 relationship at all between any sort of cancer in 23 people? 24 A. No, I did not say that. I said that the 25 evidence in support of a causal relationship is WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 80 1 by no means clearly established, and it is 2 impossible, at this time, to determine, in my 3 mind, what, if any, human cancers are 4 specifically associated in a causal relationship 5 with those exposures. 6 The data is out. The -- I think a 7 conclusion is not yet forthcoming from the data 8 we currently have. 9 Q. Would you recognize that other experts 10 may voice a different opinion with regard to a 11 causal relationship between butadiene exposure, 12 either singularly or in combination with styrene, 13 and its causal relationship with cancers? Are 14 you aware of that opinion being held in the 15 epidemiological field and the toxicological 16 field? 17 A. There's currently considerable 18 discussion and controversy over the quality and 19 the nature of studies that have been performed. 20 Some of them contradict each other. Some 21 individuals hold one opinion, some old hold 22 another. The literature is by no means clear. 23 Q. And, again, that's the opinion you've 24 gleaned from reading the epidemiological 25 investigations and -WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 81 1 A. That's correct. 2 Q. -- studies? 3 Have you issued a report, whether it be 4 a preliminary or final report in this case, as 5 you've been retained as an expert by Marathon? 6 Have you issued a report? 7 A. No. 8 Q. Do you plan on issuing a report? 9 A. No. 10 Q. Do you have any plans, sir, to appear 11 live at trial of this case, to give testimony on 12 behalf of Marathon Oil Company? 13 A. If I am asked, I will do so. 14 Q. I'd like the jury to have a clear 15 understanding of what your expertise is, and what 16 I'd like to know is: Do you consider yourself 17 and hold yourself out as an expert in toxicology? 18 A. Yes, sir. 19 Q. Are there any other fields that you 20 consider yourself or hold yourself out to be an 21 expert? 22 A. Experimental hematology. And I do serve 23 as a member of the Department of Pathology at the 24 University of Colorado in the -- in the training 25 and differen -- providing expertise in terms of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 82 1 differential diagnoses associated with the 2 morphology and/or laboratory differential 3 diagnostics of lesions involving hematopoietic 4 and immune system. 5 Q. So if I can summarize this for the jury, 6 you hold yourself out as an expert, consider 7 yourself an expert in the fields of toxicology, 8 experimental hematology, and some aspects of 9 pathology? 10 A. That's correct. 11 Q. You don't hold yourself as an expert in 12 epidemiology, do you? 13 A. I don't consider myself and 14 epidemiologist, but I teach epidemiology, I'm 15 called upon to review data in epidemiology, and 16 to render opinions with respect to the quality of 17 that data in a variety of settings. 18 Q. Are you here today, sir, to give us 19 expert opinion in the field of epidemiology? 20 MR. SCOTT: I object to the form of 21 the question. He's already referred to the 22 epidemiologic literature in providing the 23 opinions and bases for -- that he has provided. 24 A. As a toxicologist, I am frequently 25 called upon to both teach and to evaluate the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 83 1 epidemiology data -- data in the literature. So 2 as a toxicologist, I feel competent to review 3 epidemiology data. 4 If you're asking me whether I would go 5 out and design, without collaborating with an 6 epidemiologist, an epidemiology study, the answer 7 is no. But I certainly am qualified to evaluate 8 the experimental design and results that are 9 obtained in epidemiology studies. 10 MR. BARRIE: Well, I object to the 11 nonresponsiveness of the answer. 12 Q. (By Mr. Barrie) You've brought for us, 13 here today, sir, some documents in this blue 14 binder that's been marked as an exhibit. Are 15 those the articles of which there are some, 16 perhaps, in the field of industrial -- some of 17 which contain epidemiological investigations on 18 which you're relying in forming the basis of some 19 of your opinions in this case? 20 A. Yes, sir. 21 Q. When were you first contacted in this 22 case, sir? 23 A. I'm not sure exactly, but I believe it 24 was in December. 25 Q. Of 1990? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 84 1 A. Yes. 2 Q. And who contacted you? 3 A. I believe it was Mr. Scott. 4 Q. And I believe Mr. Scott represents 5 Monsanto in this case; is that your 6 understanding? 7 A. That's my understanding, yes. 8 Q. When Mr. Scott contacted you, what did 9 he ask you to do? 10 A. He asked me to take a look at the 11 medical records in this case and to review the 12 literature and to render an opinion as to the 13 issues that we've been discussing here today. 14 Q. Have you ever been contacted by 15 Mr. Galbraith, who represents Marathon? 16 A. No. 17 Q. Aside from the medical records, 18 Plaintiffs' First Amended Complaint, the lawsuit 19 that was -- the papers that were filed in the 20 lawsuit, some information on depositions, is 21 there anything else that was provided to you for 22 you to review and inspect, at all? 23 A. No, not to my knowledge. 24 Q. Now, you mentioned that summaries of the 25 depositions of Mr. Chambers and Mrs. Chambers WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/HEAUMONT(409)833-0016 84 1 were provided to you? 2 A. Yes. 3 Q. Did you actually read Mr. Chambers' 4 entire deposition, or Mrs. Chambers' entire 5 deposition, or did you really rely on the 6 summaries that were provided to you? 7 A. I relied on the summaries to obtain an 8 idea of the character of the allegations in the 9 Complaint. I did not rely on the summaries 10 for -- as a basis for any of the opinions that 11 I've given. 12 Q. Did you read Mr. Chambers' or Mrs. 13 Chambers' entire deposition? 14 A. No, sir, I did not. 15 Q. Who prepared the summaries of their 16 testimony for you? 17 A. I don't know. They were given to me by 18 Mr. Scott. 19 Q. You also mentioned that you reviewed the 20 depositions of Dr. Savitz, who is an 21 epidemiologist, and Dr. Fehir, who is a 22 hematologist, oncologist, internist? 23 A. Yes. 24 Q. Can you tell me, sir, of what importance 25 or reliance you've placed on those particular WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 86 1 depositions? 2 A. Well, I reviewed those depositions and 3 the opinions of those two individuals and 4 evaluated their -- both the information and the 5 literature on which they base their opinions, 6 along with their opinions, in arriving at my own. 7 Q. You are familiar, in general, with the 8 field of hematology, as you've told us a moment 9 ago, correct? 10 A. Yes, sir. 11 Q. Do hematologists look at diseases of the 12 blood and the blood-forming organs, such as 13 leukemias and lymphomas and other types of 14 diseases or cancers? 15 A. Principally the leukemias. 16 Q. Are you suggesting that hematologists 17 limit their investigation into leukemias or -18 A. No. I'm -- I'm just saying that 19 hematologists principally focus on diseases of 20 the blood of which leukemias are an example. 21 Occasionally, hematologists will deal 22 with lymphomas. Oncologists deal with lymphomas, 23 as well. The -- the disciplinary bounds are 24 somewhat fuzzy. 25 Q. Part of a job of a hematologist is to WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 87 1 not only treat the patient, but to also look at 2 what may be the cause of a particular disease of 3 the blood-forming organs, correct? 4 A. On occasion that can be the case, yes. 5 Q. So they're not just trying to treat a 6 patient. Part of their job, also, in taking a 7 clinical history, is to also determine what is 8 the etiological agent, or what caused their 9 particular blood dyscrasia or problems in their 10 blood-forming organs, correct? 11 A. I would say that that's correct, with 12 the caveat that certainly most practicing 13 clinicians are -- emphasize, in their daily 14 activities, primarily the diagnosis and 15 treatment, as opposed to the more research 16 oriented activities, such as determining 17 etiology, although they can participate in those 18 activities, as well. 19 Q. Is there anything that you plan on doing 20 in this case, sir, that you haven't done yet, 21 that may affect, in any way, any of the opinions 22 that you've already given to us today? 23 A. Not to my knowledge, no. 24 Q. Have you been asked to do something that 25 you haven't done? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 88 1 A. Not that I know of. 2 Q. And one of the reasons I ask that, sir, 3 is I -- I just want to know if you're going to do 4 something else, so if it affects your opinion in 5 any way, I want to just have an opportunity to 6 question on you on that, and that's why I asked 7 that question. 8 A. Understood. 9 Q. Is chronic lymphocytic leukemia, "CLL," 10 as it's called by initials, is that a disease of 11 the blood and the blood-forming organs? 12 A. Yes, it is. 13 Q. Is the disease acute myelogenous 14 leukemia, or "AML" by initials, also a disease of 15 the blood and the blood-forming organs? 16 A. Yes. 17 Q. Is the disease chronic myelogenous 18 leukemia, or by the initials, "CML," a disease of 19 the blood and the blood-forming organs? 20 A. They're all diseases of the 21 blood-forming organs, yes. 22 Q. Or in general, so we can make it a 23 little bit simpler, diseases of the hematopoietic 24 system? 25 A. Yes. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 89 1 Q. Also, they can be called "blood 2 dyscrasias" or "blood problems," am I correct? 3 A. In a general -- in a very general way, 4 yes. 5 Q. The reason I use those terms, sir, is 6 that the jury may hear those terms throughout the 7 course of the trial, and I want them to 8 understand that we're talking generally about the 9 same problem, right? 10 MR. SCOTT: I object to the form of 11 the question. What do you mean when you're 12 talking about the same problem"? 13 Q. (By Mr. Barrie) We're all talking about 14 diseases in the blood, the bone marrow, those 15 types of diseases, are we not? 16 A. These are all different diseases that 17 are associated with the blood and the 18 blood-forming organs. 19 Q. But chronic myelogenous leukemia, acute 20 myelogenous leukemia, chronic lymphocytic 21 leukemia, they're blood dyscrasias? 22 A. They are diseases of the blood. Blood 23 dyscrasia is simply a fancy word for 24 abnormalities of the blood, so, yes. 25 Q. And they're diseases of the blood and WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 90 1 the blood-forming organs, correct? 2 A. Yes. 3 Q. Now, you've given us here today, sir, 4 two of the opinions that you've formed in this 5 case; am I correct? 6 A. Yes. 7 Q. Are there any other opinions that you 8 have formed that you're going to tell the jury 9 about in this case, other than those two? 10 A. No, not that I know of. 11 Q. You mentioned in your first opinion 12 that, in your opinion, there is no -- and I think 13 this is a quote -- "reliable evidence," unquote, 14 that benzene or any other agent has a 15 relationship, a causal relationship, to the 16 disease chronic lymphocytic leukemia. Did I 17 understand that correctly? 18 A. That's correct. 19 Q. By that statement, sir, are you 20 suggesting to the jury that there is no evidence 21 at all of a causal relationship between benzene 22 exposure or products that contain benzene and 23 this type of leukemia, this CLL? 24 A. Well, as I mentioned earlier this 25 morning, in fact, I discussed, summarized the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 91 1 work of McMichael, et al., that originally 2 suggested there might be an association. So, 3 obviously, I'm not saying that. 4 What I'm saying is that followup studies 5 by the same group have changed their initial 6 opinion with respect to the nature of benzene 7 exposure and the findings in that study. 8 Q. So the study by McMichael identified, in 9 that study, a causal relationship between benzene 10 exposure or that cohort or group and the disease 11 chronic lymphocytic leukemia? 12 A. No, sir. No, sir. A single 13 epidemiology study can define an association. 14 The chances that a single study would be so 15 well-designed and the findings so clearcut that a 16 causal relationship would be established is very 17 remote. 18 What the McMichael study did was 19 indicate a possible association or correlation 20 between what was presumed to be benzene exposure, 21 without looking at it closely, and lymphoid 22 neoplasms, which included, within that group, 23 CLL. 24 Q. Did they report, sir, workers who were 25 exposed to benzene, and the workers that were WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 92 1 similarly exposed that had chronic lymphocytic 2 leukemia? Did it identify cases such as that? 3 A. It did not deal with exposure, her se. 4 Exposure to benzene was a point of departure for 5 the study. They did not look at exposures, per 6 se, in that study. 7 Q. Well, were they looking at workers who 8 were working in areas where benzene exposure, 9 more likely than not, could occur in some of 10 those individuals having the diagnosis of chronic 11 lymphocytic leukemia? 12 A. They examined individuals -- they 13 examined workers who worked in situations where 14 benzene was one of the possible exposures that 15 they could have had. 16 Q. And some of those individuals had the 17 diagnosis of chronic lymphocytic leukemia, 18 correct? 19 A. Some of those individuals had lymphoid 20 neoplasms and, within that group, there were some 21 patients with CLL, as I recall. 22 Q. And I want the jury to understand when 23 we're talking about epidemiological 24 investigations, what we're talking about is 25 studies that are done on large groups of people, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 93 1 and we're looking at controlling everything 2 except for, in this case, exposure to benzene, to 3 see if there's an incidence among that exposed 4 group relative to those that are not exposed, of 5 whether there is a type of disease that they have 6 to draw a causal inference among the group 7 whether benzene may have a causal relationship to 8 the disease. Am I correct? 9 A. That would be the ideal situation, yes, 10 sir. 11 Q. I don't want the jury to understand that 12 epidemiological investigations establish 13 causation in a person. Am I correct in that? 14 A. That's correct. 15 Q. So when we talk about epidemiological 16 studies and what findings they give us, we're not 17 establishing causation in a person, but rather 18 we're looking at groups of people and what an 19 inference may be, correct? 20 A. That's correct. 21 Q. You mentioned that in the McMichael 22 study, there were other solvents. Can you tell 23 me, sir, what those other solvents were? 24 A. From the list -- certainly, from the 25 followup studies, the potential exposures WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 94 1 involved a wide range of compounds. I can 2 provide you with a list, if you'd like. 3 The two particular agents that in the 4 followup studies were much more markedly 5 associated with lymphoid neoplasms than benzene 6 were carbon tetrachloride and carbon disulfide. 7 Now, I should add, to be complete, that 8 that's the only association, or potential 9 association with those two compounds and any 10 lymphoid neoplasms that I'm aware of. And 11 whether or not that proves to be a real causal 12 related association would require a great deal 13 more study. 14 MR BARRIE: I'll object to the 15 nonresponsiveness of the answer. 16 Q. (By Mr. Barrie) Do you have an opinion, 17 sir, whether carbon tetrachloride has any causal 18 association with chronic lymphocytic leukemia? 19 A. Not to my knowledge, not in the study. 20 Q. What about -- what about carbon 21 disulfide, do you have an opinion whether that 22 has a causal relationship to the disease chronic 23 lymphocytic leukemia? 24 A. Not to my knowledge. 25 Q. Is benzene a leukemogen? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 95 1 A. In individuals chronically exposed to 2 high concentrations of benzene, there is a clear 3 and generally accepted relationship with acute 4 myelogenous leukemia. So, by definition, benzene 5 is a human leukemogen. 6 MR. BARRIE: I'll object to the 7 nonresponsive portion of that answer. 8 Q. (By Mr. Barrie) When was it established, 9 in your mind, sir, that benzene was a leukemogen, 10 in the scientific community? 