Document qmyZJb08Kw4L84w8nrJ6oexNk

1 1 IN THE UNITED STATES DISTRICT COURT 2 FOR THE DISTRICT OF COLUMBIA 3 Civil Action No. 93-0561 (HHG, DAR) 4 BETSY LAKIE, 5 Plaintiff, 6 vs. 7 SMITHKLINE BEECHAM, et al., 8 Defendants. 9 DEPOSITION OF RICHARD D. IRONS 10 April 12, 1996 11 1860 Blake Street 12 Fifth Floor 13 Denver, Colorado 14 A P P E A R A N C E S 15 16 17 HARVEY S. WILLIAMS, Esq. 1019 19th Street, N.W. 18 Suite 800 Washington, D.C. 20036 19 Appearing for the Plaintiff. 20 DANIEL W. WHITNEY, Esq. 21 HOWELL, GATELY, WHITNEY & CARTER Twelfth Floor 22 401 Washington Avenue Towson, Maryland 21204 23 Appearing for the Defendant 24 SmithKline Beecham. 25 2 1 The deposition of RICHARD D. IRONS, 2 produced, sworn and examined upon oath on the 12th 3 day of April, 1996 at 10:04 a.m., at 1860 Blake 4 Street, City and County of Denver, State of Colorado, 5 before me, Jessica Swaim, a Registered Professional 6 Reporter and a Notary Public within and for the City 7 and County of Denver, State of Colorado, pursuant to 8 the Federal Rules of Civil Procedure for the 9 examination of the said RICHARD D. IRONS, a witness 10 called for examination by the plaintiff herein. 11 12 INDEX 13 Witness: Pane No. 14 RICHARD D. IRONS 15 Examination by Mr. Williams 3 16 Marked at 17 Exhibit No. Pace No. 18 Irons Depo Exh. 1 5 19 (Command to Appear at Deposition) Irons Depo Exh. 2 5 20 (List of Cases) Irons Depo Exh. 3 83 21 (Irons notebook) Irons Depo Exh. 4 158 22 (Irons file) 23 24 25 AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 3 1 RICHARD D. IRONS, 2 being first duly sworn to state the truth, the whole 3 truth and nothing but the truth, testified on oath as 4 follows: 5 EXAMINATION 6 BY MR. WILLIAMS: 7 Q. State your name for the record, 8 please. 9 A. Richard D. Irons. 10 Q. And what is your occupation, sir? 11 A. I'm a toxicologist at the University of 12 Colorado Health Sciences Center. 13 Q. How long have you had that position? 14 A. Since January 1989. 15 Q. I'm going to show you what we'll mark 16 as Exhibit 1, and ask if you can identify that. 17 A. It's a deposition notice. 18 Q. Is that for the deposition today? 19 A. Yes. 20 Q. Did you receive a copy of that prior to 21 today? 22 A. I saw it briefly yesterday. 23 Q. Okay. Were you able to bring the 24 documents requested? 25 A. Some o= them. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 4 1 Q. What weren't you able to bring? 2 MR. WHITNEY: We object to category 7 3 and 18 as usual. 4 MR. WILLIAMS: Did you fax 12 to my 5 off ice? 6 MR. WHITNEY: Yeah. And also we 7 object to item 14, which is sort of a conditional 8 objection, since I'm not quite sure of the status, if 9 one of the documents is responsive. That relates to 10 a report in another opinion case. And I don't want 11 to breach someone else's work product. So I need to 12 contact those attorneys to find out exactly where the 13 case is. 14 MR. WILLIAMS: Is that a case that Dr. 15 Irons is working on? 16 MR. WHITNEY: (Indicating.) 17 A. Eleven, to the extent that I have 18 submitted the report, my report in this case. 19 Q. (BY MR. WILLIAMS) okay. Paragraph 11 20 refers to cases where you've testified either in 21 deposition or at trial; correct? 22 A. Yes. 23 Q. The list of cases I have were started 24 in 1992 through 1995. Is that what you're referring 25 to? AVERY/WOODS REPORTING SERVICE, INC. (,303) 825-6119 5 1 A. Yes. 2 Q. Did you have any-- did you participate 3 in any litigation prior to 1992? 4 A. Yes. I don't have any record of those 5 cases. That is what I had at the time that I 6 responded to the report, the report submission. 7 Q. Okay. Did you bring a copy of your 8 report that you submitted in this case? 9 A. Yes. 10 Q. Are the cases listed on your CV or on 11 your report? 12 A. Neither. It was submitted with the 13 report, but it's not attached to the report. This is 14 just a copy of the report. 15 Q. Okay. And did you bring the list of 16 the cases with you here today? Is it with you? 17 A. No. 18 (Whereupon, documents were marked Irons 19 Deposition Exhibits 1 and 2 for identification by the 20 reporter.) 21 A. Twenty-one in particular and to a 22 certain extent 22, I did not attempt to bring every 23 article or manuscript that I possess relating to 24 benzene or myelodysplastic syndrome. It would be in 25 the thousands. AVERY/WOODS REPORTT_NG SERVICE, INC. (303)325-6119 6 1 Q. Okay. Did you bring all the articles 2 which are relevant to your opinions in this case? 3 A. I believe so, yes. 4 Q. Okay. I want to refer again to Exhibit 5 2. Can you identify this for the record? 6 A. Yes. 7 Q. And what is Exhibit 2? 8 A. It's a list of cases that I've 9 testified in either by deposition or trial testimony 10 from 1992 through the time that I submitted my 11 report, which was in September 1995. 12 Q. Okay. Is this a complete list of cases 13 from 1992 to the14 A. It's-- they're-- I have given, I 15 believe, two depositions since then. It is complete, 16 as I recall, up until September 1995. 17 Q. And that was the last case listed as 18 Lavender V. Miles? 19 A. Yes. 20 Q. What cases were you involved in 21 subsequent to Lavender? 22 A. I have given a deposition in a case 23 called Poston V. Monsanto. 24 Q. Is it P-o-s-t-e-n? 25 A. It o-n, I believe. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 7 1 Q. When was that deposition? 2 A. It may be-- that was given I believe3 it was either late 1:95 or early January. I think it 4 was late 1995. 5 Q. And what's the jurisdiction of that 6 case? 7 A. Texas. 8 Q. Is it in U.S. District Court? 9 A. I believe it was state court, 10 Galveston. 11 Q. And do you know who the attorneys are 12 in the case? 13 A. The case is settled. It's no longer 14 pending. The attorneys were Jeffrey Kilgore15 Q. He was the attorney for the plaintiff? 16 A. Plaintiff. And-- let's see-- I believe 17 it was Robert Jones. 18 Q. Was the attorney for Monsanto? 19 A. Yes. 20 Q. Were you working for Monsanto in that 21 case? 22 A. Yes. 23 Q. Do you have information on you today as 24 to the phone numbers or addresses for Jeffrey 25 Kilgore? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 8 1 A. No. 2 Q. Would you have that in your office? 3 A. No, not to my knowledge. 4 Q. Would you have the case number5 A. No. 6 Q. -- of the case? 7 A. No. 8 Q. You know when it settled? 9 A. I believe it was December 1995. I'm 10 not positive though. 11 Q. Okay. Did that case involve exposure 12 to benzene? 13 A. Yes. That was the allegation. 14 Q. What type of exposure was it? 15 A. Occupational. 16 Q. Do you know what the levels alleged 17 were? 18 A. No. I don't recall. 19 Q. Did you prepare a report in that case, 20 as you have in this case? 21 A. I believe so. 22 Q. Do you recall what the disease 23 manifested by the plaintiff was in the case? 24 A. It was multiple myeloma. 25 Q. Were there any other chemical exposures AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 9 1 other than benzene? 2 A. I don't recall the specific 3 allegations. I believe benzene was certainly the 4 major chemical that was at issue in the case. 5 Q. Where was the plant where the exposure 6 occurred? 7 A. I don't recall. It would be Texas. 8 Q. Okay. Texas refinery? 9 A. I'm not sure it was a refinery. It may 10 have been. 11 Q. Okay. And other than the Poston Versus 12 Monsanto case, have there been any others? 13 A. Testified in a case called McFarland. 14 Q. McFarland is the plaintiff? 15 A. Was the plaintiff. The defendants in 16 that case were a group of insurance companies. 17 Q. Do you know the name of the group? 18 A. I think Hartford was one of them. 19 Q. Did that case involve a chemical 20 exposure? 21 A. The allegation was benzene again, and 22 the disease was multiple myeloma. 23 Q. What type of exposure? 24 A. Again, I don't recall. Basically my 25 testimony in both of these .cases dealt primarily with AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 10 1 causation, and the exposures were not as important to 2 my opinion as the nature of the disease. 3 Q. Your opinion was that benzene does not 4 cause multiple myeloma? 5 A. That's correct. 6 Q. Under any set of circumstances? 7 A. Under any set of circumstances. 8 Q. When did you testify in that case? 9 A. It was over the same period, so it was 10 in the late-- it was the fall or winter of 1995. 11 Q. And where is that case pending? 12 A. I believe again that case is settled. 13 It was-- I believe it was set in Calcasieu Parish, 14 Louisiana. 15 Q. And do you know who the plaintiff's 16 attorney was? 17 A. Herschel Hobson. 18 Q. Hobson? 19 A. Hobson. 20 Q. Do you know where his office is? 21 A. I know. I'm blanking. East of 22 Houston. 23 Q. His office is in Texas? 24 A. Yes. Lubbock. Lubbock, Texas. 25 Q. And the defendant's attorneys. AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 11 1 A. Jeffrey Balfour. 2 Q. Is he in Louisiana or Texas? 3 A. Take Charles. 4 Q. Was it federal court or state court? 5 A. The state court. 6 Q. Do you know the case number? 7 A. No. 8 Q. Was it in Lake Charles court? 9 A. It never got to court, so I don't 10 recall specifically where it was set. I do believe 11 it was in Calcasieu Parish. I recall that. 12 Q. Which parish? 13 A. Calcasieu. 14 Q. Okay. Do you know where the exposure 15 occurred in that case? 16 A. I don't recall the specifics at this 17 time. 18 Q. Other than those two, are there any 19 other additional cases? 20 A. Those are the only cases that I've 21 testified in since the time of this report. 22 Q. Do you have the information I've been 23 asking you about those cases with regard to the 24 attorneys' names and where the cases were pending? 25 Do you have that information for the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 12 1 cases listed on Exhibit 2? 2 A. In certain-- in some cases, yes; in 3 some cases, no. This was constructed from memory, 4 and I don't have complete information on all of 5 them. I have no case number information. on any of 6 them. 7 Q. Okay. Would you mind getting what 8 information you have that's responsive to this 9 paragraph 11 of the deposition notice with regard to 10 those other cases? 11 A. To the extent that I can recall that, I 12 can do that. 13 Q. Okay. Thanks. I have a question on 14 paragraph 14 of the deposition notice. Have you been 15 consulted or are you working on any case involving 16 myelodysplastic syndrome? 17 A. Yes, I am. 18 Q. Where is that case pending? 19 A. Beaumont, Texas. 20 Q. Are you working for the plaintiff or 21 the defendant? 22 A. Defendant. 23 Q. Who is the defendant? 24 A. It's a group of defendants. I'm not 25 sure I can name to you who the companies are. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 13 1 Q. Is it a benzene exposure case? 2 A. That's the allegation. I've seen no 3 information that would lead me to believe that there 4 was any exposure to benzene. 5 Q. The allegation, though, is the 6 chemical7 A. Yes. 8 Q. -- involved in the case is benzene? 9 A. Yes. 10 Q. And the disease alleged is which one of 11 the four listed? 12 A. It's a refractory anemia. 13 Q. Simple refractory anemia? 14 A. Yes. 15 Q. Which would also be myelodysplastic 16 syndrome; right? 17 A. Refractory anemia is included within 18 the broader rubric of myelodysplastic syndrome. 19 Q. Okay. Was this an occupational 20 exposure? 21 A. That's the allegation. 22 Q. Okay. Do you know who the plaintiff's 23 attorney is? 24 A. Herschel Hobson. 25 Q. Have you rendered an opinion in that AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 14 1 case? 2 A. Yes. 3 Q. Have you issued a written report? 4 A. Yes. 5 Q. And has that been provided to the 6 plaintiff's attorney? 7 A. To my knowledge. I don't have any 8 direct knowledge of that. 9 Q. Has suit been filed? I guess it has. 10 A. Pardon? 11 Q. Suit has been filed in this case? 12 A. Yes. 13 Q. Is it pending in Texas? 14 A. Yes. 15 Q. In Beaumont, Texas? 16 A. Yes. 17 Q. State or federal court? 18 A. State, I believe. 19 Q. And I take it you haven't given any 20 testimony yet in that case? 21 A. No. 22 Q. Other than that case and this case, 23 have you been asked to give an opinion as to the 24 cause of myelodysplastic syndrome in any litigation? 25 A. I don't believe so. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 15 1 Q. And in the Beaumont, in the case we've 2 just been talking about, you know the plaintiff's 3 name? 4 A. Castro. 5 Q. And the defendant is a group of 6 companies? 7 A. I believe so. 8 Q. Is it insurance companies or9 A. I believe it's chemical companies. 10 Q. And in that case I take it your opinion 11 is that there was no exposure? 12 A. That's an oversimplification of my 13 opinion. My opinion essentially is that the presence 14 of refractory anemia in and of itself does not 15 constitute evidence of exposure to benzene. 16 Q. What would constitute evidence of 17 exposure to benzene? 18 A. Well, it would depend on-- in an 19 occupational setting one has industrial hygiene data 20 or information relative to the amount of benzene that 21 is available, the opportunity for exposure, the 22 potential concentration of benzene, the use of 23 benzene, and an itemization of the conditions under 24 which it's used, whether or not the individual used 25 protective equipment. A variety of issues relate to AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 16 1 the potential for exposure. 2 Q. I take it then that, if there was 3 evidence of an exposure, would refractory anemia be 4 evidence of benzene toxicity? 5 A. If there was sufficient exposure to 6 benzene in a chronic environment to induce bone 7 marrow injury, one would not expect to see a simple 8 refractory anemia per se, but refractory anemia would 9 be among the constellation of effects that you might 10 expect from chronic exposure to high levels of 11 benzene. 12 Q. Other than the cases we've been 13 discussing, are there any others that you haven't 14 mentioned that you've been involved with since '92? 15 A. To the best of my recollection this 16 list is complete, but it may not be. As I said, it 17 was constructed from memory. I believe it's 18 essentially complete. 19 Q. Okay. In any of the cases in Exhibit 20 2, did you testify on behalf of the plaintiff? 21 A. Yes. 22 Q. Which one? 23 A. Anschultz Versus National 24 Semiconductor. 25 Q. What was the issue in that case? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 17 1 A. It was lead. 2 Q. Lead poisoning? 3 A. Lead environmental contamination. 4 Q. On all the others have you testified on 5 behalf of defendants? 6 A. That's correct. 7 Q. Are these defendants all either 8 petroleum companies or chemical manufacturers? 9 A. KNE Energy is a utility company. 10 Q. What was the allegation in that case? 11 A. Environmental contamination. 12 Q. From what? 13 A. Benzene. 14 Q. What was the disease in that case? 15 A. That's a very good question. It was a 16 community. There were two hundred plaintiffs. To 17 the best of my recollection there were no cancers and 18 leukemias in the group. 19 Q. Was there any other evidence of bone 20 marrow toxicity in the group? 21 A. No. 22 Q. There was no blood dyscrasias? 23 A. No. 24 Q. No myelodysplastic syndromes? 25 A. No. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 18 1 Q. Other than in KNE Energy, are the rest 2 of the companies either chemical manufacturers or 3 petroleum-related industries? 4 A. I believe so. 5 Q. How many of the other cases involve 6 benzene as an element of the cause of action? 7 A. Seven or eight. 8 Q. I guess I should ask you to identify 9 the cases rather than just count them. Which ones 10 involve benzene exposure? 11 A. Albertson. 12 Q. What type of exposure did Albertson 13 involve? 14 A. The allegation was ground water 15 contamination. 16 Q. From what? 17 A. From a regional distribution site. 18 Q. Was this a regional petroleum product? 19 A. No. Natural gas. 20 Q. Was there just one plaintiff or 21 multiple plaintiffs? 22 A. It was a group of plaintiffs. 23 Q. Do you know what the diseases alleged 24 were? 25 A. No. As I said before, it was a large AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 19 1 list of miscellaneous. 2 Q. I'm sorry. Is that the same-- is that 3 the-- oh, that's the same case we just discussed. I 4 didn't realize that. I'm sorry. 5 A. Yes. 6 Q. What's the next one that involved a 7 benzene exposure? 8 A. LeBlanc Versus City Services. 9 Q. Was that an occupational exposure? 10 A. Yes. 11 Q. And what type of disease occurred in 12 that case? 13 A. I believe it was a-- there were a 14 couple of plaintiffs in that case. I believe it was 15 multiple myeloma and a non-Hodgkin's lymphoma. 16 Q. Okay. What do you have next? 17 A. Choate Versus Amoco. 18 Q. What type of exposure did that involve? 19 A. Occupational exposure. 20 Q. What was the disease? 21 A. Multiple myeloma. 22 Q. Is that case in Texas also? 23 A. Yes. 24 Q. You remember who the plaintiff's 25 attorney was? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 20 1 A. I think it was Jeffrey Kilgore. 2 Q. And which case is next on the list that 3 was a benzene exposure allegation? 4 A. Dendinger Versus Kaneb Pipeline. 5 Q. What type of exposure was that? 6 A. It was a gasoline storage container 7 underground leak. I believe the allegation was 8 benzene. It was a property case. 9 Q. Do you remember the disease in that 10 case? 11 A. I don't believe there were any. 12 Q. Okay. Were the plaintiffs alleging 13 benzene exposure and a disease? 14 A. I believe benzene was the principal 15 compound in the complaint, but gasoline was the 16 substance that was at issue. 17 Q. Benzene is contained in gasoline, 18 right? 19 A. Pardon? 20 Q. Benzene is contained in gasoline; is 21 that correct? 22 A. There are trace amounts of benzene in 23 gasoline. 24 Q. What is a trace amount? 25 A. A very small amount. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 21 1 Q. Is there a number which is in your mind 2 when you say trace amount or a range? 3 A. In the United States today, on average 4 you're looking at somewhere between a fraction of a 5 percent and maybe as much as two percent. 6 Q. So up to two percent would be 7 considered trace? 8 A. With respect to the potential for 9 contamination or exposure to benzene, yes, I would 10 call that trace. 11 Q. Is that a standard that is set in terms 12 of petroleum products by any organization? 13 A. Pardon? I don't understand the 14 question. 15 Q. Is there a level placed on how much 16 benzene can be in gasoline? 17 A. I think in general the focus is on 18 minimizing the amount of benzene that's present in 19 gasoline. So it's usually much less than two 20 percent. In Europe it tends to be more. 21 Q. What would it be called if it was five 22 percent in terms of the amount? 23 A. If it was five percent or greater, five 24 percent is often arbitrarily used as a benchmark with 25 respect to a product having a significant amount of AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 22 1 benzene, certainly as a solvent. Generally levels 2 below five percent do not tend to pose a significant 3 hazard with respect to transient exposure to the 4 product, certainly in the atmosphere, as far as 5 benzene is concerned. Below that the exposure to 6 benzene is minimal. 7 Q. Below five percent? 8 A. Usually, yes. 9 Q. So would anything under five percent be 10 considered trace? 11 A. The term "trace,, refers to, in strict 12 terminology, the measurement of small amounts of the 13 substance. With respect to the amounts of benzene 14 that are normally found in the air, using gasoline 15 products of two percent or less, the amounts that are 16 present are usually one part per million or less in 17 the air. 18 Q. In the air, in a workplace; is that 19 what you're referring to? 20 A. Yes. 21 Q. You're not referring to the air22 A. Well, with gasoline I'm talking about 23 conditions under which you will normally be pumping 24 it, such as when you fill your tank at a gas station. 25 Q. Okay. So even in an outdoor space, AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 23 1 you're saying it would be one part per million? 2 A. Within the breathing range of an 3 individual pumping gas, one part per million is 4 certainly what the EPA calculates as the average 5 potential exposure to benzene in the pumping of gas. 6 Q. And has that been determined with 7 regard to this trace amount that you've been 8 referring to? 9 A. I don't understand the question. 10 Q. If the product has two percent or less 11 of benzene in it, the gasoline, would that-- is it 12 your understanding that that's been calculated to 13 result in an ambient air level of one part per 14 million? 15 A. It isn't calculated. What I'm saying 16 is, when the EPA has measured the amount of benzene 17 in the air in and around, in the vicinity of 18 individuals pumping gasoline, that that is the level 19 that they see normally associated with that 20 operation. It's not a calculation per se. 21 Q. Have they published these findings? 22 A. Oh, yes. 23 Q. Where are they published? 24 A. Several places. I believe one of the 25 articles I brought refers to that. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 24 1 Q. Do you know -he name of the article? 2 A. It's by a min named Wallace, Lance 3 Wallace. 4 Q. Was it one of the articles you attached 5 or you referenced in your report? 6 A. Yes. 7 Q. You don't need to get it out. Is the 8 term "trace amount," is there an industry or commonly 9 accepted understanding of that term in the industry? 10 A. "Trace" is a term that is used by 11 analytic chemists or toxicologists usually to refer 12 to detectable but unquantifiable amounts of a 13 substance in another. That's the-- that is in fact 14 the precise definition of "trace". 15 Q. What does "unquantifiable" mean? 16 A. It means that the levels are not 17 determinable based upon the sensitivity of the method 18 accurately enough to place a number on them. 19 Q. I suppose then that one percent, that 20 would be a number21 A. When I first used the term "trace," I 22 was using it loosely. I was not using it to refer to 23 a technical or specific definition. I was using it 24 to refer to small amounts of a substance in another. 25 Our discussion so far has focused on AVERY/WOODS REPORTING SERVICE, !NC. (303) 825-6119 25 1 solvents, gasoline being a mixture of solvents. In a 2 solvent mix, the percents we're talking about 3 represent a small amount of benzene in that product. 4 I don't think it is technically accurate to refer to 5 it as trace if you're talking about trace as an 6 analytical term. 7 Q. Okay. So the strict definition of 8 "trace" would appear as an analytical, chemical 9 word, or toxicological word and would refer to those 10 amounts that you can detect but can't measure? 11 A. In a very strict sense, yes, but the 12 word "trace" is also used in other contexts. For 13 instance, "trace element" is used repeatedly to refer 14 to small amounts of elements that are present in the 15 diet and in the atmosphere and elsewhere. And in 16 most of those cases, in many of those cases, you can 17 accurately measure the amounts that are there. 18 So it is used often to refer to small 19 amounts of a substance which, if we're talking about 20 its strict definition in an analytical sense, it 21 means something you can detect, cannot accurately 22 quantify. 23 Q. Okay. The way you just described, who 24 uses the term in that way? What group of 25 professionals would use it in that way? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 26 1 A. Toxicologists, analytical chemists, 2 environmental chemists. 3 Q. I'm not talking about the strict 4 definition. 5 A. Oh, virtually anybody involved in 6 environmental health or toxicology or nutrition. 7 Q. Okay. And the use of the word in that 8 manner does not connote an actual percentage level 9 that one would expect to find? 10 A. No. 11 Q. We're still on your list. Any other 12 cases involve benzene exposure, Exhibit 2? 13 A. I believe Salazar Versus Ecolab was a 14 benzene allegation. 15 Q. What was the exposure? 16 A. I believe it was occupational. 17 Q. Did you know what the disease was? 18 A. Chronic myelogenous leukemia. 19 Q. Do you remember what the exposure level 20 was? 21 A. No. 22 Q. Where was that case pending? 23 A. Texas. 24 Q. Do you recall who the attorney was? 25 A. No. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 27 1 Q. Do you know where in Texas? 2 A. No. 3 Q. Was it in the Beaumont area or4 A. I don't believe so. 5 Q. Okay. And any other benzene-related 6 cases? 7 A. Taylor Versus Gulf may be a benzene 8 exposure case, but I don't remember anything about 9 it. 10 Q. You just remember that you testified in 11 it? 12 A. I gave a deposition in that case. I 13 don't remember who was involved or what the issues 14 were. 15 Q. Okay. 16 A. Guidry Versus SmithKline, the 17 allegation was benzene exposure. 18 Q. Okay. Have you testified in any other 19 cases for SmithKline Beecham other than Guidry in 20 this case? 21 A. No. 22 Q. Have you been consulted on any others 23 for SmithKline Beecham? 24 A. I believe I have. 25 Q. Do you recall which ones? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 28 1 A. A case called Cavanaugh. 2 Q. Were you retained as an expert in 3 Cavanaugh? 4 A. I believe so, yes. 5 Q. But you didn't give testimony? 6 A. No. 7 Q. Have you ever worked for-- other than 8 those three cases, have you ever done work for 9 SmithKline Beecham before? 10 A. I don't believe so. I don't believe 11 so. Certainly with respect to litigation I don't 12 believe so. 13 Q. You may have done some consulting work 14 with them though? 15 A. I don't think I have. I don't think 16 SmithKline is a pharmaceutical company that I've 17 consulted for. 18 Q. Have you ever done any work for Mr. 19 Whitney's law firm before? 20 A. No. 21 Q. For any lawyers from Mr. Whitney's law 22 firm? 23 A. I don't believe so. 24 Q. Any other benzene cases on the list? I 25 know we're getting towards the end there. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 29 1 A. Lavender Versus Miles. 2 Q. What kind of exposure was that? 3 A. it's occupational exposure. 4 Q. Have you testified in trial in that 5 case? 6 A. No. 7 Q. Is there a trial date set in Lavender? 8 A. No. 9 Q. Do you know what the disease was? 10 A. It's leukemia. 11 Q. What type of leukemia? 12 A. Myelogenous, acute myelogenous. 13 Q. AML? 14 A. I believe so. 15 Q. Is AML considered to be one of the 16 leukemias that is caused by benzene exposure? 17 A. Certain subtypes of AML can be 18 associated with benzene exposure. That's correct. 19 Q. What types of20 A. Using the FAB classification, usually 21 you're talking M1, M2. 22 Q. What is M1 and M2? 23 A. Mi would be acute myelodysplastic 24 leukemia. M2 would be acute myelodysplastic leukemia 25 with maturation. M4 would be myelomonocytic. M5, AVERY/WOODS REPORTING SERVICE, INC, (303) 825-6119 30 1 rarely, if at all, would be monocyzic. M6 is 2 erythroleukemia that has been associated with benzene 3 exposure. M7 is basically, in the older terminolcgy, 4 a myelofibrosis. 5 The information available on 6 myelofibrosis is so scant one cannot say one way or 7 the other, not only the morphologic subtype but also 8 the cytogenetic subreport in evaluating the potential 9 for causation associated with benzene, especially 10 when you don't have-- when you either have evidence 11 that does not suggest exposure or you have virtually 12 no evidence of exposure. 13 Q. In what way are they cytogenetic? 14 A. (No audible response.) 15 Q. In what way are these cytogenetics 16 important in an analysis of whether AML is caused by 17 benzene exposure? 18 A. Secondary leukemias-- by that I mean 19 leukemias that are the result of exposure to 20 chemotherapeutic agents, radiation, or cohorts of 21 which the only known cause is benzene present with a 22 different pattern of distribution of abnormalities 23 than one sees in de novo leukemias or those arising 24 spontaneously with no previous history of exposure to 25 benzene or chemotherapeutic agents. AVERY/WOODS REPORTING SERVICE, INC. (303", 825-6119 31 1 Q. Are these cytogenetic abnormalities, 2 chemotherapy, and benzene similar? 3 A. Yes. Yes, they are. Their use with 4 respect to evocation is based upon differences in the 5 pattern or incidence of their involvement in 6 different leukemias that we're discussing. For 7 example, if one looks at demonstrably clonal 8 chromosomal abnormalities arising in AML, slightly 9 over half of primary AMLs, de novo AMLs, will possess 10 cytogenetic abnormality. Arguably, ninety-five 11 percent or greater of secondary AMLs will possess an 12 abnormality. 13 Q. So if, in fact, you have an AML, is the 14 issue-- is it more likely than not that that AML is 15 secondary or primary? 16 A. If there are no clonal chromosomal 17 aberrations associated with it, it is more probable 18 than not that it is a primary. 19 Q. The primary being non-exposure cases? 20 A. Yes. 21 Q. And in ninety-five percent of the 22 exposure cases you're finding chromosomal 23 abnormalities? 24 A. (Indicating.) 25 Q. Are these non-random abnormalities? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 32 1 A. They tend to cluster to some extent, 2 actually to a great extent. 3 Q. Where do they cluster? 4 A. Secondary leukemias, secondary AMLs 5 associated with chemotherapy and with occupational 6 exposure, show a very high predisposition for 7 involvement in chromosomes 5 and/or 7. There are 8 also others that are seen, but they're seen with 9 equal frequency in both primary and secondaries. 10 Q. So primarily, when you do an analysis 11 of this, you're looking for cytogenetic abnormalities 12 surrounding chromosome 5 and/or 7? 13 A. Five or 7 certainly. Certainly 5 or 7 14 are seen together to a much greater extent in 15 secondary AMLs than they are in primaries. In 16 secondary AMLs they constitute together about-- it 17 depends on the study, but somewhere between eighty 18 and ninety percent of the secondary AMLs will involve 19 5 and/or 7 together. That's opposed to about 20 fifteen-- ten to fifteen percent of primaries. So it 21 is found with less frequency in primaries than 22 secondaries. 23 Q. Seems like a pretty large difference? 24 A. It's a fairly large difference. 25 Q. Are the abnormalities you find-- what AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 33 1 abnormalities do you find in 5 or 7 in these types of 2 cases? 3 A. Seven usually-- one either finds the 4 loss of all or part of the chromosomes or both of 5 them, one set. You almost never-- well, it would be 6 incompatible with the life of a cell to lack both 7 chromosomes, both 5's or both 7's, but one will see 8 loss of 5, loss of 7, 5q-, which means loss of the 9 long arm of 5, or 7q-, loss of the long arm of 7. In 10 the case of 5, it's almost always an interstitial 11 lesion if it's a loss of part of the chromosome. 12 Q. "Interstitial" meaning part of the long 13 arm? 14 A. Yes. A specific region of the long arm. 15 Q. Which region is usually found? 16 A. 5q31 is the region that appears to be 17 missing in the vast majority of cases. 18 Q. 5q31; 31 is a specific point? 19 A. Yes. 20 Q. On the arm? 21 A. Yes. 22 Q. And the range of deletion encompasses 23 that point; is that24 A. Yes. 25 Q. Is there a range of deletion that you AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 34 1 find? 2 A. Oh, there's a wide range. One of the 3 manuscripts I brought of mine reviews some of the 4 recent studies conducted at the University of Chicago 5 on that. One sees varying deletions from one case of 6 AML to another. 7 But, if one looks at where they 8 overlap, they overlap specifically in the region of 9 5q31. So that is the area that is deleted in 10 virtually every case. But the range of deletions 11 would vary depending on the individual. 12 Q. If you saw an individual with one of 13 these deletions you've just described with AML, and 14 there was evidence of benzene exposure, would your 15 opinion, given those simple parameters, be more 16 probably than not that it was caused by the benzene 17 exposure? 18 A. If there was evidence of significant 19 chronic benzene exposure, and you have an AML that 20 with respect to its presentation and criteria fits 21 the category for a secondary AML, the presence of 22 clonal lesion of 5q or 5- would provide fairly strong 23 evidence that there was a potential relationship. 24 Basically what it says is that, if you 25 have the parameters necessary to establish a link AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 35 1 between exposure to high levels of benzene or any 2 other chemotherapeutic agent and AML that evolves 3 with lesions that include 5, that is a pattern that 4 you expect to see in the secondary leukemia. 5 Q. The leukemias, you've mentioned the 6 subtypes of AML as being evidence that they're caused 7 by benzene exposure or that they can be caused by 8 benzene exposure. Is that evidence primarily 9 epidemiological studies? 10 A. The evidence associated with secondary 11 leukemia transcends the epidemiology that we have 12 available on benzene per se. Certainly there are 13 some collections of case reports and clinical 14 presentations that provide description of the types 15 of leukemias that have been seen in benzene. 