Document qaodBvZBno672KrXzgejxNKRn

622 THE COMMISSIONER w can go on th record. This la the natter of In ret Estate of Alan Ardia and Estate of Alexandre Oxollns brought against the Olln Corporation. This Is a continuation of hearings that commenced on September 13, 1983, were continued to September 14, and then t September 15, than to October 26, and th n t November 4, then to November 16, and to this date. MR. PROUTx I believe. Tour Honor# t^tje first November date was November 14, rather than November 4 -- THE COMMISSIONER! Did I say 4? MR. PRODTx Tes, Tour Honor. THE COMMISSIONER! 14. Present today, attorneys are Attorney Robert Carter for th claimant^ and for the respondent# Killian front from Wiggin 6 Dana and Barry David ff the Olln Corporation. He left off on -- I believe Hr. Pr ut was cross-examining or present -- HR. PROOTt Presenting evidence# Tour Honor. THE COMMISSIONER! I think you began to HARTFORD. CONNECTICUT 20J.H4.JWJ SANDERS. GALE ft RUSSELL Registered Profetsionil Reporters STAMFORD. CONNECTICUT 20J-)-*IIJ OLI 6183 NEW HAVEN, t IOJW24 822 THE COMMISSIONER! We can g on the record. This is the matter of in ret Estate of Alan Ardis and Estate of Alexandre Ozolins brought against the Olin Corporation. This is a continuation of hearings that commenced on September 13, 1983, were continued to September 14, and then to September 15, then to October 26, and then t November 4, then to November 16, and to this date. MR, PROOTi I believe. Tour Honor, t$U first November date was November 14, rather than November 4 -- THE COMMISSIONER! Did I say 4? MR. PRODTi Yes, Your Honor. THE COMMISSIONER! 14. Present today, attorneys are Attorney Robert Carter for the a claimant, and for the respondent, William Prout from Wiggin & Dana and Harry Davidoff the Olin Corporation. We left off on -- I believe Mr. Prout was cross-examining or present -- MR. PRODTi Presenting evidence. Your Honor. THE COMMISSIONER! I think you began to HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Registered Professional Reporceri vTAMFORD. CONNECTICUT OLI 6184 NEW HAVEN. CONNECT 1C: JOJ-O.T-*!*' 823 1 present evidence on -- Do y u want to state 2 for the record where you were when we left off 3 on November 167 4 NR. PROOT: Yes, Your Honor. We wer in 5 the midst of presenting respondent's case, we 6 had completed the testimony of Dr. Heying and 7 Dr. Meigs, and we would like to begin today 8 with the testimony of doctor Darryl Bigner -- 9 THE COMMISSIONER: All right. 10 MR. PROOT: Dr. Bigner, will you take the 11 stand, please? e* 12 DARRYL BIGNER, called as a witness* 13 having been first duly sworn by the Commissioner, 4 14 was examined and testified as follows: 15 THE COMMISSIONER: You may be seated. 16 Your full name and address, please. 17 THE WITNESS: I'm Darryl Bigner, and I I 18 live at'210 Longvood Drive in Chapel Hill, 19 Berth Carolina. ^. 20 * * MR. PROOT: May I proceed. Your Honor? 21 THE COMMISSIONER: Please. 22 MR. PROOT: Thank you. 23 DIRECT EXAMINATION. 24 BY MR. PROOT: 25 Q. Dr. Bigner, you're a neuropathologist, are y u HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Reg itccred Proicttionil Reporter* STAMFORD. CONNECTICUT OLI 6185 NEW HAVEN. CONNFCtV * 824 1 not? 2 j 3 A. _ Q. 7661 Let me show you a document which appears to b 4 your curriculum vitae and ask you if the information se 5 forth therein fairly and accurately sets forth your 6 professional training and experience, professional 7 activities and so forth? 8 A* Yes, 9 HR. PROUTt Tour Honor, I would ilk to 10 mark that as the next respondent's xhibit 11 which I believe is 13. & 12 MR. CARTER* Let me just look at it.* I 13 me inquire the purpose of the offer. 14 MR. PROOTt The purpose of the offer i 15 to provide -- to qualify Dr. Bigner as an 16 expert witness. I offer it in this fashior 17 the interest of saving time rather than asV 18 the usual series of questions about each 19 of the categories set forth in-th CV. * 20 "* MR. CARTER* I'll stipulate that he's 21 expert and that he's qualified as a 22 neuropathologist, but I would object to tl 23 offer* I stipulate that he's qualified ai LJ 24 neuropathologist is enough* 25 THE COMMISSIONER* If he agrees to h HARTFORD. CONNECTICUT .'0J.H4.JW) SANDERS. GALE ft RUSSELL Pittldiioml Reporter} 'f AMFORD CONNECTICUT ;oj.j^.*i*j OLI 6 NEW HAVEN. CO 825 qualifications, I think that's sufficient. NR. PROUTs Your Honor is going to be faced vith serious Issues of credibility in connection with testimony# only because there's testimony that's directly contrary t testimony presented by other witnesses# and I think part of the task of assessing that is to have the information as to what the individual has done. THE COMMISSIONERS You have a right to present it. MR. PROOYt All right# Your Hon r. i* I'll proceed in that fashion. THE COMMISSIONERS As long as th re's objection to it -- MR. CARTERS He's qualified. BY MR. PROUTs $ Q. Or. Signer# would you outline briefly for us your current professional and academic activities V iitfcofar as they relate to the study of brain tumors? A. I'm a professor of pathology and neuropathology at Duke University Medical Center# and I have my laboratories in the comprehensive cancer center there. My entire professional career and all f ny HAkTFOfcO. CONNECTICUT SANDERS. GALE a RUSSELL Rcpittcred Profcuioml Reporter# iTAMFOUD. CONNECTICUT OLI 6187 NEW HAVEN. CONNECT 1C 201^24.411* publicati ns have been devoted to the study o malignant br^in tumors, particularly glioblastoma multiforme. Q. Dr. Bigner, let me interrupt you for a s cond and perhaps we can shortcut this a little bit. H w long has your professional career been? A. The last 15 to 20 years. In this regard, I received my medical degree in 1965 -- THE COMMISSIONERS From where? THE WITNESS: From Duke. Q. Would you continue, please, with your current professional and academic activities as they relate*|to * brain tumors? i A. Tea. I'm -- I spend the majority of my time in research on this problem, as I stated, in the cancer center, I'm in charge of the containment facility designed and built where we test hazardous chemicals and viruses in cancer research, and I'm leader of the nervous system neoplasia team in our cancer center leading a group of some 30-odd assistant .associate p^fessors and technicians in research on this pr blem. In addition, I've just received the first major program project grant for research on brain tumors that the National Institute of Neurological Diseas s has awarded, which is a three-institution study with leven projects involving a large group of investigators there. HARTFORD. CONNECTICUT SANDERS. GALE S RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT MMHAtll OLI 6188 NEW HAVEN. CONNECT1C W).14-41)7 1 1 827 I participate -- There are only a small group 2 of .people in the world who have spent the majority of 3 their time working on this problem, and we worked 4 together world-wide in planning a series of conferences. * 5 and I participated on the advisory boards in the one | that was held in California last fall, a recent ne in 1 6 7 || Switzerland last month. 81 We are planning two others with an English 9 group this summer and a group this fall from the 10 National Toxicology Program, and then finally another 11 major international meeting we have every five yeara[ or 12 so in London this fall. .13 Q. One additional area that I'd like you to 14 I comment on or to testify concerning is your current j 15 16 editorial board and reviewing activities, again limiting it insofar as it pertains to brain tumors. 17 A. Okay. I'm -- 18 MR, CARTER: Objection. It's irrelevant. 19 |t * 20 f'- MR. PROOTt Tour Honor, I.claim it. THE COMMISSIONER: I'll allow it for the 21 weight. 22 A. I'm -- 23 THE COMMISSIONER: You may take an 24 exception. 25 A. I'm a member of seven editorial boards. I HARTFORD CONNECTICUT MI.MKI SANDERS. GALE & RUSSELL Rcantcrcd Proldiioml Reporter. "fAMFORD CONNECTICUT OLX 6189 NEW HAVEN. CONNECTIC 1 JOMH-eM- 828 1 editorial b ards in cancer. neuroscience j urnals and 2 have the responsibility for editing largely relative to 3 all aspects of brain tumor research there. 4 THE COMMISSIONER: what's the leading A5 6 neuropathology? THE WITNESS: There's a Journal f the 7 Association of American Neuropathologists, <>iS* A 8 which is a journal of neuropathology and 9 experimental neurology, and I've just been 10 elected to the editorial board of that* It 11 doesn't show on this copy of the CV. 12 The other international. Europe j urnal 13 is Acta Neuropathologica. and I'm a n mber of * 14 the editorial board of that journal. Th ir 15 articles in this field, of course, are 16 published in the general cancer literature and 17 clinical neurology and neurosurgery journals 18 as well. 19 Q. Tou stated. Dr. Blgner. that all of your 20 a*tcles and publications were related to the subject of 21 brain tumors in one aspect or another. Appr ximately 22 how many have there been? 23 A. About 130. 140. 24 Q. Now. you were present when Dr. Krigman 25 testified in connection with this case? HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL titered Profe'tionil Reporters STAMFORD CONNECTICUT OLI 6190 NEW HAVEN CONN JO!