11 A. There was no point in history where 12 everyone suddenly came to a consensus, but I 13 would say, in general, we're talking about mid to 14 late 1970's, where it became generally accepted 15 within the scientific community that there was a 16 relationship between benzene and AML. 17 Q. Are you saying that it was when there 18 was an establishment that benzene had a causal 19 relationship with a leukemia called acute 20 myelogenous leukemia, that that's when the 21 scientific community, in your opinion, said that 22 benzene is a leukemogen? 23 A. In terms of a general consensus, yes. 24 Q. Do you have any opinion whether aplastic 25 anemia is a necessary precursor to leukemia? In WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 96 1 other words, you get an association between 2 benzene exposure and acute myelogenous -- and 3 aplastic anemia, and that's necessary before you 4 can go on to get a leukemia. Do you have any 5 opinion on that regard? 6 A. Certainly, the clinical literature 7 indicates a very, very strong association between 8 those two processes, that one has to have some 9 evidence of bone marrow suppression, of which 10 aplastic anemia is an example, in order to create 11 the situation that may, in fact, lead, in some 12 individuals, to developing AML. 13 I personally think that it's much more 14 likely that our understanding of that process is 15 going to involve looking at damage at the level 16 of the stem cells. 17 What I'm trying to say here is that I do 18 think there has to be pre-existing damage 19 associated with exposure, but not necessarily the 20 evolution of aplastic anemia, although the 21 clinical literature would suggest that, in fact, 22 that is the case. 23 Q. To summarize, in your opinion, the 24 literature seems to suggest, in your opinion, 25 that aplastic anemia is a necessary precursor to WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 97 1 the development of leukemias, although there can 2 be other types of problems prior to a leukemia, 3 other than aplastic anemia? 4 MR. SCOTT: I object to the form of 5 the question. He very clearly said to a specific 6 type of leukemia, not to leukemias in general. 7 Q. (By Mr. Barrie) My question is very 8 broad, and I want you to just focus on the 9 breadth of it, if you will. 10 Is aplastic anemia a precursor to any 11 leukemias? Is it a necessary precursor? 12 A. I really do not understand the 13 question. I can describe, again, what I said 14 before or, if you could, could you reframe it? 15 Q. I'll certainly do my best. 16 Does an individual with chronic 17 lymphocytic leukemia, in your opinion, get the 18 disease immediately, chronic lymphocytic 19 leukemia, or is there some stage that precedes 20 that, whereby he has, and one must have, a 21 suppression, an aplas -- an aplastic anemia, or 22 some other condition that's necessary prior to 23 going on to get a CLL? 24 A. Chronic lymphocytic leukemia has not 25 been assoc -- it is not a secondary leukemia. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 98 1 It's isn't secondary to exposure to anything, be 2 it benzene, radiation, or anything else. 3 An individual who comes down with 4 chronic lymphocytic leukemia does not present 5 with previous symptoms associated with exposure 6 because exposure does not play a role in the 7 development of CLL. 8 MR. BARRIE: I'm going to object to 9 the nonresponsive portion of the answer. 10 Q. (By Mr. Barrie) My question is: Does a 11 person present himself with CLL, or does he 12 present him something with a precursor to CML, 13 which later becomes CLL? 14 A. I'm sorry. You said CML, then CLL. 15 Q. I'm sorry. But I'm dealing with chronic 16 lymphocytic leukemia. 17 A. Patients present spontaneously with 18 chronic lymphocytic leukemia. They are not 19 associated with previous exposure or previous 20 blood dyscrasias because they do not play a role 21 in the evolution of the disease. 22 MR. BARRIE: I'll object to the 23 nonresponsive portion of that answer. 24 Q. (By Mr. Barrie) Doctor, is benzene 25 genotoxic, by that I mean affecting chromosomes, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 99 1 the genes of an individual? 2 A. Benzene metabolites have been 3 demonstrated to cause certain types of 4 chromosomal abnormalities. 5 Q. By these metabolites, are we talking 6 about phenolic and polyphenolic compounds, and 7 others? 8 A. Yes. 9 Q. Is it your opinion that the affect of 10 benzene on the blood and the blood-forming organs 11 is caused by benzene itself or its metabolites? 12 A. Metabolites. 13 Q. Can you list for me, sir, the 14 metabolites that, in your opinion, are 15 responsible for causing the problems of the blood 16 and blood-forming organs? 17 A. This is a very complicated area. It 18 appears that the precise toxicity that's seen in 19 the bone marrow associated with benzene exposure 20 is a function of a combination of metabolites 21 that are present. It's not necessarily a single 22 metabolite that's responsible for what benzene 23 does. 24 The principal metabolites that we 25 focused on are the polyphenolics, primarily WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 100 1 hydroquinone and its terminal oxidation product, 2 benzoquinone. 3 There are also a variety of other 4 polyphenolic compounds, such as hydroquinone, 5 which are produced as a function of the 6 metabolism of benzene. And these, in concert, 7 are most likely responsible for the damage that's 8 seen in bone marrow following benzene exposure. 9 Q. You're familiar with the term 10 "initiator" and a "promoter," are you not? 11 A. Yes. 12 Q. An initiator is a compound or a chemical 13 that initiates a process, and that may go to a 14 full-blown problem or it may sit dormant and 15 later require an agent caused -- called a 16 "promoter," which will kind of kick it in, if 17 you will, which later becomes a full-blown 18 disease or problem, correct? 19 A. That's a model system in toxicology, an 20 experimental system that has been used to 21 describe carcinogenesis primarily in skin and 22 liver models. 23 Q. Do you have an opinion whether benzene 24 is an initiator or a promoter? 25 A. Well, first of all, there are no WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/HEAUMONT(409)833-0016 101 1 initiation/promotion models that are relevant to 2 any leukemias that I'm aware of, either in 3 experimental animals or in man. 4 So the initiation/promotion paradigm or 5 model, from a strictly a theoretical point of 6 view, may or may not be important in the case of 7 leukemias. 8 Benzene, in my opinion, and its 9 metabolites, are very poor actors with DNA. The 10 DNA is the molecules from which our genes are 11 made. They do not react readily or directly with 12 DNA and, therefore, in that system, they're less 13 likely to play a classic role as an initiator 14 than, say, other compounds that might interact or 15 alkylate with DNA. 16 Benzene metabolites appear to act at 17 different places much more effectively within the 18 cell, in terms of interfering with cell 19 replication and division. I would hesitate to 20 use initiation and promotion as a classification 21 or category because, again, as I said, benzene 22 doesn't appear to follow that model in other 23 systems, such as the skin or liver, and there are 24 no initiation/promotion models that I'm aware of 25 that are relevant to leukemogenesis. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 103 1 Q. You're aware of no chemical, by itself, 2 or compound that would potentiate the effects of 3 benzene on the blood and the blood-forming 4 organs? 5 A. No, not in particular. I mean, 6 obviously, you can -- you can hypothesize or 7 speculate on the combined exposure of, say, 8 benzene and chemo -- a chemotherapeutic agent or 9 other agents that show toxicity of the bone 10 marrow, and you certainly would expect that if an 11 individual was exposed to these agents all at the 12 same time, he would experience much greater 13 toxicity or effects than he might from just 14 exposure to one. But I don't know of any agents 15 that specifically synergize or exacerbate benzene 16 toxicity, per se, other than what I've said. 17 THE VIDEOGRAPHER: Mr. Barrie, I'm 18 sorry. We're pretty near down to a minute and a 19 half of tape. Are you just wanting to stop now? 20 MR. BARRIE: Sure. This is a good 21 time. 22 THE VIDEOGRAPHER: It's 12:25. 23 This is the end of Tape No. 1. We're off the 24 record. 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 104 1 (Whereupon, the proceedings continued on 2 the stenographic record as follows:) 3 4 MR. SCOTT: Let's get something to 5 eat. 6 MR. GALBRAITH: Let's just take 7 thirty minutes for lunch. 8 9 (Whereupon, there was a luncheon recess, 10 after which the video deposition continued as 11 follows:) 12 13 THE VIDEOGRAPHER: It's now 1:07. 14 This is the start of Tape No. 2, and we're back 15 on the record. 16 Q. (By Mr. Barrie) I'd like to ask you, 17 sir, have you ever talked to anybody about this 18 case, or discussed this case with anybody, and 19 have their conversations with you formed, either 20 in whole or in part, any of the opinions that 21 you've given us today? 22 A. No, actually. 23 Q. You haven't asked a colleague, either 24 where you're located, or at some other 25 university, or you haven't called anybody on the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 105 1 phone and asked them to do any calculations for 2 you or provide you with any information, or do 3 anything to assist you in any way, however small, 4 that may play some role, in whole or in part, in 5 coming to any of your opinions? 6 A. I've had technical staff perform some of 7 the arithmetic and data extraction from the 8 records, but other than that, no. 9 Q. You've not had a chance to visit with 10 any of the other experts that have been retained 11 by the Defendants in this case? 12 A. No, sir. 13 Q. I want to ask you now, sir, about the 14 toxicity of benzene and ask you, sir, if you have 15 any opinions regarding the concentration of 16 benzene that would be necessary, in your opinion, 17 to cause or contribute to the leukemia that's 18 been identified as acute myelogenous leukemia. 19 The reason I ask that, sir, and to 20 refresh the jury's memory, is that you had said 21 "at some concentration," and so I'd like to 22 know, sir, if you have an opinion about a 23 specific concentration and a duration or length 24 of time of exposure that you believe is necessary 25 before somebody can develop the disease leukemia, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 106 1 which is specifically acute myelogenous leukemia? 2 A. Well, I can only tell you the strength 3 of the evidence associated with various 4 concentrations of exposure. It's clear that 5 benzene toxicity to the bone marrow, bone marrow 6 toxicity, shows a dose-response relationship; 7 that is, that as you increase the concentration 8 to which an individual is exposed, you increase 9 the likelihood that there will be bone marrow 10 damage, and you increase the severity of that 11 damage. 12 The most severe subacute or initial 13 effect you'll see with repeated exposure to 14 benzene would be aplastic anemia, which is a 15 failure of the bone marrow to produce blood cells 16 of all types, in very simple terms. 17 It's very clear from the literature that 18 repeated exposure, continuous exposure to a 19 hundred parts per million of benzene or greater 20 for lengths of time -- certainly, six months or 21 longer, and maybe less, is associated with the 22 development of a variety of blood dyscrasias, 23 including a loss of various types of blood cells, 24 such as lymphocytopenia, which is a decrease in 25 lymphocytes, or granulocytopenia, although that's WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 107 1 rarer for benzene. Certainly, thrombocytopenia, 2 a decrease in the number of platelets, or 3 aplastic anemia can result as a function of 4 repeated exposure at those levels. 5 As we look at the data available to us 6 on lower levels of exposure, it becomes more 7 difficult to determine the relationship between 8 exposure and an effect. 9 Certainly, I have concerns about 10 exposures of 50 parts per million or greater. 11 There is evidence that, in fact, some bone marrow 12 abnormalities have occurred in patients exposed 13 at that level. 14 As we get down to, say, 25 parts per 15 million or lower, we don't have direct 16 experimental and/or clinical evidence that allows 17 us to make definitive statements about what 18 concentration produces bone marrow toxicity. 19 So as we get lower in concentration, the 20 data becomes much less reliable. 21 MR. BARRIE: I'll object to the 22 nonresponsiveness of the answer. 23 Q. (By Mr. Barrie) Sir, my question was 24 specific in that I wanted to know whether you had 25 an opinion regarding whether there was a certain WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 108 1 concentration of exposure to benzene that was 2 necessary for the development of a leukemia that 3 is called acute myelogenous leukemia? 4 A. In my opinion, the types of damage that 5 benzene causes to the bone marrow and the 6 relationship of that damage to the ultimate 7 development of acute myelogenous leukemia 8 suggests what is known as a classic dose or 9 concentration response, and one would -- that 10 follows from that that, in fact, there is a 11 threshold of exposure below which no serious side 12 effects will be seen. 13 The nature of the controversy or the 14 discussions, if you will, in the field, at this 15 point in time, evolve around what that 16 concentration is, what concentration of exposure 17 is going to be associated with an increased 18 chance of developing AML or not. 19 Q. My question, sir, is: Do you have an 20 opinion with regard to this concentration? 21 A. As I said before, as one looks at 22 progressively lower concentrations, the data 23 becomes much less reliable. There's no evidence 24 to directly determine an effect of benzene below, 25 say, somewhere between -- below 25 parts per WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 109 1 million, there's virtually no direct evidence on 2 which to base such an opinion. 3 I expect, that whatever that 4 concentration is, it's below 25 parts per 5 million. It may or may not be below 10 parts per 6 million. There's no evidence directly to support 7 or to refute that. 8 Q. So, are you able to give us a range 9 which, in your opinion, is the concentration 10 that's necessary to be exposed to benzene for a 11 prescribed period of time prior to a risk for the 12 development of acute myelogenous leukemia? 13 A. Can I ask you to rephrase that? 14 Q. Yes. And I'm sorry. Maybe it was 15 inartfully asked. 16 I'm trying to ask if you can give me a 17 range for exposure to benzene whereby an 18 individual exposed to that concentration would 19 more likely than not develop the leukemia called 20 acute myelogenous leukemia? j 21 A. Well, actually, the way you phrased the 22 question, even at exposures in excess of a 23 hundred parts per million, an individual is not 24 more likely than not to develop leukemia. A very 25 small percentage of the individuals who go on to WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 110 1 develop frank bone marrow toxicity will ever go 2 on to develop leukemia. 3 So even in populations or individuals 4 who have been exposed to concentrations that are 5 clearly associated with the development of 6 leukemia, only a small percentage of those 7 individuals will go on to actually develop the 8 leukemia. 9 Q. And of those who go on to develop 10 leukemia from exposures to benzene, do you have, 11 sir, a range or a concentration of exposure that 12 is necessary over some period of time to develop 13 the disease? 14 A. Well, as I've said, clearly, above a 15 hundred. I think that probably above fifty. And 16 we really don't know, in terms of any measurable 17 end point we currently have, that exposures below 18 twenty-five parts per million have been or are 19 associated with those effects, although I would 20 think it's reasonable to expect that somewhere 21 below twenty-five parts per million is going to 22 be a threshold. 23 Q. And you've described for the jury as a 24 threshold that, in your opinion, the 25 concentration below which there would be no WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 111 1 causal relationship between the disease being 2 established or identified? 3 A. There would be no relationship -4 benzene basically would not produce the types of 5 damage that is required or is a prerequisite for 6 the eventual development of acute myelogenous 7 leukemia. 8 Q. You mentioned, in your opinion, the 9 carcinogenesis or the leukemogenesis of benzene, 10 I believe you said, was dose-response related, 11 correct? There was a dose-response relationship 12 between the two, correct? 13 A. There is a dose-response relationship 14 between benzene and bone marrow toxicity. And, 15 in my opinion, that relationship is important 16 with respect to the development of acute 17 myelogenous leukemia. 