16 Although the studies aren't quantitative, they are 17 generally consistent with what's been seen in the 18 quantitative retrospective epidemiology that we have 19 on benzene and in the cell specific epidemology that 20 we have associated with benzene. 21 In addition to that, and I think just 22 as important, we have a much larger literature that 23 pertains to secondary leukemia associated with 24 chemotherapy, in which we have a much larger base of 25 information to characterize the biology of secondary AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 36 1 leukemias. Since leukemias are similar, if not 2 identical, it provides a useful data base and 3 literature for studying mechanisms of secondary 4 leukemogenesis. 5 Q. The leukemias are similar, if not 6 identical, in chemotherapy-related or treated 7 leukemia? 8 A. Yes. 9 Q. And mutagenic or benzene-caused 10 leukemia? 11 A. Yes. 12 Q. Correction. We won't use the mutagenic 13 part of the question. We'll just leave it at 14 benzene. 15 A. Benzene is not a mutagen. If what 16 you're asking me is does benzene-induced leukemia fit 17 a pattern that's consistent with what we see as 18 alkylating agents, the answer is certainly. From 19 what we know today the answer is yes. There are 20 still some questions remaining to be answered that 21 really relate to the weakness of the occupational 22 literature in relation to benzene exposure, but in 23 general it fits certainly and is consistent with what 24 we see following chemotherapy. 25 Q. Would you consider the lesions in both AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 37 1 instances to be similar? 2 A. Certainly with respect to the molecular 3 lesions that are seen, yes. 4 Q. When you say "molecular," do you mean 5 the lesions occurring in the stem cell? 6 A. Lesions associated with chromosomes and 7 with the genes that are involved and the processes 8 that are involved that are associated with the 9 regulation of growth and differentiation in blood 10 cells. 11 Q. That would be the same for both types 12 of the disease process? 13 A. I believe the literature supports that, 14 and certainly our own research supports that. 15 Q. Okay. The epidemiology that you're 16 referring to, I guess you were indicating that there 17 are case reports, clinical reports, in addition to 18 the epidemiological reports which all support the 19 notion that AML and the variants that you've 20 identified can be caused by benzene exposure. Is 21 that22 A. In general, yes. The specific variants 23 that are associated with secondary AML and 24 chemotherapy are much better defined in the sense 25 that we have many more cases. That is consistent AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 38 1 with what I've just described. In general, what's 2 seen in occupationally exposed populations with 3 benzene is consistent with that. 4 Q. Are you referring to the 5 epidemiological reports? 6 A. I'm referring to both. The 7 epidemiological reports, as I mentioned before, do 8 not tend to provide you with as much detail on the 9 FAB subtypes as do the clinical or the case 10 collections. 11 Q. Why is that? 12 A. Well, the epidemiolgists have tended to 13 lump things as opposed to separate them, primarily 14 because it increases the power of their studies. If 15 one is interested in causation hematology or biology, 16 lumping is a very frustrating and uninformative 17 behavior, because you can't distinguish one tumor 18 type from another. 19 Recently, studies are attempting to 20 analyze these data sets using specific information. 21 That information allows us to look at specific 22 leukemia type. We do not have quantitative 23 information from epidemiological studies that allows 24 us to go through the various subtypes and distinguish 25 one from another with that degree of resolution. AVERY/WOODS REPORTING SERVICE, INC. (303) 82S-6119 39 1 Q. Is that partially due to the fact that 2 most of these epidemiological studies are mortality 3 studies? 4 A. The only-- I would say that question 5 is-- if I answer yes to that, it's overly broad. One 6 characteristic of mortality studies is that you're 7 dealing with death certificates, which are obviously 8 a fairly-- they're certainly-- they're reliable in 9 the sense that they deal with mortality and you have 10 a very specific input. Where they're not generally 11 reliable is for a diagnosis at a level such as we're 12 talking about. You're not often going to find a 13 death certificate that says AML, FAB subtype M2. 14 You'll see-- if you're lucky, it'll say AML. If 15 you're not, it'll say leukemia. 16 So you are correct in assuming that an 17 epidemiological study that uses mortality can often 18 distinguish a leukemia class such as a CML or an AML, 19 where it may be less useful in distinguishing the 20 incidence of subtypes. That's where, as I said 21 before, some of the collected case information is 22 useful, even if it's not quantitative, because it 23 gives you some idea of what the prevailing types are 24 that have been seen. 25 And one can also look at, as I said, AVERY/WOODS REPORTING- SERVICE, INC. (303) 825-5119 40 1 the literature on secondary leukemias associated with 2 chemotherapy, where you see a very strong and 3 consistent patter, and it's consistent with what we 4 have seen with respect to benzene. 5 Q. The death certificates also, I take it, 6 would not show any kind of preexisting bone marrow 7 toxicity condition that preexisted the AML or 8 leukemias? 9 A. Not-- not necessarily. Not usually. 10 You may have a secondary condition that's listed on a 11 death certificate, but that's not always the case. 12 Q. Are most secondary leukemias preceded 13 by a myelodysplastic syndrome? 14 A. Myelodysplastic syndrome is a frequent 15 precursor to the frank development or clinical 16 development of AML secondary to exposure to 17 chemotherapeutic agents or benzene. Probably, 18 depending on the study, myelodysplastic syndrome 19 which used to go by the old rubric "preleukemia," 20 preleukemia is included in that broader definition of 21 myelodysplastic syndrome, forty to sixty percent, 22 depending upon the study. Some people think it's 23 higher. So when you say the majority of cases, I 24 would say probably the majority of cases. 25 Q. Is it your opinion that virtually all AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 41 1 the cases of benzene-induced AML are preceded by a 2 myelodysplastic syndrome if the data is available on 3 those cases? 4 A. I would not be at all surprised to find 5 the vast majority to have evidence of trilineage 6 dysplasia, certainly some preceded by 7 thrombocytopenia or lymphocytopenia leading to a 8 trilineage dysplasia, and that evolving into frank 9 AML, and that falls into the broader context of 10 myelodysplastic syndrome. I would not be surprised 11 at all to see that as the principal pattern that you 12 would see in a benzene-induced leukemia. 13 Q. Were you saying trilineage? 14 A. Yes. 15 Q. What did you mean by that? 16 A. Involvement of at least three of the 17 major lineages of blood cells, which is one of the 18 criteria that one often sees. 19 Myelodysplastic syndrome is a 20 relatively new term in that it became an officially 21 accepted rubric, if you will, in the early '80s to 22 cover a wide range of phenomena, some of which are 23 related, some of which aren't, that are associated 24 with dysplasias in the blood, blood-forming organs. 25 Trilineage dysplasia is one of the AVERY/WOODS REPORTING SERVICE, INC. (303? 825-5119 42 1 criteria that is often used to describe a persistent 2 myelodysplasia associated with preleukemia, and it's 3 included within the definition of myelodysplastic 4 syndrome for some of the categories. 5 Q. I take it then that the three major 6 blood cells would be the platelets, white blood 7 cells, and red blood cells? 8 A. There are certainly different lineages 9 of cells, and you can break them down into different 10 categories depending on what you're interested in. 11 From the standpoint of the lineages 12 that are involved when we talk about a trilineage 13 dysplasia, we're talking about red cells, we're 14 talking about platelets, we're talking about 15 granulocytes, we're talking about lymphocytes. Those 16 would be the major cell types that would be involved 17 when we are talking about a trilineage dysplasia. 18 Q. Granulocytes and lymphocytes are white 19 blood cells; is that right? 20 A. Yes. 21 Q. When you were discussing the q 22 associated with AMLs, the leukemias, as being an 23 indicator of potential benzene exposure for toxicity, 24 is that something that you've learned through 25 literature review? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 43 1 A. I wouldn't call it an indicator of 2 benzene toxicity. It is certainly a frequently 3 observed abnormality in the context of secondary 4 leukemogenesis and myelodysplastic syndrome that's 5 associated with secondary leukemogenesis. 6 Q. Is that supported by the literature? 7 A. It's supported by the literature in 8 secondary leukemogenesis, associated chemotherapy. 9 There is no direct evidence that in fact benzene 10 directly is associated with it, but I believe it to 11 be so. In an occupational setting where you have 12 exposure to solvents where benzene is the only 13 leukemogen, you do see an increased frequency of 5q 14 and leukemias that evolve in those individuals. 15 Q. When you said "direct evidence," what 16 would that constitute? 17 A. Where benzene was, as part of the 18 study, reliably demonstrated to be what the 19 exposure-- what the agent was. In other words, 20 studies that have looked at the involvement of 21 cytogenetic aberrations in secondary AML tend to have 22 fairly weak exposure characterization and use 23 occupation or questionnaires as a surrogate for any 24 information on what the exposure really was. 25 Basically the weakest exposure data is AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 44 1 associated with studies that have the strongest 2 cytogenetic information, whereas the stronger data is 3 associated with studies that don't. So you can argue 4 that the evidence for a direct role of benzene in 5q 5 associated AML isn't there, but I do believe that it 6 is. And certainly other experimental studies denote 7 that benzene metabolites are capable of inducing 8 aberration as well as several others. 9 Q. And your opinion is based on your own 10 experimental studies? 11 A. To a certain degree, yes. 12 Q. And any other studies that your opinion 13 is based on? 14 A. Yes. Those studies I mentioned with 15 respect to solvent exposure and secondary AML as well 16 as the prevailing pattern that's seen in the 17 chemotherapeutic literature associated with secondary 18 AML. 19 Q. Did you bring those articles with you 20 today? 21 A. Some of them I did, yes. 22 Q. Which ones did you bring that support 23 that view? 24 A. (No audible response.) 25 Q. Are these articles listed on your-AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 45 1 A. They're listed in-- I have a reference 2 list for the articles that I brought today. 3 Q. Okay. 4 A. Probably the most expeditious way of 5 doing this would be to look at two manuscripts I 6 brought with me that I recently authored, because 7 they summarize that data. 8 MR. WILLIAMS: Okay. Why don't we do 9 this-- I need to make a quick phone call-- take a 10 quick break. 11 (Whereupon, at 11:09 a.m., a recess was 12 taken.) 13 A. The vast majority of articles I brought 14 today deal with 5q- syndrome, which is a totally 15 separate entity than what we've been talking about. 16 And so that's what most of them deal with. 17 There are a couple of articles I have 18 written recently that summarize the secondary 19 myelodysplastic syndrome and leukemia literature, and 20 those are in here as well, and there are extensive 21 summarizes of that literature base. I did not bring 22 all that literature, because I-- my opinion deals 23 with the issue of 5q- syndrome and not secondary 24 leukemia in this case. 25 The two articles that summarize this AVERY/WOODS REPORTING SERVICE, INC. !303) 325-6119 46 1 information: in detail are one that's entitled "The 2 Process of Leukemogenesis" that's in press in 3 Environmental Health Perspectives that I wrote. 4 MR. WHITNEY: Just so the record is 5 clear, we might refer to the article, tab 19. 6 THE DEPONENT: It's tab 19. The other 7 is tab 20, which is a draft of a book chapter that 8 I've completed, again is Leukemogenesis As a Toxic 9 Response. And those summarize the literature both 10 for benzene and for chemotherapeutic agents. 11 Q. (BY MR. WILLIAMS)And those would be 12 responsive to my question about literature-- about 13 benzene causing abnormalities of the fifth 14 chromosome? 15 A. That can be and that is associated with 16 leukemias. Some of the leukemias that are found 17 follow exposure to chemotherapeutic agents or 18 benzene. 19 Q. Those are the two articles you just 20 cited? 21 A. Yes. 22 MR. WILLIAMS: Let me look quickly 23 through your book here. 24 THE DEPONENT: There is a bibliography 25 in the front. AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 47 1 MR. WILLIAMS: Okay. 2 (Whereupon, there was discussion 3 outside the record.) 4 Q. (BY MR. WILLIAMS) I want to mark the 5 whole book as an exhibit, which would be Exhibit 3. 6 In Exhibit 3 there's a reference list of cases. Are 7 these the cases you're-- or the articles-- are these 8 the articles you rely on for your opinions in this 9 case? 10 A. As they are specifically directed to 11 issues that I will present in this case, yes. 12 There's a much larger literature base that I could or 13 will rely upon that deals with other issues related 14 to leukemogenesis, if in fact those particular 15 questions are raised. This is what I had provided in 16 support of my report and my opinions as I understand 17 the issues to be in this case. 18 Q. Okay. I want to ask you some questions 19 about benzene and how it affects bone marrow. Do you 20 agree that benzene causes bone marrow toxicity? 21 A. Benzene can cause bore marrow toxicity 22 if an individual is exposed to high enough 23 concentrations for a long enough period of time. 24 Q. What is bone marrow toxicity? 25 A. Bone marrow is the major organ AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 48 1 associated with production of blood. That includes 2 most of the white cells, certainly the immature -forms 3 of all white cells, red cells, platelets. And 4 toxicity to the bone marrow involves damage to the 5 blood forming cells, either acute or subacute. That 6 means transient damage, reversible damage, or 7 irreversible damage, if in fact the insult is severe 8 enough. 9 That leads to a decrease-- that can 10 lead, in simple terms, to abnormalities in the 11 production of blood cells, a decrease in various 12 types of blood cell formation that results from 13 altered regulation of growth in the bone marrow, or 14 can lead to increase in proliferation in the 15 production of abnormal types of blood cells, as you 16 see in leukemias. 17 Q. How does the lesion occur which causes 18 these various effects? 19 A. (No audible response.) 20 Q. Does a lesion occur? 21 A. Yes. Benzene in and of itself is not 22 toxic to bone marrow. It has to be metabolized. 23 Metabolism is a process of changing it 24 chemically into other compounds. The body has a very 25 extensive system for dealing with chemicals, because AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 49 1 we live in a world of chemicals. Food is made up of 2 chemicals. We're exposed to chemicals every day. And 3 we normally process these, and the body has a means 4 of dealing with them. The overall goal is to 5 eliminate them. 6 We metabolize compounds or change them 7 into other compounds. Usually the strategy that's 8 employed is to make them more soluble so we can 9 excrete them. In the process of doing that, the body 10 converts them to benzene, to phenol, and to 11 polyphenolic molecules, hydroquinone being one of the 12 major polyphenolic molecules. 13 In combination, these molecules, if 14 you're exposed to benzene in high enough 15 concentrations for long enough periods of time, leads 16 to the production of these molecules and their 17 distribution to bone marrow, where they're capable of 18 producing damage to replicating cells primarily. 19 We know that benzene metabolites target 20 cells that are dividing. And the major effects that 21 these compounds have is in altering the process of 22 division and the mechanics of how the cells come 23 apart. 24 There are other changes that also occur 25 that have recently been identified that suggest this AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 50 1 a characteristic of a variety of compounds, including 2 benzene metabolites, is that they alter regulation of 3 differentiation in the stem cell compartments, and 4 therefore make these cells more susceptible to the 5 types of damage that undergo a division. 6 Q. Is it your view that it affects the 7 cell differentiation, the benzene metabolites? 8 A. It's certainly my view. There's 9 demonstrable evidence, both from my standpoint as 10 well as others, to indicate that that's the case. 11 The precise nature of the mechanism of that is not 12 completely understood, and we're rapidly studying it 13 now. 14 Q. Did you bring the hematology study as 15 part of the notebook? And you can identify it by tab 16 number, if you would. 17 A. Some of these studies speak to the 18 issue. A review of it is provided, a simplified 19 review is provided in number 1, dealing with 20 metabolism per se. 21 The role of metabolism is very 22 important in benzene toxicity, and it's requirement 23 in benzene Toxicity is a generally accepted tenet of 24 the field. Tabs 20, 21, 22, 23, 24, 25 deal 25 variously with benzene and the effects of AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 51 1 metabolism. They also reference other papers that 2 deal with the specific mechanisms that I've been 3 discussing. 4 I've recently proposed, for the sake of 5 generating research and discussion, a model, one 6 model for a proposed mechanism for the development of 7 leukemia associated with benzene exposure. And 8 that's summarized in 19 and 20. 9 Q. Are these the two other articles, that 10 you had mentioned? 11 A. Yes. 12 Q. These are the ones going to press now? 13 A. Yes. 14 Q. Just a quick aside. Are these 15 articles, all the other articles that have been 16 published, are they all peer reviewed articles? 17 A. Yes. 18 Q. Is peer review an important concept in 19 evaluating an article? 20 A. Yes. It's not the be all and end all, 21 but it's a very important concept in evaluating a 22 priori the value of an article with respect to being 23 able to rely on its contents. 24 Q. What does peer review mean? 25 A. Peer review is the process of AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 52 1 independent review of the information design, 2 experimentation design, and interpretations proposed 3 in the paper by colleagues that is a part of the 4 publication process that scientific journals require 5 for publishing an article in a given journal. 6 So, if you submit a paper which 7 represents the product of research or evaluation of 8 data to a journal, the editors of the journal will 9 submit it to independent reviewers to ascertain 10 whether or not the collection of data, experimental 11 design, and scientific interpretation of the data 12 that's presented is, in fact, appropriate and valid. 13 And that's one of the major processes for determining 14 suitability for publication. 15 Q. Have the items at tab number 19 and 20 16 been peer reviewed yet? 17 A. Yes. Yes. When I say "in press," that 18 means that they've been accepted for publication. 19 Nineteen is a strict peer reviewed 20 article. Twenty is a book chapter. 21 I am presenting it primarily because it 22 summarizes a lot of the information that we were 23 talking about earlier that I haven't provided. It's 24 been peer reviewed to the extent that it's been 25 reviewed independently by an editor who has deemed it AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 53 1 acceptable. It has not received-- it is a book 2 chapter. It does not have the same weight with 3 respect to peer review as the other individual 4 articles do. 5 The book chapter is useful for 6 summarizing a great deal of information and for 7 obtaining some idea as to what the state of art in a 8 given field is, if you want to determine that. If 9 you want to rely on something for reaching a 10 scientific opinion, it's much more preferable to then 11 go to the primary literature on which the chapter is 12 based and review it yourself to determine whether or 13 not the information that is summarized is in fact14 conclusions of the author are valid. So book 15 chapters are useful. But they are secondary sources 16 of information, not primary. 17 Q. Okay. Back to the discussion we were 18 having on metabolism. Is there more than one step 19 involved in metabolism? 20 A. (No audible response.) 21 Q. Does metabolism occur more than once 22 with regard to benzene? 23 A. Yes. Yes. Primary metabolism occurs 24 in the liver. That results in the production of 25 phenol. It results in the secondary production of AVERY/WOODS REPORTING SERVICE, INC: (303) 825-6119 54 1 hydroquinone, some polyphenolic molecules. These are 2 then subjected to further metabolism in different 3 organs. 4 In bone marrow, myself and my 5 laboratory and others have demonstrated, as a 6 characteristic of the cells, that cells that are the 7 precursors for development of acute myelogenous 8 leukemia, the leukoprogenitor cells, have a 9 particular pattern of metabolic capability that makes 10 them susceptible to further toxicity by being able to 11 further metabolize in particular the quinones to 12 toxic molecules that are capable of interfering with 13 cell division by binding to microtubles and the 14 spindles that are associated with pulling the 15 chromosomes apart during division. 16 Q. Is there a-- what occurs in bone marrow 17 if there is an interruption of cell differentiation 18 by the benzene metabolites? 19 A. Benzene metabolites appear to 20 facilitate or increase differentiation down the myelo 21 pathway, and what we think this is associated with is 22 an increase in proliferation in the compartment of 23 cells that are, in fact, the ultimate targets for the 24 development of acute myelogenous leukemia. And 25 anything that increases replication in a target cell AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 55 1 population presents a potential risk with respect to 2 a permanent genetic alteration, in this case 3 aneuploidy. 4 The first evidence that has been 5 associated with the evolution of leukemogenesis and 6 secondary leukemia involves the loss of all or part 7 of a chromosome. That's the first permanent event. 8 It's not the first event in the process. There are 9 then any number of subsequent events that have to 10 occur that are independent before even one gets to 11 either myelodysplastic syndrome or to leukemia. But 12 it's certainly the first event that has been 13 documented to occur. 14 Q. Aneuploidy? 15 A. Yes. 16 Q. Is there a clonal aberration that 17 occurs in the metabolic process? 18 A. The metabolic process can lead to a 19 clonal aberration. That is basically the premise on 20 which the model that we proposed is based. As I 21 said, if you look at what benzene metabolites do, 22 they are very efficient at disrupting the mechanism 23 that's evolved in the separation of chromosomes. 24 They're very inefficient at acting on DNA. But 25 they're very efficient at the process of disrupting AVLRY/WOODS REPORTING SERVICE, INC. (303) 825-6119 56 1 the proteins that are involved in the separation. of 2 chromosomes during division. 3 Q. What is the clonal aberration? Can you 4 define what that is? 5 A. The first clonal aberration that's been 6 associated with secondary leukemias appears to be 7 either the loss of all or part of chromosome 5 and/or 8 7. One certainly can't exclude 8, trisomy 8, which 9 is basically an addition of a chromosome. All are 10 included under the rubric of aneuploidy. This 11 appears to be the earliest event. It could best be 12 described as necessary but not sufficient for the 13 evolution of leukemia and is only the first stage in 14 the process. 15 I have proposed a model which, as I 16 said before, I think is architecturally sound, but 17 would probably be subjected to further modification 18 as we learn more, that I proposed last year. That's 19 associated with -- it's in this paper. And I chose 5 20 in this model, primarily because we know about genes 21 that are associated with 5. Seven is more frequently 22 involved probably. But if one is23 Q. Are these growth genes that are 24 associated with chromosome 5? 25 A. Yes. There are various hypotheses for AVERY/WOODS REPORTING SERVICE, !NC. (303) 825-5119 57 1 what is associated with that lesion. I happen to 2 think that the growth genes are probably fairly 3 important, the cytokine genes, with respect to the 4 process that they involve. But there are other 5 hypotheses that have been promulgated as well. This 6 is the model I put forward. 7 Q. We're looking at page 27 of tab 19? 8 A. Right. I have to say this basically 9 represents a hypothesis based upon facts that are 10 known with respect to the evolution and process 11 that's involved in the induction of AML secondary to 12 chemotherapy primarily. But, as I said before, we do 13 know that benzene metabolites can produce some of the 14 same effects. We're looking at a progression. 15 What this illustrates is a process 16 that's now fairly well known in cancer biology, and 17 that is that, for the vast majority of cancers, 18 there's not a single event that's associated with the 19 development. There are multiple independent events. 20 There are multiple genetic pathways that can get you 21 to the same place. 22 For example, if we look at-- we take 23 chromosome 5, for example, chromosome 5 has been 24 implicated as being involved in colon cancer as 25 well. Now, that has no relationship to AML, but does AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 58 1 play an early role in the evolution of that disease. 2 But, again, multiple independent genetic steps, some 3 of them are genetic, some of them a=a epigenetic that 4 have to occur before you get to the development of 5 cancer. 6 Q. Well, on page 24, this process leads to 7 carcinoma, and it is a 5q loss. Is that something 8 you consider to be induced by the chemotherapy or 9 benzene? 10 A. No. No. 11 Q. Is there a presumed cause of the loss 12 in this model on page 24? 13 A. Cell division. 14 Q. Cell division? 15 A. Cell division is an inherently risky 16 process. That's where aneuploidy occurs. In bone 17 marrow we know, for instance, that ineffective 18 erythropoiesis accounts for upwards of twelve to 19 fifteen percent of the replicating blood cells in the 20 bone marrow. During normal replication of red cells 21 we have aneuploidy occurring. Most of the time it 22 occurs in cells that are irrevocably committed to 23 differentiation. The worst thing that can happen is 24 they die, they disappear. 25 If it happens in an earlier cell that's AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 59 1 capable of clonality or clonogenic potential, then 2 you may, in fact, have a spontaneous lesion occurring 3 that leads to chromosomal-aberration such as 5q-. 4 These are stochastic, random events. These are 5 stochastic, random events even during the process of 6 chemical leukemogenesis. 7 There's a constellation of several 8 types that can produce or increase the potential for 9 that type of injury, increase the frequency of those 10 events. The events are still random. It's that 11 their frequency has been increased in the case of 12 colon cancer. 13 There's no-- with respect to the 14 involvement of these molecules, this is the result of 15 studies done by a number of investigators, this 16 particular model that has been published by Harold 17 Varmus and Robert Weinberg, based upon some very fine 18 work by a variety of different investigators. It 19 simply shows the fact that there are multiple ways to 20 get to the same place, and there are multiple 21 pathways involved. Some genes occur-- are involved 22 early in the progression of the disease. Some genes 23 occur later. 24 And the model that I proposed, a 25 working formulation for secondary leukemia, is AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 60 1 architecturally similar. 2 Q. Back to page 27. You indicated earlier 3 that the-- are there-- do the aberrations caused by 4 benzene metabolites affect all the blood lineages? 5 A. If you're talk-- well, certainly the 6 information we have on benzene and bone marrow 7 toxicity does not suggest that it has a random effect 8 on all lineages. For example, one of the papers I 9 presented by Leon Goldwater and Greenburg from the 10 '40s, I think, illustrates a finding that's 11 consistently seen throughout the literature with 12 respect to benzene and is actually seen to be 13 consistent in animal studies as well. Chronic 14 exposures to high concentrations of benzene can 15 produce bone marrow suppression. But what one 16 eventually sees is a thrombocytopenia, decrease in 17 platelets, or a lymphocytopenia that occurs that 18 precede any permanent effects and are associated with 19 high-level, repeated exposure, chronic exposure. You 20 may see some changes associated with anemia, but 21 those usually actually follow thrombocytopenia or 22 lymphocytopenia. 23 Curiously enough, the granulocytes are 24 usually well resolved in benzene, and one usually 25 sees a decrease in lymphocytes and a decrease in AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 61 1 platelets without a marked effect on granulocytes 2 until fairly late in bone marrow suppression or 3 toxicity. You can resolve that in asplastic anemia, 4 in which you have a generalized inability to produce 5 anything. But usually what you see early on in 6 benzene toxicity involves lymphocytes and platelets 7 first, and granulocytes are reduced much later in the 8 process. 9 Q. And would you also see refractory 10 anemia in such a process? 11 A. I couldn't characterize it as 12 refractory anemia, certain not RA as it's found in 13 the FAB classification. You usually see a trilineage 14 dysplasia. You usually see-- you may see some 15 aspects of a macrocytic anemia, but it's certainly 16 not the first thing you see. And you usually see 17 trilineage involvement. You don't see a classic 18 refractory anemia as defined by the FAB 19 classification. 20 Q. Would that be one of the things you 21 might, see? 22 A. Well, a refractory anemia has certain 23 characteristics that are included within the 24 constellation of findings that I'm talking about. 25 And refractory anemia in and of itself would not be a AVERY/WOODS REPORTIN.S' SERVICE, INC. (3~-3) 825-6119 62 1 pattern that you would expect to se` consistent with 2 benzene exposure. You usually see, as I said, 3 multiple lineage involvement. 4 Q. By that you mean reduction of red blood 5 cells, white blood cells, and platelets, for example? 6 A. Not all white blood cells. I would 7 expect to see a sparing of granulocytes, for 8 instance. Refractory anemia is not consistent with 9 the early effects associated with benzene poisoning. 10 There are aspects of refractory anemia that are 11 seen. 12 Q. Which aspects are seen? 13 A. One can see or it certainly has been 14 reported that one can see macrocytic anemia, but this 15 usually follows reduction in platelets and 16 lymphocytes. Those are usually the most sensitive 17 cell populations in humans. 18 Q. What study says that, that the 19 macrocytic anemia follows a reduction in platelets 20 and lymphocytes? 21 A. There are a number of experimental 22 studies that suggest that. I reported that in the 23 early '80's. The Goldwater/Greenburg work looking at 24 industrial workers in New York in the late '30's, the 25 mid to late '30's, suggests an absolute AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 63 1 lymphocytopenia. 2 Q. What are some of the other effects of 3 benzene toxicity? 4 A. (No audible response.) 5 Q. Would pancytopenia be an effect? 6 A. Sure. Pancytopenia is basically one of 7 the diagnostic criteria in the diagnosis of aplastic 8 anemia. 9 Q. And would leukopenia? 10 A. Leukopenia simply represents a decrease 11 in circulating white cells. Leukopenia is by 12 definition something you'd see associated with 13 pancytopenia. What's important is the cell types 14 involved and the degree of suppression one sees. 15 Leukopenia will occur in a number of 16 situations that don't necessarily have to represent 17 persistent injury or toxicity to the bone marrow per 18 se. 19 Q. And one would also expect to see 20 cytopenias? 21 A. Same thing. 22 Q. And the ones we've just been 23 discussing? 