-*!4-'*'' 829 A. Yes. Q. Dr. Krigman testified that he had r viewed certain categories of materials, and what X would like to do is -- ask you is to recite what those categories were and ask you if you've reviewed the same materials in the interest of saving time. HR. CARTER* Let me just voir dire with respect to the scope of this testimony. We've had for the respondent one neuropath 1 gist testify from the neuropathological point of view, and I'd like to, if we can, limit by agreement, just to prevent redundant 4 testimony or merely cumulative testimony, the scope of this witness' evidence. HR, PROUTs We intend to do that. Your Honor, not go over areas that I asked previous witnesses about, but it's not a $ Proper subject for voir dire. What counsel is trying to. do is * f- cross-examine at this point. THE COHHISSIONERt I think it's a well taken point, and we won't name the point, we won't call it voir dire, but how long does your presentation -- your direct-examination do you plan on taking? HARTFORD. CONNECT ICC T *0).14-5t! SANDERS. SALE ft RUSSELL RctittrtJ Pflcui<inal Reporter* -I WIFORD CONNECTICUT M.i:e.ii OLI 6191 NEW HAVEN. CONNECTl JOt-C! 4-41)7 830 HR. PROUT* Twenty minutes# perhaps# Y ur Honor# thirty minutes at most. THE COMMISSIONER! Will it be new material or -- MR. PROUT* It will relate specifically to the matter of the animal studies# and as Your Honor may recall# Dr. Krigman did not testify concerning that on direct-examination# in the face of counsel's objection# Dr. Meigs certainly didn't testify concerning that# nor did Dr. Heying. MR. CARTER! f! i* Dr. Krigman did t stify- about animal studies# pages S50 to 554, He said he reviewed the animal studies himself and found nothing useful in the animal studies with respect to the causation in this case. MR. PROOTs Now# anything regarding animal studies is claimed to be redundant. MR. CARTER! I claimed that at the end c a the last hearing. More -- I would ask that more testimony by neuropathologists on anima.' studies not be allowed because there was testimony on that before. THE COMMISSIONER* Why don't you ask th direct question# if that's agreeable# and th HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Regiucred Praltiiitail Reporter! STAMFORD. CONNECTICUT 01*1 61S NEW HAVEN. CONNEC 1 2 3 4 S 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 .. . 831 we can move on? I think the point la well taken that we should accelerate where w can. MR. PROOT: Clearly, Your Honor, and I don't Intend to ask him anything that's been asked before by me. THE COMMISSIONERS I want to give you every opportunity. He*re already in Volume 6. MR. PROOT* Or 7. THE COMMISSIONER* And for new material or for -- I think you can lead your witnecb if 1 there*8 no objection. ; MR. CARTER* Let me see how much leading he does. THE COMMISSIONER* You may take an objection, but let's have counsel speed it where we can. MR, PROOT* Yes, Your Honor. BY MR. PROOT* .'A . *- -0. The question that I intend to ask you. Dr. Bigner, is whether you have reviewed in connection with this case, these claims, the following categories f materials* The medical records of Dr. Ardis and Mr. Ozolins, employment data concerning these individuals. medical literature dealing with the subject of brain HARTFORD. CONNECTICUT SANDERS. SALE a RUSSELL Registered Profession*! Reporters STAMFORD. CONNECTICUT OLI 6193 NEW HAVEN. CONNECTICUT 20MJ4-4I> . ,------ tumors, the pathology slides of each of these individuals and of Dr* Karabinos, the exhibits which wec.e marked, I believe, Respondents Exhibits 2 through 8, which were the materials prepared under the direction of Dr. Heying, the transcript of these proceedings and the exhibits that -- the documents that have gone into evidence. Did you review each of those categories of materials? A. Yes, I reviewed all those things* Q. Did you review any additional materials lr| connection with the formulation of your opinions in this case again by category? A. Well, as I think I've indicated, I spent all of my time working on brain tumors, so I review data, literature, and my entire professional time is d voted toward considering current state of the art in this area. i r Q. Have you -- Approximately how .many * experimentally-induced animal tumors have you pers nally examined? A. Well over 10,000* MR. CARTERi Objection, without clarification. Is be talking about chemical carcinogenesis? Hartford Connecticut .01-244-55*1 SANDERS. GALE S RUSSELL Registered Professional Reporters 'TAMFORD. CONNECTICUT ;oi. >.*) oli 6194 NEW HAVEN CONNECT IC Ol-OH-JI** 833 X Q. Of those more than 10,000, can y u tell us 2 approximately how many of those were chemically-induced 3 brain tumors? 4 A. At least a third of them were 5 chemically-induced. There were virally and spontaneous 6 brain tumors in the group as well. 7 Q. Have you also reviewed series of spontaneous , # 8 animal brain tumors? w 9 A. Yes. I'm currently working with a group fr m 10 the National Toxicology Program to try to establish a IX meaningful classification for spontaneous rat brain*! A * 12 tumors that are seen in the controlled animals f r all 13 the chemical carcinogen studies in that program. 4 14 Q. One additional preliminary question. Dr. 15 Bignert Have you also had opportunity to examine human 16 brain tumors? 17 A. Yes* I had seven years of training in 18 neurology and neurosurgery and neuropathology, and in 0 19 our research work we used human tumors extensively in '*. i v,\ 20 transplanting athymic mice, and we review in my 21 laboratory* receive tissue from every malignant brain 22 tumor removed at Duke or the University of N rth 23 Carolina and have for the last ten years, 24 Q. There has been testimony previously in this 25 course of these proceedings regarding the animal HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL RRiterii ProlcMionil Reporict iTAMFORD CONNECTICUT :0l.l:4~*l$] OIiX 6195 NEW HAVEN. CONM>" - a -- 11 L 834 1 studies, the experimental work, and their relevance to 2 the question of chemical causation of human brain tumors 3 generally and specifically their relevance to the 4 question of causation with respect to the cases f Dr. 5 ! Ardis and Mr. Ozolins. 6 Are there certain principles of carcin genesis 7 which are established by the animal studies which you 8 believe bear upon each of those issues? 9 A. Yea. 10 Q. Would you tell us what those principl s ar , 11 please? *1 12 A. Well, the first general principle is that 13 brain tumors are very difficult to induce 14 experimentally, and historically, it has taken us a long 15 time to develop the tools to induce them and study them 18 in the laboratory. 17 There are a number of factors that I think may 18 be relevant to $he human brain tumors that we found over 19 the years. II * 20 For example, the species that we test is very 21 important in determining the ability to induce the 22 tumors or not. It is much more easy to induce brain 23 tumors experimentally in mice and rats than it is in 24 larger animals, and particularly in primates. 25 The genetic susceptibility is very important II HARTFORD. CONNECT ICL 1 || SANDERS. GALE a RUSSELL ReRntcreJ ProlcttiofUl Reporter* M AMFORD CONNECTICUT .n-i.e-eiii 01*1 6196 NEW HAVEN. CONNECTIC !.*!' 835 1 even within the spec! s that we work on* 2 For example* there are several strains of 3 rat.s, particularly the BD-9 strain and the Fisher 344 4 strain who differ markedly in their genetic 5 susceptibility to chemical carcinogens* 6 The age of the animals is extremely important. 7 In general * we find that young animals or neonatal 8 animals, animals during fetal time are more susceptible 9 to all of the agents than are adult animals* 10 It's quite difficult to induce brain tumors in 11 adult animals. The dose of the agents used is 12 important* |* ; 13 In general, the best results that we obtain 14 are with high -- very high doses of agents or large 15 cumulative doses of agents. 16 There's a special property of the brain that 17 we think makes it resistant to this tumor in deduction I 18 called the blood brain barrier* and with many of the 19 inducing agents, it's necessary to use highly artificial 20 meins- of introducing the cancer-causing agent into the 21 brain to make it work* 22 For example, with the polycyclic hydrocarbons, 23 it'8 necessary to take a pellet about the size of your 24 little fingernail and permanently implant it in the 25 brain of an animal to make it induce cancer. HARTFORD. CONNECTICUT Ml.Ui-iitt SANDERS. GALE a RUSSELL in(td Prolcitionil Reporter! STAMFORD. CONNECTICUT OLI 6197 NEW HAVEN. CONNECTIC: ' Lj ^ ,j 836 If you give that -- those agents systemically, the.y don't wock. The sane is true with many of th viruses with which we induce brain tumors in the lab. If you give then intravenously, they don't wock. You have to inject it directly into the brain in a very high dose to make it work. Host of the chemicals that work systemically, if. you give them by intravenous injection, hav t have special properties to work, such as high degrees f lipid solubility so that they can cross the bl od brain barrier. ft rA * So there are many special features that we think, or I think are protective of the brain that account for its relative resistance to tumor in deduction. THE COMMISSIONER: You spoke of induein brain cancer by injecting viruses directly into the brain tissue. w f- - THE WITNESS: Yes. THE COHHISSIONER: Are those viruses - obviously they're identifiable? THE WITNESS: Yes, yes. THE COMMISSIONER: What success has There been in -- from that concluding what viruses might produce brain cancer in huma HARTFORD. CONNECTICUT 20M4-HS SANDERS. GALE S RUSSELL Registered Profenionil Rcporteri STAMFORD. CONNECTICUT OLI 61 NEW HAVEN. CONI' 20M24.4IS.' 837 1 THE WITNESS 1 Well, the maj city f my 2 first ten years o work was really addr seed 3 at the question of whether viruses were 4 involved in human brain tumors, and although 5 we fully published very little of that, 6 because the data was all negative, we have not 7 been able to show that retro viruses, which 8 are in the class that are most successful in 9 terms of the experimental brain tumor 10 induction, are associated at all with human 11 brain tumors* * 12 THE COMMISSIONERS Excuse me. I just 13 want to be sure I understand. You can induce 14 a viral-induced in mice? 15 THE WITNESSt Mice, rats, dogs, cats, 16 many different species. 