18 Q. Let me ask you this, sir: Have you been 19 able to draw the dose-response or dose-incidence 20 curve for benzene and benzene leukemogenesis? 21 Have you been able to establish that curve 22 yourself? 23 A. I'm not sure what you mean by that. I 24 don't know what you're talking about, per se. 25 Q. Let me ask you: In your opinion, is the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 112 1 dose-response relationship between benzene and 2 leukemia, is that a linear relationship, a 3 straight-line relationship? 4 A. The -- certainly, from both human 5 studies and animal studies, looking at toxicity 6 and blood dyscrasias associated with benzene 7 exposure, it's clear that the relationship 8 between benzene and blood dyscrasias is a very 9 complex product of dose and duration. 10 You have to have doses or concentrations 11 of exposure that are, as I said, certainly, for 12 the experimental models, between 25 and 300 parts 13 per million, but the actual duration of exposure 14 varies in a very complex fashion. 15 Repeated exposure appears to be a very 16 important requisite or prerequisite. We're not 17 talking about single exposure. We're talking 18 about repeated exposure. And it is not yet clear 19 what the exact relationship is between the 20 product of dose and duration. 21 Q. Are you telling us, then, that you're 22 unable to draw for us the dose-response curve, or 23 relationship between the amount of dose that one 24 would receive of benzene, the exposure, if you 25 will, and the response that they may have at WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 113 1 increased dosages? Are you -i are -- are you 2 saying we don't know for sure what that line or 3 curve looks like? 4 A. Within -- within the range of 5 concentrations and scenarios that I've described 6 to you so far today, yes, we can. But, 7 certainly, the exact shape of that curve is by no 8 means established. 9 That's -- that -- that is the same thing 10 as the questions with respect to threshold or a 11 concentration that does not result in the 12 development of leukemia. It's the same question 13 from a technical standpoint. The 14 characterization of that curve is what we're 15 talking about. 16 Q. That's what I'd like to focus on. If we 17 just focus our attention right now on what you 18 believe to be about 50 parts per million over a 19 prolonged exposure period leading to the 20 development of leukemia, do we know the shape of 21 the curve from, say, 50 parts per million, to 22 greater amounts, with regard to the incidence of 23 leukemia? In other words, is that a straight 24 line? 25 A. We can certainly surmise or infer, if WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 114 1 you will, from both the human data and animal 2 data on metabolism, as well as toxicity of 3 benzene, that there is a peak concentration, if 4 you will, above which probably you're not going 5 to see any increased incidence. 6 And that concentration or saturation 7 point is probably somewhere between -- in 8 animals, it's between 100 and 300 parts per 9 million. And, in man, I would expect that it's 10 going to be somewhere above 100 parts per 11 million. 12 Q. Would it be fair to say, then, that from 13 approximately 50 parts per million up to 14 approximately 100 parts per million, we have a 15 linear relationship, in your opinion, between 16 exposure, concentration and incidence of 17 leukemia; and then, after that point, it pretty 18 much goes straight -- straight up and down, in 19 other words? 20 A. No. No, not by any means. There are 21 two basic errors there. 22 First of all, it would flatten out, not 23 go straight up and down, basically meaning we 24 reach a point at which you're not going to 25 increase the incidence of the disease, at some WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 115 1 point, theoretically. And there's no reason to 2 believe that's not the case, because for one 3 thing, toxicity to the bone marrow would become 4 so blatant that you wouldn't have survival long 5 enough to develop leukemia amongst -- among other 6 possibilities. 7 And the other issue is that between 8 fifty and a hundred parts per million, we simply 9 do not have sufficient data to describe the 10 nature of that relationship. 11 Q. So, basically, between fifty parts per 12 million and a hundred parts per million exposure 13 to benzene, we can't define the shape of the 14 curve, if you will, on the dose-response axes, in 15 terms of whether it's a linear relationship, 16 whether it's curved or linear, we just don't 17 know, in your opinion? 18 A. That's -- that's correct. 19 Q. And as we try and take the end point, 50 20 parts per million, and work backwards, are you 21 able to say, with any degree of certainty, sir, 22 whether we're able to continue that line, whether 23 it's straight or curved to the origin point, in 24 other words, zero parts per million? 25 A. There's no data on which to base those WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 116 1 characterizations. 2 Q. So it's your opinion that when we leave 3 50 parts per million and go backwards to0ards 4 zero, regardless of duration of exposure, we're 5 unable to characterize the dose-response curve or 6 line with regard .to benzene exposure and 7 leukemia? 8 A. Certainly, in terms of the human data, 9 that's correct. 10 Q. Let's talk about animal data. Is there 11 an animal model, sir, that you're aware of that 12 can be used as a predictor for human 13 leukemogenesis? 14 A. No. 15 Q. Is it your testimony that there-'s no 16 animal model that can be used as a relatively 17 accurate predictor for human leukemogenesis and 18 benzene exposure? 19 A. We have animal models that allow us to 20 look at -- called blood dyscrasias, and 21 certainly, in the mouse, I've been successful in 22 producing blood dyscrasias with very complex dose 23 product type exposures to benzene. The 24 dyscrasias in the mouse are not directly 25 extraporable to specific clinical entities in WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 117 1 man. 2 I personally think that there -- they 3 are very analogous to leukemia in general, but 4 there are no clinically accepted animal models 5 for the types of leukemia we see in man. So it's 6 very difficult to extrapolate from the animal 7 models to man, in terms of understanding what 8 benzene is doing and at what concentrations 9 you're going to see leukemia. 10 The controversies really -- really are 11 with the mouse, with respect to the morphologic 12 and clinical entities that we see, whether they 13 are, in fact, frank leukemias or not. 14 Q. In your opinion, sir, does benzene cause 15 mutational aberrations in any animal or bacterial 16 system? 17 A. Benzene is not a classic mutagen, 18 certainly, in bacterial systems, by itself. 19 As I mentioned before, it does produce 20 secondary changes in chromosomes. It does 21 produce certain abnormalities associated with 22 chromosomes that may be important with respect to 23 its toxicity. 24 Q. In your opinion, sir, is benzene a 25 clastogenic agent or an agent capable of causing WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 118 1 damages and breakages in chromosomes? 2 A. Well, by definition, if it causes 3 chromosomal breaks and/or abnormalities, it is a 4 clastogen in that sense. 5 I would classify benzene as a reasonably 6 weak clastogen. It certainly causes 7 nondisjunctional events. It cur -- it certainly 8 causes breaks. These are typical of agents that 9 interfere with DNA replication and/or cell 10 replication. 11 And we've demonstrated that benzene 12 metabolites very clearly have that effect. 13 Q. How long, in. your opinion, has that been 14 recognized, that benzene can cause breakages in 15 chromosomes? 16 A. I'd have to review the literature 17 specifically, to give you a complete answer to 18 that question, but my vague recollection is we're 19 probably talking about the early to mid '70's, 20 the first indications. I could be -- I could be 21 off by a few years there. 22 Q. Let's talk about the capability of 23 benzene to cause mutations in various model 24 systems. 25 One of the model systems that has been WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 118 1 used is the Ames Assay. Are you familiar with 2 that assay? 3 A. Yes. 4 Q. Is benzene a mutagen under the Ames 5 Assay scenario and model? 6 A. No, not by itself. It's not -7 actually, benzene is not a very potent mutagenic 8 agent in those systems at all. 9 Q. In your opinion, sir, is that true, 10 also, when there's an S-9 activation factor added 11 to that particular test? 12 A. If you metabolize benzene, you can 13 produce certain mutagenic events. But by the 14 same token, if you compare benzene with an S-9 to 15 more potent mutagenic agents, it -- it does 16 not -- it is certainly not a potent mutagenic 17 agent in those systems. 18 Q. In your opinion, sir, is benzene a 19 mutational causing agent, but it's just not, in 20 your opinion, a strong one? 21 A. In the presence an S-9 fraction, you 22 can -- you can produce mutational events in some 23 bacterial systems, using a -- a reverse mutation 24 assay, like the Ames Assay. 25 Q. And would you tell us, sir, when was it WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 120 1 recognized that benzene was an agent capable of 2 causing mutations in various test scenes -3 A. In bacteria? 4 Q. -- such as the Ames Assay? 5 A. In bacteria? Again, I don't recall 6 exactly. It's probably late -- it's either going 7 to be late '70's or early '80's, I believe. I 8 don't remember exactly when the Ames Assay first 9 came into use. 10 Q. Are you familiar, sir, with sister 11 chromatid exchanges? 12 A. Yes. 13 Q. Have you had a chance to look at that? 14 A. Yes. 15 Q. In your opinion, sir, does benzene cause 16 any sister chromatid exchanges? 17 A. Benzene metabolites certainly do. 18 Benzene administration to whole animals does. It 19 increases the rate of sister chromatid exchanges 20 that is seen in the normal animal. 21 Q. And for the benefit of us all, could you 22 tell us what it means to have a sister chromatid 23 exchange induced by a chemical such as benzene? 24 A. I wish I could, in a complete sense. 25 It's really not known what the ultimate WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 121 1 significance of the sister chromatid exchange 2 process is. 3 Q. But are we talking about, sir, a damage, 4 if you will? 5 A. No, sir, actually, we're not. There 6 is 7 Q. Okay. What are we talking about? 8 A. There's no -- when we talk about DNA, 9 and we talk about DNA damage, we're talking about 10 a loss or change in information. If we change 11 the code, we've altered the DNA. 12 In the case of normal biologic systems, 13 we know that DNA changes places, and the code 14 gets altered as a function of normal 15 development. This goes on in lymphocytes. This 16 goes on in B cells we've been talking about. It 17 goes on in T cells, these are lymphocytes, a 18 variety of different cell systems, as a part of 19 normal development. 20 Sister chromatid exchange involves the 21 transposition or movement of DNA from a 22 chromatid, which is part a chromosome, or half of 23 one, they change places. We have complementary 24 chromosome pairs for each chromosome we have. 25 And these chromatids change places in the case of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 122 1 sister chromatid exchange. 2 They don't -- there's no ostensible 3 change in the information, loss of information, 4 or change in the code. They basically, various 5 portions switch places. This goes on -- to a 6 certain extent, there is a background frequency 7 of sister chromatid exchange that goes on in the 8 absence of treatment. 9 Some agents, when the cells are exposed 10 to those agents, will go on to increase the rate 11 of sister chromatid exchange. It's been used 12 frequently as a screening tool to determine 13 whether or not a compound had any effect on DNA, 14 because it's easy to do. 15 And in this -- in this context, benzene 16 has been demonstrated to increase sister 17 chromatid exchanges in a variety of different 18 cell systems. 19 Q. When you see a pattern of sister 20 chromatid exchanges, is that not a normal finding 21 to see in a person? Is that an abnormal finding? 22 A. Well, in -- categorically, no, it's not 23 an abnormal finding. As I said, if you take 24 individual cells and you place them in culture in 25 an artificial situation in a test tube, and you WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/HEAUMONT(409)833-0016 123 1 stimulate them to divide, you're going to see a 2 background frequency of sister chromatid 3 exchange. 4 Now, if at the same time, you directly 5 expose those cells to increasing concentrations 6 of agents that are potentially toxic, some of 7 those agents are going to produce an increased 8 incidence or an increased number of sister 9 chromatid changes. Benzene is one of those 10 compounds. 11 Q. Do you have an opinion, sir, whether a 12 low level chronic exposure to benzene places a 13 person at greater risk for the development of a 14 leukemia, as opposed to an acute transient 15 exposure to the chemical benzene and its 16 relationship to the development of the disease 17 leukemia? 18 A. What do you mean by "low level"? 19 Q. We can define it any way that you would 20 like. Would you like to limit your testimony in 21 low level to 50 parts per million or less, or do 22 you have a range that you would like to talk 23 about? 24 A. As I said before, I cannot fix -- I do 25 not have a divining rod, and I cannot say that I WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUNONT(409)833-0016 124 1 know the concentration of benzene that is 2 associated with chronic exposure, the minimum 3 amount that's associated with the development of 4 AML. 5 Obviously, since I have told you that I 6 believe that there is a threshold, and that 7 everything that I have seen in the literature 8 that points to a mechanism suggests a mechanism 9 that's compatible with the dose-response and the 10 threshold, I believe that there are 11 concentrations of benzene, that following chronic 12 exposure, or with chronic exposure to those 13 concentrations, are not going to increase an 14 individual's chance, if you will, of developing 15 AML. We can play with numbers all day. 16 Q. Let's not do that. Let's talk about 17 peak exposures that individuals may have on a 18 transient basis, versus individuals who may be 19 chronically exposed to low concentrations or 20 small amounts over long periods of time. 21 And my question in that regard, sir, 22 is: Do you view a person who has transient peak 23 exposures to benzene at greater risk to the 24 development of diseases of blood and 25 blood-forming organs over a person who has WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/HEAUMONT(409)833-0016 125 1 long-term exposure to lower concentrations of 2 benzene? 3 A. If the concentrations are low enough 4 that they do not, in my opinion, constitute a 5 potential source of toxicity in the marrow, the 6 answer to your question would be "Yes." 7 I think that intermittent exposure to 8 benzene at high concentrations, repeatedly, is 9 associated with potential to cause bone marrow 10 toxicity, and eventually could lead to the 11 development of AML. But we're talking repeated 12 exposure. 13 Q. Okay. So, in your opinion, benzene has 14 a causal relationship with the leukemia, acute 15 myelogenous leukemia, correct? 16 A. Yes, sir. 17 Q. And when, in your mind, has that been 18 established? 19 A. I think we discussed it this morning. I 20 would say somewhere between the mid 1970's -21 somewhere between 1974 and 1977 or '8. 22 Q. Do you have an opinion, sir, whether 23 benzene exposure has a causal relationship to 24 multiple myeloma? 25 A. I think the whole question of multiple WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 126 1 myeloma is one that requires a lot more work 2 before we can say anything definitive about it. 3 There are some studies that would suggest that 4 there may be a relationship, but they're 5 relatively small and, again, one of the biggest 6 problems with these epidemiology studies is 7 defining the exposures. 8 If one were to rely only on the 9 McMichael study, one could reach the conclusion 10 that perhaps there was a relationship between 11 benzene and the lymphoid neoplasms seen there. 12 But the followup studies have basically negated 13 that original supposition, when they looked at 14 exposures. I think that we don't have enough 15 information, at this point, to really say one way 16 or the other whether multiple myeloma is 17 associated with benzene exposure. 18 MR. BARRIE: I'll object to the 19 nonresponsive -- nonresponsive portion of the 20 answer. 