24 A. Cytopenia refers to a specific cell 25 type. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 64 1 Q. How long has it been known that benzene 2 causes those effects? 3 A. Certainly following high-level exposure 4 to benzene it's been generally understood since the 5 late '30s, early '40s. 6 Q. Was it postulated prior to that, as 7 early as the 1890s? 8 A. Yes, following high-level exposure to 9 benzene. But at the particular point in time where 10 those studies were done we don't know what the cells 11 were. 12 Q. What other effects would you expect to 13 see that we haven't discussed yet? 14 A. With persistent exposure you're going 15 to see either a hyperplastic or a hypoplastic bone 16 marrow. 17 Q. A hypercellular bone marrow? 18 A. Either hypercellular or hypo, 19 reduction. 20 Q. Okay. 21 A. If, in fact, one proceeds on to what 22 is-- this is usually after many, many years 23 subsequent to initial exposure, many years-- you may, 24 in fact, see that type of presentation. If you do, 25 and it proceeds on to a persistent abnormality, AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 65 1 trilineage abnormality, that would be classified 2 certainly within the context of myelodysplastic 3 syndrome. Within a pattern of a few months to a year 4 or so, you have a very high likelihood it'll proceed 5 on to the development of acute myelodysplastic 6 leukemia or myeloleukemia, AML. 7 Q. And you mentioned thrombocytopenia as 8 something that would be caused by benzene toxicity? 9 A. Yes. 10 Q. Which refers to low platelets? 11 A. Very low platelets. And that can be 12 seen transiently. That can be a transient effect 13 associated with repeated exposure to high 14 concentrations over a short period of time and may be 15 totally reversible, or it could also be consistent 16 with multi-lineage involvement and a persistent 17 involvement that continues after exposure ceases. 18 These characteristics are not unique to 19 benzene in many respects. They're found with agents 20 that are toxic to bone marrow, the greatest-- the 21 most potent of which are among agents that are 22 routinely used in chemotherapy. 23 Q. And I take it MDS is also something 24 that's caused by one of the effects of benzene 25 toxicity? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 66 1 A. Myelodysplastic syndrome is part of the 2 continuum that's seen associated w_=h the development 3 of leukemia secondary to exposure =c benzene or other 4 leukogenic agents. In that context it is part and 5 parcel of the process. But that's a small fraction 6 of the total dysplasias that are seen that are 7 classified within the rubric of myelodysplastic 8 syndrome. 9 Q. I'm sorry. What is a small portion of 10 that? 11 A. Most diseases that are associated with 12 myelodysplastic syndrome are primary, spontaneous. 13 They have a different prognosis, different 14 characteristics. But it certainly is part of the 15 process that's associated with the development of 16 secondary leukemia. 17 Q. Essentially then, word you say that 18 these various manifestations of the disease process 19 are united by functional abnormalities in the growth 20 in the blood precursor cells? 21 A. Yes, they are. To the extent-- and one 22 can-- if one looks at the potential for evolution of 23 anbormality or for the evolution of disease, they 24 appear to be characterized as a part of that process 25 as well. They have often the potential for further AVERY/WOODS REPORTING SERVICE, I~:-. (303 325-6119 67 1 development and evolution of myelodysplastic syndrome 2 into AML, and to progress and to transform is a 3 function of the number of abnormalities that are 4 seen. 5 There's a very high frequency of 6 transformation in myelodysplastic syndrome into AML 7 in individuals that have more than one abnormality, 8 very low frequency of transformation in individuals 9 who only have a single abnormality. Secondary bone 10 marrow toxicity, the evolution of AML tend to involve 11 multiple channels, which is comparable to-- which is 12 basically mirrored in the model that I showed you. 13 Q. On page 2714 A. Yes. 15 Q. -- of tab 19. I believe you have MDS 16 listed in the model? 17 A. Yes. 18 Q. Would you characterize this as being a 19 continuum of the disease process, starting with 20 normal blood production, which is the hemopoiesis, 21 then an insult to the bone marrow; then would that 22 turn the continuum to leukemia? 23 A. In the context of secondary 24 leukemogenesis, it is meant to represent one pathway 25 that is both plausible and probable in the evolution AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 68 1 of secondary AML. 2 Q. I want to make sure I understand the 3 pathway. How many pathways are there? 4 A. Well, as I said before, they are 5 probably multiple. Certainly there is strong 6 evidence to suggest that multiple independent 7 pathways can get you to the same place for a variety 8 of different tumors, including leukemia. 9 Q. Okay. 10 A. The only exception is probably CML, 11 which is probably related to a single early event, 12 although later events in the history and actual 13 history of the disease are probably multiple as 14 well. But for AML there's certainly multiple 15 pathways. 16 Q. This pathway described on page 27, can 17 you describe what that pathway is? 13 A. In general detail I can't. I mean this 19 was presented basically as a straw model for' 20 discussion and to generate experimental approaches to 21 determining the evolution of the disease. 22 Basically what it refers to is that, as 23 I said before, the earliest permanent event involving 24 a change in the genetic material appears to be the 25 association of a loss of chromosomes, all or part of AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 69 1 chromosomes. Seven is most frequently seen. 2 I did not pose a model to 7, because 3 7-- we have a bunch of addresses for genes on 7, but 4 we don't know what they are. 5 Q. So your model is 5q-? 6 A. So I've chosen the model as all of or 7 part of chromosome 5. 8 Q. Let me interrupt you and ask you-- I'm 9 not trying to be rude-- I just want to make sure I 10 fully understand. Earlier you said benzene was not 11 mutagenic, but you're saying that it disrupts the 12 genetic process? 13 A. Benzene metabolites are clastogenic. 14 Q. What does that mean? 15 A. Well, to a large extent-- this is a 16 semantic argument, but to the extent the semantics 17 that are used can be confusing, I think it's 18 important to distinguish between the two. 19 "Clastogenic" means that benzene metabolites, as I 20 have discussed them, are capable of causing 21 chromosomal damage, they can cause a loss of 22 chromosomes, they can cause aneuploidy. 23 What's involved specifically in the 24 interstitial lesion of the segments of the chromosome 25 nobody really understands. But I think that AVERY/WOODS REPORTING SERVICE, INC. (303? 825-6119 70 1 certainly, as benzene metabolites are capable of 2 inducing aneuploidy and the loss of chromosome 5, 3 whether it's possible to cause interstitial lesions 4 is not that important in understanding the evolution 5 of leukemogenesis. 6 Having said that, the point is that is 7 a separate type of event from the binding of a 8 molecule to DNA, which can lead to a misreading of 9 the DNA code, and that's what we normally think of as 10 a mutation or mutagenesis. 11 In the early days of cancer biology, 12 especially from a regulatory point of view, because 13 we don't know much about cancer at all, regulatory 14 for purposes of standard setting, regulatory policy 15 was to assume that there was no threshold for cancer 16 genes and that they acted through binding through 17 DNA. They caused a mutation. A single molecule of a 18 single strand could bind to DNA, alter the code, and 19 that would cause cancer. That is no longer a 20 generally accepted tenet, and it, in fact, in many 21 cases has been demonstrated to totally misrepresent 22 what we see in the evolution of cancer. 23 The colon model I presented in this 24 model here for AML illustrates that. We're talking 25 about multiple independent events. The first one AVERY/WOODS REPORTING SERVICE, INC. (30,3) 825-6119 71 1 that we've been able to identify in a variety of 2 diseases has to do with chromosomal loss, not with a 3 point mutation, a so-called mutagenic event. 4 So when I talk about benzene not. being 5 mutagenic, there are two issues here. One, benzene 6 itself isn't mutagenic or clastogenic. It requires 7 metabolites, but beyond that benzene metabolites do 8 not tend to be very effective interacting with DNA, 9 i.e. mutagens, but they're very potent together. 10 They form a very potent capability for disrupting 11 cell division and causing events that can lead to 12 aneuploidy. 13 Q. Would you characterize that as a 14 nondysfunctional event? 15 A. Yes. 16 Q. Which can lead to chromosome breakage? 17 A. Yes. Or causes chromosome loss. 18 Chromosome breakage is another story. We have a lot 19 to learn before we fully understand that. 20 One of the reasons why I say that is, 21 for instance, if you take 5q-, almost all of us, no 22 matter what the age is or whether there's no aging 23 involved and we're talking about spontaneous deletion 24 of part of a chromosome occurring obstensibly as a 25 division accident, you see the interstitial division AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 72 1 at 5q. So the 5q- is not always but almost always an 2 interstitial deletion. Whether that 1--as chemical 3 specificity is totally conjecture. 4 Q. You've been describing the continuum of 5 the disease process? 6 A. Yes. 7 Q. You don't have a lot of the things 8 we've been discussing on here-- maybe you do in 9 broader terms-- but, if I give you a piece of paper, 10 can you draw the continuum of the disease process 11 occurring after a lesion to bone marrow caused by 12 benzene metabolism? 13 A. (No audible response.) 14 Q. Does that make sense? 15 A. No. I'm sorry. 16 Q. Why does that not make sense? 17 A. These are stochastic events. 18 Q. What does that mean? 19 A. They're random. By this model, which 20 again is a model for generation of research and 21 discussion, architecturally it would probably 22 withstand the test of time. But when the individual 23 events on the spectrum end up remaining as they are, 24 the explanation of what they do is going to require a 25 lot more research. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 73 1 So I'm not pretending to tell you that 2 this is how AML occurs. And _ can't draw you a road 3 map that tells you exactly what molecular events are 4 transpiring. 5 We do know that agents that are 6 leukemogens, and that includes benzene metabolites, 7 are capable of altering normal differentiation in the 8 stem cell compartment. Now, ostensibly that 9 alteration leads to increased hypersensitivity-- is a 10 good word-- to growth factors, specifically GMC. 11 Now, that's going to cause an increased 12 number of cells that are responsive to the growth 13 factor and are dividing. That by itself is 14 transient. It's not permanent. It has a window that 15 probably is on the order of hours, during which time 16 you have more cells dividing in the target cell 17 compartment than you would have otherwise. 18 The system has naturally evolved to 19 protect us from that kind of injury. So, for 20 instance, an agent that simply causes chromosomal 21 damage that are compounds that we know will cause 22 bone marrow supression that can cause aneuploidy that 23 are not leukemogens, probably not leukemogens, but 24 they probably do not alter regulation in the stem 25 cell compartment. And that may, in fact, alter the AVERY/WOODS REPORT=NG SERVICE, INC. 4303) 825-6119 74 1 number of target cells available for further damage. 2 Now, you can then incur the loss of a 3 chromosome. In this case I've used 5. We know 4 benzene metabolites in culture will cause 5-. No 5 evidence they cause 5q-. Certainly they cause 5-. 6 They cause 7-, 8-. They cause a random array of 7 chromosomal aberrations. 8 But what you end up seeing that 9 persists during the evolution of AML are those that 10 appear to be important with respect to the evolution 11 of the disease, and 5 is of one of them. 12 Q. 5q- would be one of them? 13 A. Yes. From what we know is going on at 14 that location on the chromosome. And it makes sense 15 that it would be involved in this process. 16 Q. Are the studies you're referring to 17 animal studies? 18 A. No. These are studies involving human 19 cells. 20 Q. Human cells? 21 A. Human cells in humans with AML. Animal 22 studies, with respect to looking at specific 23 chromosome loss and gene involvement are irrelevant, 24 because the genetic mapping of genes and their 25 location on chromosomes in animals are different than AVERY/WOODS REPORTING SERVICE, INC.. (303) 825-6119 75 1 in humans. And if one wants to look at the 2 propensity for involvement of specific chromosomes 3 and genes in the evolution of human cancer, you have 4 to look at human cells. 5 Q. How many of your studies have looked at 6 human cells? 7 A. Well, I think that probably depends on 8 what you call a study. If we're talking about9 Q. I'm going to pull this out, because we 10 might refer to it. 11 A. You're talking about individual 12 publications at this point in time. I could probably 13 give you a number. The fact is the work that we've 14 been doing for the last seven, eight years has been 15 largely devoted to looking at these processes in 16 human cells. 17 Q. What you say "we," who are you 18 referring to? 19 A. My laboratory. 20 Q. At the University of Colorado? 21 A. University of Colorado. Now, one can 22 look at processes. One can look at individual events 23 using animal models or animals cells as models. But, 24 if one wants to integrate them into a cogent model 25 for the evolution of a disease such as AML, you have AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 76 1 to basically look at the human gene and the 2 organization of genes as they are found in human 3 cells, not in animals cells. 4 Q. Have most of your studies been animal 5 studies? 6 A. If you look at my whole-- in my record 7 over the past twenty, twenty-five years, yes, most of 8 the work has been in animals. We've only recently 9 developed-- by recently I mean the last ten years10 the techniques to begin to directly look at human 11 cells. 12 In humans, what we've seen over the 13 last few years is virtually an explosion in terms of 14 our knowledge of mechanisms associated with 15 hematopoiesis and development of leukemia and 16 cancer. 17 Certainly hematology, I would say that 18 eighty percent of what we know today we've learned in 19 the last ten years, maybe five years, with the 20 exception of clinical description of diseases, 21 clinical, laboratory, traditional morphologic 22 techniques. What we know about the mechanism of 23 genesis, the vast majority of our knowledge we've 24 gained in the last five years. 25 Q. You have your resume in front of you? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 77 1 A. Yes. 2 Q. Which one of your studies on there were 3 human cell studies related to benzene toxicity? 4 A. Well, certainly the European Journal of 5 Haematology, Environmental Health Perspectives, in 6 Press. 7 Q. Are you talking about articles now? 8 A. Yes. I don't know how you want to do 9 this. 10 Q. Why don't you identify the page number 11 of your CV? 12 A. Page 10. 13 Q. And you can just read the title of the 14 article. 15 A. "The Effects of Benzene and other 16 Leukemogenic Agents on Hematopoietic Stem and 17 Progenitor Cell Differentiation" is human. 18 "A Epidemiologic Study of Benzene's 19 Early Biologic Effects in Heavily Exposed Workers in 20 Shanghai, China" is obviously human. 21 "The Process of Leukemogensis," 1966, 22 is human. "Impact of Benzene Metabolites on 23 Differentiation of Bone Marrow Progenitor Cells" is 24 human. 25 "Dideoxycytidine-Induced Thymic AVERY/WOODS REPORTING SERVICE, INC. (303) 825-5119 78 1 Lymphoma Correlates with Species-Specific Suppression 2 of a Subpopulation of Primitive Hematopoietic 3 Progenitor Cells in Mouse but not Rat o= Human Bone 4 Marrow" deals with human. 5 "Peroxidase Activity in Murine and 6 Human Hematopoietic Progenitor Cells: Potential 7 Relevance to Benzene-Induced Toxicity" deals with 8 human. 9 Those are the current papers that I 10 have that deal directly with looking at the effects 11 of benzene and other leukemogenic actions or leukemia 12 agents in humans. 13 Q. And did any of those studies determine 14 that benzene metabolites caused damage to the fifth 15 chromosome? 16 A. No. We're currently conducting those 17 studies. I'll probably be ready to publish that 18 information. within a month or so. 19 Q. Is there a point at which benzene, the 20 metabolism of benzene, becomes saturated? 21 A. Primary metabolism is probably 22 saturated at about one hundred parts per million, 23 maybe between one hundred and three hundred parts per 24 million. Secondary metabolism is probably saturated 25 somewhere within that range. But we don't completely AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 79 1 understand that. 2 Q. So the only one you have an opinion on 3 within a reasonable degree of medical certainty-or 4 scientific certainty is primary metabolism as to the 5 when6 A. When saturated? 7 Q. Yeah. 8 A. Yes. 9 Q. What does it mean to say it's 10 saturated? 11 A. It means that basically you have 12 maximized the process, and there is no increase in 13 the rate of transformation of molecules that can 14 occur by increasing the concentration. 15 Q. And does that mean that the amount 16 which is absorbed above that saturation point is not 17 going to be metabolized? 18 A. Essentially, yes. 19 Q. So, if someone inhaled air or was 20 exposed to benzene in parts per million which 21 exceeded a hundred, the amount above one hundred 22 parts per million would not be metabolized; is that a 23 fair statement? 24 A. No. The rate of transformation of 25 benzene into the metabolites will not increase. You AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 80 1 basically will then have a constant rate of formation 2 of primary metabolites. Doesn't mean that secondary 3 transformation or tertiary transformation, which are 4 just as important with respect to toxicity, will not 5 continue to occur. 6 Q. But, as of today, we don't know that? 7 A. I think we do know that. We know that 8 it occurs. We just don't know precisely what the 9 saturation is for cell specific production of 10 individual metabolites under those circumstances. 11 Whether or not saturation occurs is 12 really not all that important. I think that's an 13 overly-- I think there's too much attention paid on 14 saturation. It's important for pharmacokinetic 15 modeling, but it doesn't, I think, give you a great 16 deal of information with respect to potential 17 toxicity. 18 Q. Well, with regard to primary 19 metabolism, if a person is exposed to amounts over 20 one hundred parts per million, will that excess 21 amount pass into the body unmetabolized, or is there 22 a percentage that you can say will pass into the body 23 unmetabolized? 24 A. Yes. And, as a matter oz fact, it can 25 happen at lower concentrations. You don't have to AVERY/WOODS REPORTING SERVICE, INC. '303) 825-6119 81 1 reach saturation with a compound that can be 2 spontaneously excreted. 3 And benzene is volatile. And the 4 primary route of excretion of benzene is through the 5 lung, inhaled. And so, in a situation like that, 6 you're going to see excretion of benzene at 7 concentrations below saturation. 8 Q. The primary route of excretion for any 9 level of benzene is through the lung, unchanged? 10 A. No. 11 Q. If it's inhaled? 12 A. No. In a very, very low concentration, 13 the primary route of excretion is going to come from 14 excretion through the urine or the feces, primarily 15 the urine. A higher concentration, at some point16 it's incompletely understood, but generally well 17 recognized-- exhalation of benzene becomes the 18 primary route of excretion. But19 Q. What approximate point is that? 20 A. Certainly above a hundred and probably 21 somewhere, I would say, around fifty you begin to see 22 it lipping up. But the fact of the matter is you can 23 measure benzene readily in exhaled breath of 24 individuals. 25 In smokers it's quite high, and in AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 82 1 individuals with no exposure to benzene you can still 2 measure benzene excretion via the lungs. So there's 3 benzene in your breath right now. It can be 4 measured. 5 Q. So at fifty parts per million exposure 6 you would start to see larger percentages not 7 metabolized of the benzene? 8 A. I would expect so, yes. 9 Q. And after one hundred parts per 10 million? 11 A. You've reached a point where any 12 benzene taken in, the major increase in its fate or 13 the major-- its major fate will be exhalation. 14 Q. At some point I take it. Okay. Is 15 there a percentage? Is it ninety percent16 A. It depends. I would suspect that above 17 one hundred parts per million you could be talking as 18 much as eighty percent. But I mean these numbers are 19 by no means hard and fast. 20 Q. But, if you were around eighty percent, 21 you would expect to see at one hundred and above 22 which would be excreted unmetabolized? 23 A. Yes. 24 Q. Then I take it that goes down, that 25 percentage that's excreted unmetabolized decreases as AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 83 1 you get closer to the saturation point coming down 2 the scale, and then get below the saturation point; 3 is that a fair4 A. It is. But I mean these are-- it's not 5 that simple. If you're talking about mass balance; 6 that's true. But, as I mentioned, even as ambient 7 levels of exposure to benzene that occur every day, 8 there is benzene excreted unchanged via the lungs. 9 Q. Even at background exposures? 10 A. Yes. It's been demonstrated. The EPA 11 has measured benzene in the breath. 12 Q. Well, if it's in someone's breath, they 13 must have been exposed somewhere, wouldn't you say? 14 A. Sure. Everybody is, every day. 15 Q. So let's take, say, ten parts per 16 million, air concentration; would you expect to see 17 most of that benzene metabolized? 18 A. Ten parts per million, probably, yes. 19 Q. And I guess-- would that hold true for 20 one part per million as well? 21 A. Yes. 22 MR. WILLIAMS: Take a one-second 23 break. 24 (Whereupon, a document was marked Irons 25 Deposition Exhibit 3 for identification by the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 84 1 reporter.) 2 Q. (BY MR. WILLIAMS) Is the metabolism of 3 benzene the same in all species? 4 A. Qualitatively, probably so. There 5 certainly aren't any major differences that have come 6 to light, although there could be some minor 7 difference's. 8 Q. Are there any studies which would 9 support your view that the metabolism is the same? 10 A. Many. There's certainly no 11 appreciation in the literature related to benzene 12 metabolism that humans have a different pattern of 13 metabolism: The cell specific metabolism is probably 14 much more important than overall metabolism in terms 15 of conferring susceptibility, and there you do see 16 differences. 17 In rats the target organ for benzene is 18 the Zymbal gland, and in mice one sees toxicity in a 19 gland called the preputial gland. And one 20 characteristic of human bone marrow, the Zymbal gland 21 and preputial gland, is the concentration of 22 myeloperoxidase, which is known to be a very 23 important enzyme in the terminal oxidation. of 24 hydroquinone. 25- Recent studies in humans suggest that AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 85 1 also a detoxifying enzyme called DT-diaphroase or 2 NQ01 is an important enzyme in benzene toxicity. Its 3 absence in the bone marrow of humans, polymorphisms 4 in the gene that's associated with NQ01 appear to be 5 correlating with benzene toxicity in studies that are 6 ongoing in China and elsewhere. 7 Q. Have you cited these human studies in 8 your list of articles that's included in Exhibit 3? 9 A. No. 10 Q. And these are not studies you have 11 participated in? 12 A. Yes. Some of them aren't, and some of 13 them are. One of the articles that I do cite here is 14 where it was demonstrated that, in fact, peroxidase 15 is found in the hematopoietic progenitor cells in 16 humans. And much of this work has been conducted at 17 the University of Colorado, either in my laboratory 18 or that of Dr. Ross, who has been actively looking at 19 polymorphisms associated with DT-diaphroa se as well. 20 Q. Has the metabolism of benzene been 21 studied in liver cells in vitro? 22 A. Yes. Yes. 23 Q. By you? 24 A. In the past I've participated in a 25 number of studies that would look at in vitro and in AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 86 1 vivo metabolism of benzene. I haven't done any liver 2 work in many, many years. 3 Q. When was the last time? 4 A. It was when I was at CIIT. It would 5 have been the late '70s, early '80s. 6 Q. Benzene is primarily in humans 7 metabolized in the liver; is that8 A. Primary metabolism is the liver, and 9 that's humans, mice, rats, virtually all species that 10 have been examined. 11 Q. And we're talking about animal studies 12 now. Are these animal studies important in or useful 13 in understanding the metabolism process of humans? 14 A. Yes. 15 Q. So the results of these animal studies 16 would be extrapolated to human subjects? 17 A. Animal studies are extremely important 18 for understanding individual processes, when you're 19 talking about metabolism or toxicity. The problem 20 with animal studies is there is no animal that is a 21 complete and total surrogate for humans. 22 So you can extrapolate, you can 23 compare, you can reach conclusions that are based 24 upon experiments in animals, but you have to be able 25 to validate the major tenets of those conclusions AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 87 1 using human material or analogy to human studies, the 2 point being you can extrapolate many aspects of 3 processes that are 4nvolved in metabolism of benzene 4 to humans. 5 If you want a model for the 6 pharmacokinetic modeling of humans, you have to use 7 some human material co fill out the picture. You 8 can't simply take a mouse or a rat and say this is a 9 small human and directly use that data to predict 10 precisely or quantitatively what will happen in 11 humans. 12 But pharmacokinetic-- physiologically 13 based pharmacokinetic models made extensive use of 14 animal materials. Uses in vitro human studies as 15 well to fine-tune and test the parameters and the 16 results that are seen from the animal studies and 17 then produce a model that predicts what happens in 18 humans. 19 Q. And these in vitro studies would be 20 with liver21 A. Some of them. 22 Q -- cells? 23 A. Some of them. I think the most 24 important ones today with respect to understanding 25 what's going on occur in bone marrow. We know a lot AVERY/WOODS REPORTING SERVICE, INC.-(303) 825-6119 88 1 about the liver process in all species. The liver is 2 not where the terminal or endpoint of metabolism 3 occurs that's associated with benzene toxicity. It's 4 the bone marrow. So5 Q. Does a secondary, tertiary metabolism 6 occur in the bone marrow? 7 A. Yes. 8 Q. Do you agree that benzene itself, 9 without being metabolized, can have a toxic effect on 10 bone marrow? 11 A. No, not at concentrations that are of 12 any physiological relevance whatsoever. Benzene by 13 itself is virtually inert until you get to 14 concentrations that basically dissolve in liquid, and 15 that's not compatible with life. 16 Q. Is that a subject of debate, whether 17 benzene itself causes damage to bone marrow? 18 A. It has been, but I don't think it is 19 now. It's been demonstrated. There are a number of 20 different laboratories now that have not been able to 21 demonstrate that primary metabolism occurs in bone 22 marrow of humans. There have been studies that have 23 looked at the effects of benzene by itself and have 24 suggested it might have some effect on the process of 25 influencing, but the concentrations of benzene that AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 89 1 were used are not physiologically relevant. 2 Q. Do the liver cells from different 3 individuals metabolize benzene differently on a 4 quantitative basis? 5 A. There's some evidence that the specific 6 types of enzymes that are associated with primary7 the specific enzyme associated with primary 8 metabolism of benzene is an enzyme called QE1. It is 9 an isotype or isoform of an enzyme. It's a 10 constellation of enzymes that are called QE1, 11 Cytochromes P-450. 12 There's some evidence that, in fact, 13 there is some polymorphism in humans with respect to 14 metabolism of a variety of compounds associated with 15 cytochrome P-450 with respect to human toxicity. 16 Humans tend to show less variability with respect to 17 that process than various strains of rodents do. 18 At this point the polymorphism that 19 appears to be the most important in susceptibility, 20 certainly associated with benzene poisoning in 21 humans, is the enzyme I talked to you about before, 22 NQO1, which has been associated with secondary 23 detoxification. Now it appears to be-- polymorphism 24 appears to segregate with toxicity, at least in 25 studies that. have been done in China. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 90 1 Q. That would indicate a variability in 2 toxicity among individuals? 3 A. Sure. We've seen that. We've seen 4 that in the benzene literature already. I don't 5 think that's subject to discussion. 6 Q. That individuals vary in their 7 susceptibility to benzene toxicity? 8 A. Certainly. If you take any population, 9 even the Turkish shoe workers or Italian shoe workers 10 that were exposed to egregious concentrations of 11 benzene following World War II, where we had massive 12 epidemics of benzene poisoning in individuals exposed 13 to hundreds and hundreds of parts per million of 14 benzene chronically, repeatedly, over and over, not 15 just for eight hours but for twenty-four hours a day, 16 we still only see a fraction of individuals that 17 develop bone marrow suppression. We only see a 18 subfraction of those that go on to develop persistent 19 lesions, and even a smaller fraction of those go on 20 to develop acute myelogenous leukemia. So clearly at 21 concentrations that are toxic to bone marrow you only 22 see a subset of individuals that get sick. 23 Q. And you attribute that to individual 24 susceptibility? 25 A. Certainly, by definition. AVERY/WOODS REPORTING SERVICE, INC. (3031 825-6119 91 1 Q. Is differences _n the way individuals 2 metabolize benzene the only =actor that affects 3 susceptibility? 4 A. I'm convinced it's probably a major 5 factor. But, by the same token, I have spent a great 6 deal of my time and effort looking at alterations and 7 regulations of specific cells, at bone marrow 8 function in humans, and I would not be surprised at 9 all to find that there are some other differences 10 that may impact on that. 11 Certainly to date we haven't seen any 12 major ones. We certainly have not seen any major 13 polymorphisms, if you will, with respect to the 14 response of human bone marrow to benzene metabolites 15 or to other chemotherapeutic agents. 16 But metabolism clearly is an area where 17 there's likely to be an impact on susceptibility 18 related to individual factors. 19 Q. What other factors might be important 20 in that? 21 A. Other exposures, other behaviors, 22 environments. I think smoking is likely to play a 23 role. 24 Q. You mean life-style? Would you include 25 it in the lifestyle category? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 92 1 A. Lifestyle, diet, individual variations 2 in stem cell differentiation and progression. 3 Q. Would that be a genetic concept, 4 individual differences in stem cell differentiation? 5 A. Some of those-- certainly the ones that 6 I think are the most likely hypotheses to date are 7 environmental. But they remain to be tested. We are 8 in the process of designing experiments, conducting 9 experiments to look at the influence of smoking on 10 that process. 11 Smoking increases white count 12 dramatically. No one knows why. If, in fact, it's 13 altered cell differentiation rather than a terminal 14 maturation process or margination, it could readily 15 influence a susceptibility to agents that target 15 dividing cells. 17 At present I don't know of any, with 18 the exception of defined diseases, where we know that 19 there are processes that are abnormal to begin with 20 and that are associated with various anemias or what 21 have you. I'm not aware of any hypotheses that 22 directly relate to genetically determined differences 23 in, say, stem cell susceptibility. 24 Q. Would you agree that the genetic makeup 25 of different people might enable some people to fight AVERY/WOODS REPORTING SERVICE, INC. (303) 825-5119 93 1 off disease more readily than others? 