17 THE COMMISSIONER! And you have not been 18 able to duplicate this in a human? 19 THE WITNESS! Well, we can't do the human 20 experiments -- 21 THE COMMISSIONER! I wanted to see if you 22 were listening. 23 THE WITNESS! You can do it in primates 24 with the virus -25 THE COMMISSIONER! YOU can? HARTFORD. CONNECTICUT I SANDERS. GALE ft RUSSELL Reentered Prolettionil Reporter! nTAMFORO CONNECTICUT ;oi.i.'T-iij OLI 6199 NEW HAVEN. CONN EC IW" 20|.<-Jl'* 83 8 THE WITNESS! Yes, ma'am. It's n t glioblastoma. THE COMMISSIONER! I didn't talk about the instant one. I was just interested in your answer. So, what is your deduction on that from the animal studies on viruses not dealing with the Instant cancer but in general? THE WITNESS! Well, we either -- either viruses are not associated with human brain tumors or we haven't found the way to lootd f r them and the right ones. You know, we haven't found many viruses in many human cancers. The recent success with the human T-cell leukemia virus is the only success in finding that class of viruses associated with any human cancer, and it took some very sp cial tools to do that with. So, I think recently, there is another class of viruses that most of us haven't worked with that extensively that there's som< clues it may be associated with human brain tumors. These are called the papova viruses, and they have recently been shown to induce glioblastoma like turn r in HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL RRit(crJ 5,rol,*ion,l Rcpotiert STAMFORD CONNECTICUT oiil 6200 NEW HAVEN CNNH" X 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 * 20 21 22 23 24 25 839 monkeys* and the fingerprints of that virus in the meeting I was just at in Switzerland* a very respected virology group in West Germany were reported to be involved in them* and I think that needs to be explored* but the data is all negative in toto now relative to virus involvement. A 1 THE COMMISSIONER! Are there more cases of glioblastomas being diagnosed with the level of knowledge increasing? THE WITNESS! The incidence overall ifs A i increasing somewhat* but I think the only real Influence of CAT-scanning and these sort of things is how some of these patients would die in nursing homes in the past* and be signed out on death certificates as having strokes; whereas* we would have some warning now with 4 CAT scan, and non-invasive kinds of diagnostic methods to suspect it* but ther-e's been n * real major shift in the diagnoses or incidence. THE COMMISSIONER! All right. Go ahead. MR. PROUT! Thank you. BY MR. PROOTi Q. Dr. Bigner* in response to my question HARTFORD. CONNEC1 ICC I SANDERS. GALE a RUSSELL Reporter* *:*MFORD CONNECTfCVT .'M.l.'-*!*> OLI 6201 NEW HAVEN. CONNECTIO N m).24.4ir --^ * "" 1 --i } n 840 1 X directed to principles of carcin genesis, y u listed a 2 number of factors, and I won't reiterate them at this 3 point. 4 Will you tell us in your opinion what the 5 I significance of those factors is when applied to the 6 question of causation with respect to the claims of Dr. 7 Ardis and Mr. Ozolins in these proceedings? 8 A. Well, the fundamental thing that I believe, 9 and most of us as cancer biologists believe, is that the 10 principles are the same in animals as pertain to man. 11 and we use those principles as one of the factors tiaf 12 look at cases of -- and causation of human canc r, and 13 these were the questions that led me, when I was first 14 approached by Olin, to think about what was going n 15 here. 16 The immediate questions that vent through my 17 mind were to determine if there had been a -- common II * 18 agents worked with, and any evidence for exposure to 19 agents that would have the properties that we know work || * 20 in-animal systems, such as lipid solubility, and the 21 ability to cause -- cross the blood brain barrier, these 22 sorts of things, and particularly if there was any 23 evidence of any prolonged and high dose contact that had 24 taken place. j5 Q. When you applied these factors, what 1 HARTFORD, CONNECTICUT SANDERS. GALE ft RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT OLI 6202 NEW HAVEN CONNFCI 1C 841 1 conclusion did y u come to with respect to the Issue f 2 causation as to these two claims? 3 HR. CARTER: Objection without 4 clarification. Is he testifying just from the 5 review of the materials that you suggested and 6 his animal wort? 7 MR. FROOTt Yes. 8 HR. CARTERi Is this based also* then, 9 upon his review of hufian epidemiol glcal 10 studies? 11 MR. FROOTt No, at this point the onl|y 4* 12 thing I'm asking him about is -- 13 Q. -- are the conclusions which you draw from the 14 principles of carcinogenesis which emerge from the 15 animal studies. Did you understand my question t be 16 directed to that? 17 A. Yes. No, based on applying those -- Hell, * 18 you're asking qie -- Let me just elaborate. 19 As a physician and a pathologist and as a 20 career biologist, I am trained and do look at the total 21 situation. I have to evaluate all of the evidence that 22 I have, and I would not make a limited conclusion basec 23 on one set of data, or apply one narrow set of 24 principles to reach a conclusion. 25 Q. All right. Hell, let me ask you, then, what HARTFORD. CONNECTICUT .0J.244-JJ4) SANDERS. GALE a RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT OLI 6203 NEW HAVEN. CONNECT tOM3-alS7 842 I 1 additional mat rials are y u relying upon with r spect 2 to .the conclusions that you draw from the animal studies 3 and these principles of carcinogenesis that emerge from 4 the animal studies? 5 j. A. Putting all of those principles together with 6 a comparison of the morphology of the tumors in these 7 particular cases, which I personally reviewed in great 8 detail and had some of my other colleagues review as 9 well, together with the epidemiological data, I don't 10 believe that either is there any evidence or conclusion 11 I can put together about the cause of the brain tumdrs l ** 12 in these three cases or -- nor could I find anything tc 13 pointed me towards in my research, which was my real 14 interest here. 15 I have not come away enriched or knowing any 16 better how to approach the problem from the study f 17 these three cases, what chemicals to look at or what n 18 mechanisms to,consider for cause of glioblastoma 19 multiforme. 20 f- -Q. Tou indicated in your response just n w, Dr 21 Signer, that one of the factors that you to k int 22 account and found significant was the morphol gy of t 23 tissue samples that you reviewed. 24 What significance did you draw from the r v LJ 25 of the tissue samples? HARTFORD CONNECTICUT SANDERS. SALE & RUSSELL Reaiitcred Proleuiontl Reporter! 'TAMFORD CONNECTICUT OLI 6 NEW maVEN CONN 843 1 A. Well/ first of all, our institution has been ! 2 the. pathology referee institution for all the treatment I 3 trials on glioblastoma that are conducted throughout the ! 4 country, and we've come to recognize that diagnostic \ 5 errors are not infrequent, even from other pathologists, 6 about the tissues. 7 So my first instinct was to be absolutely sure 8 in my own mind by re-examination that we were dealing 9 with glioblastoma here and ve were -- all three cases 10 are what I would describe as garden variety glioblast ma IX multiforme cases with all of the more logical hallmarks 12 of the disease. 13 This is a well-described disease, Verc*how 14 found the same findings and described them in G rman in 15 1865. it hasn't changed for we will over one hundred 16 years. 