21 Q. (By Mr. Barrie) Do you have an opinion, 22 sir, whether benzene exposure has a causal 23 relationship with lymphomas, whether they be 24 Hodgkin's lymphomas or non-Hodgkin's lymphomas? 25 A. I think, again, the principal -- the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 127 1 studies where benzene exposures have been high 2 and where they've been relatively the only 3 exposures, these diseases have not been seen. 4 I would refer to Infante, in particular, 5 and several others, Vigliani. 6 Where we have exposures that are very 7 complex and involve more than benzene, we begin 8 to see a totally different pattern. That has 9 been seen in the rubber industry. And as I've 10 said before, if one looks at the sum total of 11 that literature, one's left with the conclusion 12 that benzene is not the actor in that particular 13 situation. And in those studies, there is an 14 indication that there may be an increased 15 incidence of lymphoid neoplasms. 16 The problem there, again, is depending 17 upon how the cases have been categorized and how 18 they've been lumped together the way 19 epidemiologists lump them, it becomes difficult 20 to make distinctions between one disease type and 21 another. And that requires very careful 22 experimental design and a study large enough to 23 distinguish between the different biological 24 types. 25 Q. So, basically, if the study design in an WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 128 1 epidemiological study is not, in your words, 2 particular enough, you may or may not pick up a 3 certain type of leukemia, such as chronic 4 lymphocytic leukemia, it may or may not be 5 reported? 6 A. No, no. That's -- that -- that's not 7 really what I mean. What I mean is that -- that 8 epidemiologists are usually striving to get 9 enough of -- to get a large enough sample size to 10 see something, if there's something there. 11 So the tendency is to lump different 12 diseases together in terms of categorization. 13 For example, if you classify neoplasms as 14 lymphoid, you may lump lymphomas or 15 lymphosarcomas or chronic lymphocytic leukemia in 16 the same pot, and when you're through, what you 17 have is an increase in lymphoid neoplasms. 18 What you cannot say from that is any 19 particular neoplasm has been increased, but 20 you've got a very broad category that's 21 increased. 22 The difficulty with that is that 23 biologically we know these diseases are 24 different, we know their origins are different, 25 their progression is different, the cell types WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 129 1 are different, the prognosis is different. And 2 it requires further study to characterize, in 3 fact, if there's a specific association with one 4 or more of those diseases. 5 Q. And one of the opinions you've reached 6 in this case is that benzene exposure has no 7 relationship, causally, to the disease of chronic 8 lymphocytic leukemia, correct? 9 A. That's correct. 10 Q. And that, in your opinion, is true 11 regardless of the concentration exposure, 12 correct? 13 A. That's correct. 14 Q. And the articles on which you base your 15 opinion are those that are contained in Exhibit 16 No. 2? 17 A. In particular, yes. There are obviously 18 many other articles that have helped contribute 19 to the basis of my opinion, but if I brought 20 everything in my file, I would have filled the 21 room. The literature, in general, and in 22 particular, supports my opinion, and the specific 23 papers I brought I thought were pertinent to this 24 specific issue. 25 Q. So with regard to the articles you've WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 130 1 brought in Exhibit No. 2, these are the ones you 2 place particular emphasis on to support your 3 position that benzene exposure, regardless of 4 concentrations, has no causal relationship to the 5 disease chronic lymphocytic leukemia? 6 A. That's correct. 7 Q. I'd like to move on now, sir, to the 8 second opinion that you've rendered. And that, I 9 believe, is that, in your opinion, Mr. Chambers' 10 chronic lymphocytic leukemia was something that 11 either preceded his birth, or shortly thereafter, 12 in your opinion, correct? 13 A. Yes. 14 Q. And in order to come to that conclusion, 15 you've done some analysis based on his blood 16 count, his lymphocyte count, and done some 17 analysis to reach that conclusion, right? 18 A. Yes. 19 Q. Is the article that sets forth the model 20 that you used to come to that conclusion 21 contained within Exhibit No. 2? 22 A. Yes. 23 Q. Okay. And I think you told us 24 originally that that model was used for prognosis 25 of individuals with chronic lymphocytic leukemia, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 131 1 correct? 2 A. Yes. 3 Q. And what you've done is you've based a 4 technique of regression analysis to work 5 backwards from that model, to come to your 6 particular conclusion? 7 A. Yes, sir. 8 Q. And will you tell me, sir, all of the 9 assumptions that you had to make in order to 10 perform this multivariant regression analysis to 11 ultimately come to your conclusion that 12 Mr. Chambers had his disease prior to his birth,. 13 or certainly sometime thereafter? 14 A. Well, I used the approach to calculating 15 lymphocyte doubling time that is referred to in 16 the papers that are in this binder that have been 17 demonstrated by Montserrat and others to, in 18 fact, be a very good prognostic indicator of the 19 progression of the disease. 20 The -- once the line is established or 21 the slope the line is established, the only other 22 assumption with respect to using it in the 23 regression analysis, is that, in fact -- the 24 principal assumption is that chronic lymphocytic 25 leukemia is a monoclonal disease being derived WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 132 1 from a single cell. 2 Q. The disease chronic lymphocytic leukemia 3 coming from a single cell, what takes place 4 within that cell that initiates it, if you will, 5 or causes it to develop into a lymphocytic 6 leukemia? 7 A. Well, leukemia we generally think of as 8 a multifactorial process, and that requires a 9 number of different changes to occur. If we had 10 a very clear understanding of all those changes, 11 we'd understand the cause of leukemia in general, 12 and specifically for each leukemia. 13 So we're not at that stage yet, in terms 14 of being able to -- to say exactly what happens. 15 But certainly in the case of a disease like 16 chronic lymphocytic leukemia, there are changes 17 that occur, ostensibly at the level of the DNA, 18 or within the cell during its early development 19 that leads to it becoming a malignant cell. 20 As a malignant cell, it no longer abides 21 by the same rules, if you will, and/or is -- it's 22 no longer affected by the normal regulatory 23 mechanisms that control the behavior of these 24 cells in the body. 25 Q. This DNA, this DNA is a part of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 133 1 chromosomes, are they not? 2 A. That's correct. In fact, in CLL, it's 3 well known in CLL patients that there are 4 chromosomal abnormalities that are specifically 5 associated with CLL, that are not normally seen 6 in other types of leukemias. 7 The most prevailing type of chromosomal 8 abnormality that's seen in CLL's is called 9 trisomy 12, or you basically have an extra 10 Chromosome No. 12. 11 There are also, in a subpopulation of 12 patients, seen other abnormalities, such as a 13 deletion of part of Chromosome 14,,called 14 Q 14 minus. This does not appear to appear early in 15 patients with the disease, but only after the 16 disease has manifest itself, for the most part. 17 Q. If I can, I'd like to just kind of 18 reduce that, if I can. That was an awful lot 19 for, I'm sure, us all to gather. But, basically, 20 it's a held opinion that benzene affects the DNA, 21 and DNA is part of the chromosomes, and that is a 22 thought as to how chronic lymphocytic leukemia is 23 developed. Would that be a very simple way of 24 reducing it? 25 A. No, that's misleading, in terms of our WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 134 1 knowledge and the conclusions that can be derived 2 from it. If you look at leukemias that are 3 associated with exposure to benzene, or 4 chemotherapy with alkylating agents, you see, 5 first of all, AML as the leukemia, not CLL. 6 Secondly, the types of chromosomal 7 abnormalities that are seen in the -- there's a 8 striking incidence of specific types of 9 chromosomal abnormalities that are seen in 10 secondary AML. These are five -- deletion of 11 Chromosome 5 or 7 -- 5Q minus, 7Q minus. We are 12 talking about a different pattern of chromosomal 13 aberration and abnormality that are seen in CLL. 14 Q. Let's talk a little bit about this graph 15 that you've done and its relationship to-, in your 16 opinion, Mr. Chambers having his disease prior to 17 his birth, or shortly thereafter. 18 You used various lymphocyte counts that 19 were taken from approximately nineteen sixty to 20 nineteen -- '67, approximately, to 1989, correct? 21 A. Yes. 22 Q. And from that, you derived a line with a 23 particular slope on what's been marked as 24 Exhibit 4, correct? 25 A. That's correct. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 135 1 Q. Let me ask you, sir, how you were able 2 to draw that line from the 1967 point, backwards, 3 when there was no particular information to fill 4 in to make sure that the line was A, straight; B, 5 going to the origin along one of the axes that 6 you have. What assumptions did you have to make? 7 A. The basic assumption, the most important 8 one is that the doubling time was constant. That 9 is based -- that, in fact, is the reason that 10 doubling time is a valuable prognostic indicator 11 in C LL, because, in fact, for CLL, and CLL, 12 alone, is it -- is there information that 13 indicates that the doubling time and the kinetics 14 of cell replication and cell loss are constant. 15 For other leukemias, this type of 16 analysis is of not very much prognostic value, 17 because the kinetics of the disease, the kinetics 18 of replication can change. The -- as I see it, 19 the proof is in the pudding. The calculation of 20 doubling time and its constancy for CLL is the 21 cornerstone of why that type of analysis is 22 useful for prognosis. 23 And, in reverse, that it is reasonable 24 to extrapolate, as well, backwards, with respect 25 to obtaining some indication of the rate of tumor WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 136 1 development and increased body burden. 2 Since we're dealing with a monoclonal 3 disease, it's reasonable, based on that to make 4 some -- arrive at some conclusions with respect 5 to the relationship between the time of the 6 initiation of the disease and its progression. 7 Q. What -- what I'm trying to -- to get at 8 here is you have this line on Exhibit No. 4 9 hitting a part on one of the axes that's 10 labeled "Cell Number" somewhere around 10 to the 11 6th, correct? 12 A. Yes. 13 Q. Is there a level below that which you 14 would opine that this gentleman did not, at birth 15 or shortly thereafter, have this disease? 16 A. Well, if -- if the line clearly 17 intersected the X axis at some time prior to 18 1930, or since 1930, excuse me, one would -- one 19 would surmise that within a certain margin of 20 error that that was the most likely point at 21 which the clonal expansion, certainly of his 22 tumor, began. 23 In this case, that's not the case. We 24 basically do not intersect that axis prior to 25 reaching his date of birth. The -- based on WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 137 1 other studies, looking at twins, looking at the 2 familial predisposition of families and siblings 3 to the development of CLL, it's reasonable to 4 assume, in the absence of any other information, 5 that the -- that the initial event that resulted 6 in the creation of this population occurred at 7 some point either prior to birth, or shortly 8 thereafter. 9 Q. In Mr. Chambers' family, nobody has had 10 any chronic lymphocytic leukemia, that you're 11 aware of, in his family, are you? 12 A. Not to my knowledge. 13 Q. Is your reliance on this particular 14 study that identifies the prognostic tool for 15 looking at chronic lymphocytic leukemia,-is that 16 article the article that you're going to rely on 17 in coming to your opinion that this gentleman, 18 Mr. Chambers, had his disease prior to birth, or 19 shortly thereafter? 20 A. There's several articles in the 21 literature, numerous articles which discuss the 22 kinetics of lymphocyte replication and CLL and 23 the use of doubling time as a prognostic 24 indicator. 25 I have included the majority of those in WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 138 1 the documents I've provided. There are some 2 others, however, that I have not included simply 3 because these, I felt, were sufficient. 4 There are one or two others, that if you 5 search the literature, you will find and they, in 6 my opinion, are entirely consistent with those 7 that I have provided here. 8 Q. Is there going to be some other article 9 that you're going to rely on, other than what 10 you've provided here, that will support your 11 opinion that Mr. Chambers had this disease prior 12 to birth, or shortly thereafter, any other 13 specific articles that you're going to rely on? 14 A. Not -- not to my knowledge at the 15 present time. As I -- as I mentioned earlier, if 16 I'm asked questions that specifically deal or 17 require me to rely on articles I have not 18 provided, I will do so, but it's not my intention 19 to do so, unless I'm required to. 20 Q. But you've given us, today, the opinions 21 you have in this case? 22 A. Yes, sir. 23 Q. And you have no other opinions? 24 A. No, sir. 25 MR. BARRIE: We'll just take five WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 139 1 minutes. 2 MR. SCOTT: That would be great. I 3 was hoping somebody would say that. 4 THE VIDEOGRAPHER: It's 12:41, and 5 we're off the record. 6 7 (Whereupon, after a brief recess, the 8 video deposition continued as follows:) 9 10 THE VIDEOGRAPHER: It's nine till 11 1:00. We're back on the record. 12 Q. (By Mr. Barrie) Sir, you've given us an 13 opinion of yours that -- regarding. Mr. Chambers' 14 chronic lymphocytic leukemia. In your opinion, 15 it's not caused by his benzene exposure,-and I'd 16 like to ask you this question: Do you have an 17 opinion of what did cause his chronic lymphocytic 18 leukemia? 19 A. Well, as I think I've said, it's more 20 probable than not that he was either born with 21 it, or he developed it very shortly after birth. 22 Chronic lymphocytic leukemia has not been 23 associated with exposure to hazardous agents. 24 It's one of the very few leukemias for which it's 25 reasonably clear that radiation doesn't even WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 140 1 cause it. And radiation causes most. 2 Q. And I understand, sir, that's your 3 opinion. And what I'd like to know now is: 4 Other than his, in your opinion, having it prior 5 to birth, or after the birth, is there any other 6 etiological agent or cause that you can subscribe 7 that may have caused or contributed to his 8 disease? 9 A. No. 10 Q. Do you have a contract, sir, with any 11 attorney that's hired you in this case, a written 12 contract? 13 A. No. 14 Q. Who would you be directing your bill in 15 this case to? 16 A. That's a good question. I'll probably 17 send it to Mr. Scott. 18 MR. BARRIE: I'll pass the 19 witness. 20 21 EXAMINATION 22 QUESTIONS BY MR. SCOTT: 23 24 Q. I'd like to, Dr. Irons, if we might, do 25 a couple of things. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 141 1 First, I want to talk a little bit about 2 more about some of the educational experiences 3 you've had and some of the work experiences you 4 have had. 5 You mentioned earlier that you had 6 you were involved in a study of the effects on 7 the hematopoi -- hematopoietic system of extended 8 space flight. For whom are you doing that work? 9 A. The National Aeronautics Space 10 Administration. The University of Colorado and 11 the University of Rochester have a consortium 12 research effort that has resulted in us being 13 awarded a center grant from NASA to examine the 14 potential adverse effects associated with the 15 space flight environment, principally associated 16 with exposure to toxic agents, although, because 17 the space environment is so foreign compared to 18 that which we experience on earth, we have to 19 look at a variety of different phenomenon in 20 terms of evaluating potential hazards in space. 