2 A. It's almost -- well, the answer to the 3 question is obviously yes. But that's like asking do 4 you believe in mother and apple pie. I mean genetic 5 makeup is all we are. All we are is a product of our 6 genes. And we each have a different legacy with 7 respect to the genes we've gotten. We interact with 8 our environment. 9 So obviously our genetic makeup is 10 important in influencing our susceptibility to the 11 development of various diseases and our ultimate 12 fate, whether we're destined to develop 13 cardiovascular disease or colon cancer or what have 14 you. 15 (Whereupon, from 12:51 p.m. to 1:08 16 p.m., a recess was taken.) 17 Q. (BY MR. WILLIAMS) Doctor, we've been 18 discussing the initial insults to bone marrow that 19 can be caused by benzene. And my understanding is 20 that benzene metabolites can cause a lesion which 21 leads to a disruption in cell differentiation. Is 22 that a fair statement as the initial point in the 23 process? 24 A. They certainly disrupt or alter 25 differentiation. Whether there is a lesion or not AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 94 1 that's, I guess, a semantic question. It's a 2 transient effect. It's temporal. It is probably3 it's probably associated with changes in signal 4 transduction from the surface of a cell to the 5 interior and not with a genetic event. 6 The first genetic event that is 7 associated with-- that we know is associated with 8 secondary leukemia development and with benzene 9 metabolites, their chemistry is consistent with, is 10 aneuploidy, the loss of all or part of a chromosome 11 that then can lead to further alterations with time. 12 Q. So the first step in the process could 13 be the disruption of cell differentiation, then a 14 chromosomal abnormality or aneuploidy? 15 A. Occurring in that population, yes. 16 Q. Subsequent to those events, does there 17 then occur a disease process that can eventually lead 18 to AML, or have we already started the disease 19 process? 20 A. No. The outcome is by no means fixed 21 in time at that stage. 22 Q. I understand. Okay. At that stage 23 what can happen? Can a person manifest symptoms of 24 toxicity? 25 A. One looks at the concentration of AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 95 1 metabolites that are necessary to produce those 2 events. 3 If one looks at chromosomal aberrations 4 that occur in individuals following chemotherapy or 5 exposure to benzene, it's clear that the levels of 6 exposure that are consistent with that type of 7 abnormality are consistent with some effect at the 8 level of the bone marrow at that stage. One should9 it would not be unlikely to see lymphocytopenia or a 10 transient suppression in blood cells at that point in 11 time. 12 Q. That would be no red blood cells? 13 A. Yes. Although you have to keep in mind 14 that the half-life of red blood cells is very long in 15 circulation. So if you have a transient effect that 16 even involves exposure over a period of days, they're 17 going to be much less-- red cells are going to be a 18 much less sensitive tool than, say, for instance the 19 lymphocytes, which have a much shorter transient 20 period in peripheral blood. 21 Q. If a transient benzene exposure has 22 caused these effects, is it possible that the effects 23 will dissipate too on removal from the exposure? 24 A. The effects we've just talked about, 25 yes. AVERY/WOODS REPORTING SERVICE, INC. (303? 825-6119 96 1 Q. At what point do the effects become 2 permanent and not removable or not curable by removal 3 from the exposure? Can you even quantity that? 4 A. At this point in time, the development 5 of permanent or persistent cytopenias, 6 myelodysplasia, AML associated with exposure to 7 benzene or any of the other agents that are known 8 leukemogens, the precise dose duration product is not 9 understood. It clearly represents a chronic event. 10 We're talking about repetitive exposure that 11 increases the likelihood that a permanent event will 12 occur. 13 Now, when we talk about the progression 14 or mechanisms that are involved in the progression of 15 the development of AML, we're talking about events 16 that happen in single cells. It's a rare event. 17 Whether it leads ultimately to the evolution of 18 leukemia is a stochastic process. 19 Q. What does that mean? 20 A. It's random, as I said before. 21 Exposure can alter the frequency or the probability 22 that that type of an event will occur. It does not 23 specifically produce a selective event. 24 So, if you have, for instance, a clone 25 of cells that survive an exposure insult in which 97 1 aneuploidy has occurred and involves chromosome 5 and 2 7, that clone may persist for years. If it continues 3 to divide and replicate, it may -- replication is 4 controlled by interaction of those cells with their 5 environment, which includes the stromal cells of the 6 bone marrow and any other external factors. 7 It's a regulatory process. That 8 ostensibly is disrupted if you have lesions such as 9 what I'm describing. As that begins to unfold, you 10 may begin to see clinically or functionally 11 processes-- a process developing such as 12 myelodysplasia, dysplastic changes in the bone 13 marrow, multiple cytopenias persisting. 14 If that clone continues to evolve, you 15 may-- you then have increased frequency of division 16 or turnover occurring. And those cells are 17 susceptible to other random events. Those events can 18 involve endpoint mutations, loss of function of genes 19 that change the biology of the cell. And that's 20 basically the type of process that occurs in the 21 evolution of a disease like AML. 22 Q. So no one knows at what point an 23 exposure or duration will produce that exact effect? 24 A. Not precisely. We do have a lot of 25 information with respect to the latency or the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 98 1 duration of time that's associated between 2 significant exposure to benzene and to onset of 3 disease. We know the types of and the frequency 5 of manifestations of toxicity that are seen in many 6 cases that then ultimately correlate with the 7 evolution of the disease. But, with respect to 8 whether or not a specific event at a place and time 9 is going to lead to the evolution of leukemia, we 10 can't predict on an individual basis. 11 So, even if an individual has clonal, 12 chromosomal aberrations, there is no way of 13 predicting what the chances are that he will go on to 14 develop leukemia. 15 Q. Okay. Would continued exposure to 16 benzene worsen the clonal aberration once it's 17 formed? 18 A. I think you could make a much mc-e 19 cogent argument that it would lessen. Between 1900 20 and 19-- possibly the end of the 1930s, actually 21 benzene was used as a chemotherapeutic agent. It was 22 used in the treatment of leukemia. 23 It's not very effective. It's fairly 24 weak compared to most of the therapeutic agents that 25 we have today. But it was used as a drug for the AVERY/WOODS REPORTING SERVICE, INC. '.303) 825-6119 99 1 treatment of leukemia. 2 If you already have a persistent clone 3 that's undergone proliferation that is -rot 4 regulated-- normally benzene's cycle specific and 5 cytotoxic-- the same process that can lead to the 6 evolution of the abnormal clone can also kill those 7 cells. And that process is what occurs during the 8 events that you see in acute benzene poisoning, where 9 you have high-level exposure and you have transient 10 effects in the bone marrow. 11 What benzene is doing is causing not 12 dysjunctional events that lead to cell death. It's 13 inhibiting lymphocyte proliferation at those 14 concentrations. It's subsequent exposure is not 15 likely to exacerbate the process. It's likely, if 16 you have significant exposure, if it's going to do 17 anything, it's likely to impede it. 18 Q. So, once the clonal aberration is 19 present and persisting, the damage is already done in 20 terms of the disease process? 21 A. No. That's the first-- that is one 22 step in the process. There are now multiple steps 23 that have to occur. 24 What I'm saying is that where benzene 25 metabolites act is very likely to be early in the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 100 1 process, not late. The types of effects that are 2 seen are consistent with the earliest effects that 3 are seen in the evolution of AML, not late effects. 4 Q. The effects we've been discussing 5 earlier, the cytopenias and6 A. Yes. And the types of aberrations that 7 are seen. The lesions that are associated with late 8 events in the evolution of AML are probably at random 9 and are governed by the rate of replication in the 10 cells. Benzene can target those cells and kill 11 them. 12 When I speak about benzene, I'm 13 referring really to metabolites, not benzene itself. 14 In that context, high-level benzene exposure, it's 15 more plausible that benzene is going to impede the 16 process, not exacerbate it. 17 Q. So would intermittent benzene exposure 18 be potentially more damaging than chronic? 19 A. Intermittent is chronic. In an 20 occupational setting or a setting where individuals 21 are exposed to levels of benzene that are high level 22 to produce bone marrow toxicity, you're almost 23 dealing with intermittent exposure. 24 Q. By "intermittent" you just mean lack of 25 completely continuous? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 101 1 A. Yes. 2 Q. Okay. 3 A. Benzene is cycle specific. It's been 4 known for years. 5 Q. Once you have this pathogenesis, once 6 the lesion has occurred and the clone has been 7 formed, the chromosomal aberration, what types of 8 manifestations do you see at that point, or do they 9 vary per individual? 10 A. The precise role of a given chromosomal 11 aberration in the evolution of the disease is not 12 understood. There are processes that are currently 13 being studied. And there is a very-- there are 14 some-- there's some evidence to support alternative 15 hypotheses. 16 The best example I can think of is17 let's talk about 5q-. In individuals who have solely 18 5q- and nothing else, no other chromosomal 19 aberrations, the evolution to progressive 20 myelodysplasia or transformation to AML is very rare, 21 less than ten percent. 22 Q. So those occur in just those patients 23 with just that chromosomal aberration; is that 24 correct? 25 A. It can, yes. I said less than ten AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 102 1 percent. A small minority of those individuals can 2 go on to develop-- to transform, yes. But the 3 likelihood is that it won't. 4 That is a distinct population vis-a-vis 5 other types of aberrations or multiple aberrations in 6 terms of chromosomal aberrations. And it is also 7 consistent with what one sees in terms of the 8 findings. 9 5q- by itself is seen often in the 10 aging populations. And that in that context it's 11 associated with refractory anemia. And refractory 12 anemia has cytoblasts. It has about a ten percent or 13 less conversion rate to AML. That tends to be what 14 one sees. 15 If one sees multiple chromosomal 16 aberrations, say if instead of 5q- you've got -5,-7, 17 or a combination thereof, or other potential 18 aberrations as well irrespective of the origin of 19 that lesion, you now have a totally different 20 prognosis with respect to potential for evolution. 21 Those individuals tend to have a higher rate of 22 transformation, a much more rapid rate of 23 transformation and progression of the disease, and a 24 very high incidence of conversion to AML. 25 One also sees, instead of just seeing AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 103 1 the refractory anemia or macrocytic anemia-- one 2 tends to see trilineage involvement. One sees what 3 the FAB would call refractory anemia with excess 4 blasts, increase in immature forms, lack of 5 maturation. 6 Q. Which is the hypercellular bone marrow? 7 A. It's the hypercellular bone marrow in 8 all of them basically. 9 Q. Would you see a lowering of platelets? 10 A. Well, trilineage involvement would mean 11 a cytopenia very often involving platelets. In the 12 case of benzene you usually see that early. 13 Q. And you'd also see leukopenia? 14 A. Which is part of the same. Leukopenia 15 simply refers to a decrease in white cells. That 16 would be due to a decrease in basophils or a decrease 17 in neutrophils or both. 18 Q. So these various blood dyscrasias we've 19 been discussing are part of the continuum of the 20 disease process? 21 A. In the context of the evolution of 22 secondary leukemia, secondary to exposure to high 23 levels of benzene or other leukemogens, yes. In the 24 context of spontaneous evolution of diseases such as 25 the 5q- syndrome, no. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 104 1 Q. Do you believe that 5q- syndrome is 2 only spontaneously induced? 3 A. If you are defining 5;- syndrome, there 4 is only evidence to support that it is a spontaneous 5 lesion. If you are talking about tie evolution of 6 involvement of chromosome 5, as in other diseases 7 such as secondary leukemogenesis or colon cancer, 8 it's clear that chromosome 5 can be involve4 in a 9 variety of different disease processes. 10 I have seen nothing in the 11 epidemiological literature associated with 12 mechanistic study looking at mechanisms of 13 leukemogenesis that would support the notion that 5q 14 syndrome is the same thing. 15 Q. Is 5q- syndrome, as you're calling it, 16 a form of bone marrow depression? 17 A. Ostensibly, yes. It leads to an 18 anemia. It may lead to cytopenias of one type or 19 another, often involving granulocytes. Again, that's 20 a pattern you don't see very often associated with 21 secondary leukemogenesis. 22 Q. What studies are you referring to that 23 show that 5q- cannot be caused by benzene exposure? 24 A. First of all, I think it's misleading 25 to characterize that as a scientist Dr science has AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 105 1 studies that prove a negative. Second of all, 5q-, 2 if you're talking about the loss of the chromosome, 3 I've already testified to the fact that I think 4 involvement of chromosome 5 is consistent with 5 secondary leukemogenesis. 6 If you're talking about 5q- syndrome, 7 there is plenty of evidence to suggest that, with 8 respect to origin, age distribution, prognosis, 9 treatment, and characteristics of the disease, that 10 it's a separate syndrome. I have brought with me 11 several articles that indicate that. 12 Again, if you're asking me to point to 13 studies that prove 5q- syndrome is not related to any 14 type of exposure to benzene, the fact of the matter 15 is science doesn't prove negatives. That's not 16 something that we can do. 17 Q. What is the incidence of MDS? 18 A. It's variants dependent. The only 19 quantitative study that I've seen which is consistent 20 with certainly the clinical impression one sees in 21 the literature is the study in Texas, which showed 22 very clear age dependence. 23 The overall incidence age-adjusted is 24 on the order of .006 per hundred thousand. The 25 incidence in individuals 20 to 29 is on the order of AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 106 1 about that. No. The overall incidence is two to 2 2.9. 3 In the second decade of life it has an 4 incidence of about .06. With age it goes up 5 dramatically. In the seventh decade the incidence is 6 on the order of twenty per hundred thousand. 7 Q. Twenty per hundred thousand? 8 A. Yes. 9 Q. How many people did you have to study 10 to show a significant increase in the incidence of 11 MDS? 12 A. It would depend on the population 13 you're talking about. If you're talking about the 14 second decade of life, where the incidence is 15 extremely low, one would have to-- I can't do it 16 without sitting down with book and a calculator and 17 working through a power calculation, but I can tell 18 you that, based on the relative incidence from one 19 decade to another, it becomes easier the rarer it 20 is. 21 Certainly in-- where you have an 22 incidence of twenty per hundred thousand, in order to 23 see a two-fold increase, which would be significant, 24 you'd have to basically be looking at an incidence of 25 forty per hundred thousand in a given population. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 107 1 Q. But how many people would you have to 2 study in an epidemiological study? 3 A. In order to do that responsibly, I 4 would have to sit down with textbook and a calculator 5 and work it out. I can't do it as we're sitting 6 here. 7 Q. Do you know if any study has attempted 8 to study the effects of benzene or benzene on 5q-? 9 A. Yes. Well, certainly in an 10 occupational setting, benzene itself. 11 Q. Do you know of any studies that have 12 looked for the incidence of 5q- or MDS among 13 benzene-exposed workers? 14 A. When you're talking about 5q-, if 15 you're talking about the chromosomal aberration, 16 benzene workers were studied in that context. 17 Q. Those are the articles you cited 18 earlier? 19 A. They're certainly referenced in the 20 papers that I've provided. Golomb has looked at it. 21 Several have. 22 Q. And these authors have found that there 23 is a relationship, a causal relationship between 24 benzene exposure and damage to the fifth chromosome, 25 correct? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6'19 108 A. If you look at AML associated with 2 exposure to a source of benzene, as I said earlier, 3 you'd see an increased frequency of involvement of 4 chromosome 5. I don't think there is any doubt about 5 that. There are some who will argue that it has been 6 proven directly for benzene. I don't agree that that 7 is necessarily likely to prove to be any different, 8 especially since my own work demonstrates benzene is 9 capable of altering that chromosome along with many 10 others. 11 Q. You agree that benzene causes deletion 12 of the long arm of the fifth chromosome? 13 A. In the context of the evolution of AML, 14 yes. 15 Q. But weren't you using AML to look back 16 and then make your conclusion that there was a 17 benzene-induced event previously? 18 A. (No audible response.) 17 Q. Weren't you using the fact that a 20 worker might or a person might get AML to then 21 conclude that the chromosomal abnormality caused by 22 the fifth chromosome is related to benzene exposure? 23 A. The initial link is between benzene 24 exposure or exposure to chemotherapeutic agents and 25 the evolution of AML. Subsequent to that, it has AVERY/WOODS REPORTING SERVICE, INC. (.303) 825-6119 109 1 been demonstrated there is a very high frequency of 2 involvement of specific chromosomes in AMLs that are 3 associated with the evolution of that disease. 4 Q. Are these studies all involving people 5 who have AML and then are looking backward at their 6 progression? 7 A. Yes. The only opportunity we have to 8 look at, at present, any progressive development of 9 disease is where we have populations that are exposed 10 to significant amounts of benzene. Right now the 11 only one I'm aware of is in China. 12 Q. Which study is that? 13 A. I've referred to it in my CV. It is 14 the NCI study of Chinese workers. 15 Q. Which one is that? Your CV is 16 lengthy. 17 A. There is only one article on the 18 subject. It's a study by Rothmiller. It's a huge 19 study. It's basically epidemiologically based. 20 There are a lot of potential problems with it. But 21 it does certainly provide us with an opportunity to 22 look at heavily exposed individuals. 23 It's the only population that I'm aware 24 of for which we have any characterization at all 25 where we continue to have substantive exposures to AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 110 1 benzene. 2 Q. Did you bring that article there in 3 your book? 4 A. No. 5 Q. That article is a prospective study? 6 A. It's a combination of retrospective and 7 prospective. There are many articles that have come 8 out on them. They vary in terms of what they find, 9 in terms of what they report on. They vary with 10 respect to quality. This is a very, very large 11 study, and it's likely to be associated with 12 production of dozens of papers. 13 Q. What is dose-dependent toxicity? 14 A. Virtually all effects, whether they're 15 positive or adverse, that are associated with 16 exposure to chemicals or drugs are characterized by 17 what's called a dose-response. As you increase the 18 dose, you increase the severity or the frequency of 19 the response and, as you decrease the dose, you 20 decrease the severity or the frequency of the 21 response. 22 Dose-dependent toxicity simply means 23 that the toxicity that's seen is-- follows a 24 dose-dependent-- it can be characterized as a 25 dose-dependent process. Virtually all processes, AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 111 1 including the potential for the development of 2 cancer, are characterized by dose-response. 3 Q. So as you increase the concentration of 4 exposure, you increase the severity of damage, you 5 see bone marrow toxicity? 6 A. Yes. Basically going from no effect to 7 severe bone marrow suppression. But you can look at 8 it two different ways, and both are valid in this 9 case. For a given individual, the probability that 10 they will develop bone marrow suppression is 11 dependent on the dose. 12 As I said before, not everybody that's 13 exposed to even extremely high concentrations of 14 benzene will show bone marrow suppression, but some 15 individuals will. So the fractional response is 16 subject to dose, just as the potential for an 17 individual to develop symptomatology and the severity 18 of that symptomatology can be associated with dose. 19 Q. That would vary from individual to 20 individual? 21 A. To a certain extent, yes. Individual 22 variability is a common feature of dose-response 23 curves that involve populations. 24 Q. And the length of exposure, wouldn't 25 that also increase the severity of bone marrow AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 112 1 toxicity? 2 A. Not necessarily. Depends on what your 3 endpoint is. If an individual is susceptible, 4 there's obviously some minimum duration of exposure 5 that's going to be required to produce effects. For 6 the same interval exposure or duration, you still see 7 individuals that will develop toxicity and those that 8 won't. 9 Q. That would be true at any level of 10 exposure, wouldn't it? 11 A. No. At low levels of exposure, if you 12 increase the duration, you don't necessarily-- if 13 you're below a dose level and you have no 14 demonstrable toxicity, increased duration of exposure 15 is not necessarily going to produce any effect 16 whatsoever. 17 Q. But no one can say that it will not 18 produce such an effect, can they? 19 A. (No audible response.) 20 Q. They can say it, but is there any 21 evidence to suggest that there is a known safe level 22 of exposure to benzene at which bone marrow toxicity 23 will not occur? 24 A. It is misleading, as I said before, to 25 suggest that one can prove a negative. With respect AVERY/WOOS REPORT-LNG SERVICE, INC. (303) 825-6119 113 1 to the concentration of benzene, that is the point of 2 departure between a level that no one will exhibit 3 toxicity following exposure and some other 4 concentration where toxicity can occur. There is no 5 precise dose or duration product I can point to and 6 tell you exactly where that is. 7 Now, having said that, there is plenty 8 of evidence to indicate or to suggest that certain 9 levels of exposure for periods of time ranging 10 virtually to infinity are not associated with any 11 adverse health effects associated with benzene. 12 We're all exposed to benzene every day. 13 And there's no evidence that will support the notion 14 that exposure at those levels is associated with any 15 health risk associated with bone marrow toxicity. So 16 there's plenty of evidence to suggest or to indicate 17 that certain exposure levels are not associated with 18 health effects, and there is evidence to suggest that 19 exposure levels at certain levels are associated with 20 health effects in some individuals. 21 Q. Do you have an opinion as to whether 22 there is a known safe level of exposure to benzene at 23 which the various bone marrow toxicities which we've 24 been discussing will not occur? 25 A. There are-- yes, I do. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 114 1 Q. What's your opinion? 2 A. My opinion is that exposure to levels 3 associated with ambient environmental levels. 4 Q. What is that? 5 A. Let's look at it from the standpoint of 6 what science can-- what one can reasonably, reliably 7 say with respect to the exposure to benzene that's 8 associated with toxicity. 9 The scientific community-- within the 10 scientific and medical community there is certainly 11 consensus that chronic exposure to a hundred parts 12 per million in air of benzene is associated with the 13 potential to develop bone marrow toxicity, bone 14 marrow suppression, cytopenia, aplastic anemia, and 15 all of those individuals go on to eventually develop 16 AML. I don't think there's anyone who would argue 17 with that. 18 The evidence supporting a link between 19 benzene exposure and bone mayor toxicity in any of 20 those endpoints between fifty parts per million and a 21 hundred parts per million is much less cogent, and 22 the strength of that evidence is less. 23 Q. That is based on epidemiological 24 studies? 25 A. Based on epidemiological studies, based AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 115 1 on anecdotal information with respect to occupational 2 settings. That information is much less-- one can be 3 much less confident in exposures at that level. 4 Q. When you say various endpoints-- I'm 5 sorry. Go ahead. 6 A. I personally am concerned about 7 exposures at that level. So I am an individual who 8 thinks that bone marrow toxicity may be encountered 9 in some individuals who are repeatedly exposed to the 10 level of fifty parts per million. I am concerned 11 about that. I can't say that that is a threshold. 12 I'm concerned about exposures, chronic exposures 13 between fifty and a hundred parts per million. 14 Q. Over what time period? 15 A. Over a period of time ranging certainly 16 on the order of years, probably not months, but 17 certainly on the order of years. 18 Q. So one year? 19 A. There are virtually--there are very 20 few cases, even in the epidemiological literature, 21 except where there's arbitrary inclusion of 22 individuals who may have only worked for a very short 23 period of time. The epidemiological literature 24 probably can't support one year of exposure. 25 Certainly exposures somewhere between-- on the order AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 116 1 of five years is certainly significant in the order 2 of a hundred parts per million. And I wouldn't be 3 surprised to see the same at fifty or to see the same 4 at thirty. 5 When one starts talking about 6 exposures, chronic exposures below fifty parts per 7 million, the evidence both in the epidemiological or 8 anecdotal literature becomes far less strong and less 9 valid. There is a great deal of argument and 10 controversy over whether exposures between 11 twenty-five and fifty are associated with any adverse 12 health effects in humans related to bone marrow 13 suppression or the evolution of AML. 14 Below twenty-five, we don't have any 15 data that is really extrapolable or based on risk 16 assessment or other processes that don't involve 17 direct measurement or analysis of exposure 18 scenarios. There's no evidence that at one part per 19 million there are any adverse health effects other 20 than extrapolated again from mathematical models or 21 risk assessments. 22 Q. There are risk assessments which 23 indicate that there would be an increase in leukemia 24 deaths at one part per million exposures, aren't 25 there? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 117 1 A. Risk assessments don't indicate 2 effects, and they are not evidence of causation. 3 They are simply mathematical projections tray are 4 used for calculating probabilities that are useful in 5 setting standards, but are not useful for-- they're 6 based on policy, not science. 7 Q. But there are risk assessments which 8 have been done based on epidemiological studies in 9 the Pliofilm workers and others, and Infante's 10 studies which indicate excess leukemia deaths at one 11 part per million, aren't there? 12 A. No. They project on risk assessments 13 that are made. 14 Q. They project that there would be? 15 A. If you look at the latest Rinsky study, 16 which was published two weeks ago, which again is 17 contrary to the majority of studies that characterize 18 the same exposure, the same population with respect 19 to exposure, the levels of exposure they find 20 associated with bone marrow toxicity are on the order 21 of thirty-four parts per million. And that is far 22 below those that have been seen by others who 23 evaluated that population, going back to Kipin 24 studies. 25 The most recent long evaluation of risk AVERY/WOODS REPORTING SERVICE, INC. (303) ?25-6119 118 1 of leukemia in that population, Paxton, Poston-2 there are several that suggest that the product 3 that's associated with the development of toxicity 4 and increased risk of leukemia is on the order of two 5 hundred parts per million. 6 Q. But there are other analyses which 7 indicate that there is an increased risk at one part 8 per million? 9 A. No. 10 Q. There are not? 11 A. There's no analysis based on exposure 12 data. There are mathematical projections. There's 13 no data base on which to opine that exposure to one 14 part per million will cause leukemia. 15 As a matter of fact, the OSHA standard 16 for exposure to benzene today is one part per 17 million. And, if you look at the criteria for the 18 establishment of that standard, that is an exposure 19 that an individual can be exposed to in a workplace 20 chronically, eight hours a day for forty years, 21 without evidence of adverse health effects. That is 22 a regulatory policy, and it's a standard. 23 Q. Have there been any studies of workers 24 that have been exposed to benzene in a workplace? 25 A. There are studies that include AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 119 1 populations that have had that type of exposure. 2 Epidemiologically, it's included in virtually any 3 epidemiological study. The petroleum workers, they 4 studied workers that have worked for forty years at 5 one part per million, including some of the exposures 6 within cohorts that have been studied in petroleum 7 refineries, workers that have been studied for forty 8 years at one part per million. 9 Evidence to support that one part per 10 million is associated with toxicity is virtually 11 non-existent. There are risk assessments that 12 project an increased risk above background for 13 individuals based on assumptions that are made using 14 the incidence of leukemia in populations that are 15 exposed to much higher concentrations. 16 The assumptions are many. They're 17 based on policy. They're not based on science. A 18 risk assessment is not19 Q. Which study20 A. A risk assessment is not evidence of 21 causation at any given concentration. 22 Q. Which epidemiological study has studied 23 workers for forty years at one part per million? 24 A. I don't-- as we sit here, I don't know 25 how many years the Wong and Raabe study has AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 120 1 captured. That study was forty-two years. That's 2 the population of cohort that they captured. 3 Q. Which study? 4 A. The Wong and Raabe study from '95. 5 Q. What's the name of the study? 5 A. (No audible response.) 7 Q. Is that on your list? You can just 8 tell me which tab it is. 9 A. Number 7. 10 Q. Is that a data analysis? 11 A. Yes. By definition it has to be. 12 Q. Did all the workers studied work forty 13 years in the same industry? 14 A. No. They capture individuals that 15 worked in the industry over that period. Some 16 individuals will. Some individuals won't. 17 Q. How many people worked forty years? 18 A. Excuse me. It's a fifty-three year 19 observation period. Okay. This is a retrospective 20 study that looks at fifty-three years of follow-up in 21 the petroleum industry and characterizes and 22 calculates tie incidence of leukemia related to 23 periods of exposure in ppm years. 24 I'm not sure, as we sit here, that I 25 can tell you precisely what portion of the cohort AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 121 1 worked for what particular period of time. 2 Q. These were mortality studies, weren't 3 they? 4 A. Yes. 5 Q. And they're looking at leukemia as an 6 endpoint? 7 A. Yes. 8 Q. They're not looking for myelodysplastic 9 syndrome or other blood dyscrasias, are they? 10 A. No. 11 Q. Wouldn't you agree with using leukemia 12 as an endpoint in estimating the total risk of 13 benzene exposure? 