17 So this told me that there was nothing 4 18 morphologically,, or for that matter clinically or 19 otherwise, distinctive or unusual about these cases. w 20 *- The possible Importance of this is vi wed in 21 light really of some questions we're asking in the 22 laboratory, and that is I think it's fundamentally 23 important to be able to associate cause in individual 24 cases of human cancer where we can, and we're studying 25 this question of is there morphological distinctiveness HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Regurcrcd Prole<ioml Reporter* WAMFORO CONNECTICUT OLI 6205 NEW HAVEN. CONNf. *:-  ,i 1 1 -- A ------- . *--> j r-| LJ 844 11 1 1 r lative to Inducing agents. | 2j Foe example, will ethyl nitrosoureas-induc d 3 | brain tumors or acrylonitrile brain tumors be 4 distinguishable from glioblastoma multiforme, and s i although a formal and full-length study has not been 6 completed, my opinion, based on studies of spontaneous 7 tumors in a large number of these induced tumors now, is 8 that a significant number of them can be distinguished; *- 9 that is, that the different inducing agents perhaps as 10 much as 60 to 80 percent of the time do have 11 morphologically distinctive features and can be ^ 12 separated from one another on that basis. 13 THE COMMISSIONER! Could you separate any 14 of these three cases or were they identical -- IS THE WITNESS: Well -- 16 THE COMMISSIONER! -- in the tissue? You 17 said a garden variety, and I'm not sure I 18 comprehend your garden variety and mine. 19 * 20 f- THE WITNESS! The World Health Organization has published straightforward 21 criteria that we look for in establishing the 22 diagnoses of glioblastoma multiforme in these 23 cases possessed -- each of them possessed all 24 of those criteria. 25 Now, there's some differences among the HARTFORD CONNECT ICl.l ----- -- * -- --- * -- -- SANDERS. GALE & RUSSELL Rdi'icifJ Prol,ion,l Reporiert %! CONNECTICUT M.PMIftl OLI 6206 u . ...u NEW HAVEN CONNECTK - ----------- ------------------ -- ~ * -- - -- -- -- -- -- 84S individual ones. One group of cells would be in one tumor that were not in another, and that sort of thing, but pseudopallisading necrosis in endothelial proliferation, multiple cellular forms, and no plastic cells were present in all three of these cases, and not only did I -- I showed these blindly and independently to three or four of my other colleagues who were among the most respected tumor pathologists. We all independently came up with the same thing. ** THE COMMISSIONER: In lay language, voulc it be fair to say that substantially they wer< very similar, had the components of very similar brain tissue, leading to a diagnosis of glioblastoma multiforme? THE WITNESS: Yes. They'd be like all * other eight to ten thousand glioblastomas th occur in the O.S. every year. -Nothing unusu to set them apart, which is what 1 was 1 oki for. THE COMMISSIONER: When you said you're the treatment center -- Duke is the treatme center for all glioblastoma cases, I was curious as to who designates that. Is that HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Reamcred Profcttioml Reporter! 'TAMFORO- CONNECTICUT .'tM.IN-eiU OLI 62C NEW HAVEN. CONNf 846 * - the NIH r who designates you? THE WITNESS: Let me clarify that. W 're not the treatment center. There are two -There's a large multi-institutional trial sponsored by NIH that 15 institutions participate in. Duke is the diagnostic center, the pathology diagnostic center. All the slides from all 15 institutions from patients that are entered into that cooperative tr atment trial are sent to Duke. THE COMMISSIONER: Aren't they sent to the other 14, too? THE WITNESS: No. Well, they go to their hospital pathologist, but then he sends the slides to us, and we make the official study Diagnosis so that there's a common set of I criteria applied for study purposes there. THE COMMISSIONER: That's.of all brain tumors? THE WITNESS: Yes, all malignant. This trial is limited to malignant brain tumors. THE COMMISSIONER: Now, for malignant lung tumors, are there other centers designated? HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Registered Profcuionel Reporter* STAMFORD. CONNECTICUT :oi.m-iu OLI 6208 NEW HAVEN. CONNECTICl 20)*4-Jn* I i 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 847 THE WITNESS; There are other trials of that nature where there would be an ther pathology center designated for that. THE COMMISSIONER: You're designated for the broad category of all malignant brain tumors? THE WITNESS! Yes, for that study. That's the National Brain Tumor Study Group. We also -- Or one of our pathologists reviews for the Southwestern Oncology Study Group. My program project grant has the same 1 pathologists. THE COMMISSIONER! I understand that. But you said for all throughout the whole country in -- THE WITNESS! Only for the Brain Tumor Study Group. That's the largest and ldest treatment trials. 0 THE COMMISSIONER: That's comprised of 14 ~ THE WITNESS! Fourteen to fifteen institutions. The center of it is at Memorial Sloan-Kettering in New York, Dr. Shapiro was the principal investigator, but Duke was one of the founding members. HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Rendered Profcttionel Reporter* 'TAMFORD CONNECTICUT OLI 6209 NEW HAVEN. CONNFC1 'r I --i -j i 1 BY MR. PROUT: 848 2 Q. Dc. Bigner, in your testimony a few moments 3 ago in talking about the principles of carcinogenesis* 4 you indicated that the particular substance that was j. 5 { involved in a particular animal experiment was 6 significant with respect to one's ability to induce 7 brain tumors in animals. 8 Did you look at the question in connection 9 with these cases o whether the tumor -- whether the 10 chemicals which have been successfully used in the 11 experimental studies were chemicals to which either !of 12 these individuals had a significant exposure? 13 A. Yes* That was my initial question in HI 14 discussing this case* was that Olin compile -- take the IS known list of published human carcinogens first by the 16 international agencies and then give me a contact list 17 from each of these workers* paying particular attention 18 to any agents in that list that might have ever Induced 19 experimental brain tumors in animals. 20 -Q. What did you find? 21 A* We found* first of all* that there was no 22 common agent of any kind in the carcinogenic group* and 23 secondly* the one chemical that I am presently 24 investigating in some detail as an experimental brain n 25 tumor agent* acrylonitrile or vinyl cyanide had been an 1 HARTFOKO. CONNECTICUT 1 -'0J.J44.1J61 SANDERS. GALE ft RUSSELL Repucerrd Pfofe<iionl Repofttr* STAMFORD CONNECTICUT OLI 6210 NEW HAVEN C'ANN * 849 x! agent that had been used by -- I don't remember the 2 details. You may want to give me the list to look at of 3 actually the amounts that -- Yes. 4 Both Ardis and Ozolins worked with a 5 acrylonitrile, but on questioning this, and th 6 conditions and the amounts, I am presently running a 7 study with acrylonitrile where the brain tumors in that ....3 8 study are induced only with large doses, 500 parts per ..1' 9 million or one hundred parts per million of 10 acrylonitrile in the drinking water through a continuous 11 lifetime exposure of the animals. -*j 12 Acrylonitrile is cyanide, it's vinyl cyanide. 13 and any organic chemist knows, or should know, that 14 vinyl cyanide or cyanide is an acute toxic agent and ; is would handle it with care, and the amounts and 16 I conditions under which this was handled did not convince 17 me that any significant contact with the agents, any II 1 18 significant doses occurred. II f 19 MS. PRODTi Nay I have a moment. Your 20 Honor? 21 THE COMMISSIONER: Yes. 22 (Pause in the proceedings.) 23 BY MR. PROUTi 24 Q. Dr. Bigner, on approximately how many 2S occasions did these two individuals work with that II I! HHAARRTTFFOORRDD CCOONNNNEECC1HIOCI. II 1 MMli..NN*e.-1m)61i SANDERS. GALE & RUSSELL Pialtitianil Reporters SMFORD CONNECTICUT . qLI 6211 NNEEWW HHAAVVEENN.. CCOONNNNEECCTITC' mm:4.4h* 850 1 particular substance you've identifi d as vinyl cyanide 2 or .acrylonitrile? 3 A. it looks like there are about ten listings 4 here for Ardis and four or five for Ozolins. 5 Q. All right. And do the notations there 6 indicate that the amounts were on the order of grams? 7 A. Yes. These are all gram quantities of the 8 agent. 9 Q. And that the substances were used under closed 10 system conditions? 11 A. Yes. 12 MR. CARTERS Objection. I think that's 13 without any foundation except for this 14 characterization of the list. I don't think 15 there's any review of the actual evidence 16 which is in -- -- 17 THE COMMISSIONERS I'll sustain the A 18 objection. 19 MR. PROOTs I'll withdraw the question, 20 Your Honor/ but that is part of something 21 that's already in evidence. It's redundant/ 22 if nothing else. I'll withdraw the question. 