21 There is evidence that individuals who 22 have spent an extensive amount of time in space, 23 that upon returning to earth, they have had 24 problems with anemia, with problems related to 25 calcium in their bones, and a variety of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/HEAUMONT(409)833-0016 142 1 physiological difficulties that are apparently 2 associated with extended time in space. And we 3 are part of an effort to determine just what the 4 factors are that impact and influence those 5 problems and, hopefully, to develop strategies to 6 eliminate those problems. 7 Q. What is a center grant? 8 A. A center grant is a grant to establish a 9 center, an organization that has a -- a focus on 10 dealing with a particular problem. 11 In this case, we're talking about the 12 adverse effects associated with potential 13 exposure to toxic agents in space, and/or the 14 problems associated with other conditions in 15 space, such as weightlessness, radiation, and 16 this type of thing. 17 Q. And did your group -- do you know how 18 your group was selected by NASA to -- to do this 19 work? 20 A. It was a highly competitive process in 21 which we submitted a grant proposal, and it was 22 initially reviewed on the basis of the proposal. 23 We then had a site visit, which is a 24 meeting where an independent panel of scientists 25 come and look at the site and talk to the WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 143 1 scientists, and evaluate what they propose to do 2 in light of what the requirements are to 3 determine which is the best possible site to 4 establish this center. 5 There were, initially, I think, 6 approximately thirty universities that responded 7 to this request by NASA. There were at least 8 four that were site-visited, and we won the 9 award. 10 Q. You also mentioned a -- some work that 11 you had done with the Chinese Government. Can 12 you describe how you got involved in that and 13 what your role was? 14 A. Well, I've known Dr. Yin, who is the 15 head of the -- what could best be described as 16 the Occupational Medicine Branch of the Chinese 17 Institute of Occupational Medicine, similar to 18 our NIH, or NIOSH, if you will, kind of a 19 combination. And I've known him for many years, 20 because he has an interest in benzene toxicity. 21 And -- and I believe it was in 22 nineteen -- the fall of 1988, I accepted an 23 invitation to visit the People's Republic to 24 lecture on primarily the moni -- biological 25 monitoring of workers and to participate or WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 144 1 advise them in the design of a potential 2 epidemiology study to look at the effects of 3 chronic exposure to butadiene in Chinese` 4 workers. 5 They have a population of workers who, 6 compared to western standards, have been heavily 7 exposed to butadiene for what is now almost two 8 generations, and it represents an attractive 9 group of individuals to study, from the 10 standpoint of having an opportunity to look at 11 people who have, unfortunately, had relatively 12 high exposures. 13 Q. And you did make a visit, then, to 14 China? 15 A. Yes. Yes. 16 Q. You also mentioned, that among your 17 other duties at the University of Colorado, you 18 teach in the graduate epidemiology program. And 19 I think you said you teach epidemiology graduate 20 student -- students and MD's. What group or 21 department within the University of Colorado is 22 that program? 23 A. That program is centered in the 24 Department of Preventive Medicine and biometrics. 25 Q. That may lead to my next line of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 145 1 questions, and that is, I'd Pike some of the 2 terms that you've used today to be defined for 3 us. "Biometrics" would be a good place 'to 4 start. 5 A. Oh, that's a good question. I think -6 the best way to describe biometrics is 7 biostatistics, I guess. It's the mathematical 8 process of evaluating biological populations. 9 In this case, obviously, the principal 10 focus is human populations. 11 Q. You also used the term 12 "immunopathology." What does that mean? 13 A. That's a specialization within the field 14 of pathology that deals with the diagnosis and 15 examination of tissues of of the immune system, 16 and abnormalities or diseases associated with the 17 immune system. 18 Q. Similarly, you used the term 19 "hematopathology." What does that mean? 20 A. The -- there are very -- the distinction 21 between hematopathology and immunopathology is 22 relatively fairly indistinct, because, as I said 23 before, these systems are intimately related. 24 But that simply, again, is pathology 25 associated with diseases of the blood and WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 146 1 blood-forming organs. 2 Q. You used a term called 3 "leukemogenesis." What does that mean? 4 A. The genesis of leukemia, the cause of 5 leukemia, the start of leukemia. 6 Q. Is "pathogenesis" a similarly defined 7 word? 8 A. Yes. It's the genesis, if you will, of 9 pathology in general. The progression of 10 disease, ;the natural history of the disease, and 11 what happens to an individual, or tissues, or 12 biochemical or biological parameters during the 13 course of that disease. 14 Q. You used the term "neoplasms" and 15 specifically "lymphoid neoplasms." Can you tell 16 us what those terms mean? 17 A. Neoplasm is -- is basically from the 18 Greek. It means neo or new growth. A neoplasm 19 is a growth. It can be a benign growth, or it 20 can be a malignant growth. 21 If it's a malignant growth, it's 22 cancer. As far as the lymphoid neoplasms are 23 concerned, within the lymphoid system, per se, 24 there's no such thing as a benign neoplasm, so 25 all lymphoid neoplasms are malignant diseases. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 147 1 They are cancer. 2 Q. You also used a term called "kinetics." 3 What does kinetics mean? And "cell kinetics," I 4 think, is the way you said it. 5 A. They're -- cell kinetics deals with the 6 replication of cells, the rate at which they 7 divide, and how the populations, if you will, of 8 cells change, in terms of the total number of 9 cells. It can also relate to cell cycle 10 kinetics, which is the characterization of cell 11 replication. 12 Q. Now, finally, you've used a term, 13 "monoclonal" and also "clonality." Can you tell 14 us what those terms mean? 15 A. "Monoclonal" means that a disease, such 16 as a leukemia, and CLL as an example of one that 17 does this, virtually all do, they are derived 18 from single cells, "mono" being one. 19 "Clonal" means that each group of cells 20 are clones of an original cell. So they're all 21 basically mirror images of the parent cell. They 22 all are derived from the same cell. 23 Q. How does the clonality or monoclonality 24 of leukemia cells and, in this instance, chronic 25 lymphocytic leukemia cells, help in the analysis WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 148 1 which you have done in this case? 2 A. Because they are all descended from a 3 single cell, and we know that the way cells 4 replicate, or duplicate, is to divide. We -- we 5 know that the -- there was an original cell that 6 was malignant, or changed, abnormal, and it 7 divided to produce two. Those, in turn, divided 8 to produce two, and so on. 9 So we know, that in terms of the 10 progression of the disease, it started as a 11 single cell, and we can, therefore, extrapolate, 12 with reasonable confidence, backwards with 13 respect to gaining some idea as to when the 14 process started. 15 Q. Is that the same thing as saying that 16 when a leukemia develops, and in this instance, 17 chronic lymphocytic leukemia, that the -- there 18 is an original leukemic malignant or cancerous 19 cell? 20 A. Yes. 21 Q. And that everytime that cell replicates 22 or divides, it essentially makes carbon copies of 23 itself that have the same malignancy or leukemic 24 features? 25 A. That's correct. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 149 1 Q. I have a document that I'd like for you 2 to look at, if you will. And we might want to 3 hold it to the camera first. Let me hand it to 4 you. 5 MR. SCOTT: We may want to mark 6 this as an exhibit before we put it on the 7 camera. 8 9 (Whereupon, the instrument referred to 10 by counsel was marked for identification as Irons 11 Exhibit No. 6.) 12 13 Q. (By Mr. Scott) This will be Exhibit 6 to 14 your deposition. Can you take a look at it and 15 then allow our camera operator to try to zero in 16 on it, if he can. 1? A. Can I stand up? 18 Q. Sure, if that will be helpful. 19 A. If I'm going to see it, it is. 20 THE COURT REPORTER: Your 21 microphone, Doctor. 22 THE WITNESS: Whoops. 23 THE VIDEOGRAPHER: Would you hold 24 that up again? 25 Thank you. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 150 1 MR. SCOTT: Okay. Do you have it? 2 THE VIDEOGRAPHER: All right. 3 Q. (By Mr. Scott) Can you tell me what 4 that -- what Exhibit 6 depicts? 5 A. Well, this is a schematic diagram of 6 normal blood cell development. It -- it shows 7 the general pathways and the cells of origin for 8 the various cell lines within the blood, both the 9 myeloid cells we talked about and the lymphoid 10 cells. 11 Q. In a case of chronic lymphocytic 12 leukemia, is the cell which is the original 13 cancerous or malignant cell, depicted on Exhibit 14 6? 15 A. Not directly, but we certainly know 16 where it resides on the -- on the -- the chart 17 itself, in terms of pathway. 18 Q. Can you show me where that is? 19 A. Okay. These lines, incidentally, depict 20 directions that cells mature in. It doesn't 21 depict all the different representatives of the 22 types of cells that we know are here. There are 23 many different stages going through this 24 compartment. 25 They -- it's very clear, with CLL, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 151 1 certainly the type of CLL that we're talking 2 about in terms of Mr. Chambers, that the cell 3 type that's involved are the B lymphocytes. And 4 based on the gene rearrangements that occur -5 see, this -- this cell line is the cell line that 6 produces antibodies. Every antibody-producing 7 cell produces a different antibody molecule. 8 The genes that are associated with 9 making that molecule rearrange at the point that 10 the cell becomes a mature lymphocyte and during 11 the process of development. 12 In the case of CLL, from the gene 13 rearrangements that occur in both -- there are 14 two -- there are two genes involved, one that 15 codes for the heavy chain of the immunoglobulin 16 and one that codes for the light chain. And both 17 the heavy chain rearrangements occur at this 18 level. The light chain rearrangements occur 19 right here at the point of commitment, or 20 maturation, to the lymphocyte lineage. 21 And the cell that's responsible for CLL 22 has both, and it falls right here. So we're 23 talking a relatively mature to intermediate level 24 of maturity B cell, at this stage. 25 THE VIDEOGRAPHER: Doctor, can you WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 152 1 hold the exhibit off your microphone. It 2 scratches on it. 3 THE WITNESS: Sorry. 4 THE VIDEOGRAPHER: Thank you so 5 much. 6 MR. SCOTT: I wonder, could you 7 help him try to set that up and let you look 8 around the side of it, rather than standing. 9 THE VIDEOGRAPHER: Can we go off, 10 the record for just a second? 11 MR. SCOTT: Sure. I think that's a 12 good idea. 13 THE VIDEOGRAPHER: It's 2:18, and 14 we're off the record. 15 16 (Whereupon, after a brief recess, the 17 video deposition continued as follows:) 18 19 THE VIDEOGRAPHER: It's now 2:19. 20 We're back on the record. 21 Q. (By Mr. Scott) We have just -- we've 22 made the arrangements a little more comfortable 23 to look at this exhibit now, but we had just 24 talked about the -- the target or original 25 cancerous cell in chronic lymphocytic leukemia, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 153 1 and I believe you told us that that is in the B 2 lymphocyte line, and that it is a cell of some -3 some level of maturation; is that fair? 4 A. 95 percent of CLL's arise in this line. 5 There's a small percentage that are associated 6 with T cells. However, the nature of the 7 disease, its progression and the prognosis are 8 different. They are much different than that 9 which has been experienced by Mr. Chambers. And 10 so it is reasonable to expect that this is, in 11 fact, the cell line we're talking about. 12 Q. Based upon your review of the medical 13 records of Mr. Chambers, is it your opinion that 14 that is -- that line, the B lymphocyte line, and 15 the point to which you have directed us, is the 16 target or origin cell for his chronic lymphocytic 17 leukemia? 18 A. Yes, sir. 19 Q. I'd like to try to talk about several of 20 the other leukemias, some of which Mr. Barrie 21 discussed with you earlier today. 22 Let's start with chronic myelogenous 23 leukemia. What is the target or origin cell for 24 those people who have chronic myelogenous 25 leukemia? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 154 1 A. Well, chronic myelogenous leukemia is 2 clearly a disease of the pluripotential stem 3 cell. It involves an abnormality that occurs at 4 the -- in the cell that's responsible for the 5 development of all blood cells prior to its 6 differentiation or maturation into either of 7 these major cell lines. So CML is clearly a 8 disease of this cell. 9 Q. Maybe it will be helpful to have some 10 background on the terms "differentiation," as 11 opposed -- as that term, as opposed to 12 "replication." 13 In her deposition last week, Dr. Fehir, 14 the Plaintiffs' expert told us that the 15 pluripotential stem cell had two characteristics 16 that were important. One is that it could 17 differentiate; the second is that it could 18 replicate. Do you agree with that, first? 19 A. Yes. 20 Q. Now, the cell marked "pluripotential 21 stem cell" to the far left on Exhibit 6, does 22 that cell have those characteristics? 23 A. Yes. It is capable of giving rise to 24 all the different cells that are found in the 25 blood. And it does so by becoming either a WORLDWIDE COURT REPORTERS, INC. I-IOUSTON(713)651-1100/BEAUMONT(409)833-0016 155 1 myeloid progenitor cell, or as it's indicated 2 here, a myeloid stem cell, or a lymphoid stem 3 cell. That's differentiation. 4 Differentiation is the process whereby a 5 cell begins to take on more and more specialized 6 characteristics that eventually are associated 7 with functional end stage cells. This cell has 8 very few characteristics that allow anyone to 9 distinguish it by looking at it, or it also 10 doesn't have any specialized functions like these 11 cells. 12 It has two major capabilities. One is 13 to divide and produce either one of these type of 14 cells -15 Q. For purposes of our written record, 16 "these type" are the lymphoid stem cell or the 17 myeloid stem cell. 18 A. Yes. 19 -- or it can reproduce itself. 20 "Self-renewal" is the term that's used. This 21 distinguishes it from virtually any other cell 22 within the bone marrow. It has the capacity to 23 reproduce itself without necessarily committing 24 to a differentiation pathway. 25 Q. All right. And I notice you have, in WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 156 1 the far left compartment of Exhibit 6 that 2 that is marked, "Self-Renewing Stem Cell 3 Compartment," correct? 4 A. Yes. 5 Q. In other words, the pluripotential stem 6 cell may divide to become another pluripotential 7 stem cell, or actually two of them, I suppose; 8 or, alternatively, it may divide to become either 9 a myeloid stem cell or a lymphoid stem cell? 10 A. That's correct. 11 Q. Once you get into what's marked as the 12 "Committed Stem Cell Compartment" either on the 13 lymphoid stem cell side, or the myeloid stem cell 14 side, what characteristics do those stem cells 15 have? 16 A. Well, to -- to describe these -- what 17 these cells do, I should probably say one more 18 thing about this cell, and that is, although it 19 can divide, it has a tendency to just sit there. 20 It very rarely divides. 21 At any one time, we may only have a few, 22 literally, only a few stem cells that are 23 responsible for making our blood cells, that 24 is -- that are actually dividing and producing 25 these cells. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 157 1 And you have to remember we're producing 2 over 200 billion cells a day to replace the 3 normal amount of blood cells that are destroyed 4 in natural, everyday life. 5 These cells, the -- what I prefer to 6 call the progenitor cells, rather than the stem 7 cell, myeloid progenitor cell and the lymphoid 8 progenitor cell, have an increased tendency to 9 divide. They divide much more often than this 10 cell, but they have very re -- they are 11 restricted in terms of the types of cells they 12 can become. They can't go backwards. They can't 13 go back this way. They can only go forward. 14 That's part of one of the protective mechanisms 15 that we have within the -- the bone marrow. But 16 these cells have an increased tendency to divide, 17 and they're capable of giving rise to the 18 different committed lineages. 