14 A. To the extent that myelodysplastic 15 syndrome precedes the evolution of leukemia in some 16 majority of individuals, that could be the case, 17 except the transformation rate to AML and secondary 18 myelodysplasia is on the order of eighty percent or 19 greater. So the chance that, in fact, this 20 particular type of study is going to include 21 individuals that have persistent dysplastic 22 phenomena, including leukemia, is relatively small 23 because of the rate of transformation. 24 I do agree that, if one wishes to 25 characterize at any given point in time the incidence AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 122 1 of disease associated with chronic exposure to high 2 levels of benzene, that myelodysplastic syndrome 3 should be included within that rubric. But, from a 4 transformational standpoint, mortality studies 5 capture that population in large part, because the 6 transformation rate is so high. 7 Q. And if those studies showed an increase 8 in the incidence of leukemia, wouldn't that also show 9 an increase in the incidence of MDS? 10 A. That associates MDS preceding the 11 evolution of leukemia, not MDS independent of 12 leukemia, because, as I said, secondary 13 myelodysplastic syndrome, which is a distinct disease 14 from Sq- syndrome, is associated with a very high 15 rate of transformation to AML and very high mortality 16 in and of itself. The transformation usually occurs 17 within a matter of months. 18 Q. Between MDS19 A. And AML. 20 Q. What literature supports that? 21 A. The chemotherapeutic literature looking 22 at secondary myelodysplastic syndrome. The 23 transformation rate is very quick. 24 Q. How about the benzene studies? 25 A. The benzene studies are retrospective. AVERY/WOODS REPORTING SERVICE, INC. (303; 825-6119 123 1 They do not establish quantitatively a link between 2 myelodysplastic syndrome and AML. If you look at the 3 benzene literature itself, you can't draw tat 4 conclusion, because myelodysplastic syndrome has not 5 been included in the studies. 6 Q. You're drawing the conclusion from the 7 chemotherapy studies? 8 A. I'm drawing some conclusion from that. 9 There's an analysis of myelodysplastic syndrome, it's 10 been seen in Chinese workers, again fairly high 11 transformation rate. So some studies are beginning 12 to confirm what we already know from the 13 chemotherapeutic literature. 14 Q. What is the study that just came from 15 China? 16 A. Some of it. 17 Q. Is it the Yin study? 18 A. Some of it. Yin is the first author. 19 There are other authors as well. 20 Q. Does secondary myelodysplastic 21 syndrome-- secondary meaning caused by benzene22 proceed to AML or leukemia? 23 A. I would be surprised if a very large 24 majority did not, probably on the order of eighty 25 percent at least. Whether every one does is, I AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 124 1 think, not a question that I can answer at this 2 time. 3 Q. Other than the Chinese study which 4 you've cited-- and let me get the tab number on that 5 if we could. Was that in your CV? 6 A. What? 7 Q. You were referring to a Chinese study? 8 A. The Chinese study I haven't provided, 9 because I didn't think they were relevant to this 10 particular issue. 11 Q. Not here. Okay. But you're suggesting 12 that study is showing that? 13 A. Myelodysplastic syndrome has been seen 14 in that study along with leukemia. 15 Q. That study indicated an increase of 16 myelodysplastic syndrome? 17 A. That's what I mean by seen. 18 Q. Related to benzene exposure? 19 A. Related to benzene exposure. 20 Q. Does that study indicate what the 21 exposure levels are? 22 A. Within the limits of occupational23 retrospective occupational modeling, yes, it does, to 24 a certain extent. It certainly indicates we're 25 talking about high-level exposure. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 125 1 Q. On the order of fifty parts per 2 million? 3 A. My reading of it would be, at least 4 cumulative exposure-- I don't know where 5 myelodysplastic syndrome falls out in there in the 6 rubric in their exposure characterization-- I would 7 not expect to see them have any different pattern 8 than what's seen with AML. 9 The problem you have in the Chinese 10 study is you have twenty-five thousand workers 11 significantly exposed to benzene. I don't know how 12 many thousand sites. Characterizing the exposures is 13 probably problematic. 14 However, based on individuals that we 15 know have been exposed to high levels in China that 16 are being followed and that have shown already 17 significant signs of bone marrow poisoning, we ought 18 to be able to get a better handle on the nature of 19 the duration and levels of exposure that are 20 associated with it. 21 Q. That hasn't been quantified yet? 22 A. There are-- they've quantizated 23 cumulative exposure for the entire population. I 24 don't think it's a particularly useful25z Q. Do you know how large the population AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 126 1 that was studied? 2 A. They have at least twenty-five thousand 3 captured in their exposure group. And I believe the 4 initial study started out with over five hundred 5 eighteen thousand workers. It's huge, and huge does 6 not necessarily mean good. But it is a very large 7 population. 8 Q. If you could just tell me again the 9 title of that particular study. I believe it's in 10 your CV. 11 A. Now, that one is just one paper in that 12 whole series. That's not one that deals with the 13 specific incidence of MDS. 14 Q. The one that you cited in your CV? 15 A. That one deals-- primarily looking at16 that particular paper looks at parameters in benzene 17 poisoned workers who have not developed leukemia. 18 Q. Which paper is that that we're talking 19 about? 20 A. Rothman, et al. These are individuals 21 that are exposed to high levels. They already have 22 some demonstrable sign of benzene poisoning and 23 toxicity. 24 Q. What year is that article? 25 A. It's in press. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 127 1 Q. This one is? 2 A. Yes. 3 Q. How many of these articles that are 4 listed in press did you bring as part of what you 5 brought here today? 6 A. Those that are listed on the list of 7 references that I provided are here. 8 Q. Can I get a copy of the Rothman 9 article? 10 A. I should think so. 11 Q. It's not out yet I take it? 12 A. No. 13 Q. I'd like to, if I could get a copy of 14 all the articles you've authored in press that were 15 not included in the book. 16 A. I could do that. 17 Q. Okay. Other than the Wong study, were 18 there any other epidemiological studies which 19 indicate-- or the Wong study didn't indicate-- but 20 are there any studies that studied workers working 21 for forty years continuously at one part per million? 22 A. Probably not. 23 Q. Do you know what length of time the 24 workers stay in their jobs, in the same job? 25 A. I think it varies with the industry and AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 128 1 it varies with time. That's one of the problems with 2 capturing occupational populations is how long they 3 stay in the job and where they-- whether or not 4 they're captured in any given cohort. 5 Q. Are you aware of any studies today, as 6 we sit here? 7 A. No. 8 Q. Do you know what the action level is 9 for OSHA? 10 A. In OSHA, the permissible exposure level 11 is one. The action level is, I believe-- I think 12 it's .5. 13 Q. What is the significance of the action 14 level? 15 A. That, in fact, you take steps to reduce 16 the exposure level if, in fact, it reaches that 17 point. It's an effort to prevent approaching the 18 standard. 19 Q. Do you know what is required if the 20 level reaches .5 parts per million by OSHA? 21 A. Specifically what's associated with the 22 actions that are taken at that point in time, no, not 23 as we sit here. 24 Q. How much benzene would an individual 25 absorb working an eight-hour day at one part per AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 129 1 million? 2 A. Three million micrograms. 3 Q. Three million micrograms? 4 A. Yes. I actually calculated-- I 5 actually used that in one of my calculations. On the 6 order of three million micrograms per day or one part 7 per million. I'm sorry. Did you say one or a 8 hundred? 9 Q. One. 10 A. One would be on the order of thirty 11 thousand. 12 Q. That would actually be absorbed? 13 A. If one assumes complete absorption, 14 which is an overestimation, but for the sake of 15 argument you can assume, I think, it's reasonable for 16 comparison purposes, thirty thousand micrograms per 17 day. And it's probably overly conservative in the 18 sense that that assumes inhalation of about ten cubic 19 meters of air in an eight-hour day, and that's 20 probably high. 21 Q. Ten cubic meters is probably high? 22 A. Yes. 23 Q. What rate of absorption a=a you 24 assuming, a hundred percent of what's breathed? 25 A. For the sake of simplicity, yes. AVERY/WOODS REPORTING SERVICE, INC. ~303) 825-6119 130 1 Q. Do you know what studies have been done 2 to study what amount of benzene has been absorbed by 3 inhalation? 4 A. If one looks at animal studies, one can 5 obtain a fairly good estimate. At that level, you're 6 probably talking on the order of somewhere between 7 eighty and a hundred percent. 8 Q. Do you know of any human studies that 9 have been done? 10 A. No. For the simple reason that it's 11 not ethical to expose individuals to levels of 12 benzene in particular, although I think that 13 exposures at the OSHA level are certainly possible 14 and practicable, and that individuals are exposed to 15 levels that are similar to that or at least 16 measurable in other situations. 17 Q. What is your concept of 18 bioavailability? 19 A. Bioavailability is a major tenet of 20 pharmaceutical development, and that is the amount of 21 a chemical or a drug that is actually available for 22 absorption into the body following introduction, 23 whether it's in the gut, on the skin, through 24 inhalation. Bioavailability is the amount of the 25 material that is actually taken in by the body, and AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 131 1 it is usually some fraction of the total to which an 2 individual is exposed. 3 Q. How is that measured? 4 A. There are a number of ways of going 5 about measuring it. The most-- I think the most 6 realistic and accurate approach is to look at the 7 nature of the product and to measure how much of it 8 is available. And there are a couple of ways of 9 doing it. 10 From a worst case point of view, the 11 best way to look at and most likely way, most 12 accurate way to look at bioavailability is to 13 characterize the release of a substance in the 14 physiologic solution based under conditions that are 15 likely to be found where the product is, whether it's 16 the mouth, the stomach, the lungs, the gut, what have 17 you, under conditions that mirror the Ph, time 18 duration of transient physiological conditions. One 19 can use animal data, but that's basically an extra 20 population. 21 Q. Are there any models, established 22 models, that have been established in the scientific 23 community for such a physiological approach? 24 A. The pharmaceutical industry looks at 25 bioavailability all the time. It is a frequent AVERY/WOODS REPORTING SERVICE, INC. (303) 825-519 132 1 component, if not a necessary component, in the 2 submission of pharmaceutical preparations for 3 registration of drugs with the-- certainly with the 4 US FDA and ostensibly world-wide. 5 Q. How do they do that? 6 A. There may be animal studies. There 7 usually are animal studies. There are also studies 8 that look at individual formulations in the 9 variations in either extractability or variability of 10 various preparations. 11 Q. My question was: Are there any 12 established models whereby a physiological model is 13 created to test bioavailability? 14 A. Bioavailability is usually unique to a 15 given preparation or formulation. Because of that, 16 individual character, individual parameters that are 17 used to determine what, in fact, is an appropriate 18 model of bioavailability are case specific. 19 That's similar to many aspects of 20 pharmaceutics and drug development. The individual 21 experiments, the individual results are specific to 22 the agent in question and formulation in question. 23 They aren't applied across the board to everything, 24 but in fact are evaluated on a case specific basis. 25 Q. So there's no accepted model AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 133 1 established in the scientific2 A. There are models that are used all the 3 time. To say that there is a single accepted model 4 is, I think, misleading, because there is no model 5 that is going to be appropriate for every given 6 situation or every given formulation. 7 Q. Now, earlier you said that-- I believe 8 you said that would be a worst case way to test 9 bioavailability. Is that what you said? 10 A. Yes, I believe so. 11 Q. What would a better way to test it? 12 A. Well, one way to look at 13 bioavailability which is done in some cases is in the 14 process of evaluating and range finding for doses in 15 humans is one way to look at bioavailality. 16 Q. By measuring the dose absorbed by a 17 human? 18 A. Yes. 19 Q. Have you ever done a bioavailability 20 study? 21 A. Personally, in the context of support 22 for drug registration, no. In the context o= 23 providing experimental parameters for experimental 24 design, I've done studies that are comparable to 25 bioavailab_1ity in the past. I haven't done any AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 134 1 recently. 2 Q. Have you ever administered-- been 3 involved in any tests administering drugs or 4 chemicals to individuals to test bioavailability? 5 A. No. 6 Q. Are you aware of any ethical standards 7 which would apply to administering drugs or chemicals 8 to humans? 9 A. That sounds to me like an oxymoron. 10 I'm sorry, but standards aren't ethics. Standards 11 are basically regulatory policies. Ethics, I mean if 12 you're going to talk about13 Q. I said ethical standards. 14 A. Well, there are clearly questions 15 related to the ethics of administering certain types 16 of substances to people. That is an ongoing 17 controversy in medicine and science today. 18 Q. Are there ethical considerations which 19 you are aware of which would apply to situations 20 where one wanted to administer drugs or chemicals to 21 humans? 22 A. There are certainly procedures and 23 paradigms that are predicated on ethics that are used 24 in evaluating and administering drugs to humans, also 2S chemicals. There are controversies related to the AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 135 1 administration of chemicals to humans that have no 2 known benefit. That is a continuing issue in the 3 toxicology field and probably will persist for many 4 years to come. 5 Q. Is that also related to the potential 6 harm from the chemical or drug administered? 7 A. If it's an ethical issue, it is not 8 necessarily related to harm at all. I think that 9 certainly, if we're dealing with a substance like 10 benzene, the ethical question of can you 11 intentionally administer benzene to an individual is 12 totally separate and distinct from whether or not it 13 would have any adverse health effect. 14 There's no evidence, as I said before, 15 that exposure to individuals at the level of the OSHA 16 standards have any adverse health effect. One could 17 design a study to look at absorption and 18 pharmacokinetics of benzene following administration 19 of the equivalent of eight-hour, one ppm 20 time-weighted dose without any expectation of 21 producing adverse health effects. However, there, in 22 fact, very well could be and there would be 23 individuals who would say that that was unethical. 24 Q. Would you be one of those individuals? 25 A. No. But I-AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 136 1 Q. You don't think it's unethical to 2 administer benzene to humans? 3 A. I don'-_ think that it would be strictly 4 unethical to administer benzene to an individual in 5 the context of an informed experimental study that 6 could provide information that related to its 7 distribution or metabolism in doses that are not 8 associated with adverse health effects. By the same 9 token10 Q. You said "informed." Do you mean11 A. Excuse me. I haven't finished my 12 answer. By the same token, I recognize the ethical 13 question, and I recognize that there are opinions 14 that differ with that. There are also individuals 15 who would agree with me. It is a controversy. 16 Q. Is benzene a carcinogen? 17 A. Yes, obviously. 18 Q. Would it be ethical to administer a 19 carcinogen to individuals if they were uninformed? 20 A. The issue of ethics and the issue of21 the issue, as I have been trying to say, that is a 22 very controversial area or arena. There are 23 individuals who would agree with me that the 24 intentional administration of a substance for purposes 25 of gaining valuable information with respect to AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 137 1 science is not unethical if it's done in an informed 2 context. 3 What you have to keep in mind, this is 4 an issue related to the ethics dealing with the 5 intentional administration. The fact is we're all 6 exposed to benzene every day. 7 If you drink water that is certified by 8 the Environmental Protection Agency as clean, meeting 9 the environmental standard, you are taking in 10 approximately ten micrograms a day of benzene. If 11 you eat, you're going to be exposed to benzene in 12 eggs, dairy products, in meats. Anything that 13 involves combustion is going to have some benzene in 14 it. So you're ingesting benzene every single day. 15 One can quantitate the amounts. A 16 purveyor of meats or dairy products I don't think is 17 committing an unethical act by providing you with 18 those products to eat, even though they have 19 benzene. So, when you get into questions of ethics, 20 I think you have to deal with issues that relate to 21 dose as well. 22 The intentional administration of 23 benzene de novo by itself is an issue that is 24 currently controversial with respect to the ethics. 25 I'll give you a very good example. One could monitor AVERY/WOODS REPORTING SERVICE, INC. (303) 825-611-9 138 1 the absorption and distribution of benzene following 2 administration of a dose of benzene that would be 3 less than the amount that a smoker gets in a given 4 day. 5 It's ethical to have a smoker smoke and 6 measure benzene absorption or distribution. It is 7 unethical or some people would consider it unethical 8 to give that person the same dose of benzene by 9 itself or a lesser dose of benzene by itself. 10 Q. Do the ethics turn on the-- you 11 indicated that-- would it be ethical to administer 12 benzene to someone for no known scientific purpose or 13 with no perceived benefit to the advancement of 14 medicine or science? 15 A. By itself, no. As a product of-- as a 16 function-- I mean the intentional administration of 17 benzene by itself, no. But the administration of 18 benzene in the context of its presence in foodstuffs 19 or drug products, I don't think there's-- that's an 20 issue. 21 The fact is benzene is present in a 22 great many different things. We're exposed to it 23 every day. There's no such thing as zero. There's 24 no such thing as no benzene. The question is how 25 much is there, and whether it comports with or is AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 139 1 consistent with a dose of benzene that is not 2 encountered in everyday life or that's associated 3 with levels that are-- could produce adverse health 4 effects. 5 The issue we've been talking about with 6 the intentional administration of benzene is an issue 7 now, because there are many very-- there are many 8 individuals right now in the scientific and medical 9 communities that are proposing precisely that, the 10 intentional administration of benzene at doses 11 sufficient to allow us to do reliable measurement of 12 its distribution, metabolism in humans. Some of 13 those individuals are exceedingly well regarded in 14 the scientific and medical communities. 15 Q. Who are they? 16 A. Bernie Goldstein at Rutgers is one who 17 is an advocate. 18 Q. What levels of benzene is he advocating 19 administering? 20 A. Probably on the order of the OSHA 21 standards. 22 Q. One part per million? 23 A. Yes. 24 Q. Would he administer this to unknowing 25 individuals or would he inform them? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 140 1 A. Those studies would obviously be 2 scientifically designed experiments. 3 Q. Would it be unethical to do the 4 experiment without informing the recipients of 5 benzene that they're receiving a carcinogen? 6 A. For those experiments, no. But those 7 are designed experiments with the express intention 8 of administering benzene and only benzene for the 9 purpose of the study. That's totally separate than 10 the dairy farmer who produces milk that may contain 11 trace amounts of benzene. 12 Q. How much benzene is in milk? 13 A. I'm not precisely sure. I'm more-- I'm 14 more confident about the amount that's present in 15 eggs. Eggs have a fairly high concentration of 16 benzene. 17 Q. What is the content of eggs? 18 A. I think I calculated it once. I think 19 that, depending upon who you believe in terms of the 20 analytical measurements, that a boiled egg contains 21 somewhere between ten and fifty micrograms of 22 benzene. But, again, T wouldn't swear to those 23 numbers. I think the range is probably safe. 24 The EPA has measured the average intake 25 of benzene for an individual who is not a smoker or AVERY/WOODS REPORTING SERVICE, INC. (303) 82S-6119 141 1 not exposed to smoking in an occupational setting, 2 and it varies. Various studies I've seen suggest the 3 range of background levels of benzene intake is a 4 hundred and fifty to eight hundred micrograms a day 5 for everyone of us. If you're a smoker, you can 6 multiply that by about three or four. 7 Q. It's not possible to produce eggs 8 without benzene, is it? 9 A. I don't know. It's possible to produce 10 eggs without cholesterol. 11 MR. WHITNEY: I'm not going to qualify 12 the doctor as a poultry expert, so13 MR. WILLIAMS: Do I have your promise 14 on that? 15 Q. (BY MR. WILLIAMS) Could you conceivably 16 do a bioavailability study of benzene available from 17 Orafix Special by placing Orafix Special in people's 18 mouths and then attempting to measure the benzene, 19 labeling the benzene, and then measuring the effect 20 on the person? 21 A. I think that the design of that 22 experiment would be cumbersome and probably less 23 accurate than determining the worst case scenario. 24 That is the amount of benzene that's released in a 25 physiological solution under the conditions that AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 142 1 we're likely to find in the mouth or elsewhere. 2 Q. Could you do it though? 3 A. Pardon? 4 Q. Could it be done? 5 A. I think it would be less reliable than 6 the worst case methodology. 7 Q. That's not my question. 8 A. Could you do it, could you do a bad 9 experiment? Yes. 10 Q. You could do that experiment? 11 A. You could do that experiment. It would 12 not be a good experiment. 13 Q. Would it be ethical to do that 14 experiment, not tell them you were giving them a 1S carcinogen? 16 MR. WHITNEY: Objection. 17 A. If you were doing an experiment for the 18 purpose of measuring benzene, under current standards 19 of ethics in human use or experimentation, one would 20 be required to tell them what you were doing, why you 21 were doing it, and what you were going to measure. 22 Therefore, you could not intentionally give them 23 anything, even if in fact it was candy, if you do not 24 tell them what the purpose is and what it is you're 25 trying to measure. AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 143 1 Q. (BY MR. WILLIAMS) I digressed a little 2 bit, but I asked you questions about levels. I don't 3 believe I ever got an answer to the question of do 4 you have an opinion that there is a known safe level 5 of exposure to benzene at which bone marrow toxicity 6 will not occur. 7 MR. WHITNEY: Objection. I think the 8 question has been asked and answered. 9 MR. WILLIAMS: It wasn't answered. 10 A. I believe there is no evidence that 11 would support a causal relationship between chronic 12 exposure to benzene at one part per million and any 13 adverse health effects in humans. I think that 14 there's no evidence that exposure to ten parts per 15 million, which is above current regulatory standards 16 even in an occupational setting, would produce ill 17 effects. 18 There is controversy associated with 19 that exposure between twenty-five and thirty parts 20 per million, although there's no reliable data. I 21 already discussed what the level of evidence is 22 associated with exposures of fifty parts per million 23 to a hundred parts per million. Somewhere between 24 fifty parts per million and a hundred parts per 25 million ambient exposure there's a probably a level AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 144 1 of benzene that produces a demonstrable effect. 2 Whether that's associated with any adverse health 3 effects, we have no information that would allow us 4 to reach an opinion. 5 I think at the OSHA standard and at 6 concentrations less than the OSHA standard there's no 7 reliable or demonstrable evidence of adverse health 8 effects associated with exposure at that level. 9 Q. (BY MR. WILLIAMS) Is it your opinion 10 that there is a safe level below which bone marrow 11 toxicity will not occur? 12 A. I am saying that there's no evidence to 13 suggest that that level of exposure is associated 14 with any adverse health effects. 15 Q. But are you saying that there is a safe 16 level below which17 A. If your definition18 Q. =- no known bone marrow toxicity will 19 occur? Let me finish my question. 20 A. If your definition of "safe" is that 21 there are no adverse health effects, then we can use 22 the word "safe". What I am saying is that there are 23 no adverse health effects that have been demonstrated 24 associated with benzene exposure at that level. 25 Q. But what I'm asking you for is your AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 145 1 opinion as to whether or not there is a known safe 2 level of exposure to benzene at which bone marrow 3 toxicity will not occur, and, if there is, I want 4 your opinion as to what that safe level is, below 5 which bone marrow toxicity will not occur. 6 A. I think I've answered that, but I will 7 say it once more. Certainly, at the level of one 8 part per million, there is no evidence that repeated 9 exposure, chronic exposure to one part per million in 10 air will produce any adverse health effects, 11 including bone marrow toxicity. 12 I do not believe that one ppm is the 13 demarcation between an exposure to benzene that would 14 produce toxicity and one that won't. One ppm I 15 believe does not result in any adverse health effects 16 including bone marrow toxicity. The precise point at 17 which chronic exposure can lead to the evolution of 18 bone marrow toxicity, I do not know precisely what 19 that concentration is. 20 Q. Is it fair to say you also do not know 21 at what precise point the exposure to benzene will 22 not lead to bone marrow toxicity? 23 A. As I've said before, science cannot 24 prove a negative. I can't answer that question. 25 Q. Would you be speculating to give a AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 146 1 point at which-- below which bone marrow toxicity 2 will not occur in response to benzene exposure? 3 A. With respect to a given concentration, 4 it is not speculation for me to say that there is no 5 scientific or medical evidence that will support that 6 it does occur. That I can do. What I cannot tell 7 you is what concentration of benzene is associated 8 with, what concentration is not associated with. 9 There are no studies that can prove a 10 negative. There are no studies to support that 11 exposure to one part per million will produce those 12 effects, and certainly not at lower levels. 13 Q. But you are unable to say that there is 14 a point below which bone marrow toxicity, MDS, the 15 various blood dyscrasias that we've been talking 16 about so far today will not occur; isn't that true? 17 MR. WHITNEY: Objection. This line of 18 interrogation is becoming harassment. He said you 19 can't prove a negative. 20 Q. (BY MR. WILLIAMS) So you can't give me 21 a point below which it would not occur? 22 A. I can tell you at a given concentration 23 whether there is any evidence to suggest that it can 24 occur. And I'm telling you for purposes of 25 discussion that the current OSHA standard of one part AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 147 1 per million is a concentration of exposure that has 2 not been demons-rated to be associated with any 3 adverse health effects. 4 Q. And what studies show that; you're 5 basing it on what studies exactly? 6 A. Based upon the sum total literature 7 associated with benzene toxicity. There's no8 MR. WHITNEY: Don't cut the doctor 9 off. He's been very patient all day now. 10 A. There's no evidence to support the 11 contention that exposure at the current OSHA standard 12 produces bone marrow toxicity. 13 Q. (BY MR. WILLIAMS) There's no such 14 evidence? 15 A. There's no such evidence that indicates 16 exposure at that level is associated with adverse 17 health effects. The evidence in the clinical 18 literature does not support that. 19 Q. You're not aware of any cases in any of 20 the studies where individuals were exposed to 21 approximately one part per million and developed 22 leukemia? 23 A. The design of retrospective studies 24 involves the selection of cohorts that are exposed to 25 a substance, and hopefully, under a control or not, AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 148 1 in any retrospective study you expect to see cases of 2 disease that appear spontaneously at the same rate as 3 they would in the general population. 4 It is, therefore, misleading to suggest 5 that in any given population you won't have 6 spontaneous disease occurring. I cannot tell you 7 that there has not been a case of leukemia or 8 myelodysplasia that has occurred in individuals 9 exposed to benzene at one part per million or less. 10 What I can tell you is it is much more probable than 11 not that, if they did, it is a spontaneous lesion and 12 not one associated with benzene. 13 Q. Have you ever testified before that 14 there is a level of exposure to benzene which you 15 would consider to be safe? 16 A. I have testified that I believe benzene 17 toxicity follows a threshold. I have discussed the 18 evidence many times with respect to the nature and 19 strength of the evidence associated with a given 20 exposure scenario, much as I have today. 21 Q. But I'm asking you, have you ever 22 testified before that there is a level of exposure to 23 benzene that you consider to be safe? That's a very 24 simple question. 25 A. I believe i have, and I believe I said AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 149 1 it today. We have been talking repeatedly about one 2 part per million. And I don't think exposure to less 3 than one part per million is of any consequence. 4 Q. So it's your opinion that exposure to 5 one part per million is safe, and that below that one 6 cannot get any bone marrow toxicity? 7 A. It's my opinion that exposure to one 8 part per million will not produce bone marrow 9 toxicity, and certainly exposure less than that is 10 not associated with bone marrow toxicity. 11 Q. Is it your opinion that that is safe? 12 MR. WHITNEY: Objection. 13 Q. (BY MR. WILLIAMS) At that level? 14 MR. WHITNEY: He just answered it. 15 A. I believe I've answered that. 16 MR. WILLIAMS: Read the question and 17 answer back, please. 18 (Whereupon, the reporter read the 19 question on page 149, line 4, and the answer on page 20 149, line 7.) 21 Q. (BY MR. WILLIAMS) Would you consider 22 one part per million to be a safe level of benzene 23 exposure? 24 MR. WHITNEY: Objection. He answered 25 the question. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 150 1 Q. (BY MR. WILLIAMS) Do you consider-- is 2 it your testimony-- I just want to make sure we have 3 it all straight here-- that exposure to benzene 4 levels of one part per million is safe, and below 5 that level there would be no chance of having bone 6 marrow toxicity? 7 MR. WHITNEY: Objection again. You 8 can answer one last time, and after that I'm going to 9 instruct you not to answer, because that is 10 harassment. 11 MR. WILLIAMS: Well, as long as we get 12 an answer to the question. 13 A. I believe that, based upon all the 14 evidence that we've discussed today that I've 15 referred to with respect to what we know about 16 benzene toxicity, bone marrow toxicity, that the 17 chances of developing a particular manifestation of 18 bone marrow toxicity in an individual exposed to one 19 part per million is the same chance of an individual 20 who is exposed to any concentration of benzene or no 21 benzene. It's the same. There's no evidence to 22 suggest that that level of exposure is associated 23 with bone marrow toxicity. 