23 BY MR. PROOTs 24 Q. This is part of one of the Exhibits 2 thr ugh j 25 8 that were introduced through Dr. Heying. HARTFORD. CONNECT ICU1 M)>*<))) SANOERS. GALE ft RUSSELL Reentered Proicttionil Reporters UAMFORO CONNECTICUT OLI 6212 NEW HAVEN CONNFCHf- 8S1 Dr. Signer/ do you have an opinion that you Can state with reasonable medical probability with respect to the issue o whether the glioblastoma raultiforme of each of these individuals/ that is/ Dr. Ardis and Mr. OzolinS/ arose out of or were caused by exposure to chemicals in the course of their employment at Olin Corporation? A. Yes. Q. What is that opinion?' ' A. Well/ I've stated part of my opinion as we've gone through this. My opinion is that it is not * possible to determine with all of the evidence and evaluation of this situation what the cause of these individuals' glioblastoma multiforme is. I can find nothing that sets them apart from all of the others that occur at a significant r te, significant numbers throughout the country/ and I don't think we can establish the cause of the glioblastomasin these individuals. -Q. All right. Is it your opinion -- Do you have -- Withdrawn. In your opinion/ is it reasonably probable that their cancers were caused by exposure to chemicals in the course of their employment at Olin? A. NO/ I find no reason to involve or implicate HARTFORD. CONNECTICUT .'0J.J44.mi SANDERS. GALE a RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT ;oj.ut-*iss OLI 6213 NEW HAVEN. CONNECT 1C '01-4H-4H" 8S2 1 their employment r work at Olin any more than anything 2 els.e that may have happened in their lives. I don't 3 know what the cause is. 4 MR. PROUTs I have no further questions 5 for Dr. Bigner at this time, Your Honor. 6 CROSS EXAMINATION 7 BY MR. CARTERt 8 Q. Dr. Bigner TM 9 THE COMMISSIONER: You may. 10 Q. You did diagnose all of the glioblastomas 11 multiformes, the three? ' 12 A. Yes, One of the tumors, that is a variant of .13 glioblastoma multiforme, which is gliosarcoma, but 14 they're within World Health Organization criteria as 15 glioblastomas. 16 Q. Now, you said it was important to you that 17 there was nothing distinctive or unusual about these c 18 pathological slides that you reviewed; that is, that 19 these glioblastomas looked like every other glioblastoma 20 auiti-forme, more or less. Is that correct? 21 A. Yea. I said I looked at them particularly 22 trying to determine if there was anything special or 23 distinctive about them and could find no such 24 distinctiveness. 25 Q. Does a lung cancer that's caused by asbestos HA* fFORD CONNECT !CL I SANDERS. GALE ft RUSSELL ProUttional Reported TAMFQRD CONNECTICUT OLI 6214 NEW HAVEN C"N\T<"ir : \y1 *^<1i if m " 853 11 1 look any different from lung cancer caused solely by 2 cigarettes? 3 A. I'm a neuropathologist, not a lung 4 pathologist. 1 a5 Q. You were trained as a pathologist, weren't 6 you? 7 A. No. X received one year of training in 8 anatomic pathology, and I haven't looked at any lung 9 tumors in ten years, and I'd rather not comment on the 10 morphology of lung tumors. 11 Q. So, based upon your analysis, would you expect 12 that a lung tumor from -- lung cancer from asbestos 13 would look different from a lung cancer caused by * 14 another substance, arising spontaneously? 15 MR. PROUTi Objection, Your Honor -- 16 THE COMMISSIONER! Let the doctor answer. 17 MR. CARTER: He may know the answer. 18 19 ** 20 THE COMMISSIONER! Yes. * A. I -- You know, I'd rather not. comment about * lung -tumors. I haven't studied lung tumors -- 21 THE COMMISSIONER! If you kn w. Doctor. 22 Q. If you know, answer it. 23 THE COMMISSIONER: If you don't know. 24 just say "I don't know." 25 THE WITNESS: I don't know. HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Retittcreii Prolc.'iontl Reporter. 'TAMFORD CONNFCriClT :m.i.-*-*h OLI 6215 NEW HAVE_N,,C,_O..N...N..! . . I '! 1 2 THE COMMISSIONER! All right. THE WITNESS: He's asking me to 854 j |i j i3 i1 4 speculate. ; THE COMMISSIONER: Don't speculate. Just <1 5 1 say "I don't know." ! 6 BY MR. CARTER: i ji 7 Q. Do you know anything about whether bladder 8 cancers caused by aniline dyes look any different from 9 bladder cancers arising in the background populati n? 10 A. No, I don't know anything about bladd r 11 cancer, either. * 12 Q. Would it surprise you that they all look 13 exactly the same? 14 A. I don't know -- 15 MR. PRODT: Objection. If they looked 16 exactly the same? Objection, Your Honor. I 17 think there's no foundation for the question. * 18 Q. Do you * know whether leukemia caused by benzene 19 looks on the pathological slide any different from 9 20 leukemia caused by something else or arising 21 spontaneously? 22 A. No, I don't know about benzene leukemias. 23 either. 24 Q. Do you know about any other end Organ tumors L j 25 caused by chemicals except for brain tumors or central HARTFORD CONNECMCIT SANOERS. GALE & RUSSELL Reamercd rioltmonil Reporter, ^IFORD CONNECTICUT 0>I 6216 NEW uHAi(VfeEuN CONNFC1l1C .. . .* -- * * ----- - -- 1 -* ' ' * " 1 2 3 4 *5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 *m 20 21 22 23 24 25 8S5 nervous system tumors? MR. PROUT: Are you limiting that to the specific issue of morphological appearance? '' Otherwise your question is too broad. MR. CARTER* I'll limit it. Q. Do you know any tumor -- any human tumor that has a different appearance when caused by a chemical i I ! I i ! i 1i ! ii \ exposure from that tumor, a garden variety of that tumor? A. I can tell you the tumor that I think would be best to study in that regard. Q. No, that's not what I'm asking. I'm asking if you know of anywhere the appearance is different. A. I don't think it's been studied well enough to draw much conclusion --* THE COMMISSIONER* What hasn't been studied? * THE WITNESS* There are only a handful of * f- - human tumors where we know the .cause, and y u have to have the background tumor, on that's been around for a long time, and then known specific causes to do the comparison. THE COMMISSIONER* What are the handful? THE WITNESS* The angiosarcoma of the liver would be the ideal one to study where we HARTFORD. CONNF.CTICL'I SANDERS. GALE & RUSSELL Reentered Profession*! Reporters 'TAMFORD CONNECTICUT OLI 6217 NEW HAVEN. CONNECT 8S6 have known about the tumor and where we know about vinyl chloride and where we had the old data from Thorotress, for example, s we've got the basic same kind of tumor so that the study could be carried out properly. THE COMMISSIONER: What is the other -- What others do you know about? You said there's a handful. THE WITNESS: Of human tumors? THE COMMISSIONER: Yes. THE WITNESS: Well, the asbestos-rela!ted mesotheliomas, the problem there is that tumor hasn't been recognized clearly for 20 or 30 years, and it may very well be that all mesotheliomas are associated with asbestos, so you don't have the background to compare with it in those cases. The bladder carcinomas would be another one where there are at least a handful of human cases where the study could b carried out critically. THE COMMISSIONER: What's the causation there that's been established for the bladder cancer? THE WITNESS: There are some of the dyes HARTFORD. CONNECTICUT SANDERS. GALE & RUSSELL Registered Proteuional Reporters STAMFORD. CONNECTICUT OLI 6218 NEW HAVEN. CONNECTIO 857 1 2 i *.- 3i . and some of the dye industry* particularly in old -- in the older coal* tar industry j ii 1 exposures. 4 The leukemia situation is opening up now 5 il !i 7| i 8j where with HTLB and our very sensitive markers* where we can precisely classify leukemia* where you could do those sorts of studies* and I think they need to be done. !i j i 9 THE COMMISSIONER* what is pointing as to 10 causative agents there? What are the 11 causative agents leading to the leukemias?! 12 THE WITNESS: The human T-cell leukemia 13 virus now has enabled us to -- They know that 14 I 15 the virus is associated with those tumor cells and we have antibodies to the virus proteins 16 and can very precisely identify and separate 17 that kind of leukemia relative to its cause 18 and look at it in background of all the other p 19 leukemias where we don't know the cause. * ' 20 B^MR. CARTER: 21 Q. Isn't it true that for -- that for 22 chemically-induced tumors* as far as you know* that the 23 morphology really is no help at all in determining 24 whether or not those are chemically-induced? 25 A. No, I just testified to the contrary. I think HARTFORD CONN EC llCt: I SANDERS. GALE ft RUSSELL Reanrered Prolcttiorwl Reporter* 'TWIFORD CONNECTICUT OLI 6219 new Haven connfC tf 858 1 chat I can distinguish acrylonitrile-induced brain 2 tumors across the room. They're very distinctive, they 3 stand out. 4 Q. In rats and mice? 5 A. Yes, in rats, not in mice. It's not been 6 studied in mice. 7 Q. Now, do other people working in your area feel 8 that the animal glioblastomas that are f'k 9 chemically-induced have different morphological 10 appearances from spontaneously-appearing glioblast mas? 11 A. Let me be very precise about how to answer; 12 that, when I'm -- The statements I've made are 13 referring to malignant glio brain tumors. Ther ar not 4 14 very many animal glioblastomas, and you -- if you limit 15 your comparison to animal, experimentally-induced 16 glioblastomas in animals, you're only talking about a 17 very narrow spectrum of cases. 18 Q. So that' if Harry Zimmerman -- Who is Harry p 19 Zimmerman? 20 T- - A. A very well-regarded friend and colleague in 21 this business who is the neuropathologist at Montefiore 22 at Einstein in New York. 23 Q. Would you disagree with him that over 40 24 percent of experimental gliomas produced with l, 25 carcinogens are glioblastoma multiformes? HARTFORD. CONNECT !CLt .'0 SANOERS. GALE & RUSSELL Registered ProfciMoml Reporter* STAMFORD C*>NNFCTIC'-'T OLI 6220 VE'.V HAVE* 8S9 \ 1 A. Wellr could I see what you're quoting from, ii 2 i please? i 3; ' Q. This is Dr. Zimmerman's 1969 Annal3 of the Mew i .