19 The red cell in the case -- in the case 20 of the myeloid progenitor cell, the red cell 21 platelets, granulocytes or macrophages. The 22 lymphoid progenitor cell is -- is not as well 23 characterized, but it's clear that this cell 24 gives rise to T cells and to B cells. 25 Q. To -- to try to put it in terms that I WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 158 1 can understand, then, the -- the myeloid, what's 2 called myeloid stem cell on Exhibit 6, which you 3 prefer to call "myeloid progenitor cell," may 4 differentiate, so that it replicates into cells 5 eventually becoming what are called erythrocytes 6 or red blood cells on the chart, correct? 7 A. Yes. 8 Q. And those carry oxygen in the body, is 9 that -10 A. That's correct. 11 Q. -- what red cells do? They may 12 differentiate into what you have called 13 platelets, or what are called platelets on 14 Exhibit 6. Is there a name for that cell? 15 A. The megakary -- megakaryocyte, or 16 megakaryocytic lineage, if you will. 17 Megakaryocytes are the -- are very large cells. 18 You can see them on bone marrow sections as being 19 the largest cells on the section. They are the 20 cells that actually break up the cytoplasm, which 21 is that -- the main part of the cell, not the 22 nucleus, but the rest of it, actually fragments 23 to form platelets. 24 Q. And the platelets are responsible for 25 clotting, so that we don't bleed to death with a WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 159 1 little cut? 2 A. They are responsible for clotting, and 3 it appears that they play a role in wound-healing 4 and repair, as well. 5 Q. And then, finally, there is a cell 6 coming from the myeloid progenitor cell which 7 appears to differentiate into granulocytes and 8 monocytes or macrophages. What are those cells? 9 A. Granulocytes are our first defense, 10 first cellular defense against infection. They 11 don't respond to specific `agents. They respond 12 in general to anything they see as foreign. And 13 when we get an infection, they're the very first 14 cells that come to the attack. 15 The macrophage is a cell that -- that 16 can play a similar role, but it also functions in 17 helping to regulate the interplay between this 18 system and lymphocytes in the immune response. 19 Q. Can the myeloid progenitor, or stem 20 cell, as it's marked on Exhibit 6, father, if you 21 will allow my inartful use of the term, lymphoid 22 cells? 23 A. This cell here? 24 Q. Yes. 25 A. No. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 160 1 Q. Going to the lymphocyte, or lymphoid 2 progenitor cell on the upper part of the drawing, 3 can that cell father, if you will, any of myeloid 4 cell lineage? 5 A. No. 6 Q. I've asked you where the target cell for 7 chronic myelogenous leukemia is, and you've 8 indicated what's called the "pluripotential stem 9 cell" on Exhibit 6. How do we know that? 10 A. We have, on occasion, the capability of 11 using specific genetic markers, or cytogenetic 12 markers, that allow us to follow the progeny, 13 which is simply the children, of a given cell. 14 In the case of CML, there are a couple 15 of different types of markers that have been 16 used. One is the Philadelphia chromosome, which 17 is a specific chromosomal abnormality that is 18 associated with CML in -- in a large majority of 19 cases, vast majority of cases. 20 And this particular chromosome can be 21 seen in all the cells that are daughter cells of 22 the abnormal stem cell. 23 In addition, we have markers such as the 24 gene for glucose 6-phosphate dehydrogenase, which 25 is a sex-linked gene that in some patients -- and WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 161 1 again it's sex-linked, so that we can see this in 2 female patients, associated with the woman, she 3 may have two different X chromosomes, and 4 carrying one gene and one the other. 5 In any cell, there will only be one of 6 those expressed, so you have a 50 percent chance 7 of having an A type or a B type. 8 In a disease that's monoclonal, all the 9 cells that are produced from an abnormal stem 10 cell will have only one type, so you won't see a 11 random pattern, or equal A and B. You'll see all 12 one type. So you can follow which types of cells 13 are descended from the abnormal cell. 14 In the case of CML, one can find either 15 the -- the Philadelphia chromosome or glucose 16 6-phosphate dehydrogenase homozygosity, or the 17 same type, in all of these cells. 18 So it's clear, in CML, in the patients 19 that have been followed, that we can follow, that 20 that the lesion has to reside at the level of 21 this cell. 22 Q. Is that, to try to -- to reduce it from 23 the term you just used to something that may be a 24 little easier words to understand, is that the 25 same thing as saying that there are certain WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 162 1 markers that doctors can use that will show up in 2 a CML case in every one of the blood cells, or 3 mature blood cells that descended from the 4 original cancerous cell? 5 A. That's correct. And when you see those 6 abnormalities or markers in different types of 7 cells, especially when you see them in both 8 lymphocytes, and in either red cells or 9 granulocytes, you have a means of -- of 10 concluding that it had to be this cell that was 11 responsible for all of them, because that's the 12 only cell that can give rise to all the different 13 types of blood cells. 14 THE VIDEOGRAPHER: Doctor, can you 15 scoot your microphone up a little bit. It's 16 dragging on the table. 17 THE WITNESS: Sorry. 18 THE VIDEOGRAPHER: Thank you. 19 Q. (By Mr. Scott) Now, are there similar 20 markers that can be used to determine -- or have 21 been used to determine where chronic lymphocytic 22 leukemia originates, or the target cell for it? 23 A. Well, as I said, the one -- the 24 characteristic genes that we look at for 25 determining the origin or the site of maturation, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 163 1 the maturation level for cells in the B cell 2 lineage are the immunoglobulin genes. 3 In this particular process, going from 4 the pluripotential stem cell to the lymphoid stem 5 cell, somewhere in here, we may see 6 rearrangements in the gene that codes for the 7 heavy chain of immunoglobulin. It could occur 8 even in the cell that's going to go down this 9 pathway, theoretically. And in my experience, 10 that can happen. But it doesn't mean anything, 11 unless you also see a light chain rearrangement, 12 because then you have the both chains of the 13 immunoglobulin molecule that can make a whole 14 functional immunoglobulin molecule. 15 That occurs here, and that's the point 16 at which CLL's of B cell lineage, that's the type 17 of cell we see. The rearrangements are 18 consistent with that. And, in fact, they do 19 produce small amounts, usually, of IGM, which is 20 a type of antibody molecule, on their surface. 21 Fortunately for the patient, in most 22 cases of CLL, they don't actively produce a lot 23 of this antibody, because that would be abnormal 24 and could lead to some problems. But they tend 25 to be fairly quiet cells that don't do a lot of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 164 1 damage and aren't very aggressive as they begin 2 to multiply. 3 Q. In a case of chronic lymphocytit 4 leukemia, do you see these markers you have 5 discussed in the myeloid line, or the blue cell 6 lines on Exhibit 6? 7 A. No. 8 Q. I want to quickly talk about one other 9 type of -- general type of leukemia, that is, 10 acute myelogenous leukemia, which you and 11 Mr. Barrie discussed at some length earlier. 12 What is the target cell or origin cell 13 for acute myelogenous leukemia? 14 A. Well, again, we're using the same 15 general type of marker analysis to conclude what 16 the origin might have -- or had to be. 17 In the case of certainly greater than 90 18 percent, maybe 95 percent of the AML's that have 19 been examined in this way, the cell of origin is 20 either a committed cell down here, or it's this 21 cell here. 22 There is a small number of cases which 23 we cannot say that of and, in fact, we cannot 24 determine whether it's here, or possibly here. 25 This cell is often referred to as a WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 165 1 "multipotential progenitor cell," because it is 2 capable of giving rise to different lineages. 3 These would be called "unipotential," because 4 they're capable, certainly, these two, of giving 5 rise to just single lineages. 6 Q. Let me, again, for purposes of the 7 written record, which will not be quite as clear 8 as the videoed record here, the cells you have 9 described as unipotential cells, or progenitors, 10 are the three cells on the blue lines directly 11 downstream from what's marked as "Myeloid Stem 12 Cells" on Exhibit 6, correct? 13 A. Yes. At the risk of insuring there's no 14 semantic confusion, this one is obviously -- this 15 cell here, which is the granulocyte macrophage 16 precursor, is technically multipotential, in the 17 sense that it can give rise to two different 18 lineages. But we know this cell exists. 19 Q. The cell you referred to a moment ago as 20 the multipotential progenitor is what we've 21 marked as "Myeloid Stem Cell" on Exhibit 6, 22 correct? 23 A. Yes. 24 Q. And it's multipotential because it can 25 differentiate to the erythrocytic line, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 166 1 megakaryocytic line or the granulocytic, 2 macrophage -3 A. Yes. 4 Q. -- or monocytic line? 5 A. And, in fact, in AML, there are several 6 different variants of AML that in determ -- that 7 are determined by the predominance of the 8 abnormal cell types that are seen. And they can 9 fall into any of -- they call fall into any of 10 these lineages. 11 Q. Now, is the description you have just 12 made or described for us, the target cells for 13 various types of leukemia, a hypothesis of Rich 14 Irons, or is it something accepted in the -- in 15 science and medicine? 16 A. The literature is there to support these 17 concepts. They are not my concepts. They are 18 the concepts of others. The -- as I've -- as 19 I've indicated, the -- the relationship between 20 this cell and CML -21 Q. This is the pluripotential stem cell. 22 A. -- is very clear. There is absolutely 23 no doubt about that. As I have mentioned in the 24 case of AML, the relationship with respect to 25 this cell for 95 percent, or greater than 95 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 167 1 percent of the cases is clear. There is some 2 question about some of these cases. 3 Q. That's the myeloid stem cell. 4 A. That's right. 5 In the case of CLL, the rearrangements 6 that are seen in the genes that lead to the 7 development of the cell type with the functional 8 capabilities of a mature B cell are known and 9 clearly described, and that's been clearly 10 documented in the literature. These are not 11 controversial. 12 Q. Can you give us, just by way of example, 13 text, or something like that, where we might 14 confirm that this is not just the world according 15 to Rich Irons but is accepted in the 16 hematological community? 17 A. If you want to look at a hematology 18 text, I would suggest Dr. Jandl's book, or the 19 Wintrobe text. 20 In the case of the leukemias, I would 21 direct you to the recent edition of "Leukemia" 22 which I presented. 23 In the case of additional information on 24 CLL, I direct you towards the book "Chronic 25 Lymphocytic Leukemia" by Poliak and Catovsky, WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 168 1 which I believe was last published in about 2 1986. It might be slightly later. 3 There are numerous articles in the 4 literature that deal with these subjects. I 5 could direct you to the work of Philip Fialkow, 6 who did some of original work on characterizing 7 this cell, the pluripotential stem cell in CML. 8 Q. Okay. Thank you. 9 I want to -- do you have -- we can put 10 down Exhibit 6 now. I think that's all we need 11 with that right now. 12 And do you have your blue notebook? I 13 think we marked it as Exhibit 2. 14 Earlier today, you described -- in 15 describing your opinions, you indicated that 16 there was evidence that benzene has not been 17 associated with chronic lymphocytic leukemia, and 18 I want to explore that a little more and go to 19 some specific references in the materials you 20 have. 21 Are there general statements about the 22 etiology or cause of chronic lymphocytic in any 23 of the articles you have that might be helpful to 24 us, just to know what people writing reviews and 25 articles today say on that subject? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(Q09)833-0016 169 1 A. Well, as I think I indicated earlier 2 in -- this morning to Mr. Galbraith, I've already 3 summarized a statement in the Foon review article 4 in which it's indicated that chronic lymphocytic 5 leukemia is not increased by exposure to 6 alkylating drugs, radiation or chemicals. 7 I've also included a number of other 8 reviews that say similar -- make similar 9 statements. Here's one exampled I included from 10 a 1990 pathology text. And I included this 11 simply to indicate that this is -- this level of 12 understanding and consensus is one that is 13 appreciated at the level of a general text that 14 would be used to teach medical students, and, in 15 fact, we use to teach medical students today. 16 Q. Would you read the title and editors of 17 that text and the page -- and the entry that is 18 relevant, and the page numbers? 19 A. It's "Pathology" by Emanuel Rubin and 20 John L. Farber. Dr. Rubin is Professor and 21 Chairman of Pathology at Jefferson Medical 22 College, and John Farber is a professor in that 23 department, as well. It's published by J. B. 24 Lippincott Company in Philadelphia. I believe 25 the publication date is 1990, although it may not WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 170 1 be on this particular page. 2 What I was citing was a page several 3 pages from Chapter 20, which is by Dr. Hugh 4 Bonner, and Chapter 20 deals with blood and 5 lymphoid organs. And the statement I refer to is 6 on Page 1083. And in reference to chronic 7 lymphocytic leukemia, it reads: "The cause is 8 unknown, and there is no known association with 9 ionizing radiation or with myelotoxic agents." 10 Q. Is benzene one of the myelotoxic agents? 11 A. Yes, sir, by definition. 12 Q. Let's then -- I notice on that page 13 Dr. Bonner goes on to say, "Genetic influences 14 may be important." 15 A. Yes. 16 Q. On down in that paragraph, he also 17 indicates that chronic lymphocytic leukemia is 18 the most common type of leukemia in this country. 19 Is that the case? 20 A. That's correct. 21 Q. And do people who have never been in 22 chemical plants, or around them, get chronic 23 lymphocytic leukemia? 24 A. Oh, yes. 25 Q. I think you've already read from WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 171 1 Dr. Foon's article. I want to be sure. 2 I'd like to go back to Dr. Foon's 3 article for just a moment, if you have it there. 4 A. Sure. 5 Q. And, again, trying to focus on the most 6 recent articles and reviews, can you tell us when 7 Dr. Foon's article was written and where it 8 appeared? 9 A. It was published in October of 1990, in 10 the "Annals of Internal Medicine." 11 Q. I noticed, also, that one of the 12 coauthors with Dr. Foon is a doctor named Kanti, 13 K-a-n-t-i, R. Rai, R-a-i. Who is Dr. Rai? 14 A. Dr. Rai is a well-known hematologist 15 who, along with Dr. Eugene Cronkite, was16 instrumental in developing a staging system for 17 use in the prognosis, in determining the 18 prognosis of patients with CLL. 19 They developed this system at Brookhaven 20 National Laboratory in 1968, and published it, 21 eventually, in 1975. 22 Q. Is that a system routinely used by 23 hematologists in staging chronic lymphocytic 24 leukemia patients? 25 A. Yes, that as well another system that is WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 172 1 more recent, the Binet system', has seen 2 considerable use. The Rai System is still -3 certainly, the modified Rai system, which was 4 modified in 1988, is still in use. 5 Q. I also noticed in the first -- on the 6 first page of the Foon article, Page 525, that 7 the authors -- and it's the right-hand column, it 8 looks to be the third paragraph. The authors 9 indicate, that in preparing this article, they 10 say, "In our review, we emphasize recent insights 11 into the biology and treatment of chronic 12 lymphocytic leukemia. An English-language 13 literature search was done using MEDLINE and 14 CANCERLIT (1980 to 1990), abstracts and reviews 15 from meetings, and extensive manual searches of 16 bibliographies of identified articles." 