24 Q. (BY MR. WILLIAMS) Do you consider that 25 to be a sate level of exposure as a toxicologist? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 151 1 A. If you define "safe" as meaning that 2 there are no adverse health effects associated with 3 that exposure, then I can accept your definition of 4 "safe". 5 Q. I thought your definition of "safe" is 6 a level below which no bone marrow toxicity will 7 occur? 8 A. Well, I've said that probably ten times 9 this afternoon. 10 Q. As a toxicologist, can you state that 11 the level of one part per million ambient exposure is 12 a level below which there would be no bone marrow 13 toxicity? 14 A. I'm saying that there is no evidence 15 that that level of exposure could produce bone marrow 16 toxicity. 17 Q. Can you or can you not, as a 18 toxicologist, say that there is a safe level below 19 which bone marrow toxicity couldn't be produced? It's 20 a yes or no question. 21 A. The nature of scientific inquiry and 22 evidence requires that one, in fact, use data and 23 evidence to support an opinion. I am saying there is 24 no evidence that I can point to that will allow me to 25 say that exposures at that level are associated with AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 152 1 any adverse health effect. 2 Q. But, as a toxicologist, can you 3 pinpoint a point below which there would be no 4 adverse health effects, no risk of5 A. I cannot. 6 Q. I'm not asking you for a recap of 7 epidemiological studies. I'm asking you, as a 8 toxicologist, about benzene, what you know about 9 benzene, and how it's metabolized, and how it affects 10 bone marrow; can you state that there is a point 11 below which adverse bone marrow effects cannot 12 occur? 13 A. You're asking me to essentially if I 14 can prove a negative, and I cannot do that. 15 Q. Can you do that16 A. As a scientist I cannot. 17 Q. -- as a toxicologist? 18 A. As a scientist, I cannot absolutely say 19 that something will not happen. There's a finite 20 chance that anything can happen. I'm saying there's 21 no evidence to suggest that benzene at those 22 concentrations will produce that type of an effect. 23 Q. You're basing it on the studies you 24 brought today? 25 A. And the literature associated with AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 153 1 benzene in general. 2 Q. As a scientist, as a toxicologist, you 3 cannot say that below a certain point there would be 4 no effects? 5 MR. WHTTNEY: Objection. He's 6 answered the question. 7 Q. (BY MR. WILLIAMS) Is that correct? 8 A. I've already stated what the 9 restrictions are placed upon me as a scientist in 10 rendering an opinion. 11 Q. Right. With those restrictions in 12 mind, as a scientist, as a toxicologist, you can't 13 say that there's a point below which-- there's a 14 point of benzene exposure below which there would be 15 no adverse bone marrow effects? 16 MR. WHITNEY: Objection. He's 17 answered the question. Why are you pursuing this? 18 He's answered the question. He has answered the 19 question. You don't like his answer. He's answered 20 it. 21 MR. WILLIAMS: Calm down, Dan. Go 22 ahead, Doctor. 23 A. I believe I've answered the question. 24 Q. (BY MR. WILLIAMS) Is the answer no, you 25 can't? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 154 1 A. I've stated I cannot prove a negative. 2 Q. So you can't state a point below which 3 there would be no adverse effects as a scientist? 4 A. As a scientist, I cannot tell you 5 absolutely that the sun will nor- rise in the west 6 tomorrow. But also, as a scientist, I can tell you 7 that every piece of information I know or have a: my 8 disposal would lead me to conclude that the 9 probability of that happening is virtually nil. 10 I have essentially said the same thing 11 with respect to benzene exposure at the level of one 12 part per million. 13 Q. Are there any studies which establish a 14 minimum amount of benzene necessary to cause adverse 15 bone marrow effects? 15 A. Are you talking about a cumulative 17 dose? Are you talking about an absolute amount? Are 18 you talking about a concentration? 19 Q. Any of the three. 20 A. Well, they're different. We've already 21 discussed the issues, the evidence related to chronic 22 exposure to a concentration of benzene in air of a 23 hundred parts per million, fifty parts per million, 24 what have you, if that's your definition. 25 And the answer is yes, there is AVERY/WOODS REPORTING SERVICE, INC. !303) 825-:1-19 155 1 evidence to suggest that chronic exposure to benzene 2 at a hundred pa=is per million is toxic to bone 3 marrow. 4 Q. Is that a minimum? Are there studies 5 that have established a minimum level of benzene6 A. We've been through that. 7 Q. -- necessary to cause8 A. And we've been through that. That's 9 the same discussion. I've related to you what the 10 evidence is associated with exposures to a hundred 11 parts per million or greater. The evidence is less 12 reliable between fifty and a hundred13 Q. Okay. 14 A. -- so on and so forth. 15 Q. Are there any studies that establish a 16 minimum level of benzene necessary to-- minimum 17 amount of benzene ingested orally necessary to cause 18 a bone marrow toxicity? 19 A. One can relate-- one can relate 20 absolute amounts between-- of a substance between 21 inhalation and oral. For example, we've basically 22 done that when we discussed exposure at the one ppm 23 standard in air by OSHA. It represents about thirty 24 thousand micrograms per day, which would be the same 25 dose that you would receive if you ingested the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 156 1 thirty thousand micrograms per day. One can do it at 2 a hundred parts per million. One can do it at fifty 3 parts per million. 4 The problem that you get into, 5 depending upon what question you're asking, is that 6 the product of cumulative exposure is not necessarily 7 related to toxicity. It may roughly mirror it. But, 8 if there is a threshold, a concentration below which 9 no toxicity is seen, cumulative exposure can be 10 misleading. 11 Let me give you an example. The 12 epidemiological studies, for reasons that are based 13 on limitations in what they can measure, tend to 14 relate everything to cumulative exposure. Dr. Wong's 15 study talks about risk of leukemia below and above 16 two hundred ppm years. 17 Two hundred ppm years is a product. It 18 could represent exposure to one ppm for two hundred 19 years or exposure to two hundred ppm for one year. 20 Those are basically totally different scenarios. 21 I personally would have no concern 22 about exposure to one ppm for two hundred years. 23 Obviously, two hundred years is ridiculous. But for 24 that I would expect absolutely no relationship with 25 leukemia. On the other hand, exposure to two hundred AVERY/WOODS REPORTING SERVICE, INC. !3~3) 825-6119 157 1 ppm for one year could be significant. 2 Now, for both of those we can calculate 3 an absolute dose. That is why, when I have evaluated 4 the potential exposure scenarios in this case, I have 5 basically expressed them in amounts per day as 6 opposed to some total number. 7 MR. WILLIAMS: Let's take a break. 8 (Whereupon, at 2:42 p.m., a recess was 9 taken.) 10 Q. (BY MR. WILLIAMS) Doctor, when were you 11 first contacted in this case? 12 A. Mid-July, I believe. 13 Q. Who were you contacted by? 14 A. Mr. Whitney. 15 Q. And what were you told at that time? 16 A. I was asked if I would evaluate the 17 medical records and information available on the 18 product Orafix, and arrive at a conclusion as to the 19 potential relationship between exposure to benzene 20 and the development of Ms. Lakie's disease. 21 Q. This was in July of '95? 22 A. Yes. 23 Q. Do you have a-- subsequently enter into 24 a retainer agreement with Mr. Whitney's firm? 25 A. I arrived at an agreement with respect AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 158 1 to serving as a consultant and expert. I wouldn't 2 characterize it as a retainer. 3 Q. Okay. When was that agreement entered 4 into? 5 A. At approximately the same time. I 6 believe he contacted me by phone first, and then sent 7 me the material and a letter outlining the issues in 8 the case. 9 Q. Did you-- is this agreement in writing? 10 A. Our agreement? 11 Q. Yeah. 12 A. No. 13 Q. Can I see your file? 14 A. (Complying.) 15 Q. Did you keep time records on your time 16 spent in this case? 17 A. Yes, partially. I have included there 18 a record from September through preparation for a 19 deposition today. I have a previous invoice that I 20 submitted and was paid that I cannot find a copy of. 21 As I sit here, I recall that that was on the order of 22 seven thousand dollars. 23 MR. WILLIAMS: Let's mark this Exhibit 24 4. 25 (Whereupon, a document was marked Irons AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 159 1 Deposition Exhibit 4 for identification by the 2 reporter.) 3 Q. (BY MR. WILLIAMS) Was the first invoice 4 through the first date on this time sheet which is 5 marked Exhibit 4? 6 A. It was up to that. I believe it ended 7 in September. 8 Q. Okay. So it's for the initial hours 9 you spent? 10 A. Yes. 11 Q. And would that include the days and 12 hours each day you spent reviewing the materials? 13 A. Yes. 14 Q. (BY MR. WILLIAMS) Do you have a copy of 15 that invoice, Dan? 16 MR. WHITNEY: Probably. 17 MR. WILLIAMS: Can I get a copy of 18 that? 19 MR. WHITNEY: (Indicating.) 20 Q. (BY MR. WILLIAMS) And what is-- is this 21 second invoice through April 8 complete? 22 MR. WHITNEY: That's not an invoice. 23 A. That's not an invoice. 24 Q. (BY MR. WILLIAMS) I'm sorry. Time 25 sheet. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 160 1 A. It doesn't include preparation. It 2 doesn't include today or yesterday in preparation for 3 this deposition, but up until then it's accurate. 4 Q. It's accurate through the 8th? 5 A. Yes. 6 Q. And, between the 8th and yesterday, did 7 you spend any time on this? 8 A. I don't believe so. If so, it was on 9 the order of a half hour or so prior to yesterday. 10 Q. And what did you do yesterday in 11 preparation for today's deposition? 12 A. Mr. Whitney-- I met with Mr. Whitney to 13 go over the essence of my opinion as it related to 14 this case, and to go over the documents that I would 15 be producing today. 16 Q. When did you meet with Mr. Whitney? 17 A. Yesterday afternoon. 18 Q. What time was that? 19 A. I think it was one o'clock or a little 20 after. 21 Q. Did you meet at your office? 22 A. Yes. 23 Q. How long did you meet for? 24 A. Till approximately 5:00 or 5:30. 25 Q. And you essentially went over the AVERY/WOODS REPORTING SERVICE, INC. x:303) 825-6119 161 1 opinion which is part of Exhibit 3; is that a fair 2 statement? 3 A. Yes. 4 Q. Do you have any new opinions to add to 5 what you already stated in your initial opinion 6 prepared in September? 7 A. I went over further calculations I'd 8 done with respect to various exposure scenarios which 9 are not present in my report because I didn't have 10 the information. 11 Q. Is that reflected on this yellow sheet 12 with calculations in Exhibit 4? 13 A. Yes. 14 Q. Why don't you tell me what those are? 15 A. I went through a variety of estimates 16 for potential exposure to benzene associated with Ms. 17 Lakie's use of Orafix, a range of different estimates 18 based on widely different assumptions. In my initial 19 report, I based my conclusions based solely on Dr. 20 Jacobus's analysis. 21 I also performed a number of other 22 calculations and compared those levels to levels that 23 are associated with benzene toxicity. 24 Q. Can I see that? 25 A. (Complying.) AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 162 1 Q. What are your-- did you calculate the 2 absorption at various levels of assn=lions, at 3 different assumptions? 4 A. I'm not sure I understand the 5 question. What I did-- first of all, I still think 6 that Dr. Jacobus's analysis of bioavailability is the 7 most likely, the most reasonable analysis. 8 Nevertheless, I used a number of other assumptions to 9 evaluate the potential exposure scenario. 10 What I determined as a worst case 11 scenario was I assumed a hundred percent 12 bioavailability of benzene, which I think is not 13 supportable, but for purposes of assumption and 14 discussion I did that. I then determined, based upon 15 what I have been told, the worst case scenario for 16 the amount of benzene that is present in the original 17 Gantrez. I assumed a high level-- I assumed a level 18 of Gantrez in Orafix. 19 Assuming a hundred percent 20 bioavailability, I used no corrections for absorption 21 and calculated, based upon Ms. Lakie's testimony, the 22 amount of material she used over a thirty-day period, 23 translated that into grams, and calculated based upon 24 assumption of the highest level of benzene in 25 Gantrez, highest level of Gantrez in orafix, and no AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 163 1 corrections for bioavailability what the total amount 2 of benzene would be, in other words assuming that 3 every amount of benzene that could be associated with 4 the product was absorbed. 5 And I used those numbers and compared 6 those to values of exposure on a daily basis that are 7 associated with the OSHA occupational standard or 8 with adverse health effects. I then went through9 Q. Let me interrupt one second. Did you 10 do a daily dosage? 11 A. Yes. 12 Q. Assuming a hundred percent absorption? 13 A. Right. Based upon worst case numbers, 14 I obtained a range of exposure between nine thousand 15 and ten thousand micrograms per day. 16 Q. What's the range based upon? 17 A. Based upon-- she gave two different 18 numbers with respect to her use of a large tube or a 19 small tube, which have different amounts in them. 20 And if you use-- if you extrapolate those into days, 21 you come up with slightly different use, like between 22 two and 2.4 grams of Orafix. And I took those 23 numbers and basically used those to estimate a 24 range. 25 Q. And your range is nine thousand to ten AVERY/WOODS REPORTI.NO SERVICE, INC. (303) 825-6119 164 1 thousand eight hundred micrograms per day? 2 A. Micrograms per day, assuming total that 3 the amount of benzene present was always at the level 4 of the highest amount present in Gantrez, the Gantrez 5 was present at fifteen percent all the time in 6 Orafix, and that there is a hundred percent 7 absorption. 8 Q. And what percentage of benzene did you 9 assume was in the Gantrez? 10 A. .3 percent. 11 Q. What did that translate to in terms of 12 the Orafix Special as in terms of parts per million? 13 A. Parts per million is a relative term. 14 I mean parts per million in Gantrez is a relative 15 term. I think it's more-- it makes more sense to 16 talk about absolute amounts. 17 Q. Okay. What does .3 percent benzene in 18 Gantrez translate to? 19 A. Well, three percent times fifteen 20 percent times two to 2.4 grams gives you basically 21 .009 to .011 grams per day of product, which is 22 equal to nine to ten micrograms per day or nine 23 thousand to ten thousand micrograms per day of 24 benzene. 25 Q. So-- I'm sorry-- you're assuming three AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 165 1 percent or .3 percent, .3 percent benzene in the 2 Gantrez, right? 3 A. You know, actually you're right. This 4 number overestimates by an order of magnitude the 5 amount that's really present, because I took the 6 three-tenths of a percent. It should have been three 7 percent, not three-tenths of a percent, so this 8 number is actually divisible by ten. It's nine 9 hundred to a thousand eighty, not nine thousand to 10 ten thousand. 11 Q. Whichever figure you use, nine hundred 12 to a thousand, nine thousand, ten thousand, or 13 Jacobus's figures, does it change your opinions or 14 your conclusions in the case? 15 A. No. No. Basically, even assuming the 16 numbers I have that have a mathematical error in 17 them, the level of exposure is less than the 18 occupational standard of an individual exposed to one 19 part per million. 20 Q. Is that pretty much the basis for your 21 opinion in the case that exposure is insufficient to 22 cause the disease? 23 A. It is one of my opinions. Causation is 24 an issue that relates to, one, the plausibility that 25 the disease is associated with the exposure at any AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 166 1 level, what the dose is, and what the likelihood is 2 the disease is caused by that exposure. 3 In this particular case, I believe that 4 5q- syndrome is an independent and distinct entity, 5 it's not associated with secondary myelodysplasia, 6 and that the incidence of that disease in Mrs. 7 Lakie's age group is high relative to the general 8 population. 9 Q. What is the incidence in her age group? 10 A. It is between seventy and seventy-nine, 11 it's approximately twenty per hundred thousand. 12 Q. Between seventy and seventy-nine? 13 A. Age group. 14 Q. 5q-? 15 A. Or the incidence of myelodysplastic 16 syndrome in total is on the order of twenty per 17 hundred thousand. The 5q- syndrome is associated 18 with individuals roughly between the ages of the 19 mid-forties through the eighties, with a higher 20 incidence that is at least reflected in the 21 literature of occurring in the fifth and sixth 22 decades. 23 Q. Okay. So I don't want to lose these 24 points as we go along. In the age group seventy to 25 seventy-nine, the incidence of MDS is twenty -c a AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 167 1 hundred thousand? 2 A. Yes, a- least in one study. 3 Q. Do you have figures on what the 4 incidence would be in the sixty to sixty-nine age 5 group? 6 A. No, I don't. No, I don't. Certainly, 7 if you reflect on the studies of 5q- syndrome, the 8 typical patient is a female, age greater than fifty 9 or around, within the fifth decade or later, that 10 presents with a refractory anemia. 11 Q. Right. Just in terms of incidence, do 12 you have any figures on the incidence of 13 myelodysplastic syndrome, 5q-, in any of these age 14 groups? 15 A. For age-- for age corrected or age 16 independent, it's on the order of two to 2.9, I 17 believe, 2.3. 18 Q. In total population? 19 A. Per-- yes, or-- it's either total 20 population or males. 21 Q. Or males? 22 A. Or males 23 Q. Is that what you're talking about, MDS, 24 5q-? 25 A. No. For total MDS. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 168 1 Q. Do you know of any figures for 5q-? 2 A. For a precise number, I do not know of 3 a study that provides that information. 4 Q. Okay. 5 A. The point I was making was that Ms. 6 Lakie falls into a category that is frequently 7 reported as being associated with 5q- syndrome, that 8 its prognosis and presentation is different than that 9 that's associated with secondary myelodysplasia. 10 Therefore, apriori her disease does not 11 constitute and her presentation was not one that I 12 would find to be what you'd expect to see following 13 exposure to benzene. Had I evaluated the 14 dose-response, the data with respect to the potential 15 exposure to benzene, its end product, I also don't 16 see that, in fact, the level of exposure would 17 constitute that which is associated with the 18 production of toxicity associated with benzene. 19 Q. That was my initial question. That was 20 with respect to the OSHA standard, correct? 21 A. Yeah. The OSHA standard I used 22 strictly as a matter of comparison. I also compared 23 it with exposures we've discussed today in terms of 24 where there's varying levels of evidence to indicate 25 bone marrow toxicity, and I calculated those in terms AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 169 1 of the absolute amount that would be associated with 2 that exposure. So those are, in fact, the 3 comparisons that I made. 4 Q. That's what you used for that aspect of 5 your opinion related to dose? 6 A. Yes. 7 Q. Okay. What medical records did you 8 review, and when did you review them? 9 A. I reviewed-- well10 Q. Let's pull them out. Are they all 11 there? 12 A. They're all there, and they're all 13 over. 14 Q. You mean they're all mixed up? 15 A. Yeah. 16 Q. Do you recall which medical records you 17 reviewed? 18 A. (No audible response.) 19 Q. Are these all medical records, or does 20 this also include depositions? 21 A. It includes depositions. It includes 22 everything that I received to my knowledge. I 23 included medical records, and the reports that 24 characterize basically these notes are obviously a 25 very small reflection of the medical records, but AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 170 1 those reflect the points that I made at the time I 2 read the records. 3 Q. Why don't you number these yellow pages 4 which are part of Exhibit 4, and we car refer to them by page number if we need to? 6 A. (Complying.) 7 Q. So page 3, you just numbered the notes 8 you made on medical records which you reviewed? 9 A. Yes. 10 Q. Did you review the records from Dr. 11 Swerdlow and MCV? 12 A. Yes, I did. 13 Q. Did you review the records from the 14 Mayo Clinic? 15 A. I'm not sure precisely what you're 16 referring to. 17 Q. That would be-- you indicated that you 18 did in your report on September 12? 19 A. I'm just not recollecting precisely 20 which records came from which21 Q. Let me ask you this: Does that top 22 paragraph on page 2 of your report, does this pretty 23 much give a complete recitation of the records that 24 you reviewed? 25 A. At the time of this report, yes. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 171 1 Q. Okay. Had you reviewed medical records 2 subsequent to the report? 3 A. Not medical records per se that I 4 recall. I have reviewed additional reports and other 5 material that I've received. 6 Q. Have you received any ocher medical 7 records since the date of your report? 8 A. I don't specifically recall. 9 Q. Did you10 A. I could look through the stack here, 11 but I also don't think that what I have here is going 12 to tell me precisely when I received it. 13 Q. Okay. Do you agree with Ms. Lakie's 14 treating physicians as to the diagnosis of her 15 disease? 16 A. 5q- syndrome, refractory anemia with 17 ringed sideroblasts. Based upon the descriptions 18 I've seen, I see no reason to disagree with that 19 diagnosis. 20 Q. The diagnosis is myelodysplastic 21 syndrome, 5q-, and then with the other things you 22 mentioned, a refractory anemia, ringed sideroblasts, 23 leukopenia, hypercellular bone marrow? 24 A. At the risk of quibbling, I'd say that 25 myelodysplastic syndrome is basically the broader AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 172 1 rubric under which refractory anemia is seeded. And 2 that is why the diagnosis is there. It isn't 3 myelodysplastic syndrome and refractory anemia. 4 Q. Okay. It's myelodysplastic syndrome, 5 5q-? 6 A. 5q- syndrome associated with a FAB 7 classification of refractory anemia with sideroblasts 8 in the context of myelodysplastic syndrome. I have 9 no problems with that. 10 Q. It's under the rubric of 11 myelodysplastic syndrome? 12 A. Yes. 13 Q. Her disease is under that rubric? 14 A. Yes, it is. 15 Q. The FAB classifications are not 16 cytogenetic classifications, are they? 17 A. They're not even based upon the 18 cytopenias per se. The strict FAB classification is 19 based upon the bone marrow morphology. 20 Q. Okay. When did she-- in your review 21 and in your opinion when did she first-- when did she 22 come down with myelodysplastic syndrome? 23 A. Can I24 Q. Sure. 25 A. I believe there's one report by Dr. AVERY/WOODS REPORTING SERVICE, INC. (303) 825--119 173 1 Swerdlow that indicates that the macrocytic anemia 2 was present as early as 1988. Somewhere I may have 3 the precise date. But if, in fact, that's accurate4 and I have no reason to believe it isn't-- that 5 would, I think, be consistent with when it was first 6 apparent. 7 Q. The myelodysplastic syndrome? 8 A. Yes, because that's part and parcel of 9 the refractory anemia. 10 Q. Okay. Would the clonal aberration have 11 been apparent at that point? 12 A. Most likely, yes. Most likely I say13 I never say never in this field-- but most likely, 14 yes. 15 Q. You expect the clone to be present? 16 A. Be present at the time of diagnosis, if 17 there were sufficient numbers of cells present from 18 the clone. But, of course, there again with 19 diagnosis you expect there would be, because there 20 would be a reason for performing the test in the 21 first place, which is the symptomatology. 22 Q. Which does23 A. The cytogenetic, the bone marrow 24 characterization. 25 Q. Do you know when that was performed? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 174 1 A. I could find it relatively easily. I 2 don't know precisely. Wait a minute. I believe it 3 was in October. 4 Q. Which year? 5 A. '90. 6 Q. Okay. 7 A. My point is that you would most 8 frequently find it associated with the manifestation 9 of the anemia. When you expect to see it is when 10 it's most frequently seen. 11 Q. In what type of cases? 12 A. In most cases in myelodysplastic 13 syndrome, if you're going to find a clone aberration, 14 it tends to be present at the time of diagnosis. 15 It's the earliest finding with respect to a genetic 16 finding when you see it. 17 Q. Now, part of the symptoms of Ms. 18 Lakie's disease include bone marrow depression; is 19 that correct? 20 A. Well, technically that's not a 21 symptom. It's a sign. But bone marrow, yes. She 22 has an anemia, which is consistent with bone marrow 23 suppression, and she's got a cytopenia, predominantly 24 of neutrophils, which is consistent with bone marrow 25 suppression. And all of that is consistent with what AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 175 1 you usually see in secondary myelodysplastic 2 syndrome. 3 Q. Why is that? 4 A. Because, as I said before, you usually 5 see a thrombocytopenia or a lymphocytopenia, one or 6 the other or both. Those are usually the cell lines 7 that are predominantly involved. 8 In spontaneous cases of refractory 9 anemia, one tends to see neutrophils predominantly 10 involved. And that's a pattern you don't see 11 following benzene usually. 12 Q. Is this based upon diagnostic studies? 13 A. Based upon characterization of patients 14 that have appeared in the literature as well as what 15 we know about patients following chemotherapy. 16 Q. These are based on review of literature 17 that you've done? 18 A. Yes. 19 Q. You don't treat patients; is that 20 correct? 21 A. I do not treat patients. I do consult 22 in differential diagnoses of hematologic diseases 23 based on characterization of diagnoses and laboratory 24 findings. 25 Q. So you haven't treated patients with AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 176 1 5q-? 2 A. No, I have not. 3 Q. Which studies indicate that depression 4 of the neutrophils is not something that would be 5 associated with benzene exposure? 6 A. Again, you're asking me to prove a 7 negative. What I can do is point to studies that 8 show involvement of decrease in platelets and other 9 lymphocytes, with a relative sparing of neutrophils. 10 Some of the Aksoy studies demonstrate that. 11 The Goldwater study is the first 12 controlled study of exposed workers, and that study 13 characterizes absolute lymphocytopenia as one of the 14 first findings, and the relative sparing of 15 neutrophils. You'll find references to that 16 sporadically throughout the early literature on 17 benzene. And it's also consistent with what's seen 18 in the chemotherapy, where you don't have complete 19 presence of the bone marrow to begin with. 20 My point there being, if you give a 21 dose of bone marrow that ablates the bone marrow, you 22 don't have enough of anything present that you can 23 point to. And that frequently is seen following 24 inventive chemotherapy. 25 Q. Other than the study-- is the study you AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 177 1 mentioned just now Goldwater? 2 A. Goldwater. 3 Q. Are there any studies which indicate 4 that? 5 A. I believe several clinical-- at least 6 one clinical review by Bernie Goldstein confirms 7 that. 8 Q. Is that included in your materials 9 today? 10 A. No. 11 Q. Is the Goldwater? 12 A. Yes. 13 Q. Okay. Which tab is Goldwater under? 14 A. Three. 15 Q. And which Goldstein article were you 16 referring to? 17 A. One of the reviews he's written in the 18 last several years. I couldn't, as we sit here, tell 19 you precisely. This is not-- this concept is not 20 arcane. It's referred to often in the literature. 21 And I think it's reasonably well accepted by most 22 people in the field. 23 Q. Do you know what Ms. Lakie's leukocyte 24 count is now? 25 A. As we sit here, no. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 178 1 Q. Do you know what her platelet count is? 2 A. No. Certainly everything that we have 3 reviewed in terms of her medical records suggests 4 that it was normal, low normal. 5 Q. Wasn't her platelet count, in fact, low 6 in August of '95? 7 . A. Her platelet count, I didn't see any 8 numbers that were consistent with a problem with 9 platelets as in a thrombocytopenia. Relative 10 decreases in platelets relative to her initial 11 presentation I do believe I saw. 12 But I didn't see any numbers that were 13 outside-- that were basically below the range of 14 normal function, which would be certainly below fifty 15 thousand per cubic millimeter. Something in that 16 range I didn't see. 17 Q. But they were below normal range for 18 that test than one would expect to find? 19 A. Within a normal range, but not a 20 presentation-- I would say her platelets were 21 marginally normal. She certainly would not be 22 characterized as having thrombocytopenia. And that 23 is not the characterization that her treating 24 physicians gave either. 25 Q. But they were lower than normal, they AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 179 1 were lower than the normal range? 2 A. They were not physiologically below a 3 range of normal function. And I don't believe that 4 the early measurements were necessarily below a 5 normal range, depending upon what range you're going 6 to call normal. 7 Q. You're referring to the range in August 8 of '95? 9 A. Specifically in August '95 or when she 10 presented are you talking about? 11 Q. When she presented. My. question was 12 August '95. 13 A. I'd have to look at that. I'm not 14 sure. 15 Q. You don't know, as we sit here today? 16 A. I don't. I don't think it's relevant 17 to the issue. 18 Q. Why is that? 19 A. Because that's20 Q. When she was diagnosed with the 21 disease? 22 A. She was diagnosed with the disease in 23 basically '90.That's five years prior. 24 Q. Of what significance is that? 25 A. Actually I have noted here in October AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 180 1 of '90 her platelets were normal. That's my note 2 based upon my review of that. 3 Q. Okay. Of what significance is that? 4 A. It's just not a pattern that I think is 5 consistent with what you'd expect if-, in fact, at 6 that point in time she was being exposed to benzene 7 at levels that would produce bone marrow toxicity. 8 I'd expect to see a lower platelet level, and the 9 neutrophils to be actually spared. 10 In her case, she has lower neutrophils, 11 relative sparing of lymphocytes, relative sparing of 12 platelets. 13 Q. And low red blood? 14 A. Yes. 15 Q. And she did have leukopenia? 16 A. Marginally, yes. Her white count was 17 thirty-six hundred. That's not leukopenic by most 18 normal ranges. That's marginal. That's low normal. 19 Q. And-20 A. She had a macrocytic anemia, a slightly 21 lower hemoglobin. 22 Q. And you do see macrocytic anemia in 23 conjunction with benzene cases, don't you? 24 A. It's one of the findings that has been 25 seen, but it's only one. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 181 1 Q. Ms. Lakie also has a functional 2 abnormality in the growth of her blood precursor 3 cells, doesn't she? 4 A. That comes with the disease. 5 Q. That's part of her disease? 6 A. Yes. 7 Q. Do you have an opinion that 5q--- that 8 MDS, 5q- cannot be caused by benzene? 9 A. I do not believe that the 5q- syndrome 10 is associated with exposure to benzene at any level. 11 The production of a 5q- chromosomal aberration in the 12 context of secondary myelodysplasia or the 13 development of AML, I've already testified to, I do 14 believe that that can be associated with benzene 15 exposure. 16 Q. What is it about 5q- which makes you 17 say that it is not associated with benzene exposure? 18 A. 5q- syndrome clearly presents a 19 different constellation, different events. There may 20 be ringed sideroblasts. It does not have the same 21 prognosis. It does not have the same rate of 22 transformation, anywhere near the same rate of 23 transformation, and has been characterized by many 24 clinicians as being totally distinct from 25 myelodysplastic syndrome associated with exposure to AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 182 1 agents that can lead to the development of leukemia. 2 Q. What is the prognosis? 