~ 4 York Academy. 5 A, What Dr. Zimmerman was talking about were some j experiments he did in the early 1940's that he -- It's 6 7 | a cumulative data, and what he's referring to there are 8 j these highly artificial inductions with pellets of metal 9 cholanthrene that he put in the brain of rats and mice, 10 and, yes, he was speaking about his own work in that 11 very limited set of experiments. ? 12 Q. He found that they resembled human 13 glioblastoma multiformes almost identically, didn't he? 14 j A. Yes. With metal cholanthrene pellets put in 15 the brain of rats and mice, he was not talking from 1984 16 about all the agents in the broader scope of agents 17 we've studied since, and that paper was published in 18 1969, I think. 0 19 Q. He also cites dibenzothiazine and 20 difeenzopyridine, so he was at least reviewing 21 experimental glioblastoma multiformes produced by those 22 other chemicals? 23 A. Which are all polycyclic hydrocarbons which 24 all have to be put into the brain in big pellets to 25 induce the tumors and which is regarded now as a highly HARFFORO CONNFCHCI I SANOERS. GALE & RUSSELL ReamereJ P'DlciMiinil Reporters -'\\!F*'R!> \-\ECTtClT OLI 6221 NEW HAVEN. CONNfct r' :ou*: 4-ui* 360 j artificial model and induction method. Q. How, do you believe that any human glioblastomas are induced by chemicals? A. I believe we do not know the cause of human glioblastoma reultiforme in any case except for the handful of cases associated with radiation exposures. I think it is possible and likely that the same thing will turn out with glioblastoma multiforme a it has -- as it is with other things. A small number may be caused by viruses, a small number of other cancers we know are caused by chemicals. The majority of all human cancer we don't have the foggiest idea about the cause end now. Q. You've written with Dr. Swenberg; isn't that correct? A. Yes. Q. You would disagree with the statement states by Dr. Swenberg#`It's been estimated that 80 to 90 * percent of all human cancers* -- > - MR. PROUT: May I have a clarification Are you representing that he's a co-author7 THE COMMISSIONER!. He said if he agret with Dr. Svenberg. Q. If you disagree with Dr. Swenberg's citati A. Dr. Swenberg said -- He's quoting. He sa HAH fFORD CONNECl !Cl I mm SANDERS. GALE ft RUSSELL Reanterfd ProfcttioniL Reporters '{AMFORO CONNECTICUT 01*1 t NEW HAVEN CPN 861 1 "It has been estimated by some people." He's not saying 2 "I believe that," or have evidence that 80 percent of 3 hum&n cancers are used by chemicals. 4 I j And, you know, let's put that in its proper 5 , perspective. The cancer research has waves of I 6 | enthusiasm. Fifteen years ago, we thought everything 7 was caused by viruses. 8 Now there's a big trend toward environmental 'a'it 9 agents, and it will cause a great deal of study, but we ^:rK, 10 don't know, we cannot prove, and I don't think anyone in 11 the scientific community believes that we know the clause 12 of most human cancers, especially in individual cas s. 13 Q. So, do you still feel that it's -- there's a 14 15 strong possibility that viruses cause some human brain cancer, or have you abandoned that? 16 A. l think it's a possibility that needs to be 17 explored. I'm not personally exploring it any longer. 18 19 . . 20 Q. Now, in some human -- Sorry, strike that. In some'experimental glioblastomas or animal br^ain cancer, which has been induced by chemical 21 exposure, virus particles are released, aren't they? 22 A. Yes. Dr. Zimmerman reported that and there 23 are other instances in which that's been reported. 24 Q. Now, has there been further work on that 25 mechanism? HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Registered Professional Reporter! STAMFORD. CONNECTICUT OLI 6223 NEW HAVEN. CONNECT 1C' T 662 1 A. Yes. There's been a great deal o work on 2 that mechanism. What we believe most of those viruses 3 are*/ are indiginous retro viruses whose replication or 4 multiplication is stimulated or turned on by the 5 chemical or the tumor/ and that in most cases/ that 5 doesn't have anything to do with causing the 7 transformation of the malignant process. 8 Q. Gut these virus particles or virus-like A 9 particles that are released from a brain tumor that is 10 clearly caused by chemicals/ when those are transplanted 11 into another animal's brain/ those virus particl s , 12 themselves will induce cancer; isn't that true? 13 A. There is one/ I believe/ Or. Zimmerman's work, 14 he published one or two -- unconfirmed by other 15 people -- situations in which those virus particles wer< 16 shown to induce sarcomas/ a different kind of tumor, 17 when they were injected into other hosts. 18 THE COMMISSIONER: it wasn't the same as 19 glioblastoma? 20 av. . THE WITNESS: No, it wasn't the same ki 21 of tumor at all. 22 THE COMMISSIONER: Isn't it true in hum 23 cancer that one kind of cancer often produce 24 or the body produces another type of cancer * 25 I don't know how to put it into technical HARTFORD CONNECT !CL' I SANDERS. GALE ft RUSSELL Rcvittcr/4 Pro(eion*l Reporter! MAMFORD CONNECTICUT OLI 622 NEW HAVEN LW...-. 863 terms, but if you have one cancer/ you often find a host and then you get another type of cell cancer. THE WITNESS: Yes. Again, you can take one of the brain tumor-causing chemicals, if you want to look at that ethyl nitrosoureas causes glioblastomas in rats, if you give it to gerbilS/ it causes melanomas/ and if you give it to mice, it causes lung tumors; So, the organ site is often not predictive. BY MR. CARTER: Q. In connection with that same truth of A different organ sites, did you investigate in these cases what other known human or suspected carcinogens these people were exposed to? A. Yes. I asked that, and went over the data that all known oif suspected human carcinogen contact p histories in amounts, duration and so forth, had b en compiled and analyzed, and -- i, Q* What did you find there? I mean, what were these other human carcinogens or other suspected carcinogens to which these two men were exposed? A. I*d have to go back to Dr. Heying's testimony, I believe is where that was entered into evidence, and HARTFORD. CONNECTICUT SANDERS. GALE & RUSSELL Regurered P'oftnionil Reporters tTANIFORD CONNECTICUT OLI 6225 NEW HAVEN CONNI" 86 4 look at chat. I haven't reviewed that. Q* You don't have a present recollection? A. No. I was not impressed with anything particularly striking in theref and I don't remember the details. Q. Do you recall that they were exposed to a number of known and/or suspected carcinogens? A. The most striking memory I have is there was no common contact with known carcinogens. If you took all three of them, I asked that a checkerboard b prepared so we could look across and identify very ( simply any consistent or common contact with known or suspected human carcinogens, and that's my most striking memory that that was not present. Q. So you were looking for common exposures to known or suspected carcinogens? A. No. All exposure, but particularly for -- I shouldn't say "exposure." I think contact or working w with something. We do it every day in the laboratory un4er safe conditions, and that doesn't mean you're i. exposed to it because you work with it. Q. Was there concern -- If you know, in the '50's, was there concern in laboratory work as to carcinogenicity of low dose substance? If y u kn w. HR. PROOTs Objection at this point. I'm HARTFORD CONNFC1ICLI SANDERS. GALE & RUSSELL Prolc'ttofwl Reporttrt >1AMFORD CONNECTICUT OLI 6226 86 5 1 i I 2| not sure cone rn where -- and I don't think there's any foundation for this with respect 3| to -- 4; | 5 i 6I i 7i '` THE COMMISSIONER: I'll allow it for the weight. Let the doctor answer, if he knows. I think he understands the question. If he knows. ' 8 MR. PROUT: I'll withdraw the objection. 9 Your Honor. 10 A. Well, I don't think there's any questi n that 11 our general societal awareness of safety and danger of 12 chemicals and other agents is increasing all the time, 13 and I'm sure what was done in the '50's wasn't at the 14 same level of awareness we have today about it. 15 Q. I got you off the track there. You were -- 16 You were particularly looking for common exposures to 17 known or suspected carcinogens, why would they be 18 particularly significant? 19 A. Well, really, in a sense because you didn't . - 20 21 haye. any other thing to look for. I mean, you very <. quickly exhaust what you can do in a situation like this 22 when you're trying to find out what the cause is. 23 Q. That is, you were trying to get a clue as to 24 what particular chemical might have been the cause? 25 A. Yes, as I say, my compelling interest, as HARTFORD. CONNECT ICU I SANDERS. GALE a RUSSELL ReEitrered Profeion,l Reporter! iIAMFORD CONNECTICUT MI.I'R-tllJ OLI 6227 NEW HAVEN. CONNFC'!'. .'OM'MIV  n 866 1 tragic as it would have been and is, in the case of 2 these individuals, it would have helped our research t 3 find something to work on here. 4 Q* But many chemicals might, and, in fact, d 5 cause brain cancer in animals; isn't that true? 6 A. Well, it depends on what you mean by "many.