17 What are "MEDLINE" and "CANCERLIT?" 18 Q. These are computerized databases that 19 are supported by the National Library of Medicine 20 and that all clinicians and medical scientists in 21 the country access or use in searching the 22 literature for articles that relate to subjects 23 that they're interested in. 24 Q. Are those computer tools that one -25 that you would expect one, in your field of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 173 1 expertise to -- to utilize, ifs trying to 2 determine what articles had been written on the 3 etiology or causation of chronic lymphocptic 4 leukemia? 5 A. Oh, yeah, every day. These are -- these 6 are extremely -- these are the major computerized 7 sources for current published information in the 8 field. 9 Q. Going over to Page 526 in the very first 10 paragraph in the left-hand column on the page, I 11 believe you read it earlier, but I have a 12 question about -- about it. That paragraph 13 indicates: "The cause of chronic lymphocytic 14 leukemia is unknown. Unlike other forms of 15 leukemia, the incidence of chronic lymphocytic 16 leukemia is not increased by exposure to 17 alkylating drugs, radiation or chemicals." 18 What are "alkylating drugs"? 19 A. Alkylating drugs are chemotherapeutic 20 agents, primarily, immunosuppressive and 21 chemotherapeutic agents that alkylate, which 22 implies that they bind to, in this case, DNA, and 23 alter DNA. 24 Q. Earlier, when Mr. Barrie was asking 25 questions about the mutagenicity of benzene, I WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 173 1 believe -- and I don't want to misstate what you 2 said, but I believe you said that it was 3 benzene was not as powerful a mutagen as some of 4 these alkylating agents. Is that a fair 5 statement? 6 A. That's a very fair statement. 7 Q. Can you give me some examples of these 8 alkylating agents? 9 A. Cyclophosphamide is an alkylating 10 agent. Nitrogen mustard is an alkylating agent. 11 A large number of chemotherapeutic agents that 12 are routinely used in treating leukemias and 13 other cancers are, in fact, alkylating agents. 14 Q. Now, if I understand the way alkylating 15 drugs or agents are used in chemotherapy, it is 16 that there are certain patients who have -- that 17 present with some type of cancer, that is, 18 generally not leukemia, and that in treating 19 those cancers, the doctors give them these 20 alkylating drugs or agents to treat the 21 underlying cancer; is that fair? 22 A. That's correct. 23 Q. And that in some percentage of those 24 patients who have received these alkylating 25 drugs, the -- a leukemia later develops. Is that WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 175 1 true? 2 A. In a small proportion of the patients 3 receiving these types of chemotherapeutic agents, 4 that can happen, yes. 5 Q. Does the literature show what type of 6 leukemia arises, when it does, from the 7 administration of these alkylating drugs? 8 A. Yes, it does. That literature is very 9 well developed because, unlike the situation that 10 we often have in an occupational setting, with 11 respect to characterizing exposure to chemicals, 12 in this case, the patients are basically a 13 captive audience. They have been administered 14 these drugs, which are very potent and are 15 designed to attack their cancer cells. 16 We know the doses they've received, we 17 know when they've received them, and they're 18 followed throughout their lifetime to see what 19 effects result from that. 20 So here we have a literature that's well 21 developed. The -- the individuals are well 22 defined. They're known, their exposure is 23 well-defined and known and quantitated, and the 24 outcome is also well-defined. And that 25 literature, which is considerable over the last WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 176 1 20 years or so, indicates quite clearly that 2 exposure to alkylting myelotoxic drugs results in 3 an increased incidence of acute myelogenous 4 leukemia in those populations. 5 It also indicates that they are not 6 associated with lymphoid neoplasms, per se. And, 7 in fact, I recall one reference in the leukemia 8 text that specifically addresses that -- that 9 statement, in terms of a review of the literature 10 and the conclusion that's been reached. 11 Q. That is, the author in the leukemia text 12 we have up here on the table specifically noted 13 that the lymphoid neoplasms, which I take it 14 includes chronic lymphocytic leukemia, don't show 15 up with this sort of administration of alkylating 16 agents? 17 A. That's correct. Would you like me to 18 find it? 19 Q. It might helpful if you could locate 20 it. 21 MR. BARRIE: How much longer do you 22 have? 23 MR. SCOTT: Five minutes, maybe 24 ten. 25 A. This is Chapter 14 in the "Leukemia" WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 177 1 text by Henderson and Lister, and it's -- it's 2 written by Dr. Rosner and Dr. Grunwald, who I 3 believe are at Roswell Park in Buffalo. Although 4 I'm not certain, I think that's where they are. 5 And the title is "Chemicals and 6 Leukemia." And the last paragraph of the 7 article, the book chapter, reads: "This review 8 is limited to acute myeloblastic leukemia, or one 9 of its variants, developing in patients treated 10 with cytotoxic chemotherapy for neoplastic and 11 nonneoplastic diseases. Other types of leukemia, 12 such as acute lymphocytic leukemia, acute 13 myelofibrosis, and chronic myelocytic leukemia 14 has sporadically been reported following 15 chemotherapy for a variety of neoplasms,-.but 16 without a trend or pattern, thus suggesting a 17 purely coincidental occurrence." 18 And if you'll note, they don't even 19 recognize or mention chronic lymphocytic 20 leukemia. 21 Q. Mr. Barrie had asked you earlier about 22 benzene affecting the DNA and, again, you 23 indicated that it was not a particular -- not 24 particularly powerful in that regard, certainly 25 as related to something like these alkylating WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 178 1 drugs; is that true? 2 A. Yes. 3 Q. And what the reference you have read to 4 us indicates is, that even with the use of these 5 much more powerful alkylating agents, these 6 agents that have that propensity, more so than a 7 chemical like benzene, CLL's don't show up? 8 A. That's correct. 9 Q. Are you familiar with references that 10 indicate that radiation has not been associated 11 with the development of chronic lymphocytic 12 leukemia? 13 A. Yes, sir. 14 Q. Does that fact assist you in any way in 15 reaching the conclusions you have reached 16 concerning chronic lymphocytic leukemia in this 17 case? 18 A. I think the the debate over the 19 potential relationship between chronic 20 lymphocytic leukemia and any -- and any causative 21 agent is really clarified or aided by knowledge 22 that even radiation, which we know can cause 23 virtually all types of leukemia except CLL, is 24 not associated with an increased incidence of 25 CLL. There's just no definitive, reliable body WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 179 1 of information anywhere that would lead one to 2 draw a conclusion that CLL is caused by exposure 3 to cytotoxic agents or radiation. 4 Q. I want to turn to the second opinion 5 that you have provided today, and I want to look 6 at a little bit of the literature that I -- I 7 think you've got in your notebook there related 8 to the lymphocyte doubling time analysis. 9 Again, I want to determine whether this 10 is -- the use of a lymphocyte doubling time 11 analysis or the accuracy of that type of analysis 12 is a hypothesis of yours or something that's been 13 recognized in science -- in the scientific and 14 medical literature. 15 Can you point to some articles that 16 discuss that analysis, how it's done, and the 17 prognostic uses of it? 18 A. Yes. I can do it in two ways. One, I 19 can refer to the original papers, to begin with, 20 and then, if you like, I can refer to the same 21 reviews that we've been talking about and others 22 that I have that, in discussing the biology of 23 disease, comment on the utility of lymphocyte 24 doubling time as a reliable factor for prognostic 25 purposes. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 180 1 Q. I'd appreciate it if you would do it in 2 that order, then. 3 A. Okay. The -- there are a great many 4 papers that have been written that deal with the 5 kinetics of lymphocyte replication in CLL. These 6 are papers by Sweet, et al., February 1977, 7 "Clinics in Haematology;" Zimmerman, et al., 8 1968 in "Blood;" Theml, et al., from 1973, 9 dealing with the kinetics of the tumor cells in 10 chronic lymphocytic leukemia; the lymphocyte 11 doubling time, the -- the -- probably the most 12 important paper with respect to characterizing 13 its use as a prognostic indicator ~s that of 14 Montserrat, M-o-n-t-s-e-r-r-a-t, which was 15 published in 1986, in the "British Journal of 16 Haematology." 17 And it -- it -- it demonstrates rather 18 impressively in a group of a hundred untreated 19 patients that the lymphocyte doubling time 20 distinguishes two populations, those that have a 21 doubling time of less than 12 months, and those 22 that have a doubling time of greater than 12 23 months. 24 The -- as I indicated earlier today, the 25 prognosis, or the outlook for those with a WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 181 1 doubling time of greater than 12 months is much 2 better than that for those that have a more rapid 3 turn-over. 4 The estimation of body burden that I 5 used is based on an article by Stryckmans, which 6 appeared in February of 1977 on the kinetics of 7 chronic lymphocytic leukemia. 8 Now, I've use technique because, as I 9 mentioned before, as a function of variations in 10 weight, it's a more reliable indicator than the 11 absolute lymphocyte counts in the blood. 12 By the same token, the slope of the line 13 that's created by using either the absolute 14 lymphocyte count or an estimation of body burden 15 is going to very similar, so that, in fact, in 16 this particular case, there would be no 17 appreciable or significant differences between 18 the slope generated using either. method. I chose 19 this one because it's the most conservative. 20 Q. "Conservative" in what sense? 21 A. It's considered to be a more reliable 22 indicator of body burden than the lymphocyte 23 count, which can fluctuate widely. 24 By the same the token, it should be kept 25 in mind that the absolute cell numbers that are WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 182 1 projected here are not necessarily that accurate 2 in terms of body burden. They could vary 3 considerably, but they're all going to vary the 4 same way, and it's not going to affect the slope 5 of the line. 6 That's the real value of this 7 technique. You're not using an individual blood 8 level or a blood value for an estimate on which 9 to base a -- an analysis. You're looking at the 10 total progression of the disease and the 11 development of an increased tumor load with time. 12 Q. I'd like to turn to Exhibit 4, which is 13 the graph that you discussed earlier with 14 Mr. Galbraith. And we might, again, put up our 15 document stand and see if we can have the camera 16 look at it and let you talk about it a little 17 bit. 18 THE VIDEOGRAPHER: Can you kind of 19 move that toward the Doctor, Mr. Galbraith? 20 THE WITNESS: I'm tangled up in 21 my -22 THE VIDEOGRAPHER: In your 23 umbilical? 24 THE WITNESS: Yeah. 25 MR. GALBRAITH: Like that? Can you WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 183 1 see that, Doctor? 2 THE WITNESS: (Witness nods') 3 THE VIDEOGRAPHER: Go ahead. 4 Q. (By Mr. Scott) Now, there are a number 5 of black dots on Exhibit 4. Can you tell me what 6 each one of those black dots represents and where 7 it came from? 8 A. Well, as I mentioned earlier, I took the 9 individual blood data from Mr. Chambers' chart, 10 each time that I could find blood data, and 11 determined, using his weight, the estimated body 12 burden for total lymphocytes, according to the 13 Stryckmans nomogram. 14 I then averaged that for every year, 15 because there were some years in which he had 16 multiple measurements, and they vary somewhat, 17 which is reasonable, given both the variability 18 of the peripheral blood -count, in cases of CLL, 19 as well as any laboratory variation or error. 20 So I averaged them for every year and 21 then plotted them on this graph as a function of 22 time. 23 Q. How do we know that your Exhibit 4 is 24 accurate? For instance, if one of the blood 25 counts that Mr. Chambers had, as a result of lab WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 184 1 error or something like that, was way off? 2 A. Well, as you can see from the chart, not 3 every point on that line, every point on the 4 graph is on the line. 5 So there, in fact, are variations from, 6 or deviations that you see here that are well 7 within experimental and/or clinical error. And, 8 in fact, I'm impressed with the tightness of the 9 fit. I mean, the -- for any given point, one 10 could arguably say that it's not necessarily 11 representative of what's going on in that patient 12 with time. But all the points define a line. 13 As I said before, the -- the actual cell 14 number that's defined by the line may not be 15 accurate. It could be, within plus or minus, 16 maybe even an order of magnitude of that point. 17 But the points themselves depict a line 18 or a slope that isn't going to change. 19 Q. In other words, assuming that the actual 20 number of lymphocytes measured is incorrect and 21 is off -- let's say the actual number was 22 actually one order of magnitude less than what is 23 depicted by Exhibit 4, would that have any 24 bearing on the opinions you have reached in this 25 case? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 185 1 A. No. 2 Q. And why not? 3 A. Because the slope of the line is very 4 clearly defined by those points and is not going 5 to change as a function of the estimate, because 6 the estimate, which is based on, again, the 7 Stryckmans study, is constant, so, therefore, 8 whatever that estimate is pertains to every point 9 on the line. So the asbolute number, in reality, 10 might differ, but the slope won't. 11 Q. And Exhibit 4, the -- the line that was 12 drawn was done using a technique that is set out 13 in Dr. Stryckmans' paper which is in your blue 14 book, "Cell Kinetics in Chronic Lymphocytic 15 Leukemia." 16 A. The estimate of the body burden was 17 according to Dr. Stryckmans' paper. The use of 18 it to calculate doubling time was based on the 19 Montserrat paper. 20 Q. I understand. What -- on the Y axis, 21 the "Cell Number" axis on the left-hand side of 22 the page, what is it that you are measuring? 23 What is the datapoint on the left-hand side, 24 under "Cell Number"? 25 A. That's the estimated body burden of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 186 1 lymphocytes, which in the case of a patient with 2 CLL will progressively, with time, become more 3 and more associated with the tumor. So, 4 eventually, you're dealing with a majority of 5 cells that are abnormal. 6 Early on, you're dealing with very few 7 and, in fact, you can't tell they're there. 8 Q. Is it abnormal cells that are listd -9 that are described by this graph on the Y axis on 10 left-hand side, as opposed to all lymphocytes? 11 A. It's all lymphocytes. And as we go out 12 in time, that becomes progressively, again, a 13 representative of the tumor cells. And the -14 that's characterized quite well in the Stryckmans 15 article. 16 Q. Does the fact that the line that is 17 drawn through these various datapoints on Exhibit 18 4, related to Mr. Chambers, tell you anything 19 about the constancy of the doubling time of 20 chronic lymphocytic leukemia. 21 A. You betcha. It illustrates that once 22 the -- the very well-known and appreciated 23 characteristic of CLL is that the kinetics are 24 very constant. The other thing it demonstrates, 25 in this case, is -- again, the fact that those WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 187 1 points depict a line so -- so well is 2 characteristic of a very reproducible dodbling 3 time. 4 Q. Are the opinions which you have provided 5 in this case to Mr. Galbraith, in response to the 6 questions posed by Mr. Galbraith, Mr. Barrie and 7 myself, based upon reasonable scientific 8 probability, after a review of the medical 9 records of Mr. Chambers and the various 10 scientific and medical articles you have referred 11 to, as well as your background, which you've 12 described for us? 13 A. Yes, sir. 14 Q. Have you -- during your career, have you 15 authored or edited any books in the -- on the 16 subjects of hematology, toxicology, molecular 17 toxicology, those sorts of subjects? 