3 A. The prognosis is much better. The 4 couple of studies that I have brought with me that 5 discuss the relevant survival curves actually have 6 been-- at the time of their publication were unable 7 to make complete quantitative analysis, because the 8 populations associated with 5q- syndrome didn't 9 show-- basically their survival curves have 10 flattened. 11 Q. What do you mean, they've flattened? 12 A. That, because of survival in the 13 population, it was impossible to determine what the 14 curves were, because those populations were still 15 alive. 16 Q. Do you have an opinion as to her 17 prognosis? 18 A. Only as it-- only as I have just 19 related today with respect to what I can read in the 20 literature as well as anyone else with respect to the 21 life span of individuals with 5q- syndrome that have 22 been studied. I have no personal opinion as to her 23 current prognosis is. 24 Q. You don't plan on offering an opinion 25 as to her prognosis? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6-19 183 1 A. No. 2 Q. What is the life span? 3 A. (No audible response.) 4 Q. Are you saying that it's not known what 5 the6 A. The survival of patients with 5q- is 7 demonstrably better than those associated with 8 myelodysplasia as secondary to exposure to 9 chemotherapeutic agents or where there are multiple 10 chromosomal aberrations present. 11 Q. Okay. Secondary MDS patients with 5q-, 12 what characteristics would they show that you claim 13 this lady doesn't show? 14 A. They tend to present with a trilineage 15 dysplasia, to begin with. 16 Q. So from the date that this disease is 17 diagnosed18 A. Yes. 19 Q. -- or the day that the anemia first 20 appears? 21 A. The anemia appears in the constellation 22 of the disease. And there's not a great deal of time 23 that transpires before you have the full-blown 24 characteristics that are associated with it. It may 25 even present with refractory anemia with excess AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 184 1 blasts. 2 Q. But the trilineage dysplasia presents 3 at the same time? 4 A. Usually the multiple lineage 5 involvement occurs before the anemia. You actually 6 can find thrombocytopenia or lymphocytopenia early 7 on. 8 Q. Are there studies of cases that that 9 did not happen, that it happened after the refractory 10 anemia? 11 A. I would not be at all surprised to find 12 individual cases that present with any number of 13 different variations. This is what it's my opinion 14 you are most likely going to see in that population 15 based upon what I have seen and read. 16 Q. Okay. What studies are you referring 17 to with regard to that aspect of your opinion? 18 A. The myelodysplasia literature in 19 general. Some of the Aksoy studies, Vigliani studies 20 characterize the effects of benzene. 21 Q. Did you bring those with you? 22 A. Not all of them, no. 23 Q. Which of those did you bring with you 24 that are relative to that aspect of your opinion? 25 A. This is going to take a little bit. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 185 1 Q. If you want to name them by-- I think 2 that's the biggest problem. 3 A. Certainly the involvement of the 4 prevailing presentation of absolute lymphocytopenia 5 is referred to quantitatively in the Goldwater 6 article that I referred to. 7 Q. That was tab 3? 8 A. Yeah. That was probably the first 9 clinical characterization of that associated with 10 exposure to benzene. The myelodysplastic literature 11 in general related to secondary exposure to 12 chemotherapeutic agents. There are any number of 13 articles that I could point you to. 14 They're referenced in my book chapter, 15 in this article, but I didn't bring them all with 16 me. And the Kipen article refers again to the early 17 work by Greenburg. And it talks about print shop 18 workers with varying degrees of thrombocytopenia, 19 demonstrating the effect on platelets. 20 Q. Is that article included? 21 A. Yes. Certainly the references to the 22 first description of the 5q- syndrome disorder is 23 characterized by longstanding regenerative, slightly 24 macrocytic anemia that's a refractory anemia with 25 lower hemoglobin values-- I'm paraphrasing-- low to AVERY/WOODS REPORTING SERVICE, INC. (303) 825-5119 186 1 normal lymphocyte count, and low to normal platelets. 2 Q. Which article was that? 3 A. That's number 12. 4 Q. Who is the author? 5 A. The author is Van Den Berghe, et al. 6 Another article by Van Den Berghe discusses some of 7 the characteristics of 5q-, and separates them into 8 two groups, one based upon simply 5q- as the sole 9 anomaly, and the other with patients that present 10 with that as well as additional chromosomal 11 abnormalities, and characterizes differences between 12 them. Platelet count is normal. Median granulocyte 13 count is low normal. 14 Q. Which article is that? 15 A. It's another Van Den Berghe article. 16 It's number 13 in the series. 17 Q. Which page are you referring to? 18 A. Discussion begins on 192. 19 Q. Okay. 20 A. It actually characterizes a number of 21 characteristics in the distribution within the 22 population for blood cell count, platelets, 23 granulocytes, red cells, and age distribution. It 24 does discuss age. The median is sixty-six years. 25 I should tell you that I -pink the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 187 1 clinical and morphologic findings and the pattern of 2 findings is only a point with respect to 3 distinguishing the 5q- syndrome from secondary 4 myelodysplastic syndrome. I think the evolution of 5 the disease, the prognosis, and the rate of 6 transformation is far more important than whether a 7 given individual presents with one finding first or 8 another second. That can also be an artifact of when 9 they're diagnosed in terms of the presentation of 10 their disease. 11 Q. Certainly. 12 A. Again, white count lower normal, 13 platelet count normal or elevated, by Sokal, et al. 14 It's my number 14. 15 Q. Mrs. Lakie's platelet count was normal, 16 wasn't it? 17 A. It was normal at the time of diagnosis. 18 Q. I'm sorry. Which article was that one 19 you just mentioned? 20 A. Sokal was number21 Q. Sokal? 22 A. Yeah. It's number 14. 23 Q. Okay. 24 A. The Dewald paper as well-- it's number 25 16-- separates on the basis of prognosis and AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 188 1 progression patients with 5q- from patients that have 2 multiple abnormalities or Sq- plus additional 3 abnormalities. 4 Q. Describes a different prognosis and 5 progression for those patients? 6 A. Yes. 7 Q. If they have more than one abnormality? 8 A. Yes. And the characteristics of the 9 patients are different, too. Platelet count is much 10 lower in those that have additional abnormalities. 11 The macrocytic anemia, curiously enough, is higher in 12 those that just have Sq- syndrome. 13 Those are the only ones that I 14 brought. Jandl's text also describes some 15 differences, but it's not16 Q. Jandl? 17 A. Yes. It's a book chapter. 18 Q. In addition to what you've mentioned, 19 what other factors do you consider to be important in 20 distinguishing Sq- from secondary MDS? 21 A. The prognosis with respect to 22 transformation is very significant. 23 Q. You mean it's quicker if it's secondary 24 MDS? 25 A. It's also more likely to occur by AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 189 1 virtue of the order of magnitude, ten percent 2 incidence of transformation in 5q-, and eighty to 3 ninety incidence of transformation in secondary 4 myelodysplastic syndrome. It's a huge difference. 5 Q. And did you bring your articles which 6 indicate that ten percent transformation? 7 A. Those are included wit in the articles 8 that I have discussed and that I brought today. 9 Q. And10 A. As a matter of fact, I think the Jandl 11 book chapter summarizes it quite well. Patients 12 having refractory anemia with excess blasts plus 13 nonlobulated megakaryoctyes are at risk of 14 transforming to AML, but the eventual incidence of 15 AML, as I indicated, is well under ten percent. 16 Q. Do those same articles you've already 17 cited also include or are those the articles which 18 discuss the eighty to ninety transformation from 19 secondary MDS to acute leukemia? 20 A. Some of them do. There are others, 21 too, with respect to secondary myelodysplastic 22 syndrome. 23 Q. Is that what you've brought with you 24 today? 25 A. Not all of them have T_ brought with me AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 190 1 today. I did not bring all those with me. They are, 2 however, cited in that, if not the book chapter 3 brought. 4 Q. Tab 19 on the book chapter? A. Yes. 6 Q. In addition to the presentation and the 7 transformation to acute leukemia, are there any other 8 distinguishing characteristics in your opinion? 9 A. The frequent presentation of other 10 aberrations, the rate of the transformation. 11 Q. In addition to those? 12 A. We've already discussed the pattern, 13 usually the pattern involvement of lineages of cells 14 at the time of diagnosis. That's basically-- those 15 are basically-16 MR. WHITNEY: Did you mention the 17 timing? 18 THE DEPONENT: We mentioned it 19 earlier. 20 MR. WHITNEY: Oh. 21 A. The timing, you know, the timing is 22 relatively-- for myelodysplastic syndrome that is 23 secondary to bone marrow toxicity, the transformation 24 not only occurs more-- with increased incidence, but 25 it occurs within a matter of months to a year or so. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 191 1 It's usually very quick. 2 Q. (BY MR. WILLIAMS) Are you talking about 3 the transformation? 4 A. Yes. 5 Q. Is this included in the articles that 6 you've discussed? 7 A. Yes. 8 Q. Other than the pattern, other than the 9 transformation and the presentation, you mentioned a 10 pattern of involvement of cell lineages? 11 A. Yeah. 12 Q. How would that be different in MDS, 13 5q-, and secondary MDS, 5q-? 14 A. Well, again, generally the same, as I 15 said before. And, as I said, it's not a hard and 16 fast rule, but in fact you do see more frequent 17 involvement certainly following benzene. 18 Lymphocytopenia is very frequent, absolute 19 lymphocytopenia. 20 Q. We're talking about diagnostic 21 criteria? 22 A. Yes. 23 Q. And, as you mentioned, the timing of 24 the diagnosis plays a part in what factors are noted 25 in a person's medical record, don't they AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 192 1 A. With respect to whether they present, 2 that's true. It's conceivable that a person might 3 not-- it is true. The timing is going to provide 4 some artifact with respect to what you might see. 5 But you have to keep in mind that the 6 frequency of progression for 5q- syndrome is very, 7 very small, whereas the frequency of progression for 8 myelodysplastic syndrome is very, very high. And so 9 timing is going to be a relatively small factor with 10 respect to that. And it's not likely to confuse what 11 you see in terms of characterization of diagnosis in 12 the literature, because that progression is 13 ultimately associated with terminal transformation or 14 death associated with myelodysplastic syndrome. So 15 survival is different as well. 16 Q. Would the lesion be different for 17 secondary MDS, 5q-, and MDS, 5q-? 18 A. That is a very interesting question. 19 At this point nobody knows. Janet Rowley at Chicago 20 has a hypothesis that suggests that the lesion 21 associated with 5q- secondary to exposure to 22 chemotherapeutic agents involves the deletion of an 23 undiscovered tumor suppressor gene somewhere within 24 the 5q31 region or area. One could surmise that in 25 fact that is the -- that is associated with a AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 1 different prognosis. 2 At this point in time, our approach is 3 to characterize what's associated with altered 4 function in cells that express the 5q-. So there are 5 a number of different hypotheses that are put 6 forward. Haplo insufficiency as a function of 7 deletion of one of the chromosomes has been 8 hypothesized. 9 I've included that in the model that I 10 presented in that paper as a potential selection 11 mechanism in the process. Whether that's distinct 12 between 5q- syndrome and the involvement of secondary 13 myelodysplastic syndrome I don't think is clear, but 14 it certainly is a progression. If, in fact, it 15 occurs, it must be because 5q minus has a very low 16 rate of progression, incidence of progression. 17 There are a number of theories that 18 have been put forward to suggest that there are, in 19 fact, differences. At this point we do not have a 20 clear picture of structurally what they are. 21 Q. So it's uncertain? 22 A. Yeah. 23 Q. At this time? 24 A. It's uncertain at this time. It's 25 clear that there are differences in the prognosis, so AVERY/WOODS REPORTING SERVICE, INC. (303) 825-5_19 194 1 there must be something different about it. One of 2 the characteristics that is most likely associated3 that certainly is associated with it is the very high 4 frequency of involvement of other chromosomes in 5 secondary 5q- does occur. 6 Keep in mind, when we talk about the 7 numbers and I present a study-- I present a summary 8 of some of the studies in here that show the 9 differences, the numbers, the index in here, you see 10 involvement of 5, 7, 5q-, 7q-, or both, and you 11 compare cross-studies for de novo versus secondary, 12 there is a very, very high rate associated with 13 secondary. 14 But, even in a study where you have a 15 ninety-two percent incidence in secondary, you have 16 to keep in mind that that only represents about a 17 thirty percent involvement of 5, that 7 is involved 18 forty to fifty percent of the time, and it's both of 19 them together where you see such a high number. But 20 5 is involved to a lesser extent than 7, and 21 certainly 5 by itself occurs to a lesser extent than 22 any of the others in secondary. 23 Q. 5q- does occur by itself, though, in 24 the secondary MDS leading to MDL? 25 A. To a certain extent, yes, it does. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 195 1 Q. 5q- occurs by itself without any other 2 cytogenetic abnormalities? 3 A. It can occur, yes, and has been 4 described. But it's the less frequent presentation. 5 Q. Okay. Is there anything else in 5q 6 syndrome that you distinguish from secondary MDS 7 other than what we have been discussing? 8 A. Frequently association with benzene 9 exposure at high levels, but that's-- that's 10 intrinsic to the discussion we've had today. 11 Q. Well, both occur in conjunction with 12 benzene exposure? 13 A. I do not believe 5q- syndrome has been 14 associated with elevated benzene exposure. I 15 certainly concur that secondary myelodysplastic 16 syndrome is associated with benzene exposure. 17 Q. Give me your precise definition of 5q 18 syndrome for purposes of your last statement. 19 A. 5q- syndrome is an idiopathic 20 refractory anemia that's associated with primarily 21 individuals of advancing ages, the median incidence 22 probably on the order of the mid-sixties, between 23 fifty and seventy or eighty. It tends to be 24 associated with a macrocytic anemia, more frequent 25 among women than men, and it has a relatively low AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 196 1 rate of transformation into acute myelogneous 2 leukemia relative to other myelodysplastic syndromes. 3 Q. You're defining it as idiopathic, 4 though, aren't you, which takes it out of the realm 5 of being caused by-- possibly being caused by a-- I 6 don't want to say mutant7 A. What I just gave you is a definition 8 you can read from many sources with respect to what 9 the 5q- syndrome is. When you see 5q- syndrome, 10 which is a syndrome within that constellation of 11 findings and in that particular group of individuals, 12 you see it referred to as idiopathic. 13 Q. And 5q- has been defined since what 14 time? 15 A. I included one of the earlier 16 references-- I'm not sure it's the earliest, but I 17 think it's very close to that-- as being described 18 published in 1974. Myelodysplastic syndrome really 19 wasn't recognized by the FAB, with a constellation of 20 defined criteria for diagnosis, until 1983. I think 21 it was 1983-- 1980, 1983. 22 Q. Haven't most of the epidemiological 23 studies-- weren't they performed prior to the FAB 24 classification and the articulation of the 5q 25 syndrome? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 197 1 A. Wel, not 5q- syndrome. Myelodysplastic 2 syndrome, yes. And I referred to that earlier. 3 That's one of the issues or problems in defining 4 myelodysplastic syndrome that is associated with 5 benzene exposure. 6 There are those, especially from an 7 epidemiologic perspective, who would say that 5q8 that myelodysplastic syndrome hasn't been associated 9 with benzene exposure, but the preleukemia that's 10 been described in the literature for years is 11 consistent with myelodysplastic syndrome, as are the 12 constellation of effects that are seen associated 13 with chemotherapeutics in the evolution of AML, 14 wherein you clearly have myelodysplastic syndrome as a 15 precursor. 16 Q. And you know of no literature 17 indicating cases of 5q- syndrome as being caused by 18 benzene? 19 A. I don't believe-- I've told you I don't 20 believe that 5q- syndrome is associated with 21 benzene. I do think myelodysplastic syndrome as a 22 secondary consequence of exposure to benzene occurs. 23 Now, it can involve 5. I said that. But 5q 24 syndrome is a separate entity. 25 Q. Well, defining it so that it cannot be AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 198 1 possibly caused by benzene-- let me rephrase the 2 question. 3 Do you know whether or not the=a are 4 cases describing patients with symptomatology similar 5 to Ms. Lakie's that have been thought to have 6 incurred their disease process from benzene exposure? 7 A. If you say "have been thought to," I 8 would be safe in saying yes to just about anything 9 having been published as a hypothesis if, in fact, 10 and there are for a fact-- I don't know if I brought 11 any-- discussions of individuals who present with a 12 transient or persistent cytopenia involving one cell 13 type that don't progress or go on to anything else. 14 We don't have cytogenetics on them. 15 Chances that they are, I think it's 15 unlikely that we're looking at 5q- or in most of 17 those, because the presentation doesn't look like 18 that which you see in Sq- syndrome, but it's 19 conceivable. What I'm saying is that the 5q 20 syndrome that is seen as being described in these 21 studies is a separate entity with a totally different 22 prognosis than myelodysplastic syndrome, that there's 23 no evidence to suggest that that's associated with 24 benzene exposure. 2J Q. But are there cases of patients AVERY/WOOS REPORTING SERVICE, INC. (303) 325-5119 199 1 presenting with the symptomatology that Ms. Lakie has 2 presented with who have been considered to have 3 acquired that disorder from benzene exposure or from 4 chemical exposure? 5 A. If you say "symptomatology," and you're 6 talking about a macrocytic anemia with lineage 7 involvement and one or more cell types, that clearly 8 has been associated with benzene exposure. Now, 9 whether or not it involves 5q-, there is absolutely 10 no basis on which to speculate, because cytogenetics 11 have not been associated with those earlier studies. 12 And, as a matter of fact, you can 13 probably call into question some of the morphologic 14 characteristics, because we're talking about 15 techniques and diagnoses that are not within the 16 rubric of the FAB or anything in the context of how 17 differential diagnosis is done today. 18 Q. Other than the fact that the 19 cytogenetics were not available for some of these 20 studies, the patients would present with 21 symptomatology which would closely parallel Ms. 22 Lakie's; is that correct? 23 A. Symptomatology that roughly parallels 24 Ms. Lakie's. Ms. Lakie's symptomatology closely 25 parallels and, in fact, is consonant with what has AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 200 1 been described in the literature with respect to the 2 5q- syndrome. That's not what is associated with 3 exposure to benzene as described in the literature as 4 generally being associated with benzene exposure. 5 Q. But there have been patients in the 6 literature which have had her symptomatology which 7 have been thought to have acquired that from benzene 8 exposure? 9 A. As I said, the general symptomatology 10 associated with bone marrow suppression has been 11 associated with benzene exposure. 12 Q. Okay. Were there any other 13 distinguishing characteristics you wanted to 14 articulate? 15 A. I think we've probably exhausted the 16 subject. 17 Q. So that would be the extent of the i3 basis for your opinion that 5q- syndrome is not 19 caused by benzene exposure? 20 A. Essentially, yes. 21 Q. Okay. I want to ask you a couple of 22 questions about your report, which should be in the 23 front of Exhibit 3. Do you plan on offering an 24 opinion as to the amount of benzene that was absorbed 25 by Ms. Lakie, or are you going to assume for purposes AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 201 1 of your opinion that a hundred percent was absorbed? 2 MR. WHITNEY: It all depends on how 3 you phrase the question to him. 4 A. I believe the most likely scenario that 5 describes the available concentration of benzene that 6 could be absorbed is that Dr. Jacobus has presented. 7 Of all the descriptions I've seen, that one, I think, 8 is the most cogent and likely. Now, having said 9 that, I am going to assume absorption within the 10 context of that model. 11 Q. (BY MR. WILLIAMS) Dr. Jacobus? 12 A. Yes. Now, by the same token, I'm fully 13 prepared to offer the same opinion based upon the 14 assumption that all the benzene that you could 15 possibly extract or pound out of that product was 16 absorbed. So the worst case does not present-- as 17 we've said earlier, is not going to change my 18 opinion. 19 Q. Does the model which Dr. Jacobus has 20 erected, has that been subject to peer review? 21 A. As it relates to this particular study, 22 no. 23 Q. Okay. You know whether it's ever been 24 used before by anyone for any purpose? 25 A. Precisely for this purpose, no. I'm AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 202 1 not aware of that. 2 Q. Is his physiological model that h` 3 constructed been used, if you know, by any other 4 scientist for any purpose? 5 A. Similar physiologic models are used all 6 the time to evaluate the potential for absorption of 7 drugs from the stomach, from the gut, and from 8 elsewhere that bear-- individual components of this 9 model are used all the time. Whether they've been 10 put together precisely for the purpose at hand I'm 11 not aware. 12 This is a very case specific issue. 13 The methodology and assumptions he made in 14 constructing his model I have seen many times. And 15 you can find it in classic textbooks on 16 pharmacokinetics, pharmacodynamics, and 17 pharmaceuticals. 18 Q. The models that he's constructed? 19 A. Components of them, components of the 20 model, the assumptions and the techniques. 21 Q. Which book would you refer me to for 22 those assumptions? 23 A. Any number of different textbooks 24 discuss issues related to the issue. 25 Q. Can you name an authoritative text on AVERY/WOODS REPORTING SERVICE, INC. (303) 825-:119 203 1 the subject? 2 A. I COU7 d name several. The old 3 Goldstein and Aranow text, which has now got a 4 separate set of authors, discusses various aspects of 5 this. Any text on pharmacology is going to discuss 6 absorption. 7 Q. What is the Goldstein book? Is that 8 not pharmacology? 9 A. It's Pharmacological Bases of Drug 10 Disposition, I think. I'm not certain. I could get 11 you the reference, but I don't have it at my 12 fingertips. The principal issues in there are 13 predicated on very well understood concepts. 14 Q. Any other text other than that one? 15 A. There are several. If you'd 16 like, I can provide you with those, but I can't do it 17 as I sit here right now. 18 Q. Okay. I would like. Doesn't have to 19 be a lot. One or two. 20 You are not a pharmacologist, are you? 21 A. My training is essentially that of a 22 pharmacologist. I would consider that I'm a 23 pharmacologist in many aspects. It depends on your 24 definition of pharmacology. I trained in the 25 department of pharmacology and toxicology. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 204 1 Q. Your pharmacology was part of- your 2 toxicology training, wasn't it? 3 A. Yes. 4 Q. Okay. 5 A. I have the same training a 6 pharmacologist has, and then additional training in 7 toxicology. 8 Q. You went to school to get a degree in 9 toxicology? 10 A. Yes. And pharmacologists, certainly at 11 the University of Rochester, took a portion of the 12 curriculum of toxicology. That's what they took. So 13 I took everything a pharmacologist took, plus 14 additional material. 15 Q. This was at Rochester? 16 A. Yes. You find the same at Colorado, 17 too, just about anywhere. 18 Q. Do you hold yourself out as an expert 19 in pharmacology? 20 A. Some aspects of pharmacology, yes. 21 Q. Have you ever been qualified to testify 22 in court as an expert in pharmacology? 23 A. I believe I probably have been 24 qualified as an pharmacologist, slash, toxicologist 25 on occasion. I believe I have, yes. AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 205 1 Q. And that specific term has been used in 2 addition to toxicology? 3 A. I think so. 4 Q. Can you tell me the case where that 5 occurred? 6 A. Not specifically, no. The concepts are 7 the same. 8 Q. Concepts of toxicology and 9 pharmacology? 10 A. The concepts relating to absorption, 11 distribution, dose are the same. 12 Q. You're not board certified in 13 pharmacology, though, I take it? 14 A. There are no boards in pharmacology. 15 Q. I want to ask you about your estimates 16 of benzene release, and that's page 3 of your 17 report. I want to find out how you came out with a 18 figure using Jacobus's numbers. You came out with an 19 absorption figure of forty-six to a hundred and seven 20 micrograms a day, down toward the bottom of the 21 paragraph? 22 A. Yes. 23 Q. Take me through your analysis; tell me 24 how you got to that. 25 A. I believe I took it straight from Mr. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 206 1 Jacobus's summary. 2 Q. Your understanding is that that's what 3 is his? 4 A. I believe so. That's my best 5 recollection. 6 Q. Okay. Well, let's just go quickly 7 through the figures you have here. Up at the top you 8 give three amounts for oral, stomach, and intestine 9 absorption? 10 A. Yes. 11 Q. What did you do with those figures? 12 Did you add them together? 13 A. I believe I took the-- based upon 14 residence times, I took-- I believe I bracketed 15 them. I believe that's what I did. And, as I 16 recall, I went through and checked them. I took the 17 residence times versus the amount of the variation in 18 residence times that was realistic versus the amount 19 that was released in the conditions of his analysis 20 and bracketed those. 21 Q. I don't understand what that means. 22 A. The residence times would vary to some 23 extent. There's a range. So I took the absolute 24 amount that was released as a function or the25 right-- as a function of the conditions, and then AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 207 1 calculated based upon differences in the range of 2 residence times that material would spend in each 3 compartment. 4 Q. Are those calculations indicated here? 5 A. No. They're in his report. 6 Q. Okay. So the first line of figures, 7 oral, one fifty-two micrograms a day, is that the 8 bracketed figure you came up with? 9 A. For varying residence times, yes. 10 Q. Okay. What I'm trying to find out is 11 how you got down to forty-six to one hundred seven 12 micrograms a day. 13 A. I think, if you look at Dr. Jacobus's 14 report, that that's the range that he gives. 15 Q. You say that this range that he gave 16 assumes a certain amount of Orafix Special used? 17 A. I'd have to go back and look at it. 18 Q. You don't recall? 19 A. I don't recall today. Obviously, yes. 20 It does. I know it does. It's implicit in his 21 design. But I don't know what it was. 22 Q. So these things are all from his 23 report? 24 A. I believe they are. 25 Q. Did you apply-- you then have a fifty AVERY/WOODS REPORTING SERVICE, INC. !303) 825-6119 208 1 percent rate of absorption via the oral mucosa you've 2 assumed? 3 A. I assumed a fifty percent rate via the 4 oral mucosa. Now, that's an assumption. The skin is 5 clearly much less, and the stomach or intestine is 6 much more. And so I base that on the fact that it is 7 epithelial tissue. I expect it to be higher than 8 skin but lower than the gut. 9 Q. You expect it to be absorbed through 10 the oral mucosa? 11 A. There would be some absorption through 12 the oral mucosa. 13 Q. The fifty percent rate means fifty 14 percent of the benzene in the product? 15 A. No. Fifty percent of the benzene in 16 the solution will be absorbed by the oral mucosa. 17 Q. Are you assuming-- you mean saliva 18 solution? 19 A. Yes. 20 Q. Are you assuming fifty percent of what 21 Dr. Jacobus found was bioavailable would be absorbed 22 in the oral mucosa? 23 A. Yes. 24 Q. Okay. Then you added those, that 25 amount? AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 209 1 A. Yes. 2 Q. To the amount absorbed in the stomach? 3 A. And the amount that you would expect to 4 be absorbed in the intestine. You come up with a 5 range. 6 Q. You didn't indicate what that amount 7 was here in your paragraph? 8 A. No. I-- basically I used those to 9 determine-10 Q. Did you do calculations? 11 A. Yes. 12 Q. Do you have your notes? 13 A. No, I don't. 14 Q. Where would those be? 15 A. I'm not sure. 16 Q. Did you do any draft reports? 17 A. No. 18 Q. In this case? 19 A. No. 20 Q. Was it the same amount of exposure you 21 came up with in the Petry case? 22 A. I think it's based upon a similar 23 calculation and modeling by Dr. Jacobus. I think it's 24 comparable. Certainly, if the numbers weren't 25 exactly the same, it's very close. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 210 1 Q. Did you retain your worksheets on these 2 calculations? 3 A. No. 4 Q. Those wouldn't be on computer 5 somewhere? 6 A. No. 7 Q. In the last paragraph, your 8 conclusions-- I believe you've already gone through 9 most of this-- in your opinion you say, "It is my 10 opinion, to a reasonable degree of scientific 11 certainty, that there is no reliable evidence to 12 suggest that the plaintiff's purported exposure to 13 the available benzene in Orafix Special was 14 sufficient to cause or contribute to the development 15 of her disease." 16 Reliable evidence, are you referring to 17 the materials you brought here in your notebook, 18 which is Exhibit 3? 19 A. Yes. As well as other data in the 20 epidemiologic and toxocologic literature that relate 21 to benzene. We discussed some of those today. 22 Q. And some of those would be summarized 23 in your24 A. Some of them. Some of the issues and 25 some quest=-ns. For instance, you have raised the AVERY/WOODS REPORTING SERVICE, INC. (303) 825-5119 211 1 Infante study, which I have not provided. And there 2 are other more recent studies that also look at the 3 levels of benzene associated with exposure to adverse 4 health effects. I have provided several. 5 Q. What does the Infante study indicate 6 with regard to this deposition? 7 A. It doesn't indicate anything. It 8 assumes a level of exposure that I don't believe is 9 defensible, and certainly hasn't been corroborated by 10 anyone else. 11 Q. You disagree with Infante's 12 conclusions? 13 A. I disagree with his assumptions, and I 14 disagree with his conclusions based upon these 15 assumptions. 16 Q. Which article are you referring to, the 17 Pliofilm study? 18 A. Certainly the risk analysis associated 19 with the Pliofilm study, based upon the assumed 20 exposure study, which has been repeatedly criticized. 21 I brought several articles today that characterize 22 exposure in that same population and found it to be 23 much higher. 24 Q. Are those in your book? 25 A. Yes. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 212 1 Q. Which one of these? 2 A. The Kipen articles. 3 Q. Kipin and Goldstein? 4 A. And Goldstein, Wong, Paxton. There's 5 several others, but those are the ones that I 6 brought. But, again, even the Rinsky study doesn't 7 provide material evidence that the levels we're 8 talking about here are associated with an adverse 9 effects. 10 Q. Rinsky was doing a mortality study, 11 wasn't he, studying humans? 12 A. Yes. 13 Q. I don't have, for some reason, a 14 complete copy of your CV. I wanted to ask you some 15 questions about it. Do you need to look at it, or 16 can I use yours? 17 A. Well, depends how difficult this gets 18 whether I need to see it or not. 19 Q. Hold onto it. I may not need to go 20 past page 1. I don't know. 21 You've been at University of Colorado 22 since '89? 23 A. Yes. 24 Q. Is that your primary employer? 25 A. Yes. AVERY/WOOS REPORTING SERVICE, INC. 1,303) 825-5119 213 1 Q. What is the bulk of your professional 2 time since '89? What has it been spent doing? 3 A. Research, teaching, directing a 4 training program in toxicology, serving as leader of 5 the Cancer Causation Program for the University of 6 Colorado Cancer Center, and serving as a member of 7 the Department of Pathology in the School of 8 Medicine. 9 Q. Of these three, was the bulk of your 10 time mostly spent with the Molecular and 11 Environmental Center? 12 A. Yes, I would say. 13 Q. How much of your time? 14 A. It varies from year to year. It can 15 vary, generally-- teaching can vary-dramatically, 16 anywhere from twenty to forty percent. 17 Q. Teaching in what department? 18 A. Teaching across the board, whether it's 19 in the Department of Occupational Medicine, 20 Pathology. 21 Q. Okay. 22 A. Research can vary, usually between 23 thirty and forty percent. 24 Q. The remaining percent? 25 A. Yeah. Fifteen percent service. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 214 1 Q. What does that mean? 2 A. That's consultation. 3 Q. For litigation? 4 A. Some of it's litigation. Some of it is 5 drug development. Some of it is advisory to the 6 government. 7 Q. Who have you consulted with on drug 8 development? 9 A. Several companies. 10 Q. Which ones? 11 A. Oh, Hoffmann-La Roche, Merck, 12 DuPont-Merck, Puget-Salva (phonetic). There are 13 others. Sandoz. Sandoz is another one. 14 Q. How much of your time is spent in 15 litigation, doing litigation consultation? 16 A. It varies from year to year. Last 17 year, about fifteen percent, was probably split. 18 Q. Between19 A. It was probably slightly more 20 pharmaceutical than litigation. Pharmaceutical 21 development, safety evaluation was probably about 22 fifty and some percent. The year before that 23 litigation was higher. 24 Q. What percentage of your income comes 25 from litigation work? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 215 1 A. Last year it would have been about 2 probably a third, slightly less. 3 Q. How about in '94? 4 A. It was probably close= to forty 5 percent, maybe higher. I'm not sure exactly. 6 Q. You know for '93? 7 A. No. It was probably higher in '93. 8 Q. But not by fifty percent? 9 A. It probably was close to fifty percent. 10 Q. And how about '92? 11 A. It would have been about the same. 12 We're getting down into rarefied numbers. I don't 13 remember exactly. 14 Q. Is it income separate from your income 15 from the University? 16 A. Yes. 17 Q. Is your consulting income also 18 separate? 1.9 A. All of it. 20 Q. I'm sorry. Consulting with drug 21 companies, separate? 22 A. Yes. 23 Q. Do you also do consulting with the 24 American Petroleum industry? 25 A. I do consulting on safety evaluation AVERY/WOODS REPORTING SERVICE, INC. (303)825-6119 216 1 and risk assessment for a variety of people from time 2 to time that would include companies within the 3 American Petroleum Industry. I have consulted from 4 time to time on small projects relating to bases for 5 risk assessment for the American Petroleum 6 Institute. I also do the same for regulatory 7 agencies. 8 Q. How long have you done consulting for 9 the American Petroleum Institute? 10 A. Probably, on and off, since 1989. I'm 11 not sure I consulted with them in 1989. 12 Q. And does that include consultation with 13 petroleum companies? 14 A. On issues related to, separate and 15 distinct from litigation, I'm including them all in 16 the same category, yes. 17 Q. Oh, you're including this in 18 litigation? 19 A. No. 20 Q. Oh, okay. Separate from litigation 21 have you consulted-- what petroleum companies have 22 you consulted with? 23 A. Exxon, American Petroleum Institute, 24 Amoco. That may be it. 25 Q. What chemical manufacturers have you AVERY/WOODS REPORTING SERVICE, INC. (303) 825-5-119 217 1 consulted with? 2 A. I think that basically it is in terms 3 of issues that relate to safety evaluation or 4 regulations. 5 Q. Well, are there any other issues you've 6 consulted with them on other than litigation? 7 A. Not that I recall. 8 Q. Okay. Do you know what percentage of 9 your income has come from consulting with the 10 American Petroleum Institute or any of those 11 companies? 12 A. I'd be surprised if it's one percent. 13 Q. Is that fairly consistent over the14 A. Yeah. It's a very low number. My 15 consultation with Exxon is recent, and that may 16 represent the slightly higher number. It might be on 17 the order of a few percent. 18 Q. That's for '95? 19 A. I believe so, yes. 20 Q. What number are we talking about? 21 A. What do you mean? 22 Q. What amount of money are we talking 23 about? 24 A. I won't divulge my income. It's on the 25 order of a few percent of my total income, probably AVERY/WOODS REPORTING SERVICE, INC. ''303) 825-6119 218 1 less than that. 2 Q. Okay. How about for litigation, what 3 amount are we talking about for '95? 4 A. '95, as I said, was probably on the 5 order of a third. Probably between thirty and forty, 6 thirty-five percent, something like that. 7 Q. Of what number are we talking about? 8 A. Thirty to thirty-five percent, that 9 would be my total income. 10 Q. No, in numerical, not percentage, what 11 amount of money are we talking about? 12 A. No. I won't divulge my income. Under 13 contract I am prohibited from discussing my salary 14 and income by the University. I'm talking about the 15 total percent of my income. I'd be happy to discuss 16 that with you in context. 17 Q. The University prevents you from saying 18 how much money you make from cases? 19 A. Yes. If, in divulging to you the 20 amount I make from cases, I give you the percentage, 21 you can determine my salary, I am prohibited from 22 doing that. 23 Q. You have a contract that says that? 24 A. Yes. 25 Q. What's the purpose of that? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 219 1 A. It's a peccadillo of the 2 administration. I do not know why. 3 Q. Can you furnish a copy of the contract 4 provision? 5 A. I am not sure I can do that. 6 Q. Why not? 7 A. Because basically the provisions of 8 that contract or that specific contract are 9 confidential. I have signed an agreement to that 10 effect. I can tell you precisely what the individual 11 provisions are without discussing figures. I've 12 given you some of it here with respect to the 13 distribution of my income. 14 Q. I don't want to know figures with 15 respect to this issue. I'm interested in contractual 16 prohibitions. 17 A. I am prohibited from discussing my 18 salary and income, as outlined in my letter of 19 appointment, which I have agreed to and signed. 20 Q. Would that also include if a court 21 ordered you to divulge your income? 22 A. Yes. 23 Q. If the court ordered you, you have to, 24 don't you? 25 MR. WHITNEY: What's your point? We AVERY/WOODS REPORTING SERVICE, INC.(303! 825-6119 220 1 have a discovery meeting. We'll address it the:2 It's getting close to my witching hour now. 3 Q. (BY MR. WILLIAMS) Have you ever been 4 forced to disclose that income in any other case? 5 A. No. 6 Q. Have you ever received any grants from 7 the API? 8 A. Yes. 9 Q. When was that? 10 A. I've had a grant from the API since 11 1989. 12 Q. Since 1989? 13 A. Yes. 14 Q. What is that grant for? 15 A. For research looking at proving of the 16 biological basis of risk assessments associated with 17 leukemia, leukemogenesis. 18 Q. What is the amount of the grant? 19 A. I think my direct costs this year are 20 on the order of a hundred and seventy thousand. 21 Q. What does that mean? 22 A. That means that that's the amount that 23 I see for research purposes after indirect costs and 24 other features or factors are taken out. 25 Q. That's after cost? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-E-19 221 1 A. That's the cost. That's what I see. 2 That's what I see. 3 Q. When you say "you see," is that paid to 4 you directly? 5 A. No. It's paid to me as a principal 6 investigator at the University of Colorado. 7 Q. Okay. 8 A. There are other studies that are part 9 of that, and there are indirect costs that the 10 University exacts. 11 Q. I guess it is a hundred and seventy 12 thousand dollar figure we're talking about, 1995? 13 A. '96. '95 would have been about the same. 14 Q. And that's an amount that you see after 15 your costs have been paid for? 16 A. No, not after my costs have been paid 17 for. That's what I see. That's what I have to use 18 for research purposes. 19 Q. You see a hundred and seventy thousand? 20 A. Yes. 21 Q. Okay. And has that been constant since 22 '89, or has it been higher? 23 A. It's been roughly constant. I think 24 one year there was a slight difference of maybe 25 thirty thousand dollars. There might have been a AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 222 1 fluctuation. 2 Q. Down or up? 3 A. Up. 4 Q. So one year it was two hundred 5 thousand? 6 A. Close, yes. 7 Q. In other years it's been around one 8 seventy? 9 A. Yes. 10 Q. Have you received any grants from the 11 CMA? 12 A. Yes. I've had approximately four years 13 of funding from the CMA. 14 Q. Four years through this year? 15 A. Pardon? 16 Q. Four years through this year? 17 A. Through last year. Again, my direct18 my direct costs were on the order of fifty thousand. 19 Q. Per year? 20 A. Per year. 21 Q. What has that grant been for? 22 A. That grant was for characterizing the 23 mechanisms of thymic lymphoma in mice associated with 24 butadiene exposure. 25 Q. Any benzene? AVERY/WOC-)S REPORTING SERVICE, INC. (303) 825-6119 223 1 A. No. 2 Q. Just butadiene? 3 A. Just butadiene. 4 Q. Have you received any other grants 5 other than those? 6 A. Oh, yeah. I have grants from the 7 National Institutes of Health to look at mechanisms 8 of chemically and drug-induced leukemogenesis. That 9 is in its third year. The direct costs are on the 10 order of two hundred thousand dollars a year. 11 I had a five-year grant with National 12 Aeronautic and Space Administration to look at 13 adverse health effects on the immune and hemapoietic 14 system associated with space flight and potential 15 exposure to toxic substances. 16 Q. How much was that grant? 17 A. It varied. It was on the order-- it 18 was from sixty to a hundred thousand dollars a year, 19 direct. I'm giving you direct so that you can 20 compare them. 21 Some of these things have strange22 indirect figures are different. That's University 23 contract. 24 I've had small grants from the National 25 Cancer Institute to do specific studies related to AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6'19 224 1 their China study. That's probably on the order of 2 twenty thousand dollars total. 3 Q. A year or for the whole thing? 4 A. Twenty thousand total at this point. 5 We probably will be doing some additional studies 6 with them as well. 7 Q. Who was that grant from? 8 A. National Cancer Institute. 9 Q. Okay. 10 A. I've had various-- I've had grants from 11 pharmaceutical companies to look at issues related to 12 drug development. I've done studies on DDC for 13 Hoffmann-La Roche. I think that was for two years. 14 I think that was two years at a hundred thousand a 15 year, but may have been a year and a half. 16 Q. When did that end? 17 A. 1995, beginning of '95. I've got 18 several studies pending, several grant proposals 19 pending, both with NIH as well as pharmaceutical 20 companies. So my funding base changes dynamically, 21 and it is hard to predict from one time to the next, 22 depending on what's funded and what isn't. 23 Q. Any proposals pending with SmithKline 24 Beecham? 25 A. No. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 225 1 Q. Any proposals pending with a-; 2 companies, subsidiaries or associate companies of 3 SmithKline Beecham? 4 A. Not to my knowledge. I'm not -familiar 5 with what companies are subsidiaries of SmithKline 6 Beecham, but I certainly don't think that they're -- I 7 have no studies pending with anybody that ells in 8 that category. 9 MR. WILLIAMS: Can we take a 10 one-minute break? 11 (Whereupon, at 4:29 p.m., a recess was 12 taken.) 13 Q. (BY MR. WILLIAMS) I just want to go 14 over a couple of things in your education. After you 15 graduated from college, it says here in '6816 A. Uh-huh. 17 Q. -- you got a degree in chemistry. You 18 worked at the General Hospital; how do you pronounce 19 that? 20 A. San Joaquin. 21 Q. San Joaquin? 22 A. Uh-huh. 23 Q. And did you get a degree as a medical 24 technician there? 25 A. I got a certification as a medical AVERY/WOODS REPORTING SERVICE, INC. (303) 325-6119 226 1 technologist. 2 Q. You got a certification? 3 A. Yeah. 4 Q. How long was that program? 5 A. Program was a year to a year-and-a-half 6 I believe. 7 Q. And you took courses while you were 8 working there? 9 A. I took courses as part of my training, 10 and additional courses in diagnostic hematology. 11 Q. And what courses in diagnostic 12 hematology did you take 13 A. Basically laboratory hematology at 14 University of San Francisco, University of 15 California, San Francisco. 16 Q. Was that one course? 17 A. It was several. I think there were 18 three or four. 19 Q. Three or four courses? 20 A. Yes. 21 Q. How long did that last? 22 A. They were part of the process that was 23 over the same course of time. 24 Q. Okay. Who supervises medical 25 technicians in a hospital? AVERY/WC'--"DS REPORTING SERVICE, INC. (303) 825-6119 227 1 A. It depends on the state. Depends on 2 the particular jurisdiction and the laws. 3 California, I'm licensed as a clinical laboratory 4 scientist, which by, I think, current law means that 5 I'm qualified to direct a laboratory. Some states 6 require a physician to direct a laboratory. Other 7 states don't. It varies. 8 Q. So California allows toxicologists to 9 do that? 10 A. No. It requires a licensed and 11 clinical laboratory scientist. 12 Q. What do medical technicians do? 13 A. A medical technician, which is not what 14 we're talking about, is someone who performs specific 15 laboratory tests at the direction of a technologist 16 or a laboratory director. 17 Q. What are we talking about-- I'm sorry18 MT? 19 A. Is medical technologist. 20 Q. Medical technologist? 21 A. Yes. 22 Q. What does a medical technologist do? 23 A. It is an individual who performs 24 laboratory-- diagnostic laboratory tests in a 25 clinical laboratory. That ranges from chemistry, AVERY/WOODS REPORTING SERVICE, INC. (303? 825-6119 228 1 hematology, radiology, urinalysis, bacteriology, 2 etc., etc. 3 Q. Is that done at the direction of a 4 physician? 5 A. In some cases. In other cases not. 6 Depends on-- as I said, depends on the specific 7 conditions of the state. The variation in 8 regulations that pertain to laboratory-- clinical 9 laboratories is quite large in the United States. 10 There are some states that require no certification. 11 Q. And California allows medical 12 technologists to run a lab and conduct experiments? 13 A. This has nothing to do with 14 experimentation. It is performance of clinical 15 laboratory tests. It has nothing to do with 16 experimentation. 17 MR. WHITNEY: Okay. You answered the 18 question. 19 Q. (BY MR. WILLIAMS) Have you ever run a 20 lab performing clinical laboratory tests? 21 A. Supervised laboratory clinical tests in 22 New York during my training in toxicology for part of 23 that time, and I practiced as a medical technologist 24 prior to that in California for a brief period of 25 time. AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 229 1 Q. Before you went to New York? 2 A. Right. 3 Q. Other than that period of time, have 4 you ever? 5 A. I directed a clinical laboratory 6 involved in support of chronic toxicity testing at 7 CIIT, but that's not involved in clinical testing. 8 Q. What type of clinical testing did you 9 do in New York? 10 A. Hematology, primary hematology. 11 Q. Can you be more specific? 12 A. Routine laboratory testing involving 13 blood counts, peripheral blood, morphologic analysis 14 of bone marrow, bone marrow smears. 15 Q. Was this part of your training in the 16 University? No? 17 A. No. That was independent. That was 18 independent. 19 Q. And what was your title? Was it 20 medical technologist? 21 A. I don't have any idea what my title 22 was. 23 Q. Where was the lab? What lab were you 24 working for? 25 A. Strong Memorial Hospital. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 230 1 Q. Okay. I don't see that on here. 2 Okay. Let me see your CV. I imagine it will be on 3 there, won't it? 4 A. What? 5 Q. Strong Memorial Hospital? 6 A. Yeah, but not in that context. My 7 training in pathology is, but basically we're talking 8 about what I did during the summers and at various 9 times for spending money. I don't list it as a10 Q. As a job experience? 11 A. Yeah. 12 Q. Okay. Were you working under the 13 direction of a physician? 14 A. No. No. 15 Q. Were you working under the direction of 16 anyone? 17 A. I was working under the direction of 18 the supervisor of the overall laboratory. I don't 19 remember the details. I was working primarily 20 emergency and triage. So I was working odd hours and 21 pretty much by myself. 22 Q. Was t~ supervisor a physician? 23 A. No. 24 Q. What were his qualifications or her 25 qualificati3ns? AVERY/WOOS REPOR-ING SERVICE, INC. (303) 825-6119 231 1 A. She was a medical technologist. 2 Probably had a master's degree. As I recall, she had 3 a master's degree. a Q. In medical technology? 5 A. Yes. 6 Q. Okay. After you finished the medical 7 technology program, did you apply to law school-- I 8 mean-- I'm sorry-- medical school? 9 A. I applied to graduate schools and 10 medical schools. 11 Q. And when was this? 12 A. Over the same period of time, at the 13 end of my training in medical technology. 14 Q. Did you get into medical school15 A. I was accepted at-- yes. 16 Q. Did you get into medical school the 17 first time you applied? 18 MR. WHITNEY: Objection. Now really. 19 Come on now. This is getting kind of ridiculous. 20 THE DEPONENT: What do you mean, the 21 first time? I applied. You mean the first year I 22 applied? 23 MR. WILLIAMS: Yeah. 24 A. I don't believe so. I think it was the 25 second year. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 232 1 Q. (BY MR. WILLIAMS) How many schools did 2 you apply to the first year? 3 MR. WHITNEY: Objection. 4 A. I don't remember. Several. 5 Q. (BY MR. WILLIAMS) Several? 6 A. Several. 7 Q. And this would have been after-- when 8 did you first apply? 9 MR. WHITNEY: Objection. Let's get 10 some relevant questions, okay, if you have some. 11 MR. WILLIAMS: These are relevant. 12 A. I don't recall. 13 Q. (BY MR. WILLIAMS) Was it after the 14 first year you got out of college? 15 A. Yes. 16 Q. And so you didn't get in, and then the 17 second year, the year after that, you applied to 18 medical school again? 19 A. It was after. As I said, it was a year 20 after college. That's when I was in medical 21 technology. That's when I first applied. And I 22 believe I applied one round, and then I came back and 23 applied again. 24 Q. Okay. And you say you got in that 25 time? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 233 1 A. Yes. 2 Q. Where did you get in? Where were you 3 accepted? 4 A. University of California, San 5 Francisco. 6 Q. And you did not go to medical school 7 there? 8 A. No. I was already at Rochester when I 9 got their letter. 10 Q. You had one year in the University 11 School of Medicine. Were you accepted in the School 12 of Medicine? 13 A. Yeah. I took courses in both School of 14 Medicine and toxicology program for a number of 15 years. In fact, I was still taking medical courses 16 at the-- when I began the fellowship in pathology. 17 Q. Were you auditing these courses or 18 taking them for credit? 19 A. Taking for credit. 20 Q. Were they part of your toxicology 21 program? 22 A. No. 23 Q. Were you actually accepted in the 24 School of Medicine degree program? 25 A. At the point at which I needed to enter AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 234 1 the clinical portion of the program, I left Rochester 2 and went to North Carolina. 3 Q . To worst? 4 A. Yes. 5 Q. At CIIT? 6 A. Yes. 7 Q. So your testimony is you were accepted 8 into medical school at the University of Rochester 9 with a degree program? 10 A. I was enrolled in courses of the School 11 of Medicine. I did not finish the program. I did 12 not enter the formal medical program at the point at 13 which I had to take a degree in medicine. 14 Q. Did you ever actually apply to medical 15 school at the University of Rochester? 16 A. As part of matriculating and the 17 courses that I took, yes. 18 Q. But in terms of the degree in medicine? 19 A. The M.D./Ph.D. program at Rochester 20 incorporated and assimilated students from the 21 graduate program in the M.D. program at various times 22 during the history of the program. I matriculated in 23 the program for a number of years and took courses in 24 medicine. I did not elect to formally enter the 25 clinical years and take a degree in medicine. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 235 1 Whether or not that would have been-- whether I would 2 have had that opportunity at that time I don't know. 3 I elected not to. 4 Q. You elected not to apply? 5 A. I elected not to finish, and that would 6 have required applying to the program. 7 Q. To the medical school program? 8 A. Yes. 9 Q. In a traditional four-year medical 10 school program, when does the clinical aspect of it 11 start? Is it the third and fourth year? 12 A. Year three and four. 13 Q. Did you take all the courses that would 14 have been required of a medical school student in the 15 first and second years of their academic program? 16 A. The vast majority of them. 17 Q. Do you recall which ones you took? 18 MR. WHITNEY: Objection. 19 A. The vast majority. It would probably 20 be easier to tell you the ones I didn't take. 21 Q. (BY MR. WILLIAMS) What didn't you take? 22 A. I didn't take psychiatry. 23 Q. Is that the only one? 24 A. I believe so. 25 Q. Did you take anatomy? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 236 1 A. Yes. 2 Q. Did you complete the course in anatomy? 3 A. I didn't complete neuroanatomy. 4 Q. Go ahead. I'm sorry. 5 A. I didn't complete neuroanatomy. 6 Q. Is that a second-year course? 7 A. Neuro courses are the second year 8 courses-- neuropathology, neuroanatomy, and a number 9 of other things. I took the neuropathology, but I 10 didn't take the rest of it. 11 Q. When you had postgraduate training as 12 part of pathology at Strong Memorial Hospital, what 13 did this entail? 14 A. Gross pathology, anatomic pathology, 15 some surgical pathology, hematopathology, as well as 16 research. 17 Q. The ones you just listed were the 18 courses you took? 19 A. They weren't courses. I was basically 20 serving as a fellow, reviewing cases, evaluating 21 material, participating in autopsies, reviewing 22 surgical specimens. 23 Q. Who were you working with during this 24 training? Did you have a25 A. A mentor? AVERY/WOC_S REPORTING SERVICE, INC. (303) 825-6119 237 1 Q. Yes. 2 A. Eric Schenk was a mentor. J.C.K. Lee 3 was also a mentor. 4 Q. And they're both pathologists? 5 A. Yes. 6 Q. Do you consider yourself to be an 7 expert in pathology? 8 A. Experimental pathology, yes. I am a 9 member of the-- what is now the American Association 10 of Investigative Pathology, formerly the American 11 Association of Pathologists. Yes. I have a full 12 professorship in the Department of Pathology in the 13 School of Medicine at the University of Colorado. 14 Q. And you teach experimental pathology? 15 A. I teach pathology both to graduate 16 students and medical students. 17 Q. Have you been qualified in court to 18 testify as an expert in pathology? 19 A. As an experimental pathologist, yes. 20 Q. Tell me what an experimental 21 pathologist is as opposed to an anatomical or 22 clinical pathologist. 23 A. An experimental pathologist is an 24 individual who basically studies mechanisms and 25 pathogenesis of disease, and structural alterations AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 238 1 associated with disease, very similar to what we're 2 talking about in terms of pathogenesis of leukemia. 3 Whether you say I'm a hematological 4 pathologist or an experimental pathologist or 5 experimental hematologist, I think they all basically 6 relate to the same type of expertise and activity. 7 Q. How is that different from an anatomic 8 and/or clinical pathologist? 9 A. Anatomic pathology is that branch of 10 pathology that deals primarily with either the 11 analysis of histology or gross pathology associated 12 with disease processes. 13 I'm not an M.D. I'm not a clinician. 14 I do have expertise in both of those areas. I have 15 reviewed and performed studies as a pathologist, but 16 I am not a pathologist and do not specifically 17 diagnose disease except in the context of providing 18 expert opinion on differential diagnosis of 19 hematological diseases when requested to by a 20 physician. 21 Q. Did you mention clinical pathology? 22 A. Clinical pathology deals with the 23 clinical laboratory diagnosis and the use of clinical 24 laboratory procedures in the support of clinical 25 diagnosis. AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 239 1 Q. So you don't consider you=self an 2 expert in those areas of pathology; you consider 3 yourself an expert in experimental? 4 A. I'm certainly an expert in clinical 5 pathology as it relates to the differential diagnosis 6 of hematological diseases, and I'm licensed to 7 perform those particular types of tests in 8 California. I serve as a consultant on occasion in 9 differential diagnosis of leukemias. 10 The diagnosis of leukemia has changed 11 dramatically over the course of the last several 12 decades, two decades in particular. Clinical 13 diagnosis does not usually provide a great deal of 14 information. It provides some. But the differential 15 diagnosis of leukemia types is primarily a laboratory 16 related activity at this stage. 17 Q. You're not board certified in pathology 18 I take it? 19 A. No, I am not. 20 Q. You have an associate fellowship listed 21 here in The National Society of Experimental 22 Hematology? 23 A. Yes. 24 Q. What's involved in becoming a member of 25 that society? AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 240 1 A. You have to be elected by the 2 membership based upon your research activities and 3 publications in the field. 4 Q. Where are they based? 5 A. I don't know. I'd have to tell you. 6 Q. I take it then, to be a member of the 7 American Association of Pathologists, you don't have 8 to be an M.D.? 9 A. No. But you have to be elected. 10 Q. Is it the same process, you're elected 11 by the membership? 12 A. Yes. 13 Q. Do you get someone to sponsor you for 14 that thing? Is that how it works? 15 A. No. There's a membership committee 16 that usually evaluates your credentials, and that's 17 the way most professional societies work that require 18 that. They have specific requirements with respect 19 to education, training and/or publication experience. 20 And then, when that's reviewed by a committee, the 21 committee usually makes recommendations to the 22 membership. And that's the way it's usually done. 23 Q. How many members does the International 24 Society of Experimental Hematology have? Do you 25 know? AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 241 1 A. Maybe-- I suspect it's on the order of 2 one or two thousand. 3 Q. How about the American Association of 4 Pathology? 5 A. That's a much larger organization. I 6 couldn't tell you exactly. That information is 7 readily available. 8 Q. Okay. Have you been asked to review 9 any of the plaintiff's experts' opinions in this 10 case? 11 MR. WHITNEY: If he's asked to provide 12 a rebuttal opinion, I'll let you know. Right now 13 he's not. 14 Q. (BY MR. WILLIAMS) Okay. But have you 15 been asked to review their opinions? 16 A. Specifically, no. I've been asked to 17 review their reports and their depositions with 18 respect to formulating my own opinion, but I haven't 19 been asked to render an opinion specifically relating 20 to theirs. 21 Q. So, as of today, you have no plan to 22 state a rebuttal opinion to the23 A. If called upon to do so, I will. I 24 have not been called upon to do so. 25 Q. Have you formulated any rebut=al AVERY/WOODS REPORTING SERVICE, INC. (303)825-6119 242 1 opinions at this point? 2 MR. WHITNEY: He's my witness, and if 3 he's asked to, I'll tell you. 4 MR. WILLIAMS: Well, are you going to 5 let me take his deposition again? 6 A. In general, it is clear or should be 7 clear that my opinion differs substantially from 8 opinions that have been offered by experts for the 9 plaintiffs in this case. I could go through and 10 itemize several specific points and why I disagree 11 with each of them. I have not been asked to do so. 12 I think it's obvious that my opinions are different, 13 and that I differ with the opinions that they've 14 offered. 15 Q. (BY MR. WILLIAMS) Obviously. Other 16 than with respect to what you've stated today and in 17 your report, are there any other opinions in addition 18 to those that you have in response to the deposition 19 testimony you read from the plaintiff's experts or 20 their reports? 21 A. At this point in time I believe that 22 they have all been covered within the context of my 23 opinions as offered in this case. 24 Q. Do you have any other opinions in this 25 case thus far that you have not covered yet? AVERY/WOOS REPORTING SERVICE, INC. (303) 825-6119 243 1 A. No. 2 Q. You say you've been asked to consult in 3 differential diagnosis in clinical settings? 4 A. On occasion, yes. 5 Q. Have any of those cases involved 6 myelodysplastic syndrome? 7 A. Probably, yes. I can't recall 8 specifically an individual case, but that's almost 9 certainly a yes. 10 Q. Why is that almost certainly a yes? 11 A. Because myelodysplastic syndrome is one 12 of the common abnormalities that's encountered in a 13 clinical setting relating to diseases of the blood. 14 Q. Are you called upon to consult because 15 of your research, the research you've done in the 16 field of benzene toxicity? 17 A. I'm called upon I think in part because 18 of that and in part because of my general research on 19 mechanisms of leukeogenesis, and in part because of 20 my knowledge of experimental hematology, and in part 21 because of my expertise in morphologic diagnosis and 22 idiopathic diseases of the blood. All of those are23 they're all related, and they're all expertise that I 24 have, and expertise that I use either in research or 25 on issues that are related to differential AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 244 1 diagnosis. 2 Differential diagnosis represents a 3 relatively small pa=z. of what I do. It is not a 4 routine part of my activities anymore. 5 Q. When was the last one you did? 6 A. I believe I probably-- I believe it was 7 in the fall or winter of 1995. 8 Q. Was that with Dr. Heron (phonetic) in 9 Denver? 10 A. I don't remember. I don't recall who 11 the physician was that was involved. I believe I was 12 asked in the context of confirming information, 13 laboratory information that was already available on 14 the patient. 15 Q. Obviously you were asked by the doctor? 16 A. Yes. 17 Q. How many of these differential 18 diagnosis consultations do you think you have been 19 involved in? You say that's not very frequent? 20 A. Not anymore. I mean usually it's in 21 the context of hemopathology rounds. On occasion 22 it's a specific patient. It's not a routine activity 23 that I participate in anymore. 24 At Rochester, I used to do it much more 25 often in the context of morphologic diagnosis of bone AVERY/W00-S REPORTING SERVICE, INC. (303) 825-6119 245 1 marrows. That was a long time ago. And my-- I have 2 no-- no clinical responsibilities or laboratory 3 responsibilities in the clinical laboratory at 4 Colorado. 5 Q. So, since '89, how many do you think 6 you've done, just one or two or7 A. Half a dozen maybe. 8 Q. Did you do any while you were at CIIT? 9 A. Rarely. I think maybe once when I was 10 at CIIT I did. 11 Q. So the most would have been when you 12 were at Rochester in the pathology fellowship? 13 A. Yes. 14 Q. That was back in '74 to '76? 15 A. Yes. 16 Q. Were you ever asked to consult with any 17 patients with 5q- syndrome? 18 A. I don't believe so. 19 Q. And you've never examined or treated 20 any patients with any kind of disease, have you? 21 A. For purposes of this discussion, no. 22 When I was at Rochester, I did examine patients in 23 the context of clinical activities that I was 24 involved in. That was when I was training. 25 Q. Right. And you were not involved in AVERY/WOODS REPORTING SERVICE, INC. (303) 825-6119 246 1 the treatment of those patients? 2 A. No. 3 MR. WILLIAMS: Let me just take a 4 second to go through. 5 (Whereupon, there was discussion 6 outside the record.) 7 MR. WILLIAMS: That's all I have. 8 (Whereupon, at 5:00 p.m., the 9 deposition concluded.) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 AVERY/WOOS REPORTING SERVICE, INC. (303) 825-5119