* 7 Not many out of the total human carcinogens, only a 8 handful among the known human carcinogens. 9 Q. Are there at least'28? 10 A. You know, it depends on what kind of points 11 you want to make. If you break them down by classed f r 12 compounds and related compounds, there are only a few 13 classes of compounds that induce experimental brain 14 tumors. 15 If you want to list all of them that have 16 minor ring differences from one another, you can link 17 them on either of the lists. There are quite a number 18 of chemicals and viruses and radiation that will induce 19 brain tttmocar. It's very difficult to do .and requires . . 'v. i.: 20 special'situations to make it work in general. 21 Q. So, what we're testifying to, then, is that 22 you couldn't locate a specific exposure that you 23 thought -- a specific chemical exposure that you thought 24 was fruitful for your research here, and analysis? 25 A. No. HARTFORD. CONNECTICUT 0)-24.)IJ SANDERS. GALE ft RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT 20M29-IS3 OLI 6228 NEW HAVEN. CONNECTICUT 201.624-41 ST 867 Q. Now, the issue here -- Let me -- 1*11 withdraw that. Did you entertain the possibility that there may be multiple chemical causes of brain cancer? A. Yea, in fact, another area that's just funded for research in this new grant that we have is the business of promotion. Promotion has never been demonstrated relative to nervous system tumors. There are no known promoters that increase the instance of the experimental brain tumors in animals, and that's a potential mechanism to think about, abffot r multiple action, but again, we're very ignorant in this area. We don't know that promoters work at all, and yes, any combination would have been -- -- THE COMMISSIONER; Can you explain your use of the word "promoter." THE WITNESS! A promoter is an agent which acta on so-called initiated cells that p aids in completing the transformation pr cess to full cancer, if you will. And it can act in concert with other agents to speed up or help the process. BY MR. CARTER! Q. So, do you understand, then, that the issue here is not whether we can locate a particular chemical HARTFORD. CONNECTICUT :0).244-S)J SANDERS. GALE ft RUSSELL Registered Profettionil Reporters STAMFORD. CONNECTICUT OLI 6229 NEW HAVEN. CONNECTION T I01-4J4-U f* Lj I---- 1 n 86 8 1 cause, but whether It's more probabl than not that 2 these brain cancers arose from theoccupational 3 exposure? 4 A. You know/ the issue seems to be broader than 5 that to me. It's whether you can establish a probable 6 cause for the glioblastomas in these individuals, and -- 7 Q. What do you mean when you say "a probable 8 cause"? 9 A. Anything thatwould contribute towardcausing 10 the glioblastoma multiforme in these individuals, and I 11 was able to come up with nothing. r< 12 0* And, I mean -- Would you call -- ever call a 13 particular occupation a cause of cancer without kn wing 14 the particular substance that was the pathophysi 1 gical 15 agent of causation? 16 A. Well, perhaps it's easier with a 17 nonoccupational situation with cigarette smoking. This II t 18 has come up before, in this trial. We don't kn w, and 19 a what Dr* ,Krtgman was saying and said badly was we don't I20 ki^^the^sechanism by which cigarette smoking causes 21 I cancer. We know that it does. 22 Q.Dr. Krigman didn't say he thought it caused 23 cancer, did he? 24 A. You -- 25 Q, Strike that. HARTFORD. CONNECTICUT SANDERS. GALE & RUSSELL Registered Profeuionil Reporteri STAMFORD. CONNECTICUT .tMM-tll) OLI 6230 NEW HAVEN. CONNECT Id I 869 1 NR. PROOT* I don't know that It's 2 appropriate for counsel and the witness to 3 argue over what another witness' testimony 4 might have been. It was what it was. S Q. What -- Maybe you could just answer the 6 question. Now, would you ever call a particular 7 occupation a cause of cancer? 8 HR. PROUTt Objection. There's no 9 ... .................foundation. On what facts and circumstances? 10 MR. CARTERt I'll try to analyze the 11 basis of his response to your question, that 12 is, what standard is he using. $ 13 Q. If you can't a find a particular cause, a 14 particular chemical cause, does that put an end t the 15 inquiry of whether there's an occupational cause? And I 16 think the question is proper. 17 HR. PROOTi I don't have any probl m with 18 the question as explained. w 19 THE COMMISSIONERt Let him answer. It's %\ 20 cross-examination. 21 HR. PROOT* Withdraw the objecti n. Your 22 Honor. 23 A. Yes. We could find a situation that had -- 24 where the association was strong enough that we w uld 25 say there's a link here. HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Registered Profession.! Reporters STAMFORD. CONNECTICUT OLI 6231 NEW HAVEN. CONNECTICUT 10)-6I-4tJ7 - I _l "1 n 870 1 Now, h w far we can go in determining what the 2 specifics in that link and association are varies all 3 the time, and what we -- we hope to do and study out 4 mechanisms is to further refine and refine all the time 5 and identify more specifically what it is, but 6 certainly, you could start with an association with an 7 occupation. 8 Q. And that's true at thisstage for hematite 9 mining, or do you know that? 10 a. No, I don't know that. 11 Q. Or top aide coke oven workers, do you kno*J 12 that? 13 A. No, the only industrial things I would comment 14 on would be vinyl chloride, for example, or something of 15 that nature, and there the association was with 16 repetitive exposures. Largely the people that went in . 17 and cleaned the vents out, and a clear-cut link, but -- 18 Q. how high was '-the relative risk in those 19 initial vinyl chloride studies, that is,-the relative 20 | riik'-of angiosarcoma? 21 A. Z can't comment on the specifics of that. I 22 I can make a general comment as a cancer biologist about 23 this, if you'd like. 24 ` As these stories emerge, they fit, and ther 's 25 a common theme to them. One of the things that we learn HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Rcgiiccred Professional Reporter* STAMFORD. CONNECTICUT MMIMIII OLI 6232 NEW HAVEN CONNECT ICI I 871 1 in psych logy and medicine is that things that ace true 2 in .nature occur separately in space and time, and the 3 truth emerges with time* and it doesn*t happen usually 4 I just once and in one situation. The story fits together a 5 and -- 6 7 8 9 10 11 11 12 THE COMMISSIONER! How many cases f glioblastoma percentage-wise are ther compared to other brain cancers? Bee use you say that Duke is the treatment center of all glioblastoma cases, so you must have these statistics, what are they? THE WITNESS! It varies. *f 1 The numbers 13 14 IS t 16 17 18 19 ` 20 21 22 23 24 25 vary somewhat depending on whether you're I looking at an autopsy series or a surgical series where we're just looking at biopsies. whether we're looking at patients that come from major referral centers or out, but overall* the incidence of glioblastomas of all I ' brain tumors is from 40 to 60 percent, and the H. *'*teason, of course, that we focus on them is I1I JWr,*' '* ` . that this is the most malignant one, th on that we can't treat, can't prevent. It runs I such a rapid uniformly fatal course. THE COMMISSIONER! So glioblastomas multiforme comprise about 40 to 60 percent f II || HARTFORD. CONNECTICUT SANDERS. SALE ft RUSSELL Registered Profession.! Reporters STAMFORD. CONNECTICUT OLI 6233 NEW HAVEN. CONNECTICUT 872 X all brain cancers? 2 THE WITNESS: Yes. 3 BY-MR. CARTER: 4 Q. NOW -- 5 THE WITNESS: Excluding metastatic tumors to the brain. 7 THE COMMISSIONER: I'm excluding that. 8 Primary brain tumors. 9 THE WITNESSr'Yesprimary brain turn rs. 10 Q. Nov, isn't it true, for example, with vinyl 11 chloride, you have some familiarity with vinyl ohlo^id 12 production of angiosarcoma? 13 A. Yes. 14 Q. Isn't it true that the relative increase in 15 angiosarcoma in those initial studies, and even in the 16 defined studies, was only about tenfold relative risk? 17 Do you recall that? * 18 A. No. You knov, I don't even -- The details o 19 Individual studies from where I view these things are * 20 l4fs 'important than how many of them shoved th same 21 thing, whether you can then go in and remove the agent 22 and affect the incidence of the disease, stop cigarette 23 smoking, decrease lung cancer. 24 There's another whole loop in determining 25 cause and effect, and bacterial diseases and others v HARTFORD. CONNECTICUT '01-144OI6) SANDERS. GALE ft RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT OLI 6234 NEW HAVEN. CONNECT .'OMiMir 873 talk about Koch's postulates. You don't conclude cause and effect on the basis o individual case clust rs, individual studies. You have to put the whole thing together. Q. In asbestos -- You don't know about asbest s; is that right? A. I don't know enough other than a first-year medical student would. Q. In angiosarcomas from vinyl chloride, at what stage would you have said in the investigation pr e ss that you thought there was a reasonable medical |1 probability that vinyl chloride caused angiosarcoma? A. Hell, I would have -- Let's review a little 4 bit of the data in the situation. Hhat you had and what emerged very quickly was a common agent, and -- Q. How did that emerge, if you can just explain? A. By taking this very rare tumor, which is a * different situation than we have here, this is a v ry w *, rare* very outstanding tumor where the background ?' ' iigeidence Is extremely low -- THE COMMISSIONERi The angiosarcoma? THE WITNESSt Yes. THE COMMISSIONERt What is angiosarcoma for the record? THE WITNESSt It is a malignant tumor of HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Repntercd Profctiionit Reporter! STAMFORD. CONNECTICUT .'OJ-m-fllJ Otil 6235 NEW HAVEN. CONNECT IO ni.(i4.4ir 1 ! i 1--> 2 3 4 A5 6 7 8 9 10 11 12 w 13 14 J 15 18 17 18 19 m 20 21 22 23 24 n 25 874 the blood vessels. In this case, the blood - vessels in the liver that has sarcoma implies *. a malignant transformation of fibroblastic cells. So. you had a common agent, you had it happening at more than one place in this country. There were a number of plants in which very quickly one could look at figures and incidences. BY HR. CARTER! Q. And what did they find? #j * A. Again, as the story emerged, there war nor than on* place in which an association between vinyl chloride and angiosarcoma of the liver emerged. I can't and won* t go into the details of the studies. I don't know -- Q. Didn't they find three or four cases h re and three or four cases'~there in different worker population*? 1 ; But there was a common thread. H^ thread is vinyl chloride. The common Q. First the common thread was the occupation. wasn't it? MR. PROOTt May I object. Your Bon r? The witness had not finished his respons . HARTFORD. CONNECTICUT .>> SANDERS. GALE ft RUSSELL RcgMicrcd Promotional Rcportcrt STAMFORD. CONNECTICUT OLI 6236 NEW HAVEN. CONNECTICUT wmi; 875 A. And high dose exposure over a prol nged period 0 .time to the agent stratified even among a particular class of the workers. Q. What they found at first, didn't they, were clusters of three or four workers in different worker populations? A. I don't know. I have not reviewed this literature in detail, and -- Q. Do you remember enough to say whether the increasing risk of getting angiosarcoma from this particular occupation was only about tenfold? fl A. Mo, I don't know. You asked me earlier ab ut at what point you could determine this. I don't believe -- I'm not aware of any given instance wher you can go back to a single cluster, random cluster or single first cluster even of something that ultimately became proven and be sure or have -- have general consensus and acceptance about cause at that point. 0 That's the beginning point. * *- -Q. Bow long did it take OSHA to reduce vinyl chloride exposure to one part per million after those initial few clusters were identified of angiosarcoma? A. You're making a difference between ne cluster and few clusters. Q. Pew clusters then. HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Reiiittrcd Profettionil Reporter* STAMFORD. CONNECTICUT OLI 6237 NEW HAVEN. CONNECTICI T I J n 876 1 A. I'm sure It dldn*t take long at all. 1 don't 2 kno.v specifically. 3 Q. It took about two months, didn't it? 4 A. I wouldn't be a bit surprised if they acted 5 very rapidly on that. 6 Q. How many clusters of brain cancer did you 7 review, that is, positive studies among worker 8 populations working with short chain and small aromatic 9 and especially halogenated hydrocarbons in connection 10 with this case? 11 HR. PROOT* Objection, Your Honor, rft 12 goes into an area that we didn't go int with 13 this with -- 14 THE COMMISSIONERS I'll sustain the 15 objection. Rephrase your question. I'm not 16 sure I understand. 17 NR. CARTERt I'll strike that. * 18 Q. Or. signer, you said that in expressing your 19 opinion-an*to causation, you relied upon .analysis of %, - ' V'V' 20 epidemiological literature, that is, clusters in 21 different industries of brain cancer, is that true? 22 A. Yes. 23 Q. Now, my question wast How many of these 24 clusters of brain cancer in the chemical industry did 25 you review through studies? HARTFORD. CONNECTICUT SANDERS. GALE a RUSSELL Registered Professional Reporters STAMFORD. CONNECTICUT OLI 6238 NEW HAVEN. CONNECTICUT - i$- # 1 2 3 4 ,5 7 8 9 10 11 12 .13 14 15 } 16 17 18 19 *20 21 22 23 24 25 877 HR. RROOTt Your Honor/ nay I just renew my objection foe the record/ for thia reas n, that this Is not an area that we went into n direct-examination/ that what's going to happen here/ I believe iS/ that Hr. Carter -- THE COMMISSIONER: I don't think you should foresee what's going to happen. I'm going to allow it for the weight. I think the witness can handle the question;' He'll pursue it as we go along. HR. PRODTi May I state my concern? t THE COMMISSIONER! No, I think w should let the witness answer the question. MR. PROOTi I'll withdraw the objection. Your Honor. THE COMMISSIONER! All right. It's cross-examination. You may -- Do y u remember the question? BY MR. CARTER! j- *-Q. I'm just asking -- You were saying vinyl chloride -- it took a long time before there was a consensus -- at least, 1 think was your word -- about causation from vinyl chloride monomer, and I'm looking for that point in the appearance of, you know, various clusters, various investigations of the epldemiol gy at HARTFORD. CONNECTICUT .'0J.J44.J54J SANDERS. GALE & RUSSELL Reputcrcd Promotion*! Reporter* STAMFORD. CONNECTICUT .'OJ-IM-tllJ 0LI 6239 NEW HAVEN. CONNECTICUT 201-424.411' I n # n 87 8 1 which it's c aaonable to say there's s me reasonable 2 medical probability of an association. 3 Now, I'm looking for that same analysis with 4 respect to chemical industry workers and brain cancer, 5 and I'm just asking for what you did review with respect 6 to this case -- these cases. 7 A. I reviewed -- There are 15 to 20 published 8 papers in addition to this proceeding, there ar a * 9 number of clusters that I've been called about r have 10 reviewed papers that I've even rejected -- had rejected 11 for publication about clusters of brain tumors* |l 12 In looking at this, and my conclusion is that 13 the data is contradictory, and that we are not at a * 14 point where one can make a statement about cause and 15 effect or what would you regulate* 16 If I were an OSHA man, what would I come in 17 and tell them to stop doing? A 18 Q. We're not asking about regulations. That 19 wasnft the question* This is a question .of 20 cdppensation, not regulation* 'l5T-- 21 Wow, in those studies, you said the data was 22 contradictory. What do you mean? 23 A. I mean some studies will claim an ass elation, 24 and others do not. 25 Q. Wasn't that true in the beginning of the HARTFORD. CONNECTICUT J0J.244-J)*) SANDERS. GALE & RUSSELL Registered Profession,! Reported STAMFORD. CONNECTICUT .'OMIMIII OLI 6240 NEW HAVEN. CONNECT If 1 JOMM.,11* 87 9 studies about asbestos lung cancer, if you know? A. I don't know about asbestos lung cancer. Q. Isn't it true that consistently in the brain cancer clusters, the brain cancer industrial studies, if a latency period of 10 to 20 years is accounted f r, there's been a consistent increase in relative risk of brain cancer in working in the petrochemical industry and specifically with short chain halogensted and aromatic compounds? A. Those studies are riddled with problems. Well over half of them are uncontrolled pathologically. |t There is not -- in my opinion or a consensus opini n f the serious people that work in neurooncology with this problem that we can establish cause and effect yet. Q. Now, when you say "cause and effect," y u'r talking about a particular association with it -- A. I'm not talking about anything. We don't kn w what causes or what associations exist with glioblastoma that are consistent and that would help us. -Q. Do you know who Dr. William Lloyd was? A. No, never heard of him. MR. CARTERt questions. I guess I have no furth r THE COMMISSIONER! Do you have anything? MR. PROUTi Just one. Your Honor, I HARTFORD. CONNECTICUT SANDERS. GALE & RUSSELL Rcgitrered Profetsional Reporter! iTAMFORD CONNECTICUT .tMlIAII) OLI 6241 NEW HAVEN. CONNECTICUT 880 1 believe. 2 REDIRECT EXAMINATION 3 BY-MR. PROOTi 4 0. You were asked a question concerning the 5 percentage of -- the percentage of brain tumors which is 6 made up of glioblastoma multiforme. Does that 7 percentage change as you go from one age group to 8 another? 9 A. Yes. That's an extremely important thing that 10 always should be qualified when you're asking that 11 question, because there's a clear-cut, age-relat d *' A 12 instance of glioblastomas. 13 It's very uncommon in children, for sample, 14 and peaks in middle -- to middle adult life, and th 15 relative percentage of that type is different at that -- 16 if you're comparing that age group of people than if you 17 were looking at children. 18 MR. PROOTt Nothing further, Your 19 Honor. 20 THE COMMISSIONER! Thank you very much. 21 We'll take a five-minute break here. 22 (Recess taken.) ) 23 MR. PROOTx Your Honor, at this time, I 24 would like to call Dr. Irving Kessler to the 25 stand. Doctor Kessler. HARTFORD. CONNECTICUT SANDERS. GALE ft RUSSELL Regutered Profettionil Reporter* STAMFORD. CONNECTICUT OIiI 6242 NEW HAVEN CONNECTS I