18 A. Yes, sir. 19 Q. Can you tell us the names of the books 20 which you've either authored -- authored chapters 21 in or edited, or are they listed on your CV? 22 A. They're -- they're listed in my CV. 23 Several times throughout your deposition today 24 you have said things like, "I've been successful 25 in demonstrating," or "We've been successful in WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 188 1 demonstrating" in referring to certain 2 investigations. What were you talking about? 3 A. I was referring to studies that I've 4 been involved in, or have been done in my 5 laboratory. Basically, we have -- "we" again, 6 meaning in my laboratory, either at CIIT or since 7 then, have been involved in a variety of studies 8 to characterize the effects of benzene, benzene 9 metabolites, on toxicity to the bone marrow, to 10 the stem cells in the bone marrow, to lymphocytes 11 and to the blood-forming organs and the immune 12 system. 13 And at various times today, we've 14 touched on subjects for which my own work was 15 relevant to the discussion and, in that context, 16 I've said, "I" or "We." 17 Q. One thing I want to be sure we 18 understand, when you talked about demonstrating 19 something in your lab, you're not talking about 20 just reviewing articles that someone else has 21 written; is that fair? 22 A. That's correct. 23 Q. You have actually been involved directly 24 in animal studies; is that true? 25 A. Yes, sir. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-00-16 189 1 Q. Have you been involved in -- and I 2 hesitate to use the term, and I'll hope you'll 3 tell us what it means, but in human studies? 4 A. Yes, sir. 5 Q. Obviously, we can't use, and wouldn't 6 want to use humans to study the effects of drugs, 7 chemicals, and that sort of thing, the way we can 8 with animals. How do you do human studies? What 9 are you talking about? 10 A. Well, we basically -- there are two 11 major types of research that one can do with -12 and that can be called human studies. 13 We're -- we're -- we're engaged in both. 14 The first is to compare human bone marrow cells 15 and stem cells and their behavior and their 16 susceptibility to toxic -- toxic compounds in 17 culture. And we can compare those to animal 18 cells such as the mouse. And we can, doing that, 19 obtain a -- an understanding as to the relative 20 differences and the susceptibility of the 21 individual cell types. And since we can expose 22 mice to toxic compounds, we can then begin to 23 extrapolate from the mouse to man based on what 24 we know about the relative susceptibilities and 25 effects of the different cells in culture. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 190 1 The other arena in which we can begin to 2 get a handle on the -- the nature of how-blood 3 cells work, and their susceptibility to toxic 4 agents is in the arena of therapy, where patients 5 are being treated for diseases, such as leukemia 6 or other solid tissue, tumor types, and may 7 and the therapy may, in fact, require an 8 examination of their bone marrow, or it may 9 involve a bone marrow transplantation, which is 10 now a very rapidly progressing and developing 11 area of research in terms of approach to therapy 12 for tumor types, as well as leukemia. 13 And one of the areas we're interested in 14 is understanding how one can go about taking a 15 patient's own stem cells, purifying them, 16 treating him for whatever his particular cancer 17 is, in such a way that we don't have to worry 18 about the damage it's going to cause to his bone 19 marrow, because we can then reinstall his own 20 bone marrow cells back into him, to allow him to 21 survive and recover. 22 This is a new treatment, modality, if 23 you will, that is being investigated at a number 24 of centers across the country and in various 25 types of protocols. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 191 1 Our own particular bone marrow 2 transplantation center at the University of 3 Colorado is focusing on what's called -- it's a 4 big word, but it's very simple -- autologous bone 5 marrow transplantation, which is reinfusing the 6 patient's own marrow back after treatment for 7 cancer. 8 Q. Mr. Barrie mentioned earlier a test 9 known as the "Ames Test." What types of cells 10 does the Ames Test use in determining 11 mutagenicity? 12 A. Particular strains of E. coli, which are 13 bacteria that's normally found in the gut and the 14 intestines. 15 Q. These aren't human tissue cells; then, 16 that are being used, but rather bacteria cells; 17 is that fair? 18 A. That's correct. 19 Q. And that would be as opposed to the 20 types of human tissue, marrow tissue 21 investigations you described for us a few minutes 22 ago. 23 A. Well, certainly, we're using human 24 cells, bone marrow cells. We're not using 25 bacteria. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 192 1 Q. Mr. Barrie also asked some questions 2 about the -- what's called clastogenecity of 3 benzene. I know I've had four or five cups of 4 coffee during this deposition today. Is coffee 5 or caffeine a clastogenic agent? 6 A. Yes, sir, it is. 7 Q. Are there lots of clastogenic agents 8 that each of us ingests each day of our lives? 9 A. Lots of clatogenic agents and lots of 10 carcinogenic agents. 11 MR. SCOTT: I believe that's all I 12 have. Thank you, Doctor. 13 MR. GALBRAITH: Let's take a little 14 break. 15 THE VIDEOGRAPHER: It's now 3:13. 16 We're off the record. 17 18 (Whereupon, after a brief recess, the 19 video deposition continued as follows:) 20 21 THE VIDEOGRAPHER: It's now 3:28, 22 and we're back on the record. 23 24 (Whereupon, there was a discussion held off 25 the record, after which the proceedings continued WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 193 1 as follows:) 2 3 (Whereupon, Irons Exhibit Nos. I and 8 4 were marked for identification.) 5 6 MR GALBRAITH: Dr. Irons, after 7 reviewing my notes, I have no further questions 8 for you. Thank you, sir. 9 10 RE-EXAMINATION 11 QUESTIONS BY MR. BARRIE: 12 13 Q. Sir, let me just show you what's been 14 marked as Exhibit No. 7 and ask you, sir, if you 15 can identify that document? 16 A. Yes. This is the letter that I 17 received, the cover letter I received with the 18 medical records of Mr. Chambers, when they came. 19 Q. Is that the engagement letter, if you 20 will, with Mr. Scott -21 A. Yes. 22 Q. -- retaining your services as an expert 23 in this case? 24 A. Yes. 25 Q. Let me also show you, sir, what's been WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 194 1 marked as Exhibit No. 8, and it's the last page 2 of three documents, and ask you if you can tell 3 me what that is, sir? 4 A. These are the notes of my technical 5 assistant, who I had go through Mr. Chambers' 6 medical records to determine his weight history 7 in those records and to associate his weight at 8 the time that the various blood tests were 9 performed. 10 Q. Those three pages, which is marked as 11 Exhibit 8 on the last of the page, were those the 12 documents that you used to come up with your 13 printout which is marked as Exhibit No. 5 in this 14 case? 15 A. These were used simply to correlate his 16 weight with the blood data, which was then used 17 to construct that chart. And that, in turn, was 18 used in providing the averages that are used on 19 the computerized sheet. 20 For most of those, the weight 21 corresponds to the actual day or admission when 22 the blood test was taken. When, in fact, there 23 was no weight data available, we used the nearest 24 weight we could find in the chart. Since his 25 weight doesn't vary that much, it didn't seem, to WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 195 1 me, to be particularly important. 2 Q. These three documents marked as Exhibit 3 No. 8 on the last of the third page, these report 4 weight in pounds at a specific time period? 5 A. Yes. 6 Q. And does that correlate with Exhibit 7 No. 7 to give us the weight in kilograms during 8 the same time period? 9 A. We simply translated pounds into 10 kilograms so that we could use the nomogram as 11 published by Dr. Stryckmans. 12 Q. I understand that, but I just want to 13 make sure that Exhibit No. 8 relates to number 14 Exhibit No. 7, insofar as we're transposing 15 weight in pounds to weight in kilograms, correct? 16 A Yes, sir. 17 Q. I want to just ask you some general 18 questions of Exhibit No. 7. I understand what 19 the column under "Date" means, and I'm fairly 20 sure I understand what the WBC, or the white 21 blood cell count is. 22 The next column is "Percent." 23 A. It should be "Percent Lymphocytes." 24 Q. Okay. And where did that number come 25 from? WORLDWIDE COURT REPORTERS, INC. fiOUSTON(713)651-1100/BEAUMONT(409)833-0016 196 1 A. From the differential smear -2 differential examination of the blood smear in 3 each of those particular blood tests. 4 Q. And that was reported in the medical 5 literature you reviewed? 6 A. In -- in his medical history, yes, sir. 7 Q. The next column is "Absolute" -8 "Absolute Count Lymphocytes." 9 A. Yes. 10 Q. Can you tell me where that number came 11 from? 12 A. That is simply the product of the 13 fraction of total cells that the lymphocytes 14 represent times the total blood count, so it 15 gives you the -- the quantitative number of 16 lymphocytes per cubic millimeter. 17 Q. As we move over, there's a column called 18 "Weight" in kilograms, and we've established 19 what that is. 20 The next column is the "Body Burden." 21 A. Yes. 22 Q. And there's something written on the top 23 of that I just can't read. Would you just tell 24 me what that is. 25 A. "Stryckmans." That's -WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 197 1 Q. So that's the calculation from the 2 Stryckmans' work -3 A. That's the 4 Q. -- that you talked about? 5 A. Yes. I'm extrapolating from his -- from 6 his chart. 7 Q. And then there's another column with a 8 star over -- over the top, giving some numbers. 9 And the first one, corresponding to the date 10 December 20th, 1989, 8.7 times 10 to the 11th. 11 And what number is that, sir, and how was it 12 derived? 13 A. That's the estimated body burden, which 14 would be the product of his weight in kilograms 15 times the Stryckmans' nomogram number. 16 Q. And what significance does that series 17 of numbers under that column play? 18 A. That is the estimated body burden using 19 that technique. 20 I then averaged that on a yearly basis 21 to come up with the numbers that are on the 22 computerized sheet that was then used to -- as 23 the basis for the graph. 24 Q. You're referring, of course, to Exhibit 25 No. 5? WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 198 1 A. Yes. And there's also a doubling time 2 analysis on that. 3 Q. And the way Exhibit No. 7 and Exhibit 5 4 and Exhibit 4 relate together is that you take 5 these numbers on Exhibit No. 7, as modified by 6 Exhibit No. 5, and you plot it on Exhibit No. 4? 7 A. Yes. 8 Q. Although you have the numbers under 9 Exhibit No. 4, that work around this line that 10 you've drawn through them, would it be fair to 11 say that the line, as it goes towards the axis 12 which is labeled "Cell Number" is frankly an 13 assumption on your part, based on the analysis 14 contained within the works that you've cited? 15 A. This is an extrapolation, which-by 16 definition assumes that the -- the literature 17 that I -- that has formed the basis of my opinion 18 and this analysis is, in fact, correct, yes. 19 Q. Have you understood my questions today, 20 sir? 21 A. I believe so, yes. 22 MR. BARRIE: I pass the witness. 23 MR. SCOTT: Let me grab this 24 microphone. I have just a couple of questions. 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 199 1 RE-EXAMINATION 2 QUESTIONS BY MR. SCOTT: 3 4 Q. Dr. Irons, Mr. Barrie asked you same 5 questions earlier about -- asking whether you had 6 been in either a Marathon -- Marathon Oil or a 7 Monsanto Company chemical plant or refinery. 8 Have you been in chemical plants and refineries 9 in your career? 10 A. Yes, sir, I have. 11 Q. And I understand not for either of these 12 Defendants, but for other companies, you have 13 visited and seen the types of operations that 14 those companies have in chemical plants and 15 refineries? 16 A. Yes, I have. 17 Q. He also asked you some questions 18 concerning 55-gallon drums of benzene, and you 19 indicated that the use of 55-gallon drums -20 well, I don't remember -- was outrageous or 21 outlandish, something along those lines. 22 MR. BARRIE: Let me just object to 23 the form of question. I've not asked this 24 gentleman one question about 55-gallon drums of 25 benzene. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 200 1 MR. SCOTT: Okay. 2 Q. (By Mr. Scott) I'm sorry. Mr. Barrie -3 Mr. Galbraith may have asked you those questions 4 earlier today. I want to be sure I understand 5 what you were saying. 6 First, do you have any reason to believe 7 that there were 55-gallon drums of benzene at any 8 Monsanto or Marathon facility in which 9 Mr. Chambers worked? 10 A. No. I have no information on that. 11 Q. Based upon your knowledge of the 12 processes that are involved in chemical plants 13 and refineries, do you have reason to question 14 whether there are -- there were 55-gallon drums 15 of benzene at those types of plants and 16 refineries? 17 A. Based on my knowledge of the chemical 18 industry, and only that, I would find it 19 extremely unlikely and, in fact, I can't think of 20 any reason why any company would leave 55-gallon 21 drums of benzene sitting around for any length of 22 time. 23 Benzene is flammable. It's extremely 24 flammable. It represents a fire hazard, amongst 25 other things. And keeping large amounts of WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 201 1 benzene around for use as a cleaning solvent 2 seems, to me, incredulous. It's hard to believe. 3 MR. SCOTT: I believe that's all I 4 have. Thank you. 5 6 RE-EXAMINATION 7 QUESTIONS BY MR. BARRIE: 8 9 Q. You have no personal knowledge, sir, of 10 what the standard operating procedures were of 11 the Marathon plant, or for the contractors, 12 subcontractor personnel working in that plant, or 13 of any other facility here in Texas, do you? 14 A. No, sir. 15 Q. And you mentioned it would be 16 incredulous to have barrels of benzene used for 17 cleaning solvents, from a probability 18 standpoint. Did I understand that correctly? 19 A. Yes, sir. 20 Q. Would it not also, sir, be incredulous, 21 from a health standpoint, to have barrels of 22 benzene used in a refinery for the cleaning of 23 hands and tools? 24 A. For that purpose, yes, sir. 25 MR. BARRIE: I pass the witness. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 202 1 MR. SCOTT: I think that's all I 2 have. Thank you. 3 THE VIDEOGRAPHER: It's now 3:37. 4 This is the end of Tape No. 3. We're off the 5 record. 6 7 (Whereupon, after a brief discussion off 8 the record, the stenographic record continued as 9 follows:) 10 11 MR. BARRIE: I just need to put a 12 statement on the record. 13 MR. SCOTT: Okay. 14 MR. BARRIE: Plaintiffs are going 15 to object to the use of this testimony in the 16 trial of the matter of this case insofar as it 17 concerns the Defendant Monsanto. 18 The Judge has ruled on several occasions 19 that the Defendants are not able to use Dr. Irons 20 as a testifying expert, and I'll object to all 21 questions being directed by Mr. Scott to this 22 gentleman. And I'll further object to its being 23 used by Mr. Scott, Ms. Lewis or Mr. Goforth in 24 the trial of the matter, pursuant to the Judge's 25 Order. WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 203 1 MR. SCOTT: Monsanto would 2 obviously comply with all orders of the Court, 3 and any reconsiderations of those. 4 5 6 7 RICHARD D. IRONS 8 9 SUBSCRIBED AND SWORN to before me, 10 the undersigned authority, on this the day 11 of 1991. 12 13 14 Notary Public 15 16 17 10 19 20 21 22 23 24 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016 204 1 THE STATE OF TEXAS 2 3 4 5 I, Emanuel A. Fontana, Jr., Certified 6 Shorthand Reporter in and for the State of Texas, 7 hereby certify that at the time and place stated 8 the witness, Richard D. Irons, personally 9 appeared before me, and after being by me first 10 duly sworn to tell the truth, was examined by 11 counsel for the respective parties hereto; that 12 the testimony of said witness was taken in 13 shorthand by me, later reduced to typewriting 14 under my direction, and the foregoing 203 pages 15 are a true and correct transcript of said 16 testimony. 17 GIVEN under my hand and seal of office 18 on this 5th day of February, 1991. 19 20 21 Emanuel A. Fonta a, Jr. 22 Certified Shorthand Reporter in and for the State of Texas 23 Reporter Certification 'Nb. 1232 Expires December 31, 1992 24 25 WORLDWIDE COURT REPORTERS, INC. HOUSTON(713)